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Validation in Partnership Ltd.

2007

GUIDANCE DOCUMENT
REFERENCE VERSION

HVAC SYSTEMS AND ENVIRONMENT CONTROL/MONITORING

Document Reference:
Date of Issue: Page:

SGD-110-ENV Rev. 08
14 May 2007 1 of 185

Author: Title: Regulatory Consultant Company: Validation in Partnership Ltd.

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DOCUMENT HISTORY Revision No. 01 02 03 04 05 06 07 08 Date: April 2000 March 2001 May 2002 January 2003 May 2004 August 2005 August 2006 May 2007

ABOUT THE AUTHOR Since 1995, Validation in Partnership has been an entirely independent organisation specialising in the successful management and support of validation and CGMP compliance projects for the life science industries supplying the European and American markets. With our proven in-house project staff and extensive network of vetted quality contract personnel, we pride ourselves on a pragmatic approach that focuses effort on process critical areas to ensure the optimum business solution to any compliance challenge. Supported by the most extensive regulatory database in existence, courtesy of which this guidance document has been compiled, our team and clients are secure in the knowledge they have instant access to up-to-the-minute regulatory fact, and our state of the art automated document generation system ensures the rapid delivery and consistent quality of your protocols and reports. Whatever your requirement, ...
Managed Validation/Compliance Projects CGMP Compliance Reviews/Audits Complete Site Validation Packages Validation Plans and Master Plans Computer Systems Validation Cleaning Validation SOPs Skilled and Vetted Contract Personnel Gap Analysis and Remedial Action Plans Validation Policies DQ, IQ, OQ, PQ Process Validation CGMP Compliance Training Complete CGMP Compliance Assistance

and whatever your industry sector


Finished Pharmaceuticals Active Pharmaceutical Ingredients Medical Devices Equipment Manufacture Biotechnology Veterinary Products Cosmetics Engineering Design and Construction

ViP is your perfect compliance partner.

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TABLE OF CONTENTS DOCUMENT HISTORY.................................................................................................................................................2 ABOUT THE AUTHOR..................................................................................................................................................2 1. 2. 3. 4. 5. 6. 7. AUTHORS NOTE .................................................................................................................................................4 PURPOSE..............................................................................................................................................................4 SCOPE ...................................................................................................................................................................4 INTRODUCTION ...................................................................................................................................................4 DESIGN GUIDANCE.............................................................................................................................................5 GLOSSARY ...........................................................................................................................................................5 ENVIRONMENT CONTROL REGULATORY GUIDANCE.............................................................................. 10
7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 7.11 HVAC System Design Considerations ......................................................................................................................10 Air Cleanliness Specification......................................................................................................................................62 Drawings .....................................................................................................................................................................79 Filtration ......................................................................................................................................................................81 Air Flow .......................................................................................................................................................................92 Air Velocity ................................................................................................................................................................101 Pressure Difference..................................................................................................................................................103 Temperature and Humidity.......................................................................................................................................110 Training .....................................................................................................................................................................111 Calibration and Maintenance ...................................................................................................................................114 Change Control ........................................................................................................................................................119

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ENVIRONMENT MONITORING REGULATORY GUIDANCE...................................................................... 121


8.1 8.2 8.3 General .....................................................................................................................................................................121 Physical.....................................................................................................................................................................144 Microbiological ..........................................................................................................................................................152

9.

VIP CONTACT DETAILS ................................................................................................................................. 185

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1.

AUTHORS NOTE This guidance document is one in a series produced by Validation in Partnership Limited to assist personnel in the life science industries in obtaining the regulatory perspective surrounding specific aspects of their work. We have long recognised that one of the issues in our industry is not that we do not possess sufficient regulatory guidance on specific topics, but that we possess too much, albeit in the wrong format to support its efficient use. Mountains of guidance documents, directives, warning letters and establishment inspection reports cover a multitude of topics in a multitude of formats. In creating this guidance document, we have used our regulatory database, the most extensive and searchable in existence, to extract individual statements from over 900 regulatory documents and compile them under logical headings to present them in a more usable form. The end product is not intended to steer the reader through the process of developing HVAC (Heating, Ventilation, Air Conditioning) and Environmental Monitoring procedures or validation packages, but simply to highlight the regulatory points he or she will need to consider along the way. Indeed, there are certain points, FDA 483 inspectional observations and warning letter extracts within the guide, with which the author does not concur. However, since each one has been derived from a regulatory information source, they have been included for consideration. It is for this reason that each regulatory point has been provided with sufficient source reference to enable the reader to further investigate any point of contention in the context, in which the statement was made. We hope you find it useful.

2.

PURPOSE To provide the regulatory perspective on the development of HVAC and Environmental Monitoring procedures and validation packages to meet the requirements of both the American (references shown in blue) and European (references shown in red) regulatory bodies.

3.

SCOPE This guidance is applicable to the HVAC and environment control and monitoring systems serving facilities used in the manufacture of healthcare products for the US and European markets. Please note: This guidance document does not include references associated with the monitoring of storage or distribution environmental conditions, unless they specifically refer to HVAC systems. Storage and distribution environmental condition references are included in our Storage and Distribution Environment Validation guidance document, which also includes regulatory considerations for Cold Chain.

4.

INTRODUCTION HVAC systems play a key role in the manufacture of healthcare products, by providing specific process environmental conditions or simply maintaining operator comfort. Demonstration of compliance with a registered process may require the monitoring and recording of the environment provided by the HVAC systems, and environment validation provides the necessary documented evidence that the HVAC system is consistently capable of providing the design conditions. This eighth revision of the guidance document has been compiled from a detailed review of: over 900 regulatory texts over 20,000 regulatory records

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over 4,200 warning letter extracts over 3,100 FDA 483 observations The end product comprises nearly 850 points for consideration when developing procedures and protocols associated with environment validation. For ease of reference, the points are collated under logical headings and sub-headings, although it is appreciated that the grouping of the points is subjective. The term "points for consideration" should be emphasised, as the document is intended to form a series of regulatory prompts rather than a definitive list of word for word requirements. Each paragraph within the guide is supported by one or more regulatory references. American references are shown in blue, European references are shown in red and references applicable to both regulatory bodies are shown in green. There are also some references shown in purple, which are from Health Canada. Although this guide incorporates the latest annexes to the EU Guide to Good Manufacturing Practice, Eudralex Volume 4, the author has chosen to include a number of extracts from selected superseded documents (marked SUPERSEDED!) alongside those from the latest versions. The author believes that the earlier texts contain a number of useful prompts that have been omitted from the latest documents. Notes: The references compiled under each of the headings in sections 7 and 8 are not intended to be a definitive listing of all regulatory points relevant to the topic. There may well be additional references scattered throughout this document which are also deemed to be relevant. In the interest of brevity, references covering more than one topic are not repeated under each relevant topic, although there are exceptions, for the purpose of emphasis. References containing information relating to both physical and microbiological elements of environmental monitoring are located under the General heading in the Environmental Monitoring section. Where text is followed or preceded by three dots ( ), this indicates that there is additional text in the original document, which has been omitted from this guide because it has no relevance to the subject matter.

5.

DESIGN GUIDANCE Detailed guidance on the design of HVAC systems is presented in Volumes 2 and 3 of the ISPE Baseline Guides for Oral Solid Dosage Forms (First edition, February 1998) and Sterile Manufacturing Facilities (First edition, January 1999) respectively. The scope of the Baseline Guides is restricted to the design, construction and operation of HVAC systems, and is intended primarily for regulatory compliance for the domestic United States (US) market. The baseline guides have been organised to assist in a logical decision process to determine the type of system required and the system design needed to provide it.

6.

GLOSSARY The following are definitions/explanations of some of the terms used in this document, together with their sources (they may have different meanings in other contexts): 1. Air lock - An enclosed space with two or more doors, and which is interposed between two or more rooms, e.g. of differing class of cleanliness, for the purpose of controlling the air-flow between those rooms when they need to be entered.

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PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) GLOSSARY Definitions given below apply to the words as used in this Guide. They may have different meanings in other contexts. Air lock [VIP ID: 187200] An enclosed space with two or more doors, and which is interposed between two or more rooms, e.g. of differing class of cleanliness, for the purpose of controlling the air-flow between those rooms when they need to be entered. An air-lock is designed for and used by either people or goods.

2.

Action Level - An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY Action Level [VIP ID: 112320] Action Level - An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.

3.

Alert Level - An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions and triggers appropriate scrutiny and follow-up to address the potential problem.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY Alert Level [VIP ID: 112310] Alert Level - An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions and triggers appropriate scrutiny and follow-up to address the potential problem. Alert levels are always lower than action levels.

4.

Alert Limits - Established microbial or particulate levels giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which require follow-up investigation.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 3. DEFINITIONS Alert limits (environmental monitoring): [VIP ID: 188808] Alert limits (environmental monitoring): Established microbial or particulate levels giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which require follow-up investigation.

5.

Aseptic techniques and manipulations - The manipulation of sterile materials in such a way as to minimise the risk of microbiological contamination from the environment.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 5. DEFINITIONS/GLOSSARY 5.4. Aseptic techniques and manipulations [VIP ID: 190436] Aseptic techniques and manipulations: The manipulation of sterile materials in such a way as to minimize the risk of microbiological contamination from the environment. These techniques usually involve eliminating surface to surface contacts (except between sterile surfaces) minimizing the area exposed and the duration of exposure.

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6.

Environmental Monitoring Programme - Defined documented programme which describes the routine particulate and microbiological monitoring of processing and manufacturing areas, and includes a corrective action plan when action levels are exceeded.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 3. DEFINITIONS Environmental monitoring programme: [VIP ID: 188818] Environmental monitoring programme: Defined documented programme which describes the routine particulate and microbiological monitoring of processing and manufacturing areas, and includes a corrective action plan when action levels are exceeded.

7.

Clean Area - An area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation and retention of contaminants within the area.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) GLOSSARY Definitions given below apply to the words as used in this Guide. They may have different meanings in other contexts. Clean area [VIP ID: 187222] An area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation and retention of contaminants within the area. Note: The different degrees of environmental control are defined in the Supplementary Guidelines for the Manufacture of sterile medicinal products.

8.

Containment: The action of confining a biological agent or other entity within a defined space. Secondary containment: A system of containment which prevents the escape of a biological agent into the external environment or into other working areas. It involves the use of rooms with specially designed air handling, the existence of airlocks and/or sterilises for the exit of materials and secure operating procedures. In many cases it may add to the effectiveness of primary containment.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) GLOSSARY Definitions given below apply to the words as used in this Guide. They may have different meanings in other contexts. Containment [VIP ID: 187226] The action of confining a biological agent or other entity within a defined space. Secondary containment: A system of containment which prevents the escape of a biological agent into the external environment or into other working areas. It involves the use of rooms with specially designed air handling, the existence of airlocks and/or sterilises for the exit of materials and secure operating procedures. In many cases it may add to the effectiveness of primary containment.

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9.

Controlled Area - An area constructed and operated in such a manner that some attempt is made to control the introduction of potential contamination and the consequences of accidental release of living organisms.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) GLOSSARY Definitions given below apply to the words as used in this Guide. They may have different meanings in other contexts. Controlled area [VIP ID: 187230] An area constructed and operated in such a manner that some attempt is made to control the introduction of potential contamination (an air supply approximating to grade D may be appropriate), and the consequences of accidental release of living organisms. The level of control exercised should reflect the nature of the organism employed in the process. At a minimum, the area should be maintained at a pressure negative to the immediate external environment and allow for the efficient removal of small quantities of airborne contaminants.

10. Critical Area - A critical area is one in which the sterilised drug product, containers, and closures are exposed to environmental conditions that must be designed to maintain product sterility.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 1) [VIP ID: 110180] A critical area is one in which the sterilized drug product, containers, and closures are exposed to environmental conditions that must be designed to maintain product sterility ( 211.42(c)(10)). Activities conducted in such areas include manipulations (e.g., aseptic connections, sterile ingredient additions) of sterile materials prior to and during filling and closing operations.

11. Critical Zone - Zone within the Aseptic Processing Area where sterile product, product components or product contact surfaces are exposed to the environment.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 5. DEFINITIONS/GLOSSARY 5.5. Critical zone [VIP ID: 190438] Critical zone: Zone within the Aseptic Processing Area where sterile product, product components or product contact surfaces are exposed to the environment.

12. HEPA Filter - High efficiency particulate air filter.


GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY HEPA filter [VIP ID: 112540] HEPA filter - High efficiency particulate air filter with minimum 0.3 m particle retaining efficiency of 99.97 percent. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 3. DEFINITIONS High efficiency particulate air (HEPA) filter: [VIP ID: 188822] High efficiency particulate air (HEPA) filter: Retentive matrix designed to remove a defined percentage of particulate matter of a defined size.

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13. HVAC - Heating, ventilation, air conditioning.


GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY HVAC [VIP ID: 112550] HVAC - Heating, ventilation, and air conditioning.

14. Industrial isolators used for aseptic processing - Industrial isolators used for aseptic processing are isolators in which the internal space and exposed surfaces are microbiologically controlled.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 5. DEFINITIONS/GLOSSARY 5.2. Industrial isolators used for aseptic processing [VIP ID: 190432] Industrial isolators used for aseptic processing: Industrial isolators used for aseptic processing are isolators in which the internal space and exposed surfaces are microbiologically controlled. Control is achieved by the use of microbiologically retentive filters, sterilization processes, sporicidal processes (usually by gassing) and prevention of recontamination from the external environment.

15. Laminar Flow - An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight line vector.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY Laminar flow [VIP ID: 112580] Laminar flow - An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight line vector.

16. Negative Controls - Refers to the sterility test controls that may be used to identify a "false positive" test result.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 5. DEFINITIONS - For the purposes of this document, the following definitions apply: 5.3 [VIP ID: 190224] negative controls: Refers to the sterility test controls that may be used to identify a "false positive" test result. Growth in the media sterility test, or environmental monitoring, or negative product controls may contribute to the verification of a "false positive" test finding and an invalid test result.

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17. Pharmaceutical Isolator - An isolator is an arrangement of physical barriers that are integrated to the extent that the isolator can be sealed in order to carry out a routine leak test based on pressure to meet specified limits. Internally it provides a workspace, which is separated from the surrounding environment. Manipulations can be carried out within the space from the outside without compromising its integrity.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 5. DEFINITIONS/GLOSSARY 5.1. Pharmaceutical Isolator [VIP ID: 190430] Pharmaceutical Isolator: An isolator is an arrangement of physical barriers that are integrated to the extent that the isolator can be sealed in order to carry out a routine leak test based on pressure to meet specified limits. Internally it provides a workspace, which is separated from the surrounding environment. Manipulations can be carried out within the space from the outside without compromising its integrity.

18. ULPA Filter - Ultra-low penetration air filter with minimum 0.3 m particle retaining efficiency of 99.999 percent.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY ULPA filter [VIP ID: 112670] ULPA filter - Ultra-low penetration air filter with minimum 0.3 m particle retaining efficiency of 99.999 percent.

19. Unidirectional Flow - An airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) GLOSSARY Unidirectional flow [VIP ID: 112650] Unidirectional flow - An airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area.

7.

ENVIRONMENT CONTROL REGULATORY GUIDANCE 7.1 HVAC System Design Considerations 7.1.1 General 1. Factors to be considered in the design of a facility should include the flow of material and personnel, the minimisation of contamination, the use of open versus closed equipment and clean rooms versus isolator technologies, the necessity for dedicated or segregated facilities or equipment and the need for utilities such as HVAC systems.
ICH HARMONISED TRIPARTITE GUIDELINE QUALITY RISK MANAGEMENT Q9 (November 2005) Annex II: Potential Applications for Quality Risk Management II.4 Quality Risk Management for Facilities, Equipment and Utilities Design of facility/equipment [VIP ID: 191166] To determine appropriate zones when designing buildings and facilities, e.g., flow of material and personnel;

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minimize contamination; open versus closed equipment; clean rooms versus isolator technologies; dedicated or segregated facilities/equipment.

To determine appropriate utilities (e.g., heating, ventilation and air conditioning (HVAC), );

2.

Facilities should be designed to provide the necessary segregation and protection, physical and environmental, to minimise the risk of contamination and cross-contamination and to ensure the appropriate air quality is maintained, both physically and microbiologically, for the operations being performed, particularly in areas where product is exposed.
Extracted from FDA warning letter VLN# 06200780 (January 2007) Extracted from FDA warning letter VLN# 06200780 USA 05-Jan-07 1 [VIP ID: 194656] Failure to establish defined areas or such other control systems to prevent contamination or mix-ups for handling and/or manufacturing potent compounds. [21 CFR 211.42(c)] For example, your firm lacked an adequate assessment of the cross-contamination risks posed by the manufacture of several potent compounds (e.g. cytotoxic and hormone products, as well as other products of high pharmacologic activity) at your facility. Controls necessary to prevent cross-contamination of products were not adequately defined. Your firm lacked documentation to determine sources of potential airborne transfer, mechanical transfer, and/or mix-up in the manufacturing and handling of these potent compounds. Specifically, potent active pharmaceutical ingredients (APIs) were introduced into the manufacturing environment during sampling of APIs, formulation of batches in open equipment, aseptic filling of solutions into open vials, and lyophilization of solutions into partially stoppered vials. Furthermore, your firm's potent compound formulation room (Class 10,000) exhausted directly into the entry room (Class 100,000) where operators move throughout the parenteral manufacturing areas, including the aseptic filling room. Your firm utilized a single air pathway for manufacturing different potent compounds. Finally, operators de-gowned after handling potent compounds in an unclassified corridor between the manufacturing area and the packaging area. Due to the above factors, possible migration of levels of potent compounds may have occurred at your manufacturing facility. 21 CFR PART 600 - BIOLOGICAL PRODUCTS: GENERAL (April 2006) Subpart B--Establishment Standards Sec. 600.11 Physical establishment, equipment, animals, and care. (a) [VIP ID: 1850] Work areas. All rooms and work areas where products are manufactured or stored shall be kept orderly, clean, and free of dirt, dust, vermin and objects not required for manufacturing. Precautions shall be taken to avoid clogging and back-siphonage of drainage systems. Precautions shall be taken to exclude extraneous infectious agents from manufacturing areas. Work rooms shall be well lighted and ventilated. The ventilation system shall be arranged so as to prevent the dissemination of microorganisms from one manufacturing area to another and to avoid other conditions unfavorable to the safety of the product. Filling rooms, and other rooms where open, sterile operations are conducted, shall be adequate to meet manufacturing needs and such rooms shall be constructed and equipped to permit thorough cleaning and to keep air-borne contaminants at a minimum. ... ICH HARMONISED TRIPARTITE GUIDELINE QUALITY RISK MANAGEMENT Q9 (November 2005) Annex II: Potential Applications for Quality Risk Management II.4 Quality Risk Management for Facilities, Equipment and Utilities Design of facility/equipment [VIP ID: 191166] To determine appropriate zones when designing buildings and facilities, e.g., flow of material and personnel; minimize contamination; pest control measures; prevention of mix-ups; open versus closed equipment; clean rooms versus isolator technologies; dedicated or segregated facilities/equipment.

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To determine appropriate product contact materials for equipment and containers (e.g., selection of stainless steel grade, gaskets, lubricants); To determine appropriate utilities (e.g., steam, gases, power source, compressed air, heating, ventilation and air conditioning (HVAC), water); To determine appropriate preventive maintenance for associated equipment (e.g., inventory of necessary spare parts). EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 4. BUILDINGS AND FACILITIES 4.2 Utilities 4.21 [VIP ID: 24540] Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These systems should be designed and constructed to minimise risks of contamination and cross-contamination and should include equipment for control of air pressure, microorganisms (if appropriate), dust, humidity, and temperature, as appropriate to the stage of manufacture. Particular attention should be given to areas where APIs are exposed to the environment. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.1 General 18.15 [VIP ID: 24835] Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems). GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT A. Regulatory Requirements para 1 [VIP ID: 187374] Proposed 21 CFR 212.30(a) would require that a PET production facility have adequate facilities to ensure the orderly handling of materials and equipment, the prevention of mix-ups, and the prevention of contamination of equipment or product by substances, personnel, or environmental conditions. GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT B. Facilities 2. Aseptic Processing Area para 1 [VIP ID: 187390] An aseptic work area should be suitable for the assembly of the aseptic components required for the preparation of a sterile PET drug product. We recommend that air quality in the aseptic processing area be controlled to limit the presence of microorganisms and particulate matter. Critical activities in the production and testing of a PET drug product that expose the PET drug product or the sterile surface of the container/closure system to the environment should be conducted within an aseptic workstation (e.g., a LAFW or barrier isolator). Examples of such activities include the aseptic assembly of sterile components (syringe, needle, filter and vial) for sterile filtration of the PET drug product, and sterility testing of the finished PET drug product. We recommend that the following precautions be taken to help maintain the appropriate air quality of the aseptic workstation: The aseptic workstation is sanitized before each operation. Items within a laminar airflow aseptic workstation are kept to a minimum and not interrupt the airflow.

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Extracted from FDA Warning Letter 05-ATL-21 (August 2005) USA 11/08/2005 [VIP ID: 171010] 2. Your firm failed to establish and maintain procedures to adequately control environmental conditions which could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(c) [FDA 483, Item 4]. You have failed to establish formal parameters for temperature, humidity, and pressure. A review of Filling Room temperature records revealed several instances where the temperature range limits (on the form) were exceeded. FDA Warning Letter SEA 05-16 (March 2005) Extracted from FDA warning letter SEA 05-16 USA 17/03/2005 [VIP ID: 135300] 3. Failure to have control systems for your firm's operations necessary to prevent contamination of drug product during aseptic processing [21 CFR 211.42(c)(10)]." . "Additionally, our inspection revealed that the HVAC system is not designed to maintain a "Class 100" or ISO "Class 5" environment within the manufacturing area used for ophthalmic drug products. Also, the air supplied to the manufacturing area has not been filtered through highefficiency particulate air (HEPA) filters, and there is no control of room pressurization to ensure that the manufacturing area will maintain significant positive pressure relative to the adjacent rooms within your facility. FDA Warning Letter [NO REFERENCE] (February 2005) Extracted from FDA warning letter USA 25/02/2005 [VIP ID: 134980] 1. Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70(c). For example: d. Appropriate procedures were not followed for controlling environmental conditions. Specifically, our Investigator observed loss of power to the 'white area' during the establishment inspection. During the power outage, your firm did not monitor the partial pressure differential and/or airflow between the 'white area' and the uncontrolled areas as described in procedure [redacted]. Further, your firm did not have an established procedure to control environmental conditions of the white area during power outages. FDA Warning Letter SJN-05-02 (December 2004) Extracted from FDA warning letter SJN-05-02 Puerto Rico 20/12/2004 [VIP ID: 133500] You stated during the inspection of your firm that the aseptic area was classified as a Class 100 (ISO Class 5) clean room. The investigator noted that the room adjacent to the aseptic area is an unclassified area utilized by ungowned personnel performing 'prescription data entry.' The only entrance into the aseptic area is through a door in the unclassified room. The areas immediately adjacent to the aseptic processing area, at a minimum, should meet Class 10,000 (ISO 7) standards under dynamic conditions. In addition, the wall separating the two areas is only a drywall partition that does not extend to the structural ceiling of the room. The 'drop ceiling' in the unclassified area extends over the partition into the aseptic area. Thus, there is no control of room pressurization to ensure that the aseptic area will maintain significant positive pressure relative to the unclassified area when employees enter/exit the aseptic area. Finally, our inspection disclosed that you perform environmental monitoring only on a semi-annual basis. You have also not established any written procedures for environmental monitoring that specifically address issues such as sample location, sample frequency, sampling technique, sample size, analytical techniques, interpretation of results, and corrective actions in the event of failures. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV Buildings and Facilities (para 1) [VIP ID: 110130] As provided for in the regulations, separate or defined areas of operation in an aseptic processing facility should be appropriately controlled to attain different degrees of air quality depending on the nature of the operation. Design of a given area involves satisfying microbiological and particle criteria as defined by the equipment, components, and products exposed, as well as the operational activities conducted in the area.

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GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities E. Design (para 2) [VIP ID: 110440] Aseptic processes are designed to minimize exposure of sterile articles to the potential contamination hazards of the manufacturing operation. Limiting the duration of exposure of sterile product elements, providing the highest possible environmental control, optimizing process flow, and designing equipment to prevent entrainment of lower quality air into the Class 100 (ISO 5) clean area are essential to achieving high assurance of sterility (Ref. 4). GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities E. Design (para 3) [VIP ID: 110450] Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures, or the surrounding environment. The layout of equipment should provide for ergonomics that optimize comfort and movement of operators. The number of personnel in an aseptic processing room should be minimized. The flow of personnel should be designed to limit the frequency with which entries and exits are made to and from an aseptic processing room and, most significant, its critical area. Regarding the latter, the number of transfers into the critical area of a traditional cleanroom, or an isolator, should be minimized. To prevent changes in air currents that introduce lower quality air, movement adjacent to the critical area should be appropriately restricted. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities E. Design (para 7) [VIP ID: 110490] Due to the interdependence of the various rooms that make up an aseptic processing facility, it is essential to carefully define and control the dynamic interactions permitted between cleanrooms. Use of a double-door or integrated sterilizer helps ensure direct product flow, often from a lower to a higher classified area. Airlocks and interlocking doors will facilitate better control of air balance throughout the aseptic processing facility. Airlocks should be installed between the aseptic manufacturing area entrance and the adjoining unclassified area. Other interfaces such as personnel transitions or material staging areas are appropriate locations for air locks. It is critical to adequately control material (e.g., in-process supplies, equipment, utensils) as it transfers from lesser to higher classified clean areas to prevent the influx of contaminants. For example, written procedures should address how materials are to be introduced into the aseptic processing room to ensure that room conditions remain uncompromised. In this regard, materials should be disinfected according to appropriate procedures or, when used in critical areas, rendered sterile by a suitable method. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III - Inspectional B. Inspection 9. GMP b. Buildings - iv. HVAC systems (para 1) [VIP ID: 77680] The HVAC system should be designed to provide containment or product protection when and where necessary. Negative pressures may be maintained during upstream processing to provide containment. Positive pressures should be maintained in downstream processing areas and the aseptic core. Separate air handling units, or single pass air, should be used in post-viral inactivation areas and the aseptic core. HEALTH CANADA - GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.1 PREMISES - C.02.004 2.1.1 [VIP ID: 65590] ARE FIRMS REQUIRED TO USE HEPA FILTERS IN THE MANUFACTURE OF NON-STERILE DOSAGE FORMS? The GMP regulations do not specifically require manufacturing facilities for non-sterile drugs to maintain highefficiency particulate air (HEPA) filtered air.

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The Regulations do require the use of equipment for adequate control over air pressure, microorganisms, dust, humidity and temperature, when appropriate. In addition, this section calls for use of air filtration systems, including prefilters and particulate matter air filters on air supplies to production areas, as appropriate. These provisions speak of measures to prevent cross contamination, and the key phrase is "when appropriate". Despite the lack of an explicit GMP requirement, some firms may elect to use HEPA filtered air systems as part of their dust control procedures. For example, firms may perform dust containment assessments and decide that such filters are warranted to prevent cross contamination of highly potent drugs that, even in small quantities, could pose a significant health hazard when carried over into other products. FDA Warning Letter 2002-DT-21 (January 2002) Extracted from FDA warning letter 2002-DT-21 USA 30/01/2002 4 [VIP ID: 48290] 4) Failure to have separate or defined areas, or such other control systems as are necessary to prevent contamination during the course of aseptic processing operations, as required by 21 CFR 211.42(c)(10). For example: a. The aseptic manufacturing area interfaces directly with an unclassified packaging area at the exit end for the filled, capped vials. ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. BUILDINGS AND FACILITIES 4.2 Utilities 4.21 [VIP ID: 153720] Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These systems should be designed and constructed to minimise risks of contamination and cross-contamination and should include equipment for control of air pressure, microorganisms (if appropriate), dust, humidity, and temperature, as appropriate to the stage of manufacture. Particular attention should be given to areas where APIs are exposed to the environment. GUIDELINE FOR QUALITY ASSURANCE IN BLOOD ESTABLISHMENTS (July 1995) APPENDICES Appendix A. Examples of 21 CFR, Parts 210 through 211 and Parts 600 through 680 Supplementing Each Other. Example 7: 606.40(b) [VIP ID: 184080] [The guidance document displays the following information in tabular form] CURRENT GOOD MANUFACTURING PRACTICE SPECIFIC FOR BLOOD AND BLOOD COMPONENTS 606.40(b) describes requirements for adequate ventilation. 211.46 describes ventilation control procedures in more detail. CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICAL (INCLUDES BLOOD AND BLOOD COMPONENTS) 211.46 (b) Equipment for adequate control over air pressure, micro-organisms, dust, humidity and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product. (c) Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas. If air is recirculated to production areas, measures shall be taken to control recirculation of dust from production. In areas where air contamination occurs during production, there shall be adequate exhaust systems or other systems adequate to control contaminants.

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3.

Cleanrooms and cleanroon equipment should be designed and constructed to ensure ease of cleaning and sanitisation. For example, areas where particles can collect should be avoided.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES - Production Area 3.10 [VIP ID: 185572] Pipe work, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities E. Design (para 9) [VIP ID: 110510] Cleanrooms are normally designed as functional units with specific purposes. The materials of construction of cleanrooms ensure ease of cleaning and sanitizing. Examples of adequate design features include seamless and rounded floor to wall junctions as well as readily accessible corners. Floors, walls, and ceilings should be constructed of smooth, hard surfaces that can be easily cleaned. Ceilings and associated HEPA filter banks should be designed to protect sterile materials from contamination. Cleanrooms also should not contain unnecessary equipment, fixtures, or materials. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities E. Design (para 11) [VIP ID: 110530] Equipment should be appropriately designed ( 211.63) to facilitate ease of sterilization. It is also important to ensure ease of installation to facilitate aseptic setup. The effect of equipment design on the cleanroom environment should be addressed. Horizontal surfaces or ledges that accumulate particles should be avoided. Equipment should not obstruct airflow and, in critical areas, its design should not disturb unidirectional airflow. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III - Inspectional B. Inspection 9. GMP b. Buildings (para 5) [VIP ID: 77570] Make certain that buildings: - Are appropriately constructed to prevent, reduce, and control potential contaminants and support the environmental control program EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - Production Area 3.10. [VIP ID: 368] Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.

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4.

Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture and storage, or the accurate functioning of equipment.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES - General 3.3 [VIP ID: 185558] Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture and storage, or the accurate functioning of equipment. PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 7. PREMISES Mobile sites 7.16 [VIP ID: 185060] When assessing the suitability of a mobile site, consideration should be given to areas such as ventilation, electrical supply, lighting, hand-washing facilities, reliable communication to the central site, donor interview facilities and blood storage. PI 008-2 PIC/S GUIDANCE DOCUMENT FOR INSPECTORS PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES (INSPECTION GUIDE) (July 2004) 13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES 13.2 PREMISES AND HYGIENE Principle: [VIP ID: 189254] Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the product, the starting material (incl. softgoods) or the accurate functioning of equipment (GMP 3.3.). EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - General 3.3. [VIP ID: 361] Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture and storage, or the accurate functioning of equipment.

5.

Gas cylinders should be stored under cover and not be subjected to extremes of temperature. Storage areas should be clean, dry, well ventilated and free of combustible materials to ensure that cylinders remain clean up to the time of use.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 6 - MANUFACTURE OF MEDICINAL GASES 7. STORAGE AND RELEASE 7.2 [VIP ID: 186558] Gas cylinders should be stored under cover and not be subjected to extremes of temperature. Storage areas should be clean, dry, well ventilated and free of combustible materials to ensure that cylinders remain clean up to the time of use.

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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 06 - MANUFACTURE OF MEDICINAL GASES (September 2001) 7. Storage and release 7.2. [VIP ID: 23310] Gas cylinders should be stored under cover and not be subjected to extremes of temperature. Storage areas should be clean, dry, well ventilated and free of combustible materials to ensure that cylinders remain clean up to the time of use.

6.

After sterilisation, a load should be stored in a controlled manner under ventilated conditions to allow residual gas and reaction products to reduce to the defined level.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS STERILISATION WITH ETHYLENE OXIDE 81 [VIP ID: 186160] After sterilisation, the load should be stored in a controlled manner under ventilated conditions to allow residual gas and reaction products to reduce to the defined level. ... EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Sterilization with ethylene oxide 81. [VIP ID: 63770] After sterilisation, the load should be stored in a controlled manner under ventilated conditions to allow residual gas and reaction products to reduce to the defined level. ...

7.

Premises for the preparation of blood components should be situated, equipped and ventilated in a suitable way and used entirely for this purpose.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS STERILISATION WITH ETHYLENE OXIDE 81 [VIP ID: 186160] After sterilisation, the load should be stored in a controlled manner under ventilated conditions to allow residual gas and reaction products to reduce to the defined level. This process should be validated. PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 7. PREMISES Production areas 7.7 [ViP ID: 185042] Premises for the preparation of blood components should be situated, equipped and ventilated in a suitable way and used entirely for this purpose.

8.

Cross-contamination should be avoided by appropriate technical or organisational measures, such as appropriate air locks and air extraction, and minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air.
EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 - PRODUCTION Prevention of cross-contamination in production 5.19. [VIP ID: 529] Cross-contamination should be avoided by appropriate technical or organisational measures, for example: (b) providing appropriate air-locks and air extraction; (c) minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air:

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GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Buildings and Facilities (a) Contamination/Cross Contamination (para 5) [VIP ID: 3421] Air handling systems for BPC plants should be designed to prevent cross-contamination. For economic reasons, it is a common practice to recycle a portion of the exhaust air back into the same area. For dedicated areas processing the same BPC, this is not objectionable. The adequacy of such a system of operation for multi-use areas, especially if several products are processed simultaneously, should be carefully analyzed. In multi-use areas where several products are completely confined in closed vessels and piping systems, the extent of filtration of the supply air (combined fresh make-up air and recycled air) is not a problem (although other regulatory agencies or company policy may impose restrictions) except when the closed system must be opened (charging). In those areas where the BPCs are in a damp or moistened form (such as filter or centrifuge cake) and may be exposed to the room air environment, filter efficiencies on the supply air system as low as 85% may be perfectly adequate. In those areas wherein one or more of the products is being processed in a dry form, even total filtration of the entire supply air flow with HEPA filters may not be adequate. In all cases, the firm should be able to demonstrate adequacy of their air handling system with data and (in case of doubt) the investigator should consider collection of product samples for analysis for cross-contamination.

9.

Changing rooms should be designed as air locks, which should not be opened simultaneously and used to provide physical separation of the different stages of changing to minimise microbial and particulate contamination of protective clothing. They should be flushed effectively with filtered air. The final stage of the changing room should, in the at rest state, be the same grade as the area into which it leads.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 27 [VIP ID: 186052] Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimise microbial and particulate contamination of protective clothing. They should be flushed effectively with filtered air. The final stage of the changing room should, in the "at rest" state, be the same grade as the area into which it leads. The use of separate changing rooms for entering and leaving clean areas is sometimes desirable. In general hand washing facilities should be provided only in the first stage of the changing rooms. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 28 [VIP ID: 186054] Both airlock doors should not be opened simultaneously. An interlocking system or a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 12 [VIP ID: 186352] Equipment passes and changing rooms should have an interlock mechanism or other appropriate system to prevent the opening of more than one door at a time. Changing rooms should be supplied with air filtered to the same standard as that for the work area, and extracts to produce an adequate air circulation independent of that of the work area. Equipment passes should normally be ventilated in the same way, but unventilated passes, or those equipped with supply air only, may be acceptable.

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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 27 (para 1) [VIP ID: 63180] Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimise microbial and particulate contamination of protective clothing. They should be flushed effectively with filtered air. The final stage of the changing room should, in the at-rest state, be the same grade as the area into which it leads. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 28 [VIP ID: 63200] Both airlock doors should not be opened simultaneously. An interlocking system or a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 12. [VIP ID: 1598] Equipment passes and changing rooms should have an interlock mechanism or other appropriate system to prevent the opening of more than one door at a time. Changing rooms should be supplied with air filtered to the same standard as that for the work area, and equipped with air extraction facilities to produce an adequate air circulation independent of that of the work area. Equipment passes should normally be ventilated in the same way, but unventilated passes, or those equipped with supply air only, may be acceptable.

10. Air supplied to non sterile preparation or formulation areas for manufacturing solutions prior to sterilisation should be filtered as necessary to control particulates. Air being supplied to product exposure areas where sterile drugs are processed and handled should be HEPA filtered under positive pressure.
GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS - CGMPR'S (October 1993) 1. Air (para 1) [VIP ID: 2666] Air supplied to the non-sterile preparation or formulation area for manufacturing solutions prior to sterilization should be filtered as necessary to control particulates. Air being supplied to product exposure areas where sterile drugs are processed and handled should be high efficiency particulate air (HEPA) filtered under positive pressure.

11. Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.5 Viral Removal/Inactivation steps 18.52 [VIP ID: 24859] Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.

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ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION 18.5 Viral Removal/Inactivation steps 18.52 [VIP ID: 156640] Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.

12. To prevent cross-contamination, mixing, granulation, drying and/or tableting operations should be segregated in enclosed areas with their own air handling system.
GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS - CGMPR'S (October 1993) Tablet and Capsule Products (para 3) [VIP ID: 2657] Tablets and capsules are susceptible to airborne contamination because of the manipulation of large quantities of dry ingredients. To prevent cross-contamination in the tableting department, pay close attention to the maintenance, cleaning, and location of equipment, and the storage of granulations and tablets. To prevent cross-contamination, the mixing, granulation, drying and/or tableting operation should be segregated in enclosed areas with its own air handling system. Determine what precautions are taken to prevent cross-contamination. When cross-contamination is suspect, investigate the problem and collect in-line samples (INV) and official samples of the suspect product. Determine what temperature, humidity, and dust collecting controls are used by the firm in manufacturing operations. Lack of temperature and humidity controls can affect the quality of the tablet.

13. The preparation of blood components should be carried out in an appropriately controlled environment, separated from activities, which are not compatible.
PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 7. PREMISES Environmental Control 7.11 [VIP ID: 185050] The preparation of blood components should be carried out in an appropriately controlled environment, separated from activities which are not compatible. ...

14. Air should only be recirculated to production areas if there is adequate filtration installed and data available, including surface and/or air sampling, to demonstrate the efficiency of the air filtration.
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -- Buildings and Facilities Sec. 211.46 Ventilation, air filtration, air heating and cooling (c) [ViP ID: 41] Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas. If air is recirculated to production areas, measures shall be taken to control recirculation of dust from production. In areas where air contamination occurs during production, there shall be adequate exhaust systems or other systems adequate to control contaminants. GUIDE TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS (August 1994) II. FACILITIES (para 3) [VIP ID: 3208] The firm's HVAC (Heating Ventilation and Air Conditioning) system may also warrant coverage particularly where potent or highly sensitizing drugs are processed. Some manufacturers recirculate air without adequate filtration. Where air is recirculated, review the firm's data which demonstrates the efficiency of air filtration such should include surface and/or air sampling.

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15. Air handling units should be specific to the processing area concerned and recirculation of air should not occur from areas handling live pathogenic organisms.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 2 - MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE PREMISES AND EQUIPMENT 14 [VIP ID: 186216] Air handling units should be specific to the processing area concerned and recirculation of air should not occur from areas handling live pathogenic organisms. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 02 - MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE (January 1993) Premises and Equipment 14. [ViP ID: 1527] Air filtration units should be specific to the processing area concerned and recirculation of air should not occur from areas handling live pathogenic organisms.

16. There must be separate facilities and completely separate air handling systems for the production of penicillin. It is also encouraged that separate facilities and air handling systems be used for the production of certain steroids, alkaloids, cephalosporins, certain hazardous or toxic drugs, pesticides, chemicals, and/or starting materials.
Selected FDA 483 Observations (March 2007) Packaging & Labelling [VIP ID: 194406] Air-handling systems for the packing of penicillin should be completely separate from those for other drug products for human use. Extracted from FDA warning letter CIN-07-30670-09 (January 2007) Extracted from FDA warning letter CIN-07-30670-09 USA 11-Jan-07 1) [VIP ID: 194702] Separate or defined areas or other control systems to prevent contamination or mixup are inadequate, and operations relating to the repacking of penicillin are not performed in facilities separate from those used for nonpenicillin drug products for human use. [21 CFR 211.42(c) and (d)] Specifically, your firm, which repacks human drugs, shares a building with a pharmacy that packs beta-lactam antibiotics, including penicillins and cephalosporins. Your facility shares a common dock area, common receiving area, doorways, an overhead door near the maintenance room, cleaning equipment, and personnel with the pharmacy. The pharmacy uses the common area to receive beta-lactams. Sufficient controls have not been established to prevent the exposure of cephalosporin drug products and non-beta-lactam drug products to cross-contamination, either with penicillin drug products or with each other. In addition, containment procedures have not been established to assure that employees, in moving about the plant, do not carry residue from penicillin into non-penicillin areas or non-penicillin beta-lactams (e.g., cephalosporin) into non-beta-lactam areas. Cephalosporin products, like penicillin products, are categorized as beta-lactam drugs and present a health hazard to consumers with sensitivities to these compounds. Consequently, under 21 CFR 211.42(c), the processing of non-penicillin beta-lactam drugs (e.g., cephalosporin) should be separate from other drug products. Pursuant to 21 CFR 211.42(d), penicillin drug products must also be separate from other drug products, including non-penicillin beta-lactams. We recommend a system-based approach that involves a complete separation of every aspect of the repackaging operation. Adequate separation should include physical barriers, air handling systems, personnel, and equipment with well established written procedures and controls. The separation should be verified by testing, auditing, and continuous monitoring if necessary.

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Extracted from FDA warning letter CIN-07-30670-09 (January 2007) Extracted from FDA warning letter CIN-07-30670-09 USA 11-Jan-07 2) [VIP ID: 194704] Air-handling systems for the packing of penicillin are not completely separate from those for other drug products for human use. [21 CFR 211.46(d)] The pharmacy and the repacking operations share a common air handling system, including common air returns, vents, and air sources. This air handling system uses nearly 100% recirculated air. Extracted from FDA warning letter CIN-07-30670-09 (January 2007) Extracted from FDA warning letter CIN-07-30670-09 USA 11-Jan-07 9) [VIP ID: 194718] Non-penicillin drug products were not tested for the presence of penicillin, when a reasonable possibility existed that a non-penicillin drug product had been exposed to cross-contamination with penicillin. [21 CFR 211.176] Specifically, your firm has not tested any of the human drug products that have been repacked by your firm for the presence of penicillin. As pointed out in items 1) and 2) above, your firm does not have separate facilities nor do you have separate air handling systems for handling penicillin products. Your firm shares the building, a common dock area, common receiving area, doorways, an overhead door near the maintenance room, cleaning equipment, personnel, and an air handling system with a pharmacy that packs beta-lactam antibiotics, including penicillins and cephalosporins. 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -- Buildings and Facilities Sec. 211.46 Ventilation, air filtration, air heating and cooling (d) [ViP ID: 42] Air-handling systems for the manufacture, processing, and packing of penicillin shall be completely separate from those for other drug products for human use. FDA Warning Letter FEI:1122528 VL#05200161 (March 2005) Extracted from FDA warning letter FEI:1122528 VL#05200161 USA 15/03/2005 [VIP ID: 135230] 1. Failure to have operations performed within specifically defined areas of adequate size as necessary to prevent contamination and to have operations relating to the manufacture, processing, and packing of penicillin and cephalosporin performed in facilities separate from those used for other drug products for human use [21 CFR 211.42(c) and (d)]. For example, penicillin products (amoxicillin and penicillin VK) and a cephalosporin product (cephalexin) were repacked using the same equipment and/or in the same production area of your facility as other non-penicillin products. Cephalosporin products, like penicillin products, are categorized as beta-lactam drugs and present a health hazard to consumers with sensitivities to these compounds. Consequently, under 21 CFR 211.42(c) and (d), the Agency requires that the manufacture, processing. and packaging of beta-lactam drugs (e.g., penicillin and cephalosporin) be separate from non-beta-lactam drugs (e.g., ibuprofen). Pursuant to 21 CFR 211.42(d), penicillin and non-penicillin beta-lactam drugs must also be separate from each other. In this case, there is neither separation of the cephalosporin and penicillin drug products repackaging processes, nor separation between the beta-lactam and non-beta-lactam products. The agency has taken the position that all three of those drug products should be separated from each other. In order to reach the goal of no cross contamination, a system-based approach towards separation should be taken. This entails a complete separation of every aspect of the manufacturing operation. Adequate separation should include physical barriers, air handling systems, personnel, and equipment with well established written procedures and controls. The separation should be verified by testing, auditing, and continuous monitoring if necessary.

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FDA Warning Letter FEI:1122528 VL#05200161 (March 2005) Extracted from FDA warning letter FEI:1122528 VL#05200161 USA 15/03/2005 [VIP ID: 135240] 2. Failure to have a completely separate air-handling system for the manufacture, processing, and packing of penicillin from those for other drug products for human use and to have an adequate air filtration system [21 CFR 211.46(c) and (d)]. For example, a single HVAC air handling system fitted with one [redacted] filter at the air intake unit located on the roof top is used to process the air supplied to the area of your facility where penicillin products (amoxicillin and penicillin VK), a cephalosporin product (cephalexin), and non-penicillin products (including but not limited to Methocarbomol, Ibuprofen, Levaquin, Macrobid) are repacked. In addition, the inspection disclosed that you have not established measures to control recirculation of contaminants (i.e. dust observed on ducts) through the HVAC air handling system. FDA Warning Letter [Reference Obliterated] (February 2004) Extracted from FDA warning letter USA 27/02/2004 [VIP ID: 126210] 2. Failure to separate completely the air handling systems for the packing of penicillin products and non-penicillin beta-lactam drug products from non-penicillin drug products. [21 CFR 211.42(c) and 211.46(d)] The same air handling system is used for the repackaging of penicillin and cephalosporins in violation of 21 CFR 211.42(c) and (d). In addition, the firm could not verify through blueprints or diagrams that the air handling system for the repackaging of penicillins is separate from the air handling system used for repackaging non-penicillin drug products that is required by 21 CFR 211.46(d). Your firm has not established minimal personnel, equipment, and material movement controls, minimal containment controls, and other control systems to prevent crosscontamination. These controls must also be applied to the re-packing of non-penicillin beta-lactam drug products (cephalosporin). HUMAN DRUG CGMP NOTES, VOLUME 09, NUMBER 01 (First Quarter, 2001) (March 2001) Brian J. Hasselbalch QUESTIONS AND ANSWERS: [Question 1] [VIP ID: 71900] Do the CGMPs allow for locating in a non-penicillin production facility a shared laboratory for testing penicillin and non-penicillin products? References: 21 CFR Sections: 211.42(d) Design and construction features; 211.46(d) Ventilation, air filtration, air-heating cooling; 211.176 Penicillin contamination. Yes. A shared laboratory can be located within a non-penicillin production facility. Although CGMPs require separate facilities for the production of penicillin and non-penicillin products, they do not require separate laboratories for the testing of penicillin and non-penicillin products. However, CGMPs require that there be adequate controls to prevent penicillin cross-contamination of non-penicillin drugs in production areas of the firm. The CGMP regulations also require that the air handling system in such a shared laboratory be separate (not connected) to non-penicillin production areas of the facility. The purpose of the referenced CGMP regulations is to avoid penicillin cross-contamination of non-penicillin products. Contact for further information: Edwin Melendez, HFD-322, (301) 594-2454 e-mail: melendeze@cder.fda.gov ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. BUILDINGS AND FACILITIES 4.4 Containment 4.40 [VIP ID: 153810] Dedicated production areas, which can include facilities, air handling equipment and/or process equipment, should be employed in the production of highly sensitizing materials, such as penicillins or cephalosporins.

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HUMAN DRUG CGMP NOTES, VOLUME 08, NUMBER 01 (March 2000) RUSS'S RAMBLINGS: PENICILLIN ISSUES: Question 1 [VIP ID: 8420] What do the CGMPs mean by separate facilities? Must the buildings be totally separated, or are the CGMPs satisfied when the floors are physically separated with separate air filtration units installed? References: 21 CFR 211.42(d) Design, and construction features; 21 CFR 211.46(d) Ventilation, air filtration, air heating and cooling; 21 CFR 211.176 Penicillin contamination Federal Register, 9/29/78 (Vol.43, No.190, Book 2) Preamble to the CGMPs at comment 142 CGMP regulations [21 CFR 211.42(d) and 211.46(d)] require separation of penicillins from non-penicillins during processing. The discussion of the comments in the preamble to the regulations note that "...isolation of penicillin production operations...can be achieved by sealing off...the two operations." "...does not necessarily mean...separate buildings." Thus, there can be a "building within a building"- i.e. two buildings are not required. However, there must be total separation of operations, meaning every aspect of the operations must be separate. Adequate separation should include physical barriers and separate air handling systems. Personnel and equipment from the penicillin facility should not enter the non-penicillin facility. These should operate with well established written procedures and controls. The separation should be audited, procedures validated, and where necessary monitored. Even with separation, if any possibility of contamination exists, the non-penicillin products must be tested (21 CFR 211.176). An example of possible contamination could be inadequate controls over movement of equipment or personnel. Section 211.176 requires non-penicillin products to be tested for traces of penicillin where the possibility of exposure exists, and not marketed if detectable levels of penicillin are found. While this section prohibits marketing of products found to be contaminated with penicillin, it does not sanction marketing of non-penicillin products based only on test results that show no detectable levels of such contamination. Other CGMP requirements must still be met. For a discussion on this issue, please review the article "Is it acceptable under section 211.176 to release products to market as long as the products are tested and no penicillin is found?" published in "Human Drug CGMP Notes" (Volume 6, Issue 2, June 1998). Cross contamination issues have been a concern for a number of years, and continue to be problematic. In one penicillin cross-contamination case reviewed it was demonstrated how a non-penicillin facility was contaminated by a separate penicillin facility located in the same manufacturing campus. This occurred due to lack of controls regarding movements of personnel, equipment and materials. In another case, CDER concurred with a district recommendation to withhold approval on a sensitizing beta-lactam manufacturing facility that was adjacent to another drug processing building, due to the lack of containment controls which ensured against cross contamination of the other drugs. HUMAN DRUG CGMP NOTES, VOLUME 08, NUMBER 01 (March 2000) RUSS'S RAMBLINGS: PENICILLIN ISSUES: Question 1 [VIP ID: 8420] What do the CGMPs mean by separate facilities? Must the buildings be totally separated, or are the CGMPs satisfied when the floors are physically separated with separate air filtration units installed? References: 21 CFR 211.42(d) Design, and construction features; 21 CFR 211.46(d) Ventilation, air filtration, air heating and cooling; 21 CFR 211.176 Penicillin contamination Federal Register, 9/29/78 (Vol.43, No.190, Book 2) Preamble to the CGMPs at comment 142 CGMP regulations [21 CFR 211.42(d) and 211.46(d)] require separation of penicillins from non-penicillins during processing. The discussion of the comments in the preamble to the regulations note that "...isolation of penicillin production operations...can be achieved by sealing off...the two operations." "...does not necessarily mean...separate buildings." Thus, there can be a "building within a building"- i.e. two buildings are not required. However, there must be total separation of operations, meaning every aspect of the operations must be separate. Adequate separation should include physical barriers and separate air handling systems. Personnel and equipment from the penicillin facility should not enter the non-penicillin facility. These should operate with well established written procedures and controls. The separation should be audited, procedures validated, and where necessary monitored. Even with separation, if any possibility of contamination exists, the non-penicillin products must be tested (21 CFR 211.176). An example of possible contamination could be inadequate controls over movement of equipment or personnel. Section 211.176 requires non-penicillin products to be tested for traces of penicillin where the possibility of exposure exists, and not marketed if detectable levels of penicillin are found. ... HUMAN DRUG CGMP NOTES, VOLUME 08, NUMBER 01 (March 2000) RUSS'S RAMBLINGS: PENICILLIN ISSUES: Question 2 [VIP ID: 8430] Is it acceptable to manufacture penicillin and non-penicillin products in the same facility on a campaign (i.e., the conversion of production facilities to a different product line on a routine basis) basis, with adequate cleaning validation procedures in place?

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References: 21 CFR 211.42(d) Design, and construction features; 21 CFR 211.46(d) Ventilation, air filtration, air heating and cooling; 21 CFR 211.176 Penicillin contamination; Federal Register, 9/29/78 (Vol.43, No.190, Book 2) Preamble to the CGMPs at comment 148 No, it is not acceptable. The discussion of the comments in the preamble to the regulations state that "...it is important to make clear in these regulations that completely separate air-handling facilities for penicillin and non-penicillin production are required.". And "...because it is possible for air-handling systems between penicillin and non-penicillin production areas to be interconnected, ...the Commissioner finds it necessary to state that any such interconnection would be unacceptable." Campaign production of penicillin and any non-penicillin product in the same facility and with the same equipment violates the CGMP regulations [211.42(d) and .46(d)]. A concern is that the cleaning validation process does not include the air handling system throughout the facility. This is important because campaign production has the potential for recontamination of the air handling systems and facilities, and can lead to cross contamination of nonpenicillin products with penicillin. The concept of decontamination is broader than a typical cleaning procedure validation, in that sampling is extended to include the environment, as well as surfaces of the facility and equipment that are to be decontaminated. A facility contaminated with penicillin could not begin non-penicillin production until extensive decontamination and clean-up of the facility is accomplished in accordance with the established procedures, and representative environmental samples demonstrate that the facility conforms with its decontamination protocol/specifications. Current technology makes decontamination of air handling systems difficult. This is because the decontamination/cleaning procedures would necessitate sampling and residual testing of other parts of the air handling system, to include the ductwork. This would be difficult because the air handling system throughout its length has uneven areas and crevices that create the possibility of penicillin residue build-up, with slough-off at undetermined periods during the non-penicillin production period. Thus penicillin contamination would not be uniformly distributed in the air handling system, and "representative" samples (retain, surface and/or air) may not be an accurate portrayal of the level of contamination. 21 CFR 211.176 indicates that where the possibility of exposure exists, non-penicillin products must be tested for traces of penicillin and not marketed if detectable levels are found. This means that representative samples from all batches of non-penicillin products produced in each campaign must be tested with an acceptable method and found non-detectable for the penicillin product produced prior to the start-up of the non-penicillin campaign. One case we reviewed demonstrated a positive environmental surface sample from the fan blade of an exhaust hood in the repack room for beta-lactam residue, even though the most recent beta-lactam repackaging operation had been performed more than six months prior to sampling. HUMAN DRUG CGMP NOTES, VOLUME 06, NUMBER 02 (June 1998) Motise's Notebook: POLICY QUESTIONS: Question 3 [VIP ID: 5901] If a firm's only operation is performing finished packaging operations for bulk tablet and capsule drug products, must it still maintain separate facilities and equipment for packaging penicillin products? Reference: 21 CFR Sections 211.42.(d), Design and construction features [Buildings and Facilities], 211.46(d), Ventilation, air filtration, air heating and cooling, and 211.176, Penicillin contamination Yes. The CGMP regulations explicitly require that operations relating to the manufacture, processing and packaging of penicillin be performed in facilities that are separate from those facilities used for other drugs. The regulations also require separate air-handling systems in facilities used for penicillin products. Furthermore, if a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, CGMPs require that the non-penicillin drug be tested for the presence of penicillin. The CGMPs make no exceptions from the foregoing for operations that are limited to repackaging solid oral dosage forms. It should be noted that the requirement for separate facilities does not necessarily mean that operations relating to penicillin products must be conducted in separate buildings from other drugs. A separate area dedicated to penicillin products within a larger facility may be acceptable if penicillin containment can be established and validated. Contact for further info: Barry Rothman, HFD-325, 301-594-0098, e-mail: rothmanb@cder.fda.gov FR FDA 05/03/96 PR 61 FR 20103 - CURRENT GOOD MANUFACTURING PRACTICE: AMENDMENT OF CERTAIN REQUIREMENTS FOR FINISHED PHARMACEUTICALS: PROPOSED RULE (May 1996) PROPOSED MODIFICATIONS (211 New Subpart M - Contamination) 211.240 Control of chemical and physical contaminants. (b) [VIP ID: 5439] Dedicated production, which may include facilities, air handling equipment, and/or process equipment, shall be employed where contaminants, such as penicillin, pose a special danger to human or animal health or if there are no reasonable methods for the cleaning and removal of drug substances and/or component residues from buildings, facilities, and equipment.

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HUMAN DRUG CGMP NOTES, VOLUME 02, NUMBER 04 (December 1994) Motise's Notebook POLICY QUESTIONS: 4) [VIP ID: 3854] What quality standard should be set for air around a capsule repacking machine where the capsules contain alpha blocker drugs? References: 21 CFR 211.42, Design and construction, and 211.46, Ventilation, air filtration, air heating and cooling. We've had similar inquires before and, unfortunately, there is no set answer. The key is to identify the most significant potential problem Particulates and microbial counts, of course, need control in a "clean room" environment where sterility must be preserved. In the case described, however, more important than air quality itself, in terms of particulates and microbial content, would be the matter of dust removal and containment to prevent cross contamination. We would not expect particle counts, per se to be as important as what those particles are, and the danger they may present if they found their way into other products. Temperature and humidity controls may also be smooth operation of the equipment. A severe cross contamination problem, such as we encounter in penicillin production would warrant separation of facilities, dedicated equipment and air handling systems, along with separation of personnel. As part of future CGMP revisions, we are reviewing the need to extend the penicillin separation provisions to other drugs that might pose unique health hazards. Nothing has been firmed up yet, but the concept is under review. Until the regulations are modified, we would advise the firm to evaluate the potential cross contamination problem, and design an environment and containment provisions that would avoid putting other products at risk. Division Contact for Further Info: Paul J. Motise, HFD-323, 301-594-1089. GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Buildings and Facilities (a) Contamination/Cross Contamination (para 1) [VIP ID: 3417] Cross contamination is not permitted under any circumstances. However, the fact that a BPC plant is, or can be, used for manufacturing multiple drugs, even simultaneously, is not in itself objectionable with only a few exceptions. There must be separate facilities and completely separate air handling systems for the production of penicillin as the CGMP regulations require for dosage form drug products. It is also encouraged that separate facilities and air handling systems be used for the production of certain steroids, alkaloids, cephalosporins, certain hazardous or toxic drugs, pesticides, chemicals, and/or starting materials. GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Buildings and Facilities (a) Contamination/Cross Contamination (para 3) [VIP ID: 3419] Even though penicillin production may take place in the same building as non-penicillin production, air handling systems must at all times be completely separate. This includes fermentation procedures. This is the only means by which cross-contamination can be prevented through air facilities.

17. Production of biological agents may take place in controlled areas provided it is carried out in totally enclosed and heat sterilised equipment, all connections being also heat sterilised after making and before breaking. It may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 17 [VIP ID: 186362] Production of biological agents may take place in controlled areas provided it is carried out in totally enclosed and heat sterilized equipment, all connections being also heat sterilized after making and before breaking. it may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage. The sterilization parameters used before breaking the connections must be validated for the organisms being used. Different products may be placed in different biogenerators, within the same area, provided that there is no risk of accidental cross-contamination. However,

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organisms generally subject to special requirements for containment should be in areas dedicated to such products. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 17. [VIP ID: 1603] Production of biological agents may take place in controlled areas provided it is carried out in totally enclosed and heat sterilized equipment, all connections being also heat sterilized after making and before breaking. It may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage. The sterilization parameters used before breaking the connections must be validated for the organisms being used. Different products may be placed in different biogenerators, within the same area, provided that there is no risk of accidental cross-contamination. However, organisms generally subject to special requirements for containment should be in areas dedicated to such products. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Equipment 23. (para 3) [VIP ID: 1615] The introduction or removal of material should take place using a sterilizable closed system, or possibly in an appropriate laminar air flow.

18. Containers, closures, and packaging materials can be sampled for receipt examination in the warehouse, if the environment is appropriate.
QUESTIONS AND ANSWERS ON CURRENT GOOD MANUFACTURING PRACTICES, GOOD GUIDANCE PRACTICES, LEVEL 2 GUIDANCE CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS AND CLOSURES (August 2004) 2 [VIP ID: 190902] Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse? Yes. Generally, we believe that sampling in a typical drug manufacturing facility warehouse would not represent a risk to the container/closure or affect the integrity of the sample results. But whether the act of collecting a sample in the warehouse violates the CGMPs requirement that containers "be opened, sampled, and sealed in a manner designed to prevent contamination of their contents..." will depend on the purported quality characteristics of the material under sample and the warehouse environment. For container/closures purporting to be sterile or depyrogenated, sampling should be under conditions equivalent to the purported quality of the material: a warehouse environment would not suffice (see 211.94 and 211.113(b)). This is to preserve the fitness for use of the remaining container/closures as well as ensure sample integrity, if they are to be examined for microbial contamination. At a minimum, any sampling should be performed in a manner to limit exposure to the environment during and after the time samples are removed (i.e., wiping outside surfaces, limiting time that the original package is open, and properly resealing original package). Well-written and followed procedures are the critical elements. Note that the CGMPs at 211.84 permit a manufacturer to release for use a shipment of containers/closures based on the supplier's certificate of analysis and a visual identification of the containers/closures. Once a supplier's reliability has been established by validation of their test results, a manufacturer could perform the visual examination entirely in the warehouse.

19. Injection of mice and removal of ascites fluid should be done in a clean environment such as under a unidirectional hood or at a station that will protect the mice from infectious agents.
BIOTECHNOLOGY INSPECTION GUIDE (November 1991) ASCITES PRODUCTION B. Manufacturing Processes 2. Tapping Procedure [VIP ID: 1058] Injection of mice and removal of ascites fluid should be done in a clean environment such as under a unidirectional hood or at a station that will protect the mice from infectious agents.

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20. Where the quality of the API can be affected by microbial contamination, manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.3 Cell Culture/Fermentation 18.31 [VIP ID: 24844] Where the quality of the API can be affected by microbial contamination, manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment. GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT B. Facilities 1. General para 2 [VIP ID: 187380] Phases of production with the potential for microbiological contamination should be performed under environmental conditions that minimize the possibility of such contamination (e.g., in a laminar airflow workbench (LAFW), or barrier isolator system). ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION 18.3 Cell Culture/Fermentation 18.31 [VIP ID: 156490] Where the quality of the API can be affected by microbial contamination, manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment.

21. Containment premises should be easily disinfected and should have the following characteristics: the absence of direct venting to the outside; a ventilation with air at negative pressure. Air should be extracted through HEPA filters and not be recirculated except to the same area, and provided further HEPA filtration is used (normally this condition would be met by routing the recirculated air through the normal supply HEPAs for that area). However, recycling of air between areas may be permissible provided that it passes through two exhaust HEPAs, the first of which is continuously monitored for integrity, and there are adequate measures for safe venting of exhaust air should this filter fail; air from manufacturing areas used for the handling of exotic organisms should be vented through two sets of HEPA filters in series, and that from production areas not recirculated; changing rooms designed and used as air locks, and equipped with washing and showering facilities if appropriate. Air pressure differentials should be such that there is no flow of air between the work area and the external environment or risk of contamination of outer clothing worn outside the area; an air lock system for the passage of equipment, which is constructed so that there is no flow of contaminated air between the work area and the external environment or risk of contamination of equipment within the lock. The air lock should be of a size which enables the effective surface decontamination of materials being passed through it. Consideration should be given to having a timing device on the door interlock to allow sufficient time for the decontamination process to be effective.

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PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 11 [VIP ID: 186350] Containment premises should be easily disinfected and should have the following characteristics: a) The absence of direct venting to the outside; b) a ventilation with air at negative pressure. Air should be extracted through HEPA filters and not be recirculated except to the same area, and provided further HEPA filtration is used (normally this condition would be met by routing the recirculated air through the normal supply HEPAs for that area). However, recycling of air between areas may be permissible provided that it passes through two exhaust HEPAs, the first of which is continuously monitored for integrity, and there are adequate measures for safe venting of exhaust air should this filter fail; c) air from manufacturing areas used for the handling of exotic organisms should be vented through 2 sets of HEPA filters in series, and that from production areas not recirculated; e) changing rooms designed and used as air locks, and equipped with washing and showering facilities if appropriate. Air pressure differentials should be such that there is no flow of air between the work area and the external environment or risk of contamination of outer clothing worn outside the area; f) an air lock system for the passage of equipment, which is constructed so that there is no flow of contaminated air between the work area and the external environment or risk of contamination of equipment within the lock. The air lock should be of a size which enables the effective surface decontamination of materials being passed through it. Consideration should be given to having a timing device on the door interlock to allow sufficient time for the decontamination process to be effective.

EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 11. [VIP ID: 1597] Containment premises should be easily disinfected and should have the following characteristics: (a) the absence of direct venting to the outside; (b) a ventilation with air at negative pressure. Air should be extracted through HEPA filters and not be re circulated except to the same area, and provided further HEPA filtration is used (normally this condition would be met by routing the recirculated air through the normal supply HEPAs for that area). However, recycling of air between areas may be permissible provided that it passes through two exhaust HEPAs, the first of which is continuously monitored for integrity, and there are adequate measures for safe venting of exhaust air should this filter fail; (c) air from manufacturing areas used for the handling of exotic organisms should be vented through 2 sets of HEPA filters in series, and that from production areas not recirculated; (e) changing rooms designed and used as air locks, and equipped with washing and showering facilities if appropriate. Air pressure differentials should be such that there is no flow of air between the work area and the external environment or risk of contamination of outer clothing worn outside the area; (f) an air lock system for the passage of equipment, which is constructed so that there is no flow of contaminated air between the work area and the external environment or risk of contamination of equipment within the lock. The air lock should be of a size which enables the effective surface decontamination of materials being passed through it. Consideration should be given to having a timing device on the door interlock to allow sufficient time for the decontamination process to be effective.

22. A Site Master File should contain a brief description of the ventilation systems. It should include schematic drawing(s) of the system(s) indicating filter challenge aerosol introduction points, if applicable, and should also include room classifications, if applicable, supply air quality, temperature, humidity, pressure differentials, air change rates and alarms. The proportions of supply, exhaust and recirculated air should be indicated, as should the type, efficiency and change limit of installed filters.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 20 [VIP ID: 186368] Documentation relating to the premises should be readily available in a plant master file.

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The manufacturing site and buildings should be described in sufficient detail (by means of plans and written explanations) so that the designation and conditions of use of all the rooms are correctly identified as well as the biological agents which are handled in them. The flow of people and product should also be clearly marked. The animal species accommodated in the animal houses or otherwise on the site should be identified. The activities carried out in the vicinity of the site should also be indicated. Plans of contained and/or clean area premises, should describe the ventilation system indicating inlets and outlets, filters and their specifications, the number of air changes per hour, and pressure gradients. They should indicate which pressure gradients are monitored by pressure indicator. PE 008-2 1 ANNEX EXPLANATORY NOTES FOR INDUSTRY ON THE PREPARATION OF A SITE MASTER FILE (July 2004) REQUIREMENT C.3 PREMISES AND EQUIPMENT Premises REQUIREMENT C.3.3 [VIP ID: 185434] REQUIREMENT C.3.3 Brief description of ventilation systems. More details should be given for critical areas with potential risks of airborne contamination (schematic drawings of the systems are desirable). Classification of the rooms used for the manufacture of sterile products should be mentioned. GUIDANCE C.3.3 Brief Description of Ventilation Systems etc. (500 words/two A4 pages) Note 2: To reduce the narrative, schematic drawings should be used. The following data should be given: C.3.3.1 Design criteria e.g. Specification of the air supply Temperature Humidity Pressure differentials and air change rate Simple pass or recirculation (%)

C.3.3.2 Filter design and efficiency e.g. - Bag 99% eff. - Hepa 99.997% eff. Details of any alarms on the ventilation system should be given. C.3.3.3 The limits for changing the filters should be given. C.3.3.4 If DOP (dioctyl-phthalate) is introduced, the point must be shown.

7.1.2 Laminar Flow Units 1. Phases of production with the potential for microbiological contamination should be performed under environmental conditions that minimise the possibility of such contamination, e.g., in a laminar air flow workbench (LAFW).
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT B. Facilities 1. General para 2 [VIP ID: 187380] Phases of production with the potential for microbiological contamination should be performed under environmental conditions that minimize the possibility of such contamination (e.g., in a laminar airflow workbench (LAFW), or barrier isolator system).

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2.

Any facility, including a laboratory, used for production of investigational drugs for use in phase 1 studies should have appropriate air handling systems (e.g. laminar flow hoods) to aid in preventing contamination and cross-contamination of product.
GUIDANCE FOR INDUSTRY INDS - APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) V. RECOMMENDATIONS FOR COMPLYING WITH THE STATUTE C. Facility and Equipment para 1 [VIP ID: 183856] Any facility, including a laboratory, used for production of investigational drugs for use in phase 1 studies should have adequate work areas and equipment for the intended task: Sufficient space, clean environment, appropriate construction Appropriate lighting, ventilation, and heating Appropriate air handling systems (e.g., laminar flow hoods) to aid in preventing contamination and crosscontamination of product Appropriate equipment that will not contaminate the product or otherwise be reactive, additive, or absorptive with the product and that is properly maintained, calibrated, cleaned, and sanitized at appropriate intervals following written procedures

3.

For investigational new drugs intended to be sterile, consideration should be given to conducting aseptic manipulations in an aseptic workstation, such as a laminar air flow workbench, under laminar flow conditions in an air classification of Class 100, while ensuring that the laminar air flow is not interrupted.
GUIDANCE FOR INDUSTRY INDS - APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) VI. SPECIAL PRODUCTION SITUATIONS D. Sterile Products/Aseptically Processed Products [VIP ID: 183918] We recommend that special precautions be taken for investigational new drugs intended to be sterile. Thorough consideration should be given to controls for aseptic processing. The following examples are recommendations that should be considered: Conducting aseptic manipulation in an aseptic workstation under laminar flow conditions (e.g., an air classification of Class 100). Some examples of workstations include a laminar air flow workbench, biosafety cabinets, or barrier isolator system. Disinfecting the entire aseptic workstation as appropriate (e.g., before aseptic manipulation, or between different operations during the same day). Ensuring that items within a laminar airflow aseptic workstation not interrupt the airflow. Disinfecting gloves or changing them frequently when working in the laminar flow hood. Disinfecting the surface of nonsterile items (e.g., test tube rack, and the overwrap for sterile syringes and filters) with sterile disinfectant solution before placing them in the laminar flow hood. Performing manipulations of drug or components subsequent to a sterilizing step under appropriate conditions. ...

4.

The environment required, where sterile radiopharmaceutical products or containers are exposed, may be achieved by the provision within the work station of a laminar flow of HEPA filtered air and by fitting air locks to entry ports.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 3 - MANUFACTURE OF RADIOPHARMACEUTICALS PREMISES AND EQUIPMENT 4 [VIP ID: 186286] For sterile products the working zone where products or containers may be exposed should comply with the environmental requirements described in the Supplement on Sterile Products. This may be achieved by the provision within the work station of a laminar flow of HEPA-filtered air and by fitting air-locks to entry ports. Total containment work stations may provide these requirements. They should be in an environment conforming to at least grade D.

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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 03 - MANUFACTURE OF RADIOPHARMACEUTICALS (January 1993) Premises and equipment 4. [VIP ID: 1562] For sterile products the working zone where products or containers may be exposed should comply with the environmental requirements described in the Supplement on Sterile Products. This may be achieved by the provision within the work station of a laminar flow of HEPA-filtered air and by fitting air-locks to entry ports. Total containment work stations may provide these requirements. They should be in an environment conforming to at least grade D.

5.

Open circuit operations involving immunological veterinary medicinal products or components not subsequently sterilised should be carried out within a laminar air flow work station (grade A) in a grade B area.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 9 [VIP ID: 186346] Open circuit operations involving products or components not subsequently sterilized should be carried out within a laminar air flow work station (grade A) in a grade B area. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 9. [VIP ID: 1595] Open circuit operations involving products or components not subsequently sterilised should be carried out within a laminar air flow work station (grade A) in a grade B area.

6.

In the production of biological agents, it may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 17 [VIP ID: 186362] Production of biological agents may take place in controlled areas provided it is carried out in totally enclosed and heat sterilized equipment, all connections being also heat sterilized after making and before breaking. it may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage. The sterilization parameters used before breaking the connections must be validated for the organisms being used. Different products may be placed in different biogenerators, within the same area, provided that there is no risk of accidental cross-contamination. However, organisms generally subject to special requirements for containment should be in areas dedicated to such products. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 17. [VIP ID: 1603] Production of biological agents may take place in controlled areas provided it is carried out in totally enclosed and heat sterilized equipment, all connections being also heat sterilized after making and before breaking. It may be acceptable for connections to be made under local laminar air flow provided these are few in number and proper aseptic techniques are used and there is no risk of leakage. The sterilization parameters used before breaking the connections must be validated for the organisms being used. Different products may be placed in different biogenerators, within the same area, provided that there is no risk of accidental cross-contamination. However, organisms generally subject to special requirements for containment should be in areas dedicated to such products.

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7.

For immunological veterinary medicinal products, the introduction or removal of material may take place in an appropriate laminar air flow.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS EQUIPMENT 23 [VIP ID: 186374] The introduction or removal of material should take place using a sterilizable closed system, or possibly in an appropriate laminar air flow. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Equipment 23. (para 3) [VIP ID: 1615] The introduction or removal of material should take place using a sterilizable closed system, or possibly in an appropriate laminar air flow.

8.

Operations involving the transfer of materials, such as sterile media, cultures or product, should be carried out in presterilised closed systems, wherever possible. Where this is not possible, transfer operations must be protected by laminar air flow workstations.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Operating principles 48. [VIP ID: 1647] Operations involving the transfer of materials such as sterile media, cultures or product should be carried out in pre-sterilized closed systems wherever possible. Where this is not possible, transfer operations must be protected by laminar airflow work stations.

9.

Where necessary, for instance when two or more fermentors are within a single area, sampling and addition ports, and connectors (after connection, before the flow of product, and again before disconnection) should be sterilised with steam. In other circumstances, chemical disinfection of ports and laminar air flow protection of connections may be acceptable.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS STARTING MATERIALS Operating principles 50 [VIP ID: 186426] When necessary, for instance when two or more fermentors are within a single area, sampling and addition ports, and connectors (after connection, before the flow of product, and again before disconnection) should be sterilized with steam. In other circumstances, chemical disinfection of ports and laminar air flow protection of connections may be acceptable. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Operating principles 50. [VIP ID: 1649] Where necessary, for instance when two or more fermentors are within a single area, sampling and addition ports, and connectors (after connection, before the flow of product, and again before disconnection) should be sterilized with steam. In other circumstances, chemical disinfection of ports and laminar air flow protection of connections may be acceptable.

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10. Critical activities in the production and testing of a PET drug product, that expose the PET drug product or the sterile surface of the container/closure system to the environment, should be conducted within an aseptic workstation, e.g. a LAFW, and it is recommended that items within a LAFW are kept to a minimum and do not interrupt the air flow.
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT B. Facilities 2. Aseptic Processing Area para 1 [VIP ID: 187390] An aseptic work area should be suitable for the assembly of the aseptic components required for the preparation of a sterile PET drug product. We recommend that air quality in the aseptic processing area be controlled to limit the presence of microorganisms and particulate matter. Critical activities in the production and testing of a PET drug product that expose the PET drug product or the sterile surface of the container/closure system to the environment should be conducted within an aseptic workstation (e.g., a LAFW or barrier isolator). Examples of such activities include the aseptic assembly of sterile components (syringe, needle, filter and vial) for sterile filtration of the PET drug product, and sterility testing of the finished PET drug product. We recommend that the following precautions be taken to help maintain the appropriate air quality of the aseptic workstation: - The aseptic workstation is sanitized before each operation. - Items within a laminar airflow aseptic workstation are kept to a minimum and not interrupt the airflow.

11. It is recommended that microbiological testing for Sterile PET drugs is conducted in a controlled area such as a laminar airflow workbench (LAFW) with clean room apparel.
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) XI. FINISHED DRUG PRODUCT CONTROLS AND ACCEPTANCE CRITERIA C. Microbiological Tests for Sterile PET Drugs para 2 [VIP ID: 187558] We recommend that testing be conducted in a controlled area such as a laminar airflow workbench (LAFW) with clean-room apparel. ...

12. Filled and partially stoppered vials should be transported and loaded into a lyophiliser under a primary barrier such as a laminar flow hood.
GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Filling (para 5) [VIP ID: 2757] Once filled and partially stoppered, vials are transported and loaded into the lyophilizer. The transfer and handling, such as loading of the lyophilizer, should take place under primary barriers, such as the laminar flow hoods under which the vials were filled. Validation of this handling should also include the use media fills. GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Filling (para 9) [VIP ID: 2762] In the transport of vials to the lyophilizer, since they are not sealed, there is concern for the potential for contamination. During inspections and in the review of new facilities, the failure to provide laminar flow coverage or a primary barrier for the transport and loading areas of a lyophilizer has been regarded as an objectionable condition. One manufacturer as a means of correction developed a laminar flow cart to transport the vials from the filling line to the lyophilizer. Other manufacturers building new facilities have located the filling line close to the lyophilizer and have provided a primary barrier extending from the filling line to the lyophilizer.

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13. Information to be included in drug applications for aseptic fill manufacturing processes should include a brief description of the building and facilities indicating the placement of critical equipment such as laminar flow hoods.
GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. A. Buildings and Facilities [VIP ID: 17240] A brief description of the manufacturing building and facilities should be provided. The following information should be included: 1. Floor Plan A floor plan of the areas holding the aseptic filling facilities including preparation and holding areas, filtering and filling areas, and gowning rooms should be included. The air cleanliness class of each area should be identified (e.g. Class 100,Class 10,000, Class 100,000). Isolators or barrier systems should be identified. 2. Location of Equipment The placement of all critical equipment, including, but not limited to, laminar flow hoods, autoclaves, lyophilizers, and filling heads, should be identified. Equipment within barrier or isolation systems should be noted. STERILIZATION PROCESS VALIDATION - SUPERSEDED! (January 1993) II. Information for Aseptic Fill Manufacturing Processes Which Should Be Included in Drug Applications The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. A. [VIP ID: 3030] Provide a brief description of the building and facilities. This should include the following types of information: 1. A floor plan of the areas holding the aseptic filling facilities including preparation and holding areas, filtering and filling areas, gowning rooms, etc. The air cleanliness class of each area should be identified (e.g., Class 100, Class 10,000, Class 100,000, etc.). 2. The placement of all critical equipment such as laminar flow hoods, autoclaves, lyophilizers, filling heads, etc., should be identified.

14. A laminar air flow workstation for aseptic manipulations should be situated in the section of the room with the lowest traffic and lowest activity.
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT B. Facilities 2. Aseptic Processing Area para 2 [VIP ID: 187392] We recommend that conditions in the room where aseptic manipulations are conducted not present a challenge to the operating capability of the aseptic workstation. For example, the room should not be carpeted nor have overhanging pipes or hanging light fixtures. All areas of the production and processing room should be easily accessible for cleaning. Surfaces of the walls, floors, and ceilings in the aseptic work areas should be easily cleaned. Cleaning should be performed frequently to ensure consistent control of the environmental quality. In addition, the aseptic processing area (e.g., LAFW) should be situated in the section of the room with the lowest traffic and lowest activity. Cartons and boxes should not be stored or opened in the production area to minimize ingress of dust and particulate into the aseptic work area.

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15. There should be documented performance specifications and action or alert limits to prompt investigation or corrective action for laminar air flow hoods within aseptic filling rooms.
Selected FDA 483 Observations (April 1997) Sterile Product Manufacture [VIP ID: 2472] There should be documented performance specifications and action or alert limits to prompt investigation or corrective action for laminar air flow hoods within aseptic filling rooms.

16. The local clean area for high risk operations in the manufacture of sterile medicinal products, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections should be Grade A. Normally this environment is provided by a laminar air flow workstation, which should provide a homogenous air speed of 0.36 - 0.54 m/s (guidance value) at the working position and have a Grade B background environment.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS GENERAL 3. paras 3 to 7 inc. [ViP ID: 185986] The in operation and at rest states should be defined for each clean room or suite of clean rooms. For the manufacture of sterile medicinal products 4 grades can be distinguished. Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 - 0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated. A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes. Grade B: For aseptic preparation and filling, this is the background environment for grade A zone. Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 3 For the manufacture of sterile medicinal products 4 grades can be distinguished Grade A: [VIP ID: 62370] The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 - 0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated. A unidirectional air flow and lower velocities may be used in closed isolators and glove boxes. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) General 3. (para 3) [VIP ID: 1369] For the manufacture of sterile medicinal products there are normally 4 grades of clean areas. Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide an homogenous air speed of 0.45 m/s +/- 20% (guidance value) at the working position. Grade B: For aseptic preparation and filling, this is the background environment for grade A zone. Grades C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.

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17. There should be certification for laminar flow hoods in micro labs and filters in Class 100,000 areas.
FDA Warning Letter 320-01-11 (September 2001) Extracted from FDA warning letter 320-01-11 USA 05/09/2001 [VIP ID: 43210] The laminar flow hood in the micro lab and **** filters in the Class 100,000 production area had not been certified.

18. Laminar flow hood HEPA filters in aseptic filling areas should be integrity tested more frequently than once a year.
Selected FDA 483 Observations (April 2001) Sterile Product Manufacture [VIP ID: 27740] Laminar flow hood HEPA filters in aseptic filling areas should be integrity tested more frequently than once a year.

For a laminar air flow workbench for aseptic procedures, it is recommended that integrity testing of the HEPA filter be performed when the unit is initially installed and at least every 6 months thereafter (and after each change of the HEPA filter) to ensure the desired air quality. More frequent testing may be appropriate if air quality is found to be unacceptable.
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. Equipment 1. Production Equipment para 6 b. Aseptic Workstation para 1 [VIP ID: 187410] The aseptic workstation should provide an appropriate environment for aseptic procedures. Examples of workstations include a laminar air flow workbench (LAFW) or barrier isolator system. We recommend that an integrity test be conducted at installation (including after each change of the high-efficiency particulate air (HEPA) filter) to ensure proper performance. We recommend that certification (integrity testing of the HEPA filter) of the aseptic workstation be performed when the unit is initially installed and at least every 6 months thereafter to ensure the desired air quality. More frequent testing may be appropriate if air quality is found to be unacceptable, for example, as part of an investigation into a finding of sterility failure in a PET drug, or if leakage or decrease in optimal airflow is found.

19. It is recommended that a qualified operator change the prefilters in an aseptic workstation periodically in accordance with written procedures and preventive maintenance schedules. For laminar flow hoods equipped with easily readable static pressure gauges to indicate when the pressure builds up behind the filter because of the clogging of the filter, it is recommended that the filter be changed when clogging is detected.
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. Equipment 1. Production Equipment para 6 b. Aseptic Workstation para 2 [VIP ID: 187412] We recommend that a qualified operator change the prefilters in the aseptic workstation periodically in accordance with written procedures and preventive maintenance schedules. Some laminar flow hoods are equipped with easily readable static pressure gauges that indicate when the pressure builds up behind the filter because of the clogging of the filter. We recommend that the filter be changed when clogging is detected.

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FDA Warning Letter CBER-98-024 (August 1998) Extracted from FDA warning letter CBER-98-024 USA 14/08/1998 [VIP ID: 12170] Failure to clean, maintain, and sanitize equipment, utensils, and supplies at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength quality or purity of the drug product, to establish or maintain written procedures for cleaning and maintenance of equipment, and to maintain records [21 CFR 211.67 and 600.12], in that: a. equipment has not been maintained or replaced as per SOP entitled "---" For example: iii. the laminar air flow hood pre-filters have not been replaced.

20. Laminar air flow hood replacement frequency should be documented.


Selected FDA 483 Observations (February 1998) Sterile Product Manufacture [VIP ID: 6324] Laminar air flow hood replacement frequency should be documented.

21. There should be documentation that laminar flow hood calibration is performed when scheduled and that cleaning is documented as required by procedures.
FDA Warning Letter 2001-DT-07 (January 2001) Extracted from FDA warning letter 2001-DT-07 USA 16/01/2001 [VIP ID: 28430] 4. 211.194 Laboratory Controls-Laboratory Records The laboratory records fail to consistently and accurately include complete data derived from all tests necessary to assure compliance with specifications and standards. Examples from the FDA-483 are: i. Item 21. There is no documentation that equipment calibration was performed when scheduled as stated in your firms procedures (e.g. incubator, LFH, balances, thermometers). 211.194(d) k. item 24. Cleaning of the Laminar flow hood the day after samples are processed in the hood, as required by your firms procedure (EM 5), is not always documented. 211.194(a)(8) [FDA Investigators: Renee L. Rice and Miah I. Schneider]

22. There should be documentation to support that procedures for cleaning a laminar flow hood are effective from microbiological contamination.
FDA Warning Letter 2001-DT-07 (January 2001) Extracted from FDA warning letter 2001-DT-07 USA 16/01/2001 [VIP ID: 28420] 3. 211.160 Laboratory Controls-General Requirements. Your firm failed to have in place written procedures for many of the operations performed by your laboratory, that were drafted by an appropriate organizational unit and reviewed and approved by a quality control unit. These procedures should include scientifically sound specifications and test procedures. Some examples from the FDA483 are: f. Item 25. There is no documentation to support that the procedures for cleaning the laboratory benches and laminar flow hood are effective from microbiological contamination. 211.160(b)(1) [FDA Investigators: Renee L. Rice and Miah I. Schneider]

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23. Environmental monitoring should be performed under operational (dynamic) conditions in the laminar air flow and associated background areas.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. ENVIRONMENTAL MONITORING 10.2 [VIP ID: 190296] Environmental monitoring should be performed under operational (dynamic) conditions either within the isolator or in the laminar airflow and associated background areas.

24. It is recommended that aseptic workstation laminar air flow velocities are monitored periodically at the work surface as well as at the HEPA filter face to ensure adequate uniformity of flow throughout the critical area, that operators are trained in the importance of minimising objects and equipment within the critical area so laminar air flow is not disrupted, and that microbiological monitoring (e.g. using settle plate) in the LAFW be conducted during sterility testing and critical aseptic manipulation.
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. Equipment 1. Production Equipment para 6 b. Aseptic Workstation para 3 [VIP ID: 187414] We recommend laminar airflow velocities be monitored periodically at the work surface as well as at the HEPA filter face to ensure adequate uniformity of flow throughout the critical area. We recommend that operators be trained on the importance of minimizing objects and equipment within the critical area so laminar airflow is not disrupted. We recommend that microbiological monitoring (e.g., using settle plate) in the LAFW be conducted during sterility testing and critical aseptic manipulation.

The air flow in critical areas should be laminar when delivered to the point of use.
CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 28. [VIP ID: 2180] Is the air flow in critical areas laminar when delivered to the point of use? At what velocity? Is velocity determined at the critical area or at the filter face?

The location of an environmental monitoring sample device should not compromise the laminarity of the air flow in the critical zone.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING 7.2 Non-viable monitoring 7.2.1 [VIP ID: 188974] The location chosen for monitoring should be checked to ensure that the positions reflect the worst case. For room monitoring, the counts should be performed in locations where there is most operator activity. For the filling environment the counts should be performed adjacent to the filling zone and where components are exposed in such way as to detect operator activity within these areas. Monitoring with sampling probes located in such a way that they monitor the air from the HEPA filter rather than the air immediately surrounding the critical zones should be avoided. However the location of the sample device should not compromise the laminarity of the air flow in the critical zone. Initial validation should be checked to confirm that worst case positions have been adequately identified. These may be reconfirmed during process simulation tests.

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A sterility test may be conducted within a class A laminar air flow cabinet located within a class B clean room, and material should be placed in such a way that it does not disrupt the laminar air flow.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.1 CLEAN ROOM DESIGN 8.1.1 Classification 8.1.1.1 [VIP ID: 190250] The sterility test should be conducted within a class A laminar airflow cabinet located within a class B clean room, or in an isolator that need not be located within a controlled environment. The test may also be performed within a class A clean room, if available. Sterility testing should be carried out in a work zone that offers sufficient space and material should be placed in such a way that it does not disrupt the laminar airflow. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) LABORATORY Environment 285. [VIP ID: 2437] What air quality is specified for sterility testing areas? Is laminar air flow provided?

25. A sterility test environment, which includes a laminar air flow cabinet, should be certified at least annually by a competent person for compliance with the specified standard conditions.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.1 CLEAN ROOM DESIGN 8.1.1 Classification 8.1.1.2 [VIP ID: 190252] The test environment, which includes the laminar airflow cabinet or isolator, should be certified at least annually by a competent person for compliance with the specified standard conditions.

26. If a laminar flow hood fails a sterility test, cleaning it until acceptable sterility test results are obtained is not good practice.
FDA Warning Letter 2001-DT-07 (January 2001) Extracted from FDA warning letter 2001-DT-07 USA 16/01/2001 [VIP ID: 28400] 1. 211.22 Responsibility of the quality control unit. Failure to have a quality control unit adequate to perform its functions and responsibilities, as required by 21 CFR 211.22. Your failure to have an adequate quality control unit is demonstrated by the number and types of inspectional observations made during this inspection. Some examples from the FDA-483 are: c. Item 15. The laminar flow hood failed a sterility test, but was used for subsequent testing after an invalidated cleaning procedure was performed, until acceptable sterility test results were obtained **** days later. 211.22(b) [FDA Investigators: Renee L. Rice and Miah I. Schneider]

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27. Media fills and smoke studies can provide enough meaningful information to correct a problem with air currents resulting in rebound contamination off the floor into a vertical laminar flow hood.
GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Filling (para 10) [VIP ID: 2763] In order to correct this type of problem, another manufacturer installed a vertical laminar flow hood between the filling line and lyophilizer. Initially, high velocities with inadequate return caused a contamination problem in a media fill. It was speculated that new air currents resulted in rebound contamination off the floor. Fortunately, media fills and smoke studies provided enough meaningful information that the problem could be corrected prior to the manufacture of product. Typically, the lyophilization process includes the stoppering of vials in the chamber.

7.1.3 Isolators 1. An isolator provides full separation of two environments, the enclosed environment in which a product is processed and the environment surrounding the isolator. A barrier provides partial separation of the manufacturing and surrounding environments.
HUMAN DRUG CGMP NOTES, VOLUME 09, NUMBER 02 (Second Quarter, 2001) (June 2001) Brian J. Hasselbalch QUESTIONS AND ANSWERS: [Question 4] [VIP ID: 72060] What is an aseptic processing isolator? What is the difference between an isolator and a barrier? An aseptic processing isolator ("isolator") can be fundamentally defined as a unit that provides full separation of two environments: an enclosed environment in which a product is processed or manipulated, and that which surrounds the isolator. A barrier, on the other hand, is a physical partition that affords aseptic manufacturing zone protection by partially separating it from the surrounding area (which is, with few exceptions, of lower air cleanliness) and activities occurring near the processing line. Some have used the tandem term "barrier-isolator," but this term does not connote a single technology, and instead very broadly refers to both. Knowledge of the definitions of the separate terms is becoming increasingly important as these two technologies evolve and gain in popularity. Isolators and barriers are used by aseptic processors in order to help satisfy 21 CFR 211.113, which requires that procedures be designed to prevent microbiological contamination of drug products purporting to be sterile. Aseptic processing operations utilizing isolators designed and operated in accord with CGMP's (e.g., 21 CFR 211.42, 211.63, and 211.65) can be quite effective in diminishing such microbiological contamination risks to the product. Barriers are also frequently helpful in fulfilling this CGMP requirement. There are some further key differences in operation and design of aseptic processing lines contained in an isolator versus one that utilizes barriers. One major distinction lies in the need for an isolator to employ an air pressure differential that provides uncompromised, continuous isolation of its interior from the external environment (e.g., surrounding room air and personnel). In addition, the interior of isolators, which is supplied with HEPA or ULPAfiltered air, is also regularly biodecontaminated (i.e., surface-sterilized) with a sporicidal agent. In contrast with isolators, which are full enclosures, barriers provide a partial barricade. They are normally found as carefully placed flexible plastic curtains or rigid shields (e.g., Plexiglas). In some cases, firms have essentially enclosed parts of the processing line with the latter rigid walls, but the resulting box-like structure is not designed to employ a separative pressure differential and operators routinely access the line by opening panel doors found throughout the line to monitor and control the aseptic tilling process. This design represents an extensive barrier, but does not provide for isolation of the aseptic line from the surrounding environment.

Isolators could be seen as a more encompassing development of the barriers used in conventional clean rooms. The clean room barriers evolved from plastic flexible curtains through to rigid barriers with glove ports.

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PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 2. INTRODUCTION 2.4 [VIP ID: 190416] Isolators could be seen as a more encompassing development of the barriers used in conventional clean rooms. The clean room barriers evolved from plastic flexible curtains through to rigid barriers with glove ports. The objectives of barriers are to increasingly separate the surrounding clean room including the operator from the critical zone where aseptic operations are carried out and sterile materials are exposed. When the degree of containment is nearly complete, the sporicidal procedures used for many years in other applications could be applied without harming the operators.

A "closed" isolator is a unit that does not include any portals that directly communicate air with the surrounding. An "open" isolator, popular for high speed/output lines, includes an exit portal for product egress. Both normally interface with the surrounding environment through aseptic transfer ports and air filters (e.g. HEPA, ULPA, or microbial-retentive filters), and are also known as positivepressure isolators because they operate under air pressures greater than the external environment.
HUMAN DRUG CGMP NOTES, VOLUME 09, NUMBER 02 (Second Quarter, 2001) (June 2001) Brian J. Hasselbalch QUESTIONS AND ANSWERS: [Question 5] [VIP ID: 72070] What is the difference between an open and closed isolator system? What is a positive pressure isolator? It is helpful to become acquainted with some of the terms used to characterize the different types of isolators. For example, isolators have been categorized as either "open" or "closed": A "closed" isolator is a unit that does not include any portals (or "mouseholes," as they are commonly called) that directly communicate air with the surrounding environment. Closed isolators are most commonly used in sterility testing laboratories and for smaller batch applications, such as clinical-scale aseptic filling operations. Their use is limited by the quantity of filled units that can be stored in or transferred out of the isolator during operation. An "open" isolator, popular for high speed/output lines, includes an exit portal for product egress. Thus, while both open and closed isolators normally interface with the surrounding environment through aseptic transfer ports and air filters (e.g., HEPA, ULPA, or microbial-retentive filters), the open isolator also includes an exit portal in its design. Both are also known as positive-pressure isolators because they operate under air pressures greater than the external environment. An important part of qualifying an open isolator is demonstrating that its design and the positive pressure differential used achieve full physical separation from the external environment at the product exit portal. An appropriately qualified minimum positive air pressure differential specification should be established and followed to ensure the continuous isolation of environments. For example, it is important to demonstrate that the air overpressure remains acceptable during use of gloves and half-suits, and is unaffected by activities in the external environment, such as opening and closing cleanroom doors. While we have described the use of positive pressure isolators as protection to the exposed sterile product and container-closures throughout operations, negative pressure isolators also exist. However, the objective of a negative pressure isolator is to protect workers by providing containment of a potent or toxic drug. These isolators have been used for various non-sterile applications and, in some cases, sterile operations. When used for aseptic operations, it is necessary for firms to include special design provisions to assure protection of the exposed sterile product. Since negative pressure isolators have significant potential to exchange air with the surrounding environment, common industry practice is to place these units in a Class 10,000, or when needed, a cleanroom environment of higher air cleanliness, when used for aseptic processing applications. Furthermore, personnel gowning would reflect that used in a traditional aseptic processing operation. References: 21 CFR 211.42: Design and construction features 21 CFR 211.46: Ventilation, air filtration, air heating and cooling 21 CFR 211.63: Equipment design, size, and location 21 CFR 211.65: Equipment construction 21 CFR 211.113: Control of microbiological contamination a Guideline on Sterile Drug Products Produced by Aseptic Processing, 1987. PDA Technical Report No. 34, Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products, Supplement, PDA J. Pharm. Sci. Technol., 55, No. 5 (2001) Contact for further information:

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Richard L. Friedman, HFD-325301-827-7284 Friedmanr@cder.fda.gov GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. Design 1. Airflow (para 1) [VIP ID: 111930] There are two types of aseptic processing isolators: open and closed. Closed isolators employ connections with auxiliary equipment for material transfer. Open isolators have openings to the surrounding environment that are carefully engineered to segregate the inner isolator environment from the surrounding room via overpressure.

A well designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and control, offers tangible advantages over traditional aseptic processing.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators (para 1) [VIP ID: 111890] Aseptic processing using isolation systems separates the external cleanroom environment from the aseptic processing line and minimizes its exposure to personnel. A well-designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and control, offers tangible advantages over traditional aseptic processing, including fewer opportunities for microbial contamination during processing. However, users should remain vigilant to potential sources of operational risk. Manufacturers should also be aware of the need to establish new procedures addressing issues unique to isolators.

One type of isolator has the main objective of providing containment for the handling of dangerous materials either aseptically or not. Another has the main objective of providing a microbiologically controlled environment within which aseptic operations can be carried out.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ISOLATOR TECHNOLOGY 7 [VIP ID: 185998] The utilisation of isolator technology to minimise human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechanisms. The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognised that laminar air flow may not exist in the working zone of all such devices. The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing be at least grade D. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 2. INTRODUCTION 2.1 [VIP ID: 190410] The term Isolator as used in the Pharmaceutical Industry covers a variety of pieces of equipment. One group has the main objective of providing containment for the handling of dangerous materials either aseptically or not. Another group has the main objective of providing a microbiologically controlled environment within which aseptic operations can be carried out.

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Containment isolators often employ negative internal air pressure and most isolators used for aseptic processing employ positive pressure. A sporicidal process, usually delivered by gassing, can be used to aid microbiological control. Some large scale isolators provide an opening, often called a mousehole, to permit continuous removal of sealed product. Other isolators remain sealed throughout production operations. The capability for the isolator to be sealed allows operations to be carried out in controlled gaseous environments e.g. anaerobic conditions. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 6. PRINCIPLES RELATED TO THE SELECTION AND USE OF ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 6.2 [VIP ID: 190442] The reasons for selecting an isolator include containment, to protect the operator and environment, and reducing the risk of microbiological and other contamination of the product from the environment. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 6. PRINCIPLES RELATED TO THE SELECTION AND USE OF ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 6.3 [VIP ID: 190444] This Recommendation focuses on the aspect of reducing the risk of microbiological contamination arising from the environment. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.1 Principles related to the selection and use of isolators subjected to a sporicidal process. 9.1.2 [VIP ID: 190510] This Recommendation focuses on the aspect of reducing the risk of microbiological contamination arising from the environment. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Isolator technology 7 (para 1) [VIP ID: 62850] The utilisation of isolator technology to minimise human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechanisms.

2.

Phases of production with the potential for microbiological contamination should be performed under environmental conditions that minimise the possibility of such contamination (e.g. in a barrier isolator system).
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT B. Facilities 1. General para 2 [VIP ID: 187380] Phases of production with the potential for microbiological contamination should be performed under environmental conditions that minimize the possibility of such contamination (e.g., in a laminar airflow workbench (LAFW), or barrier isolator system).

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Critical activities in the production and testing of a PET drug product that expose the PET drug product or the sterile surface of the container/closure system to the environment should be conducted within an aseptic workstation such as a barrier isolator. Examples of such activities include the aseptic assembly of sterile components (syringe, needle, filter and vial) for sterile filtration of the PET drug product, and sterility testing of the finished PET drug product.
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT B. Facilities 2. Aseptic Processing Area para 1 [VIP ID: 187390] An aseptic work area should be suitable for the assembly of the aseptic components required for the preparation of a sterile PET drug product. We recommend that air quality in the aseptic processing area be controlled to limit the presence of microorganisms and particulate matter. Critical activities in the production and testing of a PET drug product that expose the PET drug product or the sterile surface of the container/closure system to the environment should be conducted within an aseptic workstation (e.g., a LAFW or barrier isolator). Examples of such activities include the aseptic assembly of sterile components (syringe, needle, filter and vial) for sterile filtration of the PET drug product, and sterility testing of the finished PET drug product. We recommend that the following precautions be taken to help maintain the appropriate air quality of the aseptic workstation: The aseptic workstation is sanitized before each operation. Items within a laminar airflow aseptic workstation are kept to a minimum and not interrupt the airflow.

3.

All gases, fluids and air supplied to the isolator, or that may gain access, should be filtered using microbiologically retentive filters or sterilised prior to entry.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. 7.5 The prevention of recontamination 7.5.1 [VIP ID: 190490] All gases, fluids and air supplied to the isolator or that may gain access, should be filtered using microbiologically retentive filters or sterilized prior to entry. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.1 [VIP ID: 190582] All gases, fluids and air supplied to the isolator or that may gain access, should be filtered using microbiologically retentive filters or sterilized prior to entry. All gases and fluids passing into the isolator should be filtered using microbiologically retentive filters or sterilized prior to entry through the envelope so that any escape inside the isolator will be of uncontaminated material. Any vacuum points should be guarded by filters. Consideration should be given to providing a HEPA prefilter for the air inlet system mainly to provide redundancy in the event of failure of one of the filters. The duty to exclude penetration by microorganisms in the incoming air is probably higher than for conventional clean rooms as discussed in 9.1. The air that is supplied to the critical zone of a conventional clean room is generally double HEPA filtered i.e. once into the room and again into the Grade A zone. HEPA filtration is not absolute and a rare penetration is to be expected. The main intention is to provide redundant filtration because if only single filtration is used in the isolator a filter failure could increase the risk of contamination significantly. HEPA filtration of the exhaust system is a standard precaution against backflow.

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4.

The air classification required for an aseptic processing isolator background environment should be at least grade D.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ISOLATOR TECHNOLOGY 7 [VIP ID: 185998] The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing be at least grade D. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. Design 4. Clean Area Classifications [VIP ID: 111980] The interior of the isolator should meet Class 100 (ISO 5) standards. The classification of the environment surrounding the isolator should be based on the design of its interfaces (e.g., transfer ports), as well as the number of transfers into and out of the isolator. A Class 100,000 (ISO 8) background is commonly used based on consideration of isolator design and manufacturing situations. An aseptic processing isolator should not be located in an unclassified room. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Isolator technology 7 (para 3) [VIP ID: 62870] The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing it should be at least grade D.

5.

A sterility test may be conducted within an isolator that need not be located within a controlled environment.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.1 CLEAN ROOM DESIGN 8.1.1 Classification 8.1.1.1 [VIP ID: 190250] The sterility test should be conducted within a class A laminar airflow cabinet located within a class B clean room, or in an isolator that need not be located within a controlled environment. The test may also be performed within a class A clean room, if available. Sterility testing should be carried out in a work zone that offers sufficient space and material should be placed in such a way that it does not disrupt the laminar airflow. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 2. INTRODUCTION 2.3 [VIP ID: 190414] Controlled environments for aseptic operations are currently mainly provided by conventional clean rooms, of Grade B, containing workstations, of Grade A complying with the PIC/S and EC guide to GMP. A smaller number of controlled environments are provided by clean rooms, of Grade D or better containing equipment called isolators providing a Grade A environment. When isolators are used for sterility testing there is no formal requirement for them to be placed in a Grade D environment. The environment should be controlled e.g. allow access only to trained staff, but not necessarily classified.

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6.

Particular attention should be paid to microbiologically retentive filters used to treat services to and from an isolator. When a sporicidal process cannot be assured, the use of presterilised filters may be necessary.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.3 [VIP ID: 190518] The materials that should be sterilized i.e. treated using a validated sterilization process as specified in the Pharmacopoeia, and those that should be subjected to a sporicidal process, should be identified. The rationale used should be documented, the list should be a controlled document and consistent with that used in validation. Particular attention should be paid to microbiologically retentive filters used to treat services to and from the isolator. When the sporicidal process cannot be assured the use of presterilized filters may be necessary. There is a hierarchy of risk leading to direct product contact parts being subject to a conventional sterilization process e.g. filling needles, stoppers etc. Non product contact surfaces including machine surfaces, gloves etc are exposed to a sporicidal process. The indirect product contact surfaces such as stopper hoppers and delivery chutes should ideally be sterilized into the isolator to prepare for the start of each batch of product. Whether it is possible to maintain these surfaces in a satisfactory condition by a sporicidal process for some sequence of batches is unresolved. If the indirect product contact surfaces are exposed to the environment surrounding the isolator by being removed or due to loss of integrity of the isolator, then sterilization is necessary before reuse.

Any air supplied by the generator, e.g. during a purge stage, should be filtered though microbiologically retentive filters that have been sterilised or subjected to a sporicidal process. All of the gas should ideally enter by all of the air inlet filters and leave by all of the exhaust filters. If this is not possible arrangements should be made to assure that all terminal inlet and exhaust filters are exposed to gas. If part of the process involves a reversal of the flow through a filter, the possibility of the filter becoming unseated should be investigated.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.4 9.4.6 [VIP ID: 190530] The delivery of gas from the generator into the isolator should assure that only the gas generated is supplied. All inlet and outlet filters associated with the isolator should be exposed to gas or sterilized. Any air supplied by the generator e.g. during a purge stage, should be filtered though microbiologically retentive filters that have been sterilized or subjected to a sporicidal process. The delivery of gas to the isolator should be via defined ducts with no possibility of loss or contamination. Dispersed oil droplets used for integrity testing HEPA filters may break down the gas. This should be examined during validation and it may be necessary to consider the first gassing after testing as a neutralising operation. All of the gas should ideally enter by all of the air inlet filters and leave by all of the exhaust filters. If this is not possible arrangements should be made to assure that all terminal inlet and exhaust filters are exposed to gas. If part of the process involves a reversal of the flow through a filter, the possibility of the filter becoming unseated should be investigated.

7.

The isolator should be designed to enable access to all surfaces for cleaning without major dismantling. Inlet and exhaust air pathways should be designed with this in mind.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.4 9.4.8 [VIP ID: 190534] The isolator should be cleaned prior to the sporicidal process. The surfaces of packaged materials and all other items to be exposed to the sporicidal process within the isolator should be clean.

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All the surfaces inside the isolator should be clean prior to exposure to the sporicidal process. Apart from removing chemical residues that may contaminate subsequent production, the presence of deposits may enable microorganisms to survive the process by physical shielding or neutralization of the process of inactivation. The isolator should be designed to enable access to all surfaces for cleaning without major dismantling. Inlet and exhaust air pathways should be designed with this in mind. If clean in place systems are used, any risks that may arise from the presence of spray balls, drains and retained fluids should be identified and eliminated. Whichever cleaning method is used it should result in a visibly clean dry surface free from risk of residues.

8.

The test environment, which includes the isolator, should be certified at least annually by a competent person for compliance with the specified standard conditions.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.1 CLEAN ROOM DESIGN 8.1.1 Classification 8.1.1.2 [VIP ID: 190252] The test environment, which includes the laminar airflow cabinet or isolator, should be certified at least annually by a competent person for compliance with the specified standard conditions.

9.

Environmental monitoring should be performed under operational (dynamic) conditions within an isolator.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. ENVIRONMENTAL MONITORING 10.2 [VIP ID: 190296] Environmental monitoring should be performed under operational (dynamic) conditions either within the isolator or in the laminar airflow and associated background areas.

10. The principles necessary to assure a microbiologically controlled environment for production, are also appropriate, in most cases, for isolators used for sterility testing.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 2. INTRODUCTION 2.2 [VIP ID: 190412] Aseptic operations can include sterility testing or aseptic processing to produce medicinal products. This Recommendation deals mainly with the provision of a microbiologically controlled environment for aseptic processing for producing medicinal products labelled as sterile. The principles necessary to assure a microbiologically controlled environment for production, are also appropriate, in most cases, for isolators used for sterility testing.

11. A suitable positive differential air pressure should be maintained between the isolator and the surrounding room to protect against unforeseen circumstances. The maintenance of positive pressure should be monitored and fitted with an alarm. If requirements for operator safety drive the need to use a negative pressure critical zone, consideration should be given to enclosing it in a positive pressure envelope.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. Design 3. Pressure Differential (para 1) [VIP ID: 111960] Isolators that include an open portal should be designed to ensure complete physical separation from the external environment. A positive air pressure differential adequate to achieve this separation should be employed and

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supported by qualification studies. Positive air pressure differentials from the isolator to the surrounding environment have largely ranged from approximately 17.5 to 50 Pascals [22]. The appropriate minimum pressure differential established by a firm will depend on the systems design and, when applicable, its exit port. Air balance between the isolator and other direct interfaces (e.g., dry heat tunnel) should also be qualified. [22] 0.07" to 0.20" water gauge. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. 7.5 The prevention of recontamination 7.5.2 [VIP ID: 190492] The control of leaks between the isolator and surrounding room and between different parts of the isolator system as necessary, should be assured as far as possible. As a guide a minimum of 10 Pascal positive differential air pressure should be maintained to protect against unforeseen circumstances. The maintenance of positive pressure should be monitored and fitted with an alarm. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.2 [VIP ID: 190584] The control of leaks between the isolator and surrounding room and between different parts of the isolator system as necessary, should be assured as far as possible. As a guide a minimum of 10 Pascal positive differential air pressure should be maintained to protect against unforeseen circumstances. The maintenance of positive pressure should be monitored and fitted with an alarm. The isolator should be designed to be free from leaks that are a microbiological risk and maintained in that state. It is recognized that there will be some leakage, but this should be due to essential engineering tolerances as opposed to poor design, construction and maintenance. There should be a program to reduce the risk of leaks due to accident and means of detecting them which have known sensitivity e.g. pressure hold tests, tracer gas penetration etc. The risk posed by undetected leaks and unanticipated deterioration can be reduced by operating the isolator at positive pressure with respect to lower grade connecting and surrounding areas. A pressure sufficient to maintain a differential of at least 10Pa under all operating conditions is suggested. If requirements for operator safety drive the need to use a negative pressure critical zone, consideration should be given to enclosing it in a positive pressure envelope.

12. An isolator opening to the external environment should be appropriately designed to prevent potential ingress of surrounding room air by induction.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. Design 3. Pressure Differential (para 2) [VIP ID: 111970] The positive pressure differential should be coupled with an appropriately designed opening to the external environment to prevent potential ingress of surrounding room air by induction. Induction can result from local turbulent flow causing air swirls or pressure waves that might push extraneous particles into the isolator. Local Class 100 (ISO 5) protection at an opening is an example of a design provision that can provide a further barrier to the external environment.

13. The design of the isolator system should include consideration of air change rate, the use of laminar, unidirectional or turbulent air flow, the application of aseptic technique and risk of error due to human fallibility. The rationale for the decisions taken should be documented.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. 7.5 The prevention of recontamination

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7.5.6 Air change, laminar/turbulent, aseptic technique, and ergonomics 7.5.6.1 [VIP ID: 190500] The design of the isolator system should include consideration of air change rate, the use of laminar, unidirectional or turbulent airflow, the application of aseptic technique and risk of error due to human fallibility. The rationale for the decisions taken should be documented.

14. An environmental monitoring programme should be established that routinely ensures acceptable microbiological quality of air, surfaces, and gloves (or half-suits) as well as particle levels, within the isolator. Air quality should be monitored periodically during each shift.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators F. Environmental Monitoring [VIP ID: 112070] An environmental monitoring program should be established that routinely ensures acceptable microbiological quality of air, surfaces, and gloves (or half-suits) as well as particle levels, within the isolator. Nutrient media should be cleaned off of surfaces following a contact plate sample. Air quality should be monitored periodically during each shift. For example, we recommend monitoring the exit port for particles to detect any unusual results. Media used for environmental monitoring should not be exposed to decontamination cycle residues, as recovery of microorganisms would be inhibited.

15. The use of settle plates, contact plates, swabs and the presence of sampling points for active air samplers or particle counters during microbiological monitoring may add risk to an isolator subjected to a sporicidal process. Some of the ways this may be addressed include sampling at the end of production and sampling at potentially worst case positions, e.g. in an exhaust. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. 7.6 Monitoring and testing 7.6.2 [VIP ID: 190504] Microbiological monitoring should take into account the special requirements for sensitivity of testing in isolators subjected to a sporicidal process and avoid compromising operations. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.1 Principles related to the selection and use of isolators subjected to a sporicidal process. 9.1.3 [VIP ID: 190512] This position leads to an apparent paradox as to whether an isolator that has been subjected to a sporicidal process that demonstrates a classical clean room pattern of the occasional detection of microorganisms, is acceptable for aseptic processing. It is difficult to conceive of an isolator that has been subjected to a sporicidal process being designed and validated to assure and demonstrate clean room performance if it is working correctly. The choice of an isolator that has been subjected to a sporicidal process inevitably drives up the standard; the presence of microorganisms implies that the validated condition probably no longer prevails and the fault should be identified and corrected. Another factor to take into account is the method of use of the isolator. The lower risk of contamination may be used to justify different practices than used in clean rooms; these may include the following: Reduced frequency of autoclaving of indirect product contact parts. (See below). Extend the allowable period of exposure of sterile surfaces and materials. Reduce the need to discard open containers surrounding an intervention via the glove ports.

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PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.7 Monitoring and testing 9.5.7.2 Microbiological monitoring should take into account the special requirements for sensitivity of testing in isolators subjected to a sporicidal process and avoid compromising operations. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system. 9.5.7.2.1 [VIP ID: 190612] Media fills and sterility testing should be carried out as normal for aseptic processing. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.7 Monitoring and testing 9.5.7.2 Microbiological monitoring should take into account the special requirements for sensitivity of testing in isolators subjected to a sporicidal process and avoid compromising operations. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system. 9.5.7.2.2 [VIP ID: 190614] Environmental monitoring within the isolator should not interfere with zone protection, and in process controls should not carry any risk for production. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.7 Monitoring and testing 9.5.7.2 Microbiological monitoring should take into account the special requirements for sensitivity of testing in isolators subjected to a sporicidal process and avoid compromising operations. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system. 9.5.7.2.3 [VIP ID: 190616] The use of settle plates, contact plates, swabs and the presence of sampling points for active air samplers or particle counters may add risk to the system subjected to a sporicidal process. Some of the ways that this may be addressed include the following: Sampling at the end of production. Sampling at potentially worst case positions e.g. in an exhaust. Using multiple wrapped irradiated plates and swabs etc. may reduce the risk of introducing contamination into the system, but there have been instances when the supplier has made changes or mistakes and compromised processes. The fertility of irradiated media should be given special attention. Testing the suppliers formula at extremes of the irradiation treatment using local isolates as well as standard cultures should be considered. The effect of exposure of wrapped plates etc. to the sporicidal process should be examined in case of loss of fertility due to penetration of the agent. A significant risk to the interpretation of results is the accidental infection of plates etc. by subsequent handling, so incubation in sealed sterile pass out bags may be necessary. Another risk to the interpretation of results is the presence of a colony that developed prior to irradiation. Built in sampling systems should be gassed or otherwise assured to be free from contamination and not compromise operations, special arrangements of filters and/or valves may be used. Quantitative results are not as relevant as in conventional clean rooms because the detection of any contamination probably indicates something has failed. Conventional sampling may be replaced by in house devices known to be sterile, such as settling pots full of media or transport fluid. Large areas of the gloves and isolator surfaces may be swabbed and the swab incubated in sterile broth.

PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004)

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9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.7 Monitoring and testing 9.5.7.2 Microbiological monitoring should take into account the special requirements for sensitivity of testing in isolators subjected to a sporicidal process and avoid compromising operations. The interpretation of results of environmental monitoring should be based on the premise that the detection of any microbiological contamination probably indicates a failure of the system. 9.5.7.2.4 [VIP ID: 190618] Evaluation of results The detection of any microorganisms from environmental monitoring inside the isolator should be considered as requiring a full scale investigation. Consideration should be given to the wisdom of releasing product still in house and the continued use of the isolator may not be appropriate. If a clear cause is found, the implications on existing product could be evaluated based on the likely level and type of environmental contamination, together with the probability of contamination of product. Loss of integrity of gloves, mistakes in transfer of materials into the system, and contaminated settle plates have been implicated as causes based on past experience. If no clear cause is found after a genuinely searching investigation; and intensive monitoring shows no further contamination; this may be a case when the slight imperfections of the system are revealed, and as long as they do not reoccur they may have to be accepted. A positive media fill unit or positive sterility test unit is a more serious event and the effects on product in the field may have to be considered as there is some evidence of non-sterile product being produced and supplied. In this case the investigation would not only involve possible failure of the isolator to control the environment, but the whole sterility assurance system including components, formulated drug sterilization, on site and any off site sterilization processes, product integrity etc. It is only when the cause is found that appropriate action can be taken.

16. Physical testing of an isolator should be organised to monitor the parameters considered to be critical, together with their alarm systems. These may include: Gas detection in the isolator/exhaust Gas concentration in the isolator/exhaust Air flow in Air flow out Gas inlet temperature Isolator pressure Pressure drop across filters Airborne particles Condensation detection Temperature of the external surface of the isolator Temperature of internal points in the isolator Humidity in the isolator Absence of alarm conditions Correct operation and position of gas drivers such as fans, pumps and evacuation Displacement to expose occluded surfaces Gas concentration during ventilation Process step times.

PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.7 Monitoring and testing 9.5.7.1 Physical monitoring and testing should be based on a systematic failure mode analysis or a suitable alternative and assure the detection of change, failure or aging that could compromise operations. - 9.5.7.1.1 [VIP ID: 190608]

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The main thrust of control of this type of isolator is physical; therefore, physical monitoring and testing is preeminent. The testing should be organized to monitor the parameters considered to be critical together with their alarm systems. Alarms should be latched so that the occurrence of the alarm is still evident even though the deviation leading to the alarm being triggered has corrected itself. This is valuable when the isolator is left unattended e.g. at night. The following should be considered. Isolator pressure. Airflow in. Airflow out. Pressure change across filters. Temperature/Humidity-depends on process. Airborne particles, the position of the sampling probe for continuous monitoring should be carefully considered. If it is positioned just to sample a limited output of the air inlet filter it is unlikely to provide useful information. Sampling near the point of fill, in the recirculation ducts or exhaust ducts may be more informative. When powders are handled the sampling program should select times and positions to provide relevant information.

PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.4 9.4.12 [VIP ID: 190542] The range of parameters and events that should be monitored to assure the delivery of the validated process should be defined. The delivery of the validated process will involve monitoring parameters and events in addition to those from the gas generator. These may include the following: Gas detection in the isolator/exhaust. Gas concentration in the isolator/exhaust. Flow rate in exhaust. Gas inlet temperature. Isolator pressure. Pressure drop across filters. Condensation detection. Temperature of the external surface of the isolator. Temperature of internal points in the isolator. Absence of alarm conditions. Correct operation and position of gas drivers such as fans, pumps and evacuation. Displacement to expose occluded surfaces. Gas concentration during ventilation. Process step times.

17. An isolator subjected to a sporicidal process should undergo a standard qualification approach with the additional provision for periods of development work particularly for the sporicidal process.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.1 Principles related to the selection and use of isolators subjected to a sporicidal process. 9.1.1 [VIP ID: 190508] The principles of design, validation and use should arise from the objectives employed to make the decision to use an isolator subjected to a sporicidal process and the consequent user requirements specifications. It is recognized that the considerations may include operator protection and financial optimization as well as reduced risk of microbiological contamination of the product from the environment. Other aspects that should be considered are the principles of dedication to avoid cross contamination and mix up. These are general principles of GMP, but the particular risk of chemical contamination of the exhaust filters and potential for blowback into the adjacent critical zone should be considered. Standard approaches to design qualification, installation qualification, operational qualification and process qualification are appropriate with the additional provision for periods of development work particularly for the sporicidal process.

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18. Details of the handling and culture of biological indicators should be fully investigated and defined for validation of a sporicidal process involving gassing.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.4 9.4.13 k) [VIP ID: 190564] The design, development and validation of the sporicidal process should encompass all relevant aspects from methods of gas distribution to quantification of target lethality, selection, calibration and culture of the biological indicator and definition of the final protocols. The design, development and validation of a sporicidal process involving gassing should include at least the following steps. k) The details of handling and culture of the BIs should be fully investigated and defined. At the end of the gassing phase there will be a lag as the ventilation reduces the gas concentration. Gas may have absorbed into the material of the BI carrier and into the isolator and load. The desorption of this gas may be difficult to predict. All these factors combine together to produce the potential for residual lethality which may be outside the controlled lethality delivered by the gassing cycle. When the BI is eventually placed into the tube of broth or carrier medium prior to culture, the gas absorbed in the BI may not be inactivated and could prevent the outgrowth of survivors. The cultural conditions may not be optimized in terms of media, temperature and time for the outgrowth of survivors. The BI organism may be viable after exposure to the gas, but the recovery system may not be able to allow organisms exposed to the gassing agent to outgrow. The fertility of the particular batch of media used may have varied. All these possibilities should be studied and taken into account in the design of the testing systems.

19. Transfer of material into or out of the isolator should not compromise the critical zone.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.4 Transfer of material out [VIP ID: 190594] Transfer of material out of the isolator should not compromise the critical zone. Product and waste should ideally be removed from the isolator without loss of integrity. Alternating gassed accumulation airlocks or heat sealed sterile plastic film tube may be applicable depending on the scale of production. When it is impossible (as opposed to inconvenient) to provide a continuous gassed/sterilized/ physical barrier, the opening should be properly designed. The design should ensure that the opening should be able to be sealed during gassing or when left unattended. During use, the design should provide robust methods of preventing penetration by the use of, for example, directional airflow, transition chambers or tunnels and distance from the critical zone. When transfer out involves transition to another aseptic stage such as a lyophilizer connected to the isolator system, the transfer should assure the integrity of the isolator as well as the safety of the product. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.5 Transfer of material in [VIP ID: 190596] Transfer of material into the isolator should not compromise the critical zone. Materials to be transferred into the isolator should comply with 6.4.1 to avoid them carrying contamination into the isolator once it is in its gassed state. Transfer to the isolator should be minimized and secure to prevent penetration of contaminants during the transfer process[1]. Examples of transfer in scenarios are as follows: Secure transfer ports from a separate autoclave, isolator, or supplier of sterile components, formulated drug powder etc. Any small area of the gasket that has been exposed to the external environment and is then exposed to the inside of the isolator should be managed (this includes the 'ring of concern' of rapid transfer ports). This may include manual surface sanitisation, or use of heat or light sporicidal processes coupled with no direct or indirect product contact.

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Direct connection between the isolator and other isolators, autoclaves, hot air ovens, sterilizing tunnels etc. The interfaces should be carefully designed to withstand the stresses of extreme temperatures, expansion and contraction and retain the integrity of the isolator system. When intervening doors are opened, there should not be any exposure of non-sterile or non-gassed surfaces or ingress of unfiltered air. Ingress of steam and condensate from an autoclave should be prevented.

[1] The special problem of the cooling zone in a sterilizing tunnel has been discussed above.

The number of transfers into an isolator, should be minimised. To prevent changes in air currents that introduce lower quality air, movement adjacent to the critical area should be appropriately restricted.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities E. Design (para 3) [VIP ID: 110450] Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures, or the surrounding environment. The layout of equipment should provide for ergonomics that optimize comfort and movement of operators. The number of personnel in an aseptic processing room should be minimized. The flow of personnel should be designed to limit the frequency with which entries and exits are made to and from an aseptic processing room and, most significant, its critical area. Regarding the latter, the number of transfers into the critical area of a traditional cleanroom, or an isolator, should be minimized. To prevent changes in air currents that introduce lower quality air, movement adjacent to the critical area should be appropriately restricted.

20. The design of the isolator system should include consideration of air change rate, the use of laminar, unidirectional or turbulent air flow, the application of aseptic technique and the risk of error due to human fallibility. The rationale for the decisions taken should be documented.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. Design 1. Airflow (para 2) [VIP ID: 111940] Turbulent flow can be acceptable within closed isolators, which are normally compact in size and do not house processing lines. Other aseptic processing isolators employ unidirectional airflow that sweeps over and away from exposed sterile materials, avoiding any turbulence or stagnant airflow in the area of exposed sterilized materials, product, and container closures. In most sound designs, air showers over the critical area once and then is systematically exhausted from the enclosure. The air handling system should be capable of maintaining the requisite environmental conditions within the isolator. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.6 Air change, laminar/turbulent, aseptic technique, and ergonomics [VIP ID: 190598] The design of the isolator system should include consideration of air change rate, the use of laminar, unidirectional or turbulent airflow, the application of aseptic technique and the risk of error due to human fallibility. The rationale for the decisions taken should be documented. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.6.2 [VIP ID: 190602]

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As the absence of microorganisms is expected the questions of laminar flow versus turbulent flow and the rigour of implementation of aseptic procedure may be irrelevant. During the design of isolators it may be as convenient to arrange for incoming air to be delivered to form a laminar or unidirectional flow or as a turbulent flow. The lower air velocity generated by the laminar or unidirectional option may reduce risks of venturi effects and impacts on production operations. In these cases, it would seem sensible to also gain another increment of sterility assurance and arrange airflows and production operations accordingly.

It is recognised that laminar air flow may not exist in the working zone of all isolators.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ISOLATOR TECHNOLOGY 7 [VIP ID: 185998] The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognised that laminar air flow may not exist in the working zone of all such devices. ... EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Isolator technology 7 (para 2) [VIP ID: 62860] The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognised that laminar air flow may not exist in the working zone of all such devices.

21. Glove ports and full or half-suits present particular risks due to the air and surfaces exposed by a leak possibly being microbiologically contaminated due to the proximity of the operators body.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.3 9.5.3.1 [VIP ID: 190588] Glove ports and full or half suits present particular risks for the following reasons: They are more prone to damage. They may be very close to exposed sterile materials. They may not be protected by positive pressure due to localized sealing effects, the piston effect of arms entering the sleeves and occlusion. The air and surfaces exposed by the leak may be microbiologically contaminated due to the proximity of the operators body.

The use of aseptic techniques, to the extent possible in isolators, provides additional reduction in the risk to product arising from loss of integrity of sleeves and gloves.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.3 9.5.3.3 [VIP ID: 190592] The use of aseptic techniques, to the extent possible in isolators, provides additional reduction in the risk to product arising from loss of integrity of sleeves and gloves.

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A programme to minimise the risk of loss of integrity of gloves, sleeves and suits should be present. This should include operator practices, vigilance and the absence of sharp edges. There should also be an all encompassing preventative maintenance programme that includes specification of examination and pre-emptive replacements.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. 7.5 The prevention of recontamination 7.5.3 [VIP ID: 190494] A program to minimize the risk of loss of integrity of gloves, sleeves and suits should be present. This should include operator practices, vigilance and the absence of sharp edges. There should also be an all encompassing preventative maintenance program that includes specification of examination and preemptive replacements. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.3 [VIP ID: 190586] A program to minimize the risk of loss of integrity of gloves, sleeves and suits should be present. This should include operator practices, vigilance and the absence of sharp edges. There should also be an all encompassing preventative maintenance program that includes specification of examination and preemptive replacements. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.3 9.5.3.2 [VIP ID: 190590] The analysis of these risks should be documented and preventative actions such as the following should be considered: Selection of robust materials. Use of double skinned sleeves where puncture of one or both of the skins causes separation of the two layers and is easily detected by the operator. Operator training to avoid damage and vigilance to examine for damage. Frequent leak testing. Inner or outer sterile gloves. Sterile inner sleeves or garments. Preventative maintenance program that includes specification of examination and preemptive replacement

The integrity of isolator gloves, half-suits, and seams should receive daily attention and be addressed by a comprehensive preventative maintenance programme, as should other parts including transfer systems, gaskets, and seals. There should be routine integrity testing and replacement frequencies should be established in written procedures that ensure parts will be changed before they breakdown or degrade.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ISOLATOR TECHNOLOGY 9 [VIP ID: 186002] Monitoring should be carried out routinely and include frequent leak testing of the isolator and glove/sleeve system.

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GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators A. Maintenance 1. General [VIP ID: 111900] Maintenance of isolator systems differs in some significant respects from the traditional, non-isolated aseptic processing operations. Although no isolator forms an absolute seal, very high integrity can be achieved in a welldesigned unit. However, a leak in certain components of the system can constitute a significant breach of integrity. The integrity of gloves, half-suits, and seams should receive daily attention and be addressed by a comprehensive preventative maintenance program. Replacement frequencies should be established in written procedures that ensure parts will be changed before they breakdown or degrade. Transfer systems, gaskets, and seals are among the other parts that should be covered by the maintenance program. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators A. Maintenance 2. Glove Integrity (para 1) [VIP ID: 111910] A faulty glove or sleeve (gauntlet) assembly represents a route of contamination and a critical breach of isolator integrity. A preventative maintenance program should be established. The choice of durable glove materials, coupled with a well-justified replacement frequency, are key aspects of good manufacturing practice to be addressed. With every use, gloves should be visually evaluated for any macroscopic physical defect. Physical integrity tests should also be performed routinely. A breach in glove integrity can be of serious consequence. The monitoring and maintenance program should identify and eliminate any glove lacking integrity and minimize the possibility of placing a sterile product at risk. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators A. Maintenance 2. Glove Integrity (para 2) [VIP ID: 111920] Due to the potential for microbial migration through microscopic holes in gloves and the lack of a highly sensitive glove integrity test, we recommend affording attention to the sanitary quality of the inner surface of the installed glove and to integrating the use of a second pair of thin gloves. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Isolator technology 9. [VIP ID: 62890] Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove/sleeve system.

22. If an isolator transfer port design has the potential to compromise isolation by allowing ingress of air from the surrounding room, localised HEPA filtered unidirectional air flow cover should be provided in the area of the port.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators C. Transfer of Materials/Supplies (para 2) [VIP ID: 112000] Multiple material transfers are generally made during the processing of a batch. Frequently, transfers are performed via direct interface with manufacturing equipment. Properly maintained and operated rapid transfer ports (RTPs) are an effective transfer mechanism for aseptic transfer of materials into and out of isolators. Some transfer ports might have significant limitations, including marginal decontaminating capability (e.g., ultraviolet) or a design that has the potential to compromise isolation by allowing ingress of air from the surrounding room. In the latter

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case, localized HEPA-filtered unidirectional airflow cover in the area of such a port should be implemented. Isolators often include a mousehole or other exit port through which product is discharged, opening the isolator to the outside environment. Sufficient overpressure should be supplied and monitored on a continuous basis at this location to ensure that isolation is maintained.

23. The frequency adopted between decontamination cycles of an isolator should be established during validation studies and should be re-evaluated and increased, if production data indicate deterioration of the microbiological quality of the isolator environment.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators D. Decontamination 3. Frequency (para 1) [VIP ID: 112040] The design of the interior and content of an isolator should provide for its frequent decontamination. When an isolator is used for multiple days between decontamination cycles, the frequency adopted should be justified. This frequency, established during validation studies, should be reevaluated and increased if production data indicate deterioration of the microbiological quality of the isolator environment.

24. Potential uses of quality risk management tools and principles include the options for clean rooms versus isolator technologies.
ICH HARMONISED TRIPARTITE GUIDELINE QUALITY RISK MANAGEMENT Q9 (November 2005) Annex II: Potential Applications for Quality Risk Management II.4 Quality Risk Management for Facilities, Equipment and Utilities Design of facility/equipment [VIP ID: 191166] To determine appropriate zones when designing buildings and facilities, e.g., flow of material and personnel; minimize contamination; pest control measures; prevention of mix-ups; open versus closed equipment; clean rooms versus isolator technologies; dedicated or segregated facilities/equipment.

To determine appropriate product contact materials for equipment and containers (e.g., selection of stainless steel grade, gaskets, lubricants); To determine appropriate utilities (e.g., steam, gases, power source, compressed air, heating, ventilation and air conditioning (HVAC), water); To determine appropriate preventive maintenance for associated equipment (e.g., inventory of necessary spare parts).

7.1.4 Blow/Fill/Seal Technology 1. To satisfy the European regulatory agencies, blow/fill/seal equipment used for aseptic production, which is fitted with an effective grade A air shower, may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and non viable limits at rest and the viable limit only when in operation. Blow/fill/seal equipment used for the production of products for terminal sterilisation should be installed in at least a grade D environment.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS BLOW/FILL/SEAL TECHNOLOGY 10. para 1

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[VIP ID: 186004] Blow/fill/seal units are purpose built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and nonviable limits "at rest" and the viable limit only when in operation. Blow/fill/seal equipment used for the production of products for terminal sterilisation should be installed in at least a grade D environment. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Blow/fill/seal technology 10. (para 1) [VIP ID: 62900] Blow/fill/seal units are purpose built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and non viable limits at rest and the viable limit only when in operation. Blow/fill/seal equipment used for the production of products which are terminally sterilised should be installed in at least a grade D environment.

2.

To satisfy the FDA, the classified environment surrounding BFS machinery should generally meet Class 100,000 (ISO 8), or better, standards, depending on the design of the BFS machinery and the surrounding room. HEPA filtered or sterile air provided by membrane filters should be used during the steps when sterile products or materials are exposed (e.g. parison formation, container molding or filling steps). Air in the critical area should meet Class 100 (ISO 5) microbiological standards during operations. A well designed BFS system should also normally achieve Class 100 (ISO 5) airborne particle levels. Only personnel, who have been qualified and appropriately gowned, should enter the classified environment surrounding the BFS machinery. Refer to Section V of this document for guidance on personnel training, qualification, and monitoring.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 2: Blow-fill Seal Technology A. Equipment Design and Air Quality (para 4) [VIP ID: 112130] The classified environment surrounding BFS machinery should generally meet Class 100,000 (ISO 8), or better, standards, depending on the design of the BFS machinery and the surrounding room. HEPA-filtered or sterile air provided by membrane filters should be used during the steps when sterile products or materials are exposed (e.g., parison formation, container molding or filling steps). Air in the critical area should meet Class 100 (ISO 5) microbiological standards during operations. A well-designed BFS system should also normally achieve Class 100 (ISO 5) airborne particle levels. Only personnel who have been qualified and appropriately gowned should enter the classified environment surrounding the BFS machinery. Refer to Section V of this document for guidance on personnel training, qualification, and monitoring.

3.

Particular attention should be paid to the background clean room environment in which the equipment is located.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS BLOW/FILL/SEAL TECHNOLOGY 10. para 2 [VIP ID: 186006] Because of this special technology particular attention should be paid to at least the following: equipment design and qualification, validation and reproducibility of cleaning-in-place and sterilisation-in-place, background clean room environment in which the equipment is located, operator training and clothing, and interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Blow/fill/seal technology 10

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(para 2) [VIP ID: 62910] Because of this special technology particular attention should be paid to, at least the following: equipment design and qualification, validation and reproducibility of cleaning-in-place and sterilisation-in-place, background cleanroom environment in which the equipment is located, operator training and clothing, and interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling.

4.

Provisions for carefully controlled air flow can protect the product by forcing generated particles outward, while preventing any ingress from the adjacent environment.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 2: Blow-fill Seal Technology A. Equipment Design and Air Quality (para 5) [VIP ID: 112140] BFS equipment design typically calls for use of specialized measures to reduce particle levels that can contaminate the exposed product. In contrast to nonpharmaceutical applications using BFS machinery, control of air quality (i.e., particles) is critical for sterile drug product manufacture. Particles generated during the plastic extrusion, cutting, and sealing processes should be controlled. Provisions for carefully controlled airflow can protect the product by forcing generated particles outward while preventing any ingress from the adjacent environment. Furthermore, equipment designs that separate the filling zone from the surrounding environment provide additional product protection. Barriers, pressure vacuums, microenvironments, and appropriately directed high velocities of sterile air have been found useful in preventing contamination (Ref. 15). Smoke studies and multi-location particle data can provide valuable information when performing qualification studies to assess whether proper particle control dynamics have been achieved throughout the critical area.

5.

It is essential to monitor the microbial air quality.


GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 2: Blow-fill Seal Technology C. Batch Monitoring and Control (para 1) [VIP ID: 112190] Various in-process control parameters (e.g., container weight variation, fill weight, leakers, air pressure) provide information to monitor and facilitate ongoing process control. It is essential to monitor the microbial air quality. Samples should be taken according to a comprehensive sampling plan that provides data representative of the entire filling operation. Continuous monitoring of particles can provide valuable data relative to the control of a blow-fill-seal operation.

7.2 Air Cleanliness Specification Note: This section should be read in conjunction with the Cleanroom Classification Table, which can be freely downloaded from the Downloads section of our web site. As well as the references listed here, there may well be additional relevant references in section 7.1, the design considerations 1. Over the years, there have been various standards used for the classification of clean room environments.
CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 31. [VIP ID: 2183] Is room classification system based upon Federal Standard 209d or other?

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HUMAN DRUG CGMP NOTES, VOLUME 01, NUMBER 03 (September 1993) Motise's Notebook POLICY EMERGING: 5) [VIP ID: 3656] Item: Metrification of Federal Standard 209E (Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones, 9/11/92); Clarification. In Vol 1. No. 2 of the Human Drug CGMP Notes, we said it is not acceptable to qualify a clean room in Metric units by performing a mathematical conversion of the English values. There were two original purposes for this statement. First, was to prevent people from playing "mathematical games"; obtaining a failing result in the English system, then using some rounded off conversion factor and suddenly obtaining passing results. As the finally issued version of FS-209E uses a fairly accurate conversion factor of 3.530 particles per cubic meter for Class 100, this concern has been largely mitigated in this country, at least with respect to people "shopping around" within the Class Limits Chart. The French, however, proposed using 4,000 as their class limit, so there could be some problem in portions of Europe. The second reason was to assure that the number of sampling locations used was properly based upon the system used. In theory, based upon how "sloppy" a conversion factor was used, an insufficient number of sampling points could be used. We would not object to use of a particle counter designed to sample one cubic foot of air and convert this precisely into the equivalent number of liters. We would object to "juggling" the numbers, developing a sampling plan for the number of sampling locations based upon one system using "sloppy" conversion factors, collecting sample volumes based upon another system again with "sloppy" conversion factors, than converting that number using "sloppy" conversion factors into a number to be read against a limit to determine compliance with a specific Class. The was intended to be the "thrust" of the last editions article. Division Contact: Robert Sorensen, CSO, HFD-322. (301-594-0095) HUMAN DRUG CGMP NOTES, VOLUME 01, NUMBER 02 (May 1993) Motise's Notebook POLICY EMERGING: 1) [VIP ID: 3606] Item: Metrification of Federal Standard 209E (Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones, 9/11/92). Revised Federal Standard 209(e) includes metrification of units of measurement. The document serves as a transition from English to Metric units, so both types are presented. Metric units are preferred. The switch from English to Metric as a means of expressing particulate air quality entails some precision of conversation and sampling point differences such that it is not acceptable to qualifying a clean room in Metric units by performing a mathematical conversion of the English values. [VIP NOTE: The FDA stepped back from this statement in Vol 1. No. 3 of the Human Drug CGMP Notes Sept 1993). However, we would accept for trending purposes only, mathematical conversion of the old English system data into metric units until a sufficient data base has been established to use "pure" metric data. Our position is that a facility that has been properly certified, qualified or validated at a class in the English system need not re-qualify the facility in Metric terms to remain in compliance. The degree of cleanliness in the English system would remain acceptable. Requalification in the Metric system may be delayed until it would otherwise have been scheduled or required. Division Contact: Robert Sorensen CSO, HFD-322. (301-295-8095)

2.

Clean areas, for the manufacture of sterile products, are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS GENERAL 3. para 1 [VIP ID: 185982] Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled.

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PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS GENERAL 3. paras 3 to 7 inc. [ViP ID: 185986] The in operation and at rest states should be defined for each clean room or suite of clean rooms. For the manufacture of sterile medicinal products 4 grades can be distinguished. Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 - 0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated. A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes. Grade B: For aseptic preparation and filling, this is the background environment for grade A zone. Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 3 For the manufacture of sterile medicinal products 4 grades can be distinguished Grade A: [VIP ID: 62370] The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 - 0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated. A unidirectional air flow and lower velocities may be used in closed isolators and glove boxes. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 3 For the manufacture of sterile medicinal products 4 grades can be distinguished Grade B: [VIP ID: 62380] For aseptic preparation and filling, this is the background environment for the grade A zone. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 3 For the manufacture of sterile medicinal products 4 grades can be distinguished Grade C and D: [VIP ID: 62390] Clean areas for carrying out less critical stages in the manufacture of sterile products. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) General 3. (para 3) [VIP ID: 1369] For the manufacture of sterile medicinal products there are normally 4 grades of clean areas. Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide an homogenous air speed of 0.45 m/s +/- 20% (guidance value) at the working position.

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3.

Supporting clean areas can have various classifications and functions.


GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities B. Supporting Clean Areas (para 1) [VIP ID: 110260] Supporting clean areas can have various classifications and functions. Many support areas function as zones in which nonsterile components, formulated products, in-process materials, equipment, and container/closures are prepared, held, or transferred. These environments are soundly designed when they minimize the level of particle contaminants in the final product and control the microbiological content (bioburden) of articles and components that are subsequently sterilized. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 30. [VIP ID: 2182] What are the firm's air quality classifications for: a. exposed product areas b. filling area c. surrounding plant areas

4.

The following references explain the physical and/or microbiological properties of the various air classifications:
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS GENERAL 3. para 8 [VIP ID: 185988] The airborne particulate classification for these grades is given in the following table. at rest (b) Grade 0.5 m (d) A B (c) C (c) D (c) Notes: (a) Particle measurement based on the use of a discrete airborne particle counter to measure the concentration of particles at designated sizes equal to or greater than the threshold stated. A continuous measurement system should be used for monitoring the concentration of particles in the grade A zone, and is recommended for the surrounding grade B areas. For routine testing the total sample volume should not be less than 1 m3 for grade A and B areas and preferably also in grade C areas. (b) The particulate conditions given in the table for the "at rest" state should be achieved after a short "clean up" period of 15-20 minutes (guidance value) in an unmanned state after completion of operations. The particulate conditions for grade A "in operation" given in the table should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. It is accepted that it may not always be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself. 3,500 3,500 350,000 3,500,000
3

in operation (b)

maximum permitted number of particles/m equal to or above (a) 5 m 1 (e) 1 (e) 2,000 20,000 0.5 m (d) 3,500 350,000 3,500,000 not defined (f) 5 m 1 (e) 2,000 20,000 not defined (f)

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(c) In order to reach the B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. The air system should be provided with appropriate terminal filters such as HEPA for grades A, B and C. (d) The guidance given for the maximum permitted number of particles in the "at rest" and "in operation" conditions correspond approximately to the cleanliness classes in the EN/ISO 14644-1 at a particle size of 0.5 m. (e) These areas are expected to be completely free from particles of size greater than 5 m. As it is impossible to demonstrate the absence of particles with any statistical significance, the limits are set to 1 particle/m3. During the clean room qualification it should be shown that the areas can be maintained within the defined limits. (f) The requirements and limits will depend on the nature of the operations carried out. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV Buildings and Facilities TABLE 1- Air Classifications (a) [VIP ID: 110160]
Clean Area Classification (0.5 m particles/ft3) Microbiological Active Air Action Levels (c) (cfu/m3) Microbiological Settling Plates Action Levels (c,d) (diam. 90mm; cfu/4 hours)

ISO Designation (b)

> 0.5 m particles/m3

100 1,000 10,000 100,000 a b c d e

5 6 7 8

3,520 35,200 352,000 3,520,000

1 (e) 7 10 100

1 (e) 3 5 50

All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity. ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A. Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological action levels due to the nature of the operation or method of analysis. The additional use of settling plates is optional. Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 6) [VIP ID: 110230] HEPA-filtered [4] air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area (Ref. 3) [5] [4] High Efficiency Particulate Air filter [5] A velocity of 0.45 meters/second (90 feet per minute) has generally been established, with a range of plus or minus 20 percent around the setpoint. Higher velocities may be appropriate in operations generating high levels of particulates.

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GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 7) [VIP ID: 110240] Proper design and control prevents turbulence and stagnant air in the critical area. Once relevant parameters are established, it is crucial that airflow patterns be evaluated for turbulence or eddy currents that can act as a channel or reservoir for air contaminants (e.g., from an adjoining lower classified area). In situ air pattern analysis should be conducted at the critical area to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. The studies should be well documented with written conclusions, and include evaluation of the impact of aseptic manipulations (e.g., interventions) and equipment design. Videotape or other recording mechanisms have been found to be useful aides in assessing airflow initially as well as facilitating evaluation of subsequent equipment configuration changes. It is important to note that even successfully qualified systems can be compromised by poor operational, maintenance, or personnel practices. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 3 [Table and Notes] [VIP ID: 62400] at rest (b) Grade 0.5 m (d) A B (c) C (c) D (c) 3,500 3,500 350,000 3,500,000
3

in operation (b)

maximum permitted number of particles/m equal to or above (a) 5 m 1 (e) 1 (e) 2,000 20,000 0.5 m (d) 3,500 350,000 3,500,000 not defined (f) 5 m 1 (e) 2,000 20,000 not defined (f)

(a) Particle measurement based on the use of a discrete airborne particle counter to measure the concentration of particles at designated sizes equal to or greater than the threshold stated. A continuous measurement system should be used for monitoring the concentration of particles in the grade A zone, and is recommended for the surrounding grade B areas. For routine testing the total sample volume should not be less than 1 m3 for grade A and B areas and preferably also in grade C areas. (b) The particulate conditions given in the table for the at rest state should be achieved after a short clean up period of 15-20 minutes (guidance value) in an unmanned state after completion of operations. The particulate conditions for grade A in operation given in the table should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. It is accepted that it may not always be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself. (c) In order to reach the B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. The air system should be provided with appropriate terminal filters such as HEPA for grades A, B and C. (d) The guidance given for the maximum permitted number of particles in the at rest and in operation conditions correspond approximately to the cleanliness classes in the EN/ISO 14644-1 at a particle size of 0.5 m. (e) These areas are expected to be completely free from particles of size greater than or equal to 5 m. As it is impossible to demonstrate the absence of particles with any statistical significance the limits are set to 1 particle/ m3. During the clean room qualification it should be shown that the areas can be maintained within the defined limits. (f) The requirements and limits will depend on the nature of the operations carried out.

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5.

To maintain air quality, it is important to achieve a proper air flow from areas of higher cleanliness to adjacent less clean areas.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities C. Clean Area Separation (para 1) [VIP ID: 110280] An essential part of contamination prevention is the adequate separation of areas of operation. To maintain air quality, it is important to achieve a proper airflow from areas of higher cleanliness to adjacent less clean areas. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness. For example, a positive pressure differential of at least 10-15 Pascals (Pa) [6] should be maintained between adjacent rooms of differing classification (with doors closed). When doors are open, outward airflow should be sufficient to minimize ingress of contamination, and it is critical that the time a door can remain ajar be strictly controlled (Ref. 4). [6] Equal to 0.04-0.06 inches of water gauge. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities C. Clean Area Separation (para 2) [VIP ID: 110290] In some cases, the aseptic processing room and adjacent cleanrooms have the same classification. Maintaining a pressure differential (with doors closed) between the aseptic processing room and these adjacent rooms can provide beneficial separation. In any facility designed with an unclassified room adjacent to the aseptic processing room, a substantial overpressure (e.g., at least 12.5 Pa) from the aseptic processing room should be maintained at all times to prevent contamination. If this pressure differential drops below the minimum limit, it is important that the environmental quality of the aseptic processing room be restored and confirmed.

6.

There are various options for controlled environments for aseptic operations.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities B. Supporting Clean Areas (para 2) [VIP ID: 110270] The nature of the activities conducted in a supporting clean area determines its classification. FDA recommends that the area immediately adjacent to the aseptic processing line meet, at a minimum, Class 10,000 (ISO 7) standards (see Table 1) under dynamic conditions. Manufacturers can also classify this area as Class 1,000 (ISO 6) or maintain the entire aseptic filling room at Class 100 (ISO 5). An area classified at a Class 100,000 (ISO 8) air cleanliness level is appropriate for less critical activities (e.g., equipment cleaning). PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 2. INTRODUCTION 2.3 [VIP ID: 190414] Controlled environments for aseptic operations are currently mainly provided by conventional clean rooms, of Grade B, containing workstations, of Grade A complying with the PIC/S and EC guide to GMP. A smaller number of controlled environments are provided by clean rooms, of Grade D or better containing equipment called isolators providing a Grade A environment. When isolators are used for sterility testing there is no formal requirement for them to be placed in a Grade D environment. The environment should be controlled e.g. allow access only to trained staff, but not necessarily classified.

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7.

The following operations need to be performed in at least a Grade A (Class 100) environment:
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS TERMINALLY STERILISED PRODUCTS 11. para 3 [VIP ID: 186012] Where the product is at unusual risk of contamination from the environment, for example because the filling operation is slow or the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing, the filling should be done in a grade A zone with at least a grade C background. ... PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 1 [VIP ID: 186014] ... Handling of sterile starting materials and components, unless subjected to sterilisation or filtration through a micro-organism-retaining filter later in the process, should be done in a grade A environment with grade B background. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 2 [VIP ID: 186016] if not filtered, the preparation of materials and products should be done in a grade A environment with a grade B background. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 3 [VIP ID: 186018] Handling and filling of aseptically prepared products should be done in a grade A environment with a grade B background. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 4 [VIP ID: 186020] Transfer of partially closed containers, as used in freeze drying, should, prior to the completion of stoppering, be done either in a grade A environment with grade B background or in sealed transfer trays in a grade B environment. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 5 [VIP ID: 186022] Preparation and filling of sterile ointments, creams, suspensions and emulsions should be done in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered.

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PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 9 [VIP ID: 186346] Open circuit operations involving products or components not subsequently sterilized should be carried out within a laminar air flow work station (grade A) in a grade B area. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 2) [VIP ID: 110190] This area is critical because an exposed product is vulnerable to contamination and will not be subsequently sterilized in its immediate container. To maintain product sterility, it is essential that the environment in which aseptic operations (e.g., equipment setup, filling) are conducted be controlled and maintained at an appropriate quality. One aspect of environmental quality is the particle content of the air. Particles are significant because they can enter a product as an extraneous contaminant, and can also contaminate it biologically by acting as a vehicle for microorganisms (Ref. 2). Appropriately designed air handling systems minimize particle content of a critical area. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 3) [VIP ID: 110200] Air in the immediate proximity of exposed sterilized containers/closures and filling/closing operations would be of appropriate particle quality when it has a per-cubic-meter particle count of no more than 3520 in a size range of 0.5 m and larger when counted at representative locations normally not more than 1 foot away from the work site, within the airflow, and during filling/closing operations. This level of air cleanliness is also known as Class 100 (ISO 5). PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 11. COMPONENT PREPARATION Preparation of Components 11.7 [VIP ID: 185164] The premises used for the production of blood components in an "open process" should preferably be a grade A environment with a grade B background, as defined in the current European Guide to Good Manufacturing Practice, Annex 1. A less stringent environment may be acceptable if in combination with additional safety measures such as preparing the blood component just in time for transfusion or immediately after preparation applying storage conditions which are unfavourable to microbial growth. Personnel performing open processing should wear appropriate clothing and should receive regular training in aseptic manipulations. Aseptic processing must be validated. ('Open' processing involves a breach of the integrity of the 'closed system', and as a consequence, a risk of microbial contamination). PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.1 CLEAN ROOM DESIGN 8.1.1 Classification 8.1.1.1 [VIP ID: 190250] The sterility test should be conducted within a class A laminar airflow cabinet located within a class B clean room, or in an isolator that need not be located within a controlled environment. The test may also be performed within a class A clean room, if available. Sterility testing should be carried out in a work zone that offers sufficient space and material should be placed in such a way that it does not disrupt the laminar airflow.

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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Terminally sterilised products 11. (para 3) [VIP ID: 1419] Where the product is at unusual risk of contamination from the environment, for example because the filling operation is slow or the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing, the filling should be done in a grade A zone with at least a grade C background. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 1) [VIP ID: 1420] ... Handling of sterile starting materials and components, unless subjected to sterilization or filtration through a microorganism-retaining filter later in the process, should be done in a grade A environment with grade B background. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 2) [VIP ID: 1421] if not filtered, the preparation of materials and products should be done in a grade A environment with a grade B background. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 3) [VIP ID: 1422] Handling and filling of aseptically prepared products should be done in a grade A environment with a grade B background. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 4) [VIP ID: 1423] Prior to the completion of stoppering, transfer of partially closed containers, as used in freeze drying, should be done either in a grade A environment with grade B background or in sealed transfer trays in a grade B environment. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 5) [VIP ID: 1424] Preparation and filling of sterile ointments, creams, suspensions and emulsions should be done in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 9. [VIP ID: 1595] Open circuit operations involving products or components not subsequently sterilised should be carried out within a laminar air flow work station (grade A) in a grade B area.

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Selected FDA 483 Observations (July 2000) Sterile Product Manufacture [VIP ID: 16080] Local Class 100 LAF units used to provide localized protection for performing aseptic connections in a class 10,000 area should be validated to include environmental monitoring during use.

8.

The following operations need to be performed in at least a Grade C environment:


PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS BLOW/FILL/SEAL TECHNOLOGY 10. para 1 [VIP ID: 186004] Blow/fill/seal units are purpose built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and nonviable limits "at rest" and the viable limit only when in operation. ... PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS TERMINALLY STERILISED PRODUCTS 11. para 1 [VIP ID: 186008] ... Where there is unusual risk to the product because of microbial contamination, for example, because the product actively supports microbial growth or must be held for a long period before sterilisation or is necessarily processed not mainly in closed vessels, preparation should be done in a grade C environment. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS TERMINALLY STERILISED PRODUCTS 11. para 2 [VIP ID: 186010] Filling of products for terminal sterilisation should be done in at least a grade C environment. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS TERMINALLY STERILISED PRODUCTS 11. para 3 [VIP ID: 186012] ... Preparation and filling of ointments, creams, suspensions and emulsions should generally be done in a grade C environment before terminal sterilisation. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 2 [VIP ID: 186016] Preparation of solutions which are to be sterile filtered during the process should be done in a grade C environment; ... HEALTH CANADA - GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.13 STERILE PRODUCTS - C.02.029 2.13.4 [VIP ID: 66540] WHAT ARE THE ROOM CLASSIFICATION REQUIREMENTS FOR THE CAPPING (CRIMPING) OPERATION OF ASEPTICALLY FILLED VIALS (WITHOUT TERMINAL STERILIZATION)?

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It is important to distinguish between filling/stoppering and crimping which are 2 different operations requiring different environmental conditions. For aseptically filled vials, the filling/stoppering must be performed under Grade A conditions with a Grade B background. When this filling/stoppering is finished, the product is usually taken to a lower grade environment by means of a conveyor belt where the crimping is performed. Because complete integrity may not yet be achieved at this point, it is considered that a Grade C environment, when in operation, is the minimal grade to be used for the crimping operation. The following must also be considered: The crimping should be done as soon as possible after the stoppering. The distance between the exit of the Grade A/B to the actual point of crimping in the lower environment should be kept as short as possible. The conveyor belts for aseptically filled products must not re-enter Grade A or B from an area of lower cleanliness unless they are continuously sterilized (as per Interpretation 5 in the equipment sub-section of C.02.029). Procedures are in place to ensure that the stoppers are properly seated prior to the crimping operation. Equipment utilization logs should indicate line stoppages and time lapses. Stoppered vials which do not get crimped within the established time lapse, be segregated and disposed off in accordance with SOP.

Another important point to consider is the validation of the entire aseptic process including periodic verifications by media-fills. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Terminally sterilised products 11. (para 2) [VIP ID: 1418] Filling of products for terminal sterilization should be done in at least a grade C environment. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Terminally sterilised products 11. (para 3) [VIP ID: 1419] ... Preparation and filling of ointments, creams, suspensions and emulsions should generally be done in a grade C environment before terminal sterilization. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 2) [VIP ID: 1421] Preparation of solutions which are to be sterile filtered during the process should be done in a grade C environment; ... EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Terminally sterilised products 11. (para 1) [VIP ID: 1417] ... Where there is unusual risk to the product because of microbial contamination, for example, because the product actively supports microbial growth or must be held for a long period before sterilization or is necessarily processed not mainly in closed vessels, preparation should be done in a grade C environment.

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9.

The following operations need to be performed in at least a Grade D environment:


PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ISOLATOR TECHNOLOGY 7 [VIP ID: 185998] The utilisation of isolator technology to minimise human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechanisms. The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognised that laminar air flow may not exist in the working zone of all such devices. The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing be at least grade D. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS BLOW/FILL/SEAL TECHNOLOGY 10. para 1 [VIP ID: 186004] Blow/fill/seal equipment used for the production of products for terminal sterilisation should be installed in at least a grade D environment. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS TERMINALLY STERILISED PRODUCTS 11. para 1 [VIP ID: 186008] Preparation of components and most products should be done in at least a grade D environment in order to give low risk of microbial and particulate contamination, suitable for filtration and sterilisation. ... PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS ASEPTIC PREPARATION 12. para 1 [VIP ID: 186014] Components after washing should be handled in at least a grade D environment. ... PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 3 - MANUFACTURE OF RADIOPHARMACEUTICALS PREMISES AND EQUIPMENT 4 [VIP ID: 186286] For sterile products the working zone where products or containers may be exposed should comply with the environmental requirements described in the Supplement on Sterile Products. This may be achieved by the provision within the work station of a laminar flow of HEPA-filtered air and by fitting air-locks to entry ports. Total containment work stations may provide these requirements. They should be in an environment conforming to at least grade D.

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PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 4 - MANUFACTURE OF VETERINARY MEDICINAL PRODUCTS OTHER THAN IMMUNOLOGICALS STERILE VETERINARY MEDICINAL PRODUCTS 10 [VIP ID: 186320] Where this has been accepted by the competent authorities, terminally sterilized veterinary medicinal products may be manufactured in a clean area of a lower grade than the grade required in the annex on "Sterile preparations", but at least in a grade D environment. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 10 PREMISES AND EQUIPMENT 3 [VIP ID: 186668] Where products or clean components are exposed, the area should be fed with filtered air, should comply with the requirements of at least a Grade D environment and should be entered through airlocks. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 14 - MANUFACTURE OF PRODUCTS DERIVED FROM HUMAN BLOOD OR HUMAN PLASMA PRODUCTION AND QUALITY CONTROL 22 [VIP ID: 187022] In order to minimise the microbiological contamination of plasma for fractionation or the introduction of foreign material, the thawing and pooling should be performed at least in a grade D clean area, wearing the appropriate clothing and in addition face masks and gloves should be worn. Methods used for opening bags, pooling and thawing should be regularly monitored, e.g. by testing for bioburden. The cleanroom requirements for all other open manipulations should conform to the requirements of Annex 1 of the PIC/S guide to GMP. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 2: Blow-fill Seal Technology A. Equipment Design and Air Quality (para 4) [VIP ID: 112130] The classified environment surrounding BFS machinery should generally meet Class 100,000 (ISO 8), or better, standards, depending on the design of the BFS machinery and the surrounding room. HEPA-filtered or sterile air provided by membrane filters should be used during the steps when sterile products or materials are exposed (e.g., parison formation, container molding or filling steps). Air in the critical area should meet Class 100 (ISO 5) microbiological standards during operations. A well-designed BFS system should also normally achieve Class 100 (ISO 5) airborne particle levels. Only personnel who have been qualified and appropriately gowned should enter the classified environment surrounding the BFS machinery. Refer to Section V of this document for guidance on personnel training, qualification, and monitoring. HEALTH CANADA - GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.13 STERILE PRODUCTS - C.02.029 2.13.6 [VIP ID: 66560] WHAT ARE THE ROOM CLASSIFICATION REQUIREMENTS FOR THE PREPARATION OF CONTAINERS AND OTHER PACKAGING MATERIALS TO BE USED IN THE FABRICATION OF STERILE PRODUCTS? The preparation (cleaning, washing, etc.) of containers and packaging materials is normally performed in a "clean" room (grade C or D). After these operations, the containers and materials used for drugs sterilized by filtration (and not further subjected to terminal sterilization in their final containers) must be depyrogenated and sterilized before being introduced in the aseptic rooms by the use of double-ended sterilizers or any other validated method. The depyrogenation step can be done using pyrogen-free WFI for the last rinse prior sterilization or by performing the depyrogenation and sterilization in one operation using a dry heat oven. Filling of these products normally takes place in a class A with a B background. For products submitted to terminal sterilization, it is not mandatory to use containers and packaging materials that are sterile but those that are in direct contact with the product should be free of pyrogen. This is usually achieved by using pyrogen-free WFI for the last rinse of these materials unless they are subsequently depyrogenated by another method (ex. dry heat oven).

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In addition, the initial bioburden of these materials should meet pre-established limits (that are based on sound science) and the risk of contamination during their introduction in the filling areas should be kept to a minimum. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Isolator technology 7. (para 2) [VIP ID: 1412] The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing be at least grade D. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Terminally sterilised products 11. (para 1) [VIP ID: 1417] Preparation of components and most products should be done in at least a grade D environment in order to give low risk of microbial and particulate contamination, suitable for filtration and sterilisation. ... EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Aseptic preparation 12. (para 1) [VIP ID: 1420] Components after washing should be handled in at least a grade D environment. ... EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 03 - MANUFACTURE OF RADIOPHARMACEUTICALS (January 1993) Premises and equipment 4. [VIP ID: 1562] For sterile products the working zone where products or containers may be exposed should comply with the environmental requirements described in the Supplement on Sterile Products. This may be achieved by the provision within the work station of a laminar flow of HEPA-filtered air and by fitting air-locks to entry ports. Total containment work stations may provide these requirements. They should be in an environment conforming to at least grade D. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 04 - MANUFACTURE OF VETERINARY MEDICINAL PRODUCTS OTHER THAN IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Sterile veterinary medicinal products 10. [VIP ID: 1580] Where this has been accepted by the competent authorities, terminally sterilized veterinary medicinal products may be manufactured in a clean area of a lower grade than the grade required in the annex on "Sterile preparations", but at least in a grade D environment. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS BLOW/FILL/SEAL TECHNOLOGY 10. para 2 [VIP ID: 186006] Because of this special technology particular attention should be paid to at least the following: equipment design and qualification, validation and reproducibility of cleaning-in-place and sterilisation-in-place, background clean room environment in which the equipment is located, operator training and clothing, and interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling.

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10. For some operations there is no specified environment.


HUMAN DRUG CGMP NOTES, VOLUME 02, NUMBER 04 (December 1994) Motise's Notebook POLICY QUESTIONS: 4) [VIP ID: 3854] What quality standard should be set for air around a capsule repacking machine where the capsules contain alpha blocker drugs? References: 21 CFR 211.42, Design and construction, and 211.46, Ventilation, air filtration, air heating and cooling. We've had similar inquires before and, unfortunately, there is no set answer. The key is to identify the most significant potential problem Particulates and microbial counts, of course, need control in a "clean room" environment where sterility must be preserved. In the case described, however, more important than air quality itself, in terms of particulates and microbial content, would be the matter of dust removal and containment to prevent cross contamination. We would not expect particle counts, per se to be as important as what those particles are, and the danger they may present if they found their way into other products. Temperature and humidity controls may also be smooth operation of the equipment. A severe cross contamination problem, such as we encounter in penicillin production would warrant separation of facilities, dedicated equipment and air handling systems, along with separation of personnel. As part of future CGMP revisions, we are reviewing the need to extend the penicillin separation provisions to other drugs that might pose unique health hazards. Nothing has been firmed up yet, but the concept is under review. Until the regulations are modified, we would advise the firm to evaluate the potential cross contamination problem, and design an environment and containment provisions that would avoid putting other products at risk. Division Contact for Further Info: Paul J. Motise, HFD-323, 301-594-1089. HUMAN DRUG CGMP NOTES, VOLUME 02, NUMBER 01 (March 1994) Motise's Notebook POLICY QUESTIONS: 4) [ViP ID: 3766] What clean room classification is required for environments which house aseptic processing isolation chambers? Reference: 21 CFR 211.42(10), Design and construction features; and, Guideline on Sterile Drug Products Produced by Aseptic Processing. Isolation chambers are used to aseptically assemble drug products within highly contained, high quality environments in which humans are not a potential source of contaminants. We encourage use of isolation chambers. The need to maintain the integrity of the environments within such chambers is obviously critical. Integrity breeches would permit entry of contaminants from the unit's surrounding environment. Although we believe it is necessary to monitor and validate the environmental quality of the rooms housing such chambers. FDA has published no formal FDA policy on air quality for the rooms housing isolation chambers. However, new drug application reviewers have been calling for controlled environments that meet class 10,000 conditions for the rooms. Until more formal policy is established, we consider this level of air cleanliness to be prudent and acceptable, though not strictly a CGMP requirement. Division Contact for Further Info: Terry Munson, HFD-322, (301-594-0095).

11. The final stage of a changing room should, in the at rest state, be the same grade as the area into which it leads.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 27 [VIP ID: 186052] Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimise microbial and particulate contamination of protective clothing. They should be flushed effectively with filtered air. The final stage of the changing room should, in the "at rest" state, be the same grade as the area into which it leads. The use of separate changing rooms for entering and leaving clean areas is sometimes desirable. In general hand washing facilities should be provided only in the first stage of the changing rooms.

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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 27 (para 1) [VIP ID: 63180] Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimise microbial and particulate contamination of protective clothing. They should be flushed effectively with filtered air. The final stage of the changing room should, in the at-rest state, be the same grade as the area into which it leads.

12. Consideration should be given to conducting aseptic manipulations in an aseptic workstation under laminar flow conditions (e.g. with an air classification of Class 100).
GUIDANCE FOR INDUSTRY INDS - APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) VI. SPECIAL PRODUCTION SITUATIONS D. Sterile Products/Aseptically Processed Products [VIP ID: 183918] We recommend that special precautions be taken for investigational new drugs intended to be sterile. Thorough consideration should be given to controls for aseptic processing. The following examples are recommendations that should be considered: Conducting aseptic manipulation in an aseptic workstation under laminar flow conditions (e.g., an air classification of Class 100). Some examples of workstations include a laminar air flow workbench, biosafety cabinets, or barrier isolator system.

13. For sterile product areas, a Site Master File should include details of room and area classification and pressure differentials between adjoining areas of different classifications.
PE 008-2 1 ANNEX EXPLANATORY NOTES FOR INDUSTRY ON THE PREPARATION OF A SITE MASTER FILE (July 2004) REQUIREMENT C.3 PREMISES AND EQUIPMENT Premises REQUIREMENT C.3.1 [VIP ID: 185430] REQUIREMENT C.3.1 Simple plan or description of manufacturing areas with indication of scale (architectural or engineering drawings are not required). GUIDANCE C.3.1 C.3.1.1 Provide a site plan highlighting production areas. C.3.1.2 Provide a simple plan of each production area with indication of scale. Label areas and annotate plan with names. C.3.1.3 Plans should be legible and on A4 sheets of paper. Plans could be on A3 sheets of paper if considered necessary. C.3.1.4 For sterile product areas indicate room and area classification and pressure differentials between adjoining areas of different classifications.

14. The test environment, within a sterility test facility, which includes the laminar air flow cabinet or isolator, should be certified at least annually by a competent person for compliance with the specified standard conditions.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.1 CLEAN ROOM DESIGN 8.1.1 Classification 8.1.1.2 [VIP ID: 190252] The test environment, which includes the laminar airflow cabinet or isolator, should be certified at least annually by a competent person for compliance with the specified standard conditions.

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7.3 Drawings 1. Diagrams should be available for HVAC systems serving clean rooms.
FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42760] With regard to the air filtration system, your firm was cited for not providing HEPA-filtered air into the **** clean rooms as required by 21 CFR 211.46(c) Ventilation, Air Filtration, Air Heating and Cooling [FDA-483 Item 3]. You disagreed with the investigators observation in that HEPA-filtered air is not necessary for each of the **** clean rooms (Class **** because the aseptic processing is being performed under the biological hoods that are equipped with HEPA filters. Your justification is not adequate because you have not provided supporting documentation of (1) air cleanliness qualification data; (2) data from a routine environmental monitoring program; (3) the specific ratings of each of the successive filters found in the HVAC system that serve the Class **** clean room; and (4) diagrams/ charts of the HVAC system.

2.

The information to be provided in Drug Applications for Aseptic Fill Manufacturing Processes should include a floor plan of the areas holding the aseptic filling facilities showing the air cleanliness class of each area and the placement of all critical equipment such as laminar flow hoods.
GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. A. Buildings and Facilities [VIP ID: 17240] A brief description of the manufacturing building and facilities should be provided. The following information should be included: 1. Floor Plan A floor plan of the areas holding the aseptic filling facilities including preparation and holding areas, filtering and filling areas, and gowning rooms should be included. The air cleanliness class of each area should be identified (e.g. Class 100,Class 10,000, Class 100,000). Isolators or barrier systems should be identified. 2. Location of Equipment The placement of all critical equipment, including, but not limited to, laminar flow hoods, autoclaves, lyophilizers, and filling heads, should be identified. Equipment within barrier or isolation systems should be noted. STERILIZATION PROCESS VALIDATION - SUPERSEDED! (January 1993) II. Information for Aseptic Fill Manufacturing Processes Which Should Be Included in Drug Applications The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. A. [VIP ID: 3030] Provide a brief description of the building and facilities. This should include the following types of information: 1. A floor plan of the areas holding the aseptic filling facilities including preparation and holding areas, filtering and filling areas, gowning rooms, etc. The air cleanliness class of each area should be identified (e.g., Class 100, Class 10,000, Class 100,000, etc.). 2. The placement of all critical equipment such as laminar flow hoods, autoclaves, lyophilizers, filling heads, etc., should be identified.

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3.

Schematic drawings of ventilation systems are desirable in a Site Master File.


PE 008-2 1 ANNEX EXPLANATORY NOTES FOR INDUSTRY ON THE PREPARATION OF A SITE MASTER FILE (July 2004) REQUIREMENT C.3 PREMISES AND EQUIPMENT Premises REQUIREMENT C.3.3 [VIP ID: 185434] REQUIREMENT C.3.3 Brief description of ventilation systems. More details should be given for critical areas with potential risks of airborne contamination (schematic drawings of the systems are desirable). Classification of the rooms used for the manufacture of sterile products should be mentioned. GUIDANCE C.3.3 Brief Description of Ventilation Systems etc. (500 words/two A4 pages) Note 1: More details should be given for critical areas with potential risks of airborne contamination. This will include sterile product areas as well as areas for processing powders, granulation and tabletting. For sterile product areas a summary of the results of the most recent qualification/requalification should be given Note 2: To reduce the narrative, schematic drawings should be used. The following data should be given: C.3.3.1 Design criteria e.g. Specification of the air supply Temperature Humidity Pressure differentials and air change rate Simple pass or recirculation (%)

C.3.3.2 Filter design and efficiency e.g. - Bag 99% eff. - Hepa 99.997% eff. Details of any alarms on the ventilation system should be given. C.3.3.3 The limits for changing the filters should be given. C.3.3.4 If DOP (dioctyl-phthalate) is introduced, the point must be shown. C.3.3.5 Give the frequency of revalidation of the system.

4.

Plans of contained and/or clean area premises, should describe the ventilation system indicating inlets and outlets, filters and their specifications, the number of air changes per hour, and pressure gradients. They should indicate which pressure gradients are monitored by pressure indicator.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 20. (para 5) [VIP ID: 1610] Plans of contained and/or clean area premises, should describe the ventilation system indicating inlets and outlets, filters and their specifications, the number of air changes per hour, and pressure gradients. They should indicate which pressure gradients are monitored by pressure indicator.

5.

Diagrams of HEPA filtered air systems should be reviewed and evaluated.


GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS - CGMPR'S (October 1993) 1. Air (para 3) [VIP ID: 2668] Review the compressed air system and determine if it is filtered at the point of use to control particulates. Diagrams of the HEPA filtered and compressed air systems should be reviewed and evaluated.

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6.

The Quality Unit should review and approve engineering drawings/diagrams provided by engineering firms performing Environmental Control/HVAC System modifications.
Selected FDA 483 Observations (February 2004) Sterile Product Manufacture [VIP ID: 71060] The Quality Unit should review and approve engineering drawings/diagrams provided by engineering firms performing Environmental Control/HVAC System modifications.

7.

There should be blueprints or diagrams available showing that an air handling system serving an area where penicillin drug products are processed is separate from an air handling system used for non penicillin drug products.
FDA Warning Letter [Reference Obliterated] (February 2004) Extracted from FDA warning letter USA 27/02/2004 [VIP ID: 126210] 2. Failure to separate completely the air handling systems for the packing of penicillin products and non-penicillin beta-lactam drug products from non-penicillin drug products. [21 CFR 211.42(c) and 211.46(d)] The same air handling system is used for the repackaging of penicillin and cephalosporins in violation of 21 CFR 211.42(c) and (d). In addition, the firm could not verify through blueprints or diagrams that the air handling system for the repackaging of penicillins is separate from the air handling system used for repackaging non-penicillin drug products that is required by 21 CFR 211.46(d). Your firm has not established minimal personnel, equipment, and material movement controls, minimal containment controls, and other control systems to prevent crosscontamination. These controls must also be applied to the re-packing of non-penicillin beta-lactam drug products (cephalosporin).

7.4 Filtration 1. There should be specifications for the ratings of all HEPA filters installed in HVAC systems serving clean areas.
FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42760] With regard to the air filtration system, your firm was cited for not providing HEPA-filtered air into the **** clean rooms as required by 21 CFR 211.46(c) Ventilation, Air Filtration, Air Heating and Cooling [FDA-483 Item 3]. You disagreed with the investigators observation in that HEPA-filtered air is not necessary for each of the **** clean rooms (Class **** because the aseptic processing is being performed under the biological hoods that are equipped with HEPA filters. Your justification is not adequate because you have not provided supporting documentation of (1) air cleanliness qualification data; (2) data from a routine environmental monitoring program; (3) the specific ratings of each of the successive filters found in the HVAC system that serve the Class **** clean room; and (4) diagrams / charts of the HVAC system.

2.

HEPA filter integrity testing should include: laminar flow velocity measurements within 12" of the work surface confirmation of uniform velocities between HEPAs related to common plenums acceptance criteria defining leakage as a percentage of the challenge agent measurement of the distance between smoke entry and exit planes during laminar air flow (smoke) studies to ensure the flow is laminar more than just a narrative report to fully and accurately assess air flow patterns.

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Selected FDA 483 Observations (August 2000) Sterile Product Manufacture [VIP ID: 19420] HEPA filter integrity testing should include: a) LAF velocity measurements within 12" of the work surface b) confirmation of uniform velocities between HEPAs related to common plenums c) acceptance criteria defining leakage as a percentage of the challenge agent d) the measurement of the distance between smoke entry and exit planes during laminar airflow (smoke) studies to ensure the flow is laminar e) more than just a narrative report to fully and accurately assess airflow patterns

3.

HEPA filter procedures should address: the maximum allowable size of any leak, which can be patched or sealed the minimum cure time or set time between patching of the HEPA and turning the air handling unit back on the distance from the filter face that velocity measurements shall be taken from how the percentage of patching will be tracked throughout the life of the HEPA filter a specification pertinent to HEPA filter to HEPA filter variation the maximum air velocity above which the HEPA filter must be replaced.
HUMAN DRUG CGMP NOTES, VOLUME 04, NUMBER 04 Motise's Notebook POLICY QUESTIONS: Question 4 [ViP ID: 2954] Selected FDA 483 Observations (July 2001) Sterile Product Manufacture [VIP ID: 40260] HEPA filter procedures should address the following: (1) the maximum allowable size of any leak which can be patched (2) the minimum cure time or set time between patching of the HEPA and turning the air handling unit back on. (3) the distance from the filter face that velocity measurements shall be taken from. (4) how the percentage of patching will be tracked throughout the life of the HEPA filter. Selected FDA 483 Observations (April 1998) Sterile Product Manufacture [VIP ID: 6378] Procedures for the performance testing/monitoring of HEPA filters should specify: a. The specification for the maximum limit on the size of any individual HEPA leak that may be patched or sealed. b. A specification pertinent to HEPA filter to HEPA filter variation in the Aseptic core particularly above the filling and stoppering line. c. The maximum air velocity above which the HEPA filter must be replaced. Selected FDA 483 Observations (December 1999) Sterile Product Manufacture [VIP ID: 8730] There should be a specification for the maximum surface area of HEPA filter that can be repaired prior to replacement.

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4.

Standard Operating Procedures for HEPA certification should: indicate the frequency of certification indicate the frequencies of each individual test include the specification for velocity checks require the review/approval of data describe the remedial actions if specifications are not met describe and require all tests done under the programme require HEPA leak testing of all filters supplying air to a sterile suite.
Selected FDA 483 Observations (June 2002) Sterile Product Manufacture [VIP ID: 47190] Standard Operating Procedures (SOPs) for HEPA certification should: (a) indicate the frequency of certification. (b) indicate the frequencies of each individual test. (c) include a specification for velocity checks. (d) require the review/approval of data and describe the remedial actions if specifications are not met. (e) describe and require all tests done under the program. (f) require HEPA leak testing of all filters supplying air to the sterile suite.

5.

Laminar flow hood HEPA filters in aseptic filling areas should be integrity tested more frequently than once a year.
Selected FDA 483 Observations (April 2001) Sterile Product Manufacture [VIP ID: 27740] Laminar flow hood HEPA filters in aseptic filling areas should be integrity tested more frequently than once a year.

6.

Air from containment premises should only be recirculated to other areas if it passes through two exhaust HEPA filters.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 11. [VIP ID: 1597] Containment premises should be easily disinfected and should have the following characteristics: (b) a ventilation with air at negative pressure. Air should be extracted through HEPA filters and not be re circulated except to the same area, and provided further HEPA filtration is used (normally this condition would be met by routing the recirculated air through the normal supply HEPAs for that area). However, recycling of air between areas may be permissible provided that it passes through two exhaust HEPAs, the first of which is continuously monitored for integrity, and there are adequate measures for safe venting of exhaust air should this filter fail;

7.

Air from manufacturing areas used for the handling of exotic organisms should be vented through two sets of HEPA filters in series and not recirculated.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Premises 11. [VIP ID: 1597] Containment premises should be easily disinfected and should have the following characteristics: (c) air from manufacturing areas used for the handling of exotic organisms should be vented through 2 sets of HEPA filters in series, and that from production areas not recirculated;

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8.

Air supplied to the clean room environment should be provided through terminal HEPA filters, which should be fitted with audible and/or visual alarms to indicate any sustained, out of specification pressure differentials across the HEPA filters.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.1 CLEAN ROOM DESIGN 8.1.2 Air Supply 8.1.2.1 [VIP ID: 190254] Air supplied to the environment should be provided through terminal HEPA filters, which should be fitted with audible and/or visual alarms to indicate any sustained, out of specification pressure differentials across the HEPA filters.

9.

Air supplied to aseptic processing areas should be filtered through HEPA filters.
Extracted from FDA warning letter CHI-3-07 (December 2007) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 3) a. [VIP ID: 194578] Failure to establish an adequate air supply that is filtered through high-efficiency particulate air filter under positive pressure, regardless of whether flow is laminar or non-laminar as required by 21 CFR 211.42(c)(10)(iii). For example, a) The testing of HEPA filters in the Aseptic Core during the Winter 2006 (January 2006) shutdown, found widespread HEPA filters failures in the Class 100 areas. Leaks requiring patching or replacement were found in 75% to 100% of the HEPA filters in Fill Rooms 1, 2, 4 and 5. 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -- Buildings and Facilities Sec. 211.42 Design and construction features (c) [VIP ID: 20] Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures: (10) Aseptic processing, which includes as appropriate: (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar; CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 29. [VIP ID: 2181] How is the air filtered that is supplied to controlled areas (where unsterilized product, in-process materials, and container/closures are prepared)?

10. Firms are not required to use HEPA filters in the manufacture of tablets and capsules, but they are required, when appropriate, to use air filtration systems, including prefilters and particulate matter air filters on air supplies to production areas, and also equipment for adequate control over air pressure, microorganism, dust, humidity and temperature.
HUMAN DRUG CGMP NOTES, VOLUME 05, NUMBER 03 (September 1997) Motise's Notebook Policy Questions: 5) [VIP ID: 4025]

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Are firms required to use HEPA filters in the manufacture of tablets and capsules? References: 21 CFR 211.46, Ventilation, air filtration, air heating and cooling; 211.42, Design and construction features No. The CGMP regulations do not specifically require tablet and capsule manufacturing facilities to maintain highefficiency particulate air (HEPA) filtered air. The regulations, at 211.46, do require use of equipment for adequate control over air pressure, microorganism, dust, humidity and temperature when appropriate. In addition, this section calls for use of air filtration systems, including prefilters and particulate matter air filters on air supplies to production areas, as appropriate. These provisions speak to measures to prevent cross contamination, and the key phrase is "as appropriate". Do not confuse the 211.46 provisions with 211.42(c)(10)(iii) which calls for aseptic processing areas to be equipped, as appropriate, with an air supply filtered through HEPA filters. Whereas such filtration is the norm for aseptic areas, tablet and capsule production rooms seldom need the same level of air filtration. Despite the lack of an explicit CGMP requirement, some firms may elect to use HEPA filtered air systems as part of their dust control procedures. For example, firms may perform dust containment assessments and decide that such filters are warranted to prevent cross contamination of highly potent drugs that, even in small quantities, could pose a significant health hazard when carried over into other products. Contact for further info: Paul J. Motise, HFD-325, 301-594-1089; e-mail: motise@cder. fda. Gov

11. HEPA filters should be efficiency tested using an appropriate aerosol challenge to determine the rating of the filter.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities D. Air Filtration 2. High-Efficiency Particulate Air (HEPA) \7\ (para 3) [VIP ID: 110380] There is a major difference between filter leak testing and efficiency testing. An efficiency test is a general test used to determine the rating of the filter. [8] An intact HEPA filter should be capable of retaining at least 99.97 percent of particulates greater than 0.3 m in diameter. [8] The efficiency test uses a monodispersed aerosol of 0.3 micron sized particles and assesses filter media. Downstream readings represent an average over the entire filter surface. Efficiency tests are not intended to test for filter leaks. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 32. [VIP ID: 2184] Are HEPA filters efficiency tested?

12. HEPA filters should be integrity tested using an appropriate aerosol challenge to identify leak paths in the filter or its housing.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities D. Air Filtration 2. High-Efficiency Particulate Air (HEPA) \7\ (para 1) [VIP ID: 110360] HEPA filter integrity should be maintained to ensure aseptic conditions. Leak testing should be performed at installation to detect integrity breaches around the sealing gaskets, through the frames, or through various points on the filter media. Thereafter, leak tests should be performed at suitable time intervals for HEPA filters in the aseptic processing facility. For example, such testing should be performed twice a year for the aseptic processing room. Additional testing may be appropriate when air quality is found to be unacceptable, facility renovations might be the cause of disturbances to ceiling or wall structures, or as part of an investigation into a media fill or drug product sterility failure. ...

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[7] The same broad principles can be applied to ULPA filters. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities D. Air Filtration 2. High-Efficiency Particulate Air (HEPA) \7\ (para 4) [VIP ID: 110390] The purpose of performing regularly scheduled leak tests, on the other hand, is to detect leaks from the filter media, filter frame, or seal. The challenge involves use of a polydispersed aerosol usually composed of particles with a light-scattering mean droplet diameter in the submicron size range, [9] including a sufficient number of particles at approximately 0.3 m. Performing a leak test without introducing a sufficient upstream challenge of particles of known size upstream of the filter is ineffective for detecting leaks. It is important to introduce an aerosol upstream of the filter in a concentration that is appropriate for the accuracy of the aerosol photometer. The leak test should be done in place, and the filter face scanned on the downstream side with an appropriate photometer probe, at a sampling rate of at least one cubic foot per minute. The downstream leakage measured by the probe should then be calculated as a percent of the upstream challenge. An appropriate scan should be conducted on the entire filter face and frame, at a position about one to two inches from the face of the filter. This comprehensive scanning of HEPA filters should be fully documented. [9] Although the mean is normally less than one micron, it is greater than 0.3m. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities D. Air Filtration 2. High-Efficiency Particulate Air (HEPA) \7\ (para 5) [VIP ID: 110400] A single probe reading equivalent to 0.01 percent of the upstream challenge would be considered as indicative of a significant leak and calls for replacement of the HEPA filter or, when appropriate, repair in a limited area. A subsequent confirmatory retest should be performed in the area of any repair. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 33. [VIP ID: 2185] How often are HEPA filters integrity tested? What test method is used?

13. Emery 3004 (POA) is an acceptable substitute for Dioctyl phthalate (DOP) for integrity testing HEPA filters.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities D. Air Filtration 2. High-Efficiency Particulate Air (HEPA) \7\ (para 2) [VIP ID: 110370] Any aerosol used for challenging a HEPA filter should meet specifications for critical physicochemical attributes such as viscosity. Dioctylphthalate (DOP) and poly-alpha-olefin (PAO) are examples of appropriate leak testing aerosols. Some aerosols are problematic because they pose the risk of microbial contamination of the environment being tested. Accordingly, the evaluation of any alternative aerosol involves ensuring it does not promote microbial growth.

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HEALTH CANADA - GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.1 PREMISES - C.02.004 2.1.2 [VIP ID: 65600] IS THERE AN ACCEPTABLE SUBSTITUTE FOR DIOCTYL PHTHALATE (DOP) TO INTEGRITY TESTING OF HEPA FILTERS? Yes. Dioctyl phthalate aerosols also called Di (2-ethylhexyl) phthalate, di-sec octyl phthalate, DOP, or DEHP, have long been used to test the integrity of high efficiency particulate air (HEPA) filters but concern about the potential health effects to people working with DOP test aerosols has led to a search for a safer equivalent replacement. The product of choice from US Army testing with assistance from various private companies was a Henkel Corporation (Emery Group) product called Emery 3004 PAO. This product is a polyalphaolefin (POA) in the 4 centistoke (4 cSt) viscosity grade, used primarily as a lubricant base stock for oils, lubricants, and electrical/hydraulic fluids. Emery 3004 (POA) can replace DOP in HEPA integrity testing. HUMAN DRUG CGMP NOTES, VOLUME 04, NUMBER 04 (December 1996) Motise's Notebook POLICY QUESTIONS: Question 4 Is there an acceptable substitute for DOP to integrity test HEPA filters? Reference: 21 CFR 211.46, Ventilation, air filtration, air heating and cooling, and 211.67 Equipment cleaning and maintenance. Yes. Dioctyl phthalate aerosols also called Di (2-ethylexyl) phthalate, di-sec octyl phthalate, DOP, or DEHP, have long been used to test the integrity of high efficiency particulate air (HEPA) filters. Concern about the potential health effects to people working with DOP test aerosols has led to a search for a safer equivalent replacement. The prime candidate from U.S. Army testing with assistance from various private companies was a Henkel Corporation (Emery Group) product called Emery 3004 PAO. This product is a polyalphaoefin (POA) in the 4 centistoke (4 cSt) viscosity grade, used primarily as a lubricant base stock for oils, lubricants, and electrical/hydraulic fluids. As cited in the March 1994 Human Drug CGMP Notes, based on data submitted to FDA we have concluded that Emery 3004 (POA) can replace DOP in HEPA integrity testing. The original manufacturing site which produced the Emery 3004 (POA) for the data submitted has changed since the study and Emery 3004 (POA) is now manufactured at a different site. Discussions with the Army and the companies involved in the original studies indicate the product remains the same from the new site of manufacturing. CDER has also compared the original specifications and the new site specifications along with data from the Material Safety Data Sheets and agrees that there is no significant difference in the product from either site. The Chemical Abstracts Service (CAS) number which identifies this product also remained as 68649-12-7. Other reported alternatives used in the industry include DOS (Di (2-ethylhexyl) sebacate) and Ondina Oil. However, no manufacturer has yet submitted all the necessary data to evaluate these alternatives. As such, Emery 3004 POA with the CAS number 68649-12-7 still remains an acceptable replacement for DOP. Contact for further information: Michael J. Verdi, HFD-322, 301-594-0095; e-mail: verdim@cder.fda.gov HUMAN DRUG CGMP NOTES, VOLUME 02, NUMBER 01 (March 1994) Motise's Notebook NEW TECHNOLOGY EMERGING: 1) [VIP ID: 3769] Substitute for DOP in HEPA filter Integrity Testing Reference (on HEPA filter integrity testing) Guideline on Sterile Drugs Produced By Aseptic Processing. Dioctylphthalate (DOP) aerosols have long been used to test the integrity of high efficiency particulate air (HEPA) filters. However, concerns about the potential health risks attendant to exposure to DOP has precipitated a search for acceptable alternatives. The agency has recently accepted one of the alternatives, Emery 3004.

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Various groups in FDA have reviewed data generated by a pharmaceutical company and the U.S. Army on the use of a compound called Emery 3004, as a substitute for DOP. Emery 3004 is a poly-alpha olefin, manufactured by Henkel Corporation, that has physical properties similar to DOP. We have concluded from the data that Emery 3004 performs at least as well as DOP in hot-smoke filter pentrometer machines, and many other machines. The material is inexpensive, readily specifiable (unlike natural petroleum products), non-corrosive, clean to work with, free of natural impurities, thermally and chemically stable, and (most important) not mutagenic. Emery 3004 can replace DOP directly in existing penetrometer and other machines without machine modification, simply by adjusting existing machine controls. This means that there is no need to change the methods and procedures currently used to integrity test HEPA filters. Division Contact for Further Info: Terry Munson, HFD-322, (301-594-0095).

14. Leaks found during HEPA filter integrity testing should be documented as deviations and should be investigated to assess any impact on product.
Extracted from FDA warning letter OEWL-06-01 (June 2006) Extracted from FDA warning letter OEWL-06-01 USA 30-Jun-06 2 [VIP ID: 192172] Failure to establish a system for maintaining equipment to control aseptic conditions; failure to follow appropriate written procedures to prevent microbial contamination of drug products purporting to be sterile; and failure of the quality control unit to ensure that errors are investigated [21 CFR 211.42(c)(10)(vi), 211.113(b), and 211.22(a)]. For example, when leaks were found in the HEPA filters for final product aseptic filling in room 181 in Building 37 on June 7 ([redacted]) and on December 5, 2005 ([redacted]) the firm did not generate deviations even though the leaks violated the "Acceptance Criteria" in the firm's SOP (Number 21C22 Revision Number 06). Moreover, the firm did not investigate to determine whether using those filters had any product impact. Selected FDA 483 Observations (July 2002) Sterile Product Manufacture [VIP ID: 46810] The pattern and magnitude of HEPA filter failures should be reported to Quality Assurance/Product Release personnel to assess any product impact.

15. Records should be maintained of the service and/or replacement of air filters.
Extracted from FDA warning letter MIN 06-36 (September 2006) Extracted from FDA warning letter MIN 06-36 USA 08-Sep-06 7 [VIP ID: 192524] Failure to document that the pre and post-filters on the air handling units in your repackaging suites are changed according to the frequency specified in your SOP. Selected FDA 483 Observations (July 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 137800] Records should be maintained of the service and/or replacement of air filters.

16. Documented evidence should be maintained, on site, demonstrating the proper qualification of contract employees responsible for replacing HEPA filters and repairing HEPA leaks in the aseptic core and depyrogenation tunnels.
Selected FDA 483 Observations (June 1998) Sterile Product Manufacture [VIP ID: 6379] Documented evidence should be maintained, on site, demonstrating the proper qualification of contract employees responsible for replacing HEPA filters and repairing HEPA leaks in the aseptic core and depyrogination tunnels.

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17. HEPA filter leak testing alone is insufficient to monitor filter performance. Velocity monitoring should also be performed and air velocity sampling points should be rotated to assure a comprehensive evaluation of the filter's performance.
Selected FDA 483 Observations (August 2007) Sterile Product Manufacture [VIP ID: 193768] In the case of controls to verify and guarantee the functioning of the Heating, Ventilation, Air Conditioning (HVAC) System, air velocity sampling points should be rotated to assure a comprehensive evaluation of the filter's performance. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities D. Air Filtration 2. High-Efficiency Particulate Air (HEPA) \7\ (para 6) [VIP ID: 110410] HEPA filter leak testing alone is insufficient to monitor filter performance. It is important to conduct periodic monitoring of filter attributes such as uniformity of velocity across the filter (and relative to adjacent filters). Variations in velocity can cause turbulence that increases the possibility of contamination. Velocities of unidirectional air should be measured 6 inches from the filter face and at a defined distance proximal to the work surface for HEPA filters in the critical area. Velocity monitoring at suitable intervals can provide useful data on the critical area in which aseptic processing is performed. The measurements should correlate to the velocity range established at the time of in situ air pattern analysis studies. HEPA filters should be replaced when nonuniformity of air velocity across an area of the filter is detected or airflow patterns may be adversely affected.

18. Air velocity specifications at the filter face should be established for HEPA filters located in aseptic filling suites and should include an upper limit.
Selected FDA 483 Observations (August 2001) Sterile Product Manufacture [VIP ID: 40710] HEPA filter velocity specifications should include an upper limit. Selected FDA 483 Observations (April 2001) Sterile Product Manufacture [VIP ID: 27170] Air velocity specifications at the filter face should be established for HEPA filters located in aseptic filling suites.

19. There should be specifications for air velocities at work surfaces and for the maximum divergence that can exist between the reading from different filters.
Selected FDA 483 Observations (March 2001) Sterile Product Manufacture [VIP ID: 27180] In addition to air velocity specifications at the work surface, there should be specifications for the maximum divergence that can exist between the reading from different filters.

20. HEPA filter air velocity and pressure drop action and alert limits should be justified and should comply with the manufacturers recommendations.
Extracted from FDA warning letter CHI-3-07 (December 2007) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 3) a. [VIP ID: 194578] Failure to establish an adequate air supply that is filtered through high-efficiency particulate air filter under positive pressure, regardless of whether flow is laminar or non-laminar as required by 2I CFR 211.42(c)(10)(iii). For example,

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a) The HEPA filters used in these areas are rated for an efficacy of 99.99% for particles greater than 0.3 microns at a face velocity of 90 FPM, but much higher face velocities (from [redacted] to [redacted]) are used in some of the aseptic filling rooms. A study conducted for you by [redacted] as part of the investigation concluded that excessive non site specific penetration (ENSSP) of HEPA filters can result when filters are used at velocities for which they are not designed. The study documents a direct correlation between air flow rate and unacceptable ENSSP. Please provide your rationale for continuing to operate the aseptic filling lines at these excessive velocities until replacing them with proper filters during your planned shut down in August 2006. Selected FDA 483 Observations (November 1997) Sterile Product Manufacture [VIP ID: 6249] HEPA filter air velocity action and alert limits should be justified and should comply with the manufacturers recommendations.

21. HEPA filter velocity testing should be performed at work surfaces.


GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 6) [VIP ID: 110230] HEPA-filtered [4] air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area (Ref. 3) [5] [4] High Efficiency Particulate Air filter [5] A velocity of 0.45 meters/second (90 feet per minute) has generally been established, with a range of plus or minus 20 percent around the setpoint. Higher velocities may be appropriate in operations generating high levels of particulates. Selected FDA 483 Observations (December 2002) Sterile Product Manufacture [VIP ID: 51710] HEPA filter velocity testing should be performed at the work surfaces. Selected FDA 483 Observations (August 2002) Sterile Product Manufacture [VIP ID: 47720] Air flow velocity checks should be measured near the work surface area (where vial filling occurs) rather than at the filter surface.

22. HEPA filters should be validated and should be recertified at least annually in accordance with specifications, test methods, and acceptance criteria defined by the drug manufacturer.
Extracted from FDA Warning Letter 320-05-02 (August 2005) Extracted from FDA warning letter 320-05-02 Switzerland 16/08/2005 [VIP ID: 171110] 2. There was insufficient evidence that ventilation and air filtration systems provided adequate control over microorganisms for the manufacture, processing, packing, or holding of a drug product. 21 CFR 211.46 The following deviations were noted regarding ventilation and air filtration systems: There was no scientific justification for testing of [redacted] filters in the Class A (ISO 5) area and sterile [redacted] only once annually, the procedures did not include a specification for the required distance for taking [redacted] test measurements, or for monitoring of pressure differentials between various operational areas.

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FDA Warning Letter [NO REFERENCE] (February 2005) Extracted from FDA warning letter USA 25/02/2005 [VIP ID: 134970] 1. Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70(c). For example: c. Environmental control systems have not been inspected periodically to verify that the system, including necessary equipment, is adequate and functioning properly. Specifically, your firm has not conducted filter integrity inspections of the HEPA filters in the controlled environment room since it was installed sometime in 1996. Procedures were not established or maintained to inspect the integrity or installation of the HEPA filters supplying air into the 'white area'. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities D. Air Filtration 2. High-Efficiency Particulate Air (HEPA) \7\ (para 7) [VIP ID: 110420] Although contractors often provide these services, drug manufacturers are responsible for ensuring that equipment specifications, test methods, and acceptance criteria are defined, and that these essential certification activities are conducted satisfactorily. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III - Inspectional B. Inspection 9. GMP b. Buildings - iv. HVAC systems (para 2) [VIP ID: 77690] All HEPA filters should be validated and should be recertified at least annually. Recertification should include integrity testing of the HEPA filters with an appropriate challenge aerosol, e.g., dioctyl phthalate (DOP) or an alternative aerosol that has been determined to have similar or acceptable physical characteristics for detection of leaks; air velocity studies; particle counts, and in aseptic areas, laminarity. FDA Warning Letter 320-01-11 (September 2001) Extracted from FDA warning letter 320-01-11 USA 05/09/2001 [VIP ID: 43210] The laminar flow hood in the micro lab and **** filters in the Class 100,000 production area had not been certified.

23. There should be written procedures for the calibration of HEPA filter instrumentation.
Selected FDA 483 Observations (September 2000) Product Manufacture [VIP ID: 19330] There should be written procedures describing the calibration/certification methods and tolerance limits for all instruments used during production operations to include: (1) HEPA filters

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7.5 Air Flow 1. There should be a specification set for total air flow, data to support the specification and data to support compliance with the specification.
FDA Warning Letter W/L 08-03 (November 2002) Extracted from FDA warning letter W/L 08-03 USA 19/11/2002 [VIP ID: 54430] 10. The production area air supply lacks an appropriate air filtration system [21 CFR 211.46(c)] and [21 CFR 820.70(c)1. Specifically, your firm's specification states that HEPA filters used for clean rooms are to have an air flow between a high and low flow specification. Five HEPA filter velocities in a clean room were recorded to have average flows outside of the specification. The HEPA filter in another clean room was observed to have flow less than the specification during air handling certificates testing conducted on 6/7/2002. Extracted from FDA Warning Letter CBER-00-011 (December 1999) Extracted from FDA warning letter CBER-00-011 USA 23/12/1999 [VIP ID: 160930] 4. Failure to establish adequate control measures for air filtration systems [21 CFR 211.46] in that there were no specifications for velocity and pressure drop in the certification of the HEPA filters on the HVAC system. Additionally, there is no data to support the specification set for total airflow.

2.

The air change rate should be sufficient to ventilate the operation avoiding build up of aerosols, powder, packaging particles and flushing away micro-organisms in the unlikely event they are present.
PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.5 The prevention of recontamination 9.5.6.1 [VIP ID: 190600] The air change rate should be sufficient to ventilate the operation avoiding build up of aerosols, powder, packaging particles and flushing away microorganisms in the unlikely event they are present.

3.

For Class 100,000 (ISO 8) supporting rooms, air flow sufficient to achieve at least 20 air changes per hour is typically acceptable. Significantly higher air change rates are normally needed for Class 10,000 and Class 100 areas.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities C. Clean Area Separation (para 4) [VIP ID: 110310] Air change rate is another important cleanroom design parameter. For Class 100,000 (ISO 8) supporting rooms, airflow sufficient to achieve at least 20 air changes per hour is typically acceptable. Significantly higher air change rates are normally needed for Class 10,000 and Class 100 areas.

4.

Room filtered air flows should be monitored periodically and compared to those measured at the time of balancing.
Selected FDA 483 Observations (February 1998) Product Manufacture [VIP ID: 6825] Room filtered air flows should be monitored periodically and compared to those measured at the time of balancing.

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5.

The ventilation system should be arranged so as to prevent the dissemination of micro-organisms from one manufacturing area to another.
FDA Warning Letter CBER-98-024 (August 1998) Extracted from FDA Warning Letter CBER-98-024 USA 14/08/1998 [VIP ID: 13000] Failure to ensure that the ventilation system is arranged so as to prevent the dissemination of microorganisms from one manufacturing area to another and to avoid other conditions unfavorable to the safety of the product, in that unidirectional airflow in the class #### aseptic filling suite has not been established [21 CFR 600.11(a)].

6.

Sterile product manufacturing facilities should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 29 [ViP ID: 186056] A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. ... EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 29 (para 2) [VIP ID: 63210] A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 29 (para 2) [VIP ID: 63220] The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Premises 29. [VIP ID: 1442] A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. ...

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7.

Air flows should not distribute particles from a particle-generating person, operation or machine to a zone of higher product risk.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 30 [VIP ID: 63230] It should be demonstrated that air-flow patterns do not present a contamination risk, e.g. care should be taken to ensure that air flows do not distribute particles from a particle-generating person, operation or machine to a zone of higher product risk. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Premises 30. [VIP ID: 1443] It should be demonstrated that air-flow patterns do not present a contamination risk, e.g. care should be taken to ensure that air flows do not distribute particles from a particle-generating person, operation or machine to a zone of higher product risk.

8.

The air flow in critical areas should be laminar when delivered to the point of use.
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. Equipment 1. Production Equipment para 6 b. Aseptic Workstation para 3 [VIP ID: 187414] We recommend laminar airflow velocities be monitored periodically at the work surface as well as at the HEPA filter face to ensure adequate uniformity of flow throughout the critical area. ... GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. Personnel Training, Qualification and Monitoring A. Personnel (para 3) [VIP ID: 110600] Unidirectional airflow design is used to protect sterile equipment surfaces, container-closures, and product. Disruption of the path of unidirectional flow air in the critical area can pose a risk to product sterility. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 28. [VIP ID: 2180] Is the air flow in critical areas laminar when delivered to the point of use? At what velocity?

9.

Where a laminar air flow is required, the air flow should not be interupted.
GUIDANCE FOR INDUSTRY INDS - APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) VI. SPECIAL PRODUCTION SITUATIONS D. Sterile Products/Aseptically Processed Products [VIP ID: 183918] We recommend that special precautions be taken for investigational new drugs intended to be sterile. Thorough consideration should be given to controls for aseptic processing. The following examples are recommendations that should be considered: - Ensuring that items within a laminar airflow aseptic workstation not interrupt the airflow. ...

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GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. Equipment 1. Production Equipment para 6 b. Aseptic Workstation para 3 [VIP ID: 187414] ... We recommend that operators be trained on the importance of minimizing objects and equipment within the critical area so laminar airflow is not disrupted. ... FDA Warning Letter CBER-05-006 (December 2004) Extracted from FDA warning letter CBER-05-006 USA 09/12/2004 [VIP ID: 133220] 7. Your firm failed to establish separate or defined areas or other control systems for aseptic processing operations to prevent contamination or mix-ups. [21 CFR 211.42(c) (10) and 600.11(a)] For example, formulation rooms [redacted] and [redacted] do not meet manufacturing needs and prevent contamination, due to the equipment configurations within the Class [redacted] area, in that the airflow, above the critical area where multiple aseptic connections are made, is obstructed by the operators when making the connections.

10. Air flow studies should be performed to determine air flow patterns in aseptic areas under dynamic conditions. Records should be made of the studies and should be reviewed and approved by the quality unit.
Selected FDA 483 Observations (February 2007) Sterile Product Manufacture [VIP ID: 194290] Attributions of over action limit particulate levels in a Class 100 area to air disturbance caused by a cart in the Class 100 area are unfounded if no smoke studies have been performed with these carts in place. Extracted from FDA warning letter VLN# 06200780 (January 2007) Extracted from FDA warning letter VLN# 06200780 USA 05-Jan-07 6. a) [VIP ID: 194674] Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed. [21 CFR 211.113(b)] For example, a) your firm failed to adequately document air flow (smoke) studies to demonstrate unidirectional airflow under dynamic conditions. Your firm's air flow patterns procedure lacked specific acceptance criteria. Your airflow study documentation included hand drawings that provided insufficient information to determine whether HEPA-filtered air used in the manufacturing area (and sterility test laboratory) robustly sweeps away particles and maintains unidirectional airflow protection under dynamic production conditions. We acknowledge receipt of your September 8th and October 20th 2006, letters in response to the Form FDA-483, Inspectional Observations. We have reviewed your responses and have the following comments: Observation 4 We note in your October 20, 2006, response that your firm performed additional smoke studies including simulations of loading of the lyophilizer. Your hand drawings are insufficient documentation to determine if airflow is maintained under dynamic conditions. Therefore, regardless of additional simulations performed under your current protocol, unless substantial changes are made, your smoke study documentation is still considered inadequate. Selected FDA 483 Observations (January 2007) Sterile Product Manufacture [VIP ID: 194250] Where equipment is positioned within a Class 10,000 designated area in a Class 100 fill room, there should be an evaluation performed in order to determine that there is appropriate unidirectional airflow within the Class 100 designated area to provide an adequate barrier between the two different air classifications.

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Selected FDA 483 Observations (January 2007) Sterile Product Manufacture [VIP ID: 194252] Smoke studies should clearly or completely describe unidirectional airflow during real time conditions in order to determine that routine filling operations and personnel movement do not adversely impact upon the unidirectional flow of air during the filling process. Extracted from FDA warning letter CHI-3-07 (December 2006) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 3) b. [VIP ID: 194580] Failure to establish an adequate air supply that is filtered through high-efficiency particulate air filter under positive pressure, regardless of whether flow is laminar or non-laminar as required by 2I CFR 211.42(c)(10)(iii). For example, b) Air flow pattern testing done to demonstrate unidirectional airflow in the critical areas of the five aseptic fill lines are not done under simulated operating conditions with operators present performing routine and non-routine aseptic manipulations, such as: adding vials to the line; adding stoppers to the hopper while in the Class 100 area; removing vials from the line for weight checks while in the Class 100 area; removing fallen or defective vials while in the Class 100 area; or moving HEPA transfer carts fully into the Class 100 areas (Lines 2 and 6 only). Your response to the FDA 483 indicates that you intended to conduct some additional air flow testing in August 2006; however, you did not commit to conducting enhanced air flow pattern studies (to include the activities identified above) in the Class 100 area until December 2006. Please provide the results for the testing that occurred in August, and any corrective actions resulting from the testing. Please provide the timeframe for the review and assessment of the studies occurring in December. Selected FDA 483 Observations (November 2006) Sterile Product Manufacture [VIP ID: 194060] Smoke studies should ensure that: technicians participating in the smoke study do not have exposed skin, technicians' activities are consistent with those during actual sterile operations, and pooling and eddying is not visible in and around the sterile filling assembly. Selected FDA 483 Observations (October 2006) Sterile Product Manufacture [VIP ID: 193966] There should be adequate exhaust systems or other systems to control contaminants in areas where air contamination occurs during production. Smoke studies should be performed in sterile filtration rooms and should ensure that: personnel are properly gowned, filling technicians are clearly visible, there is no pooling between technicians and filling equipment and supplies, equipment and supplies normally present in the filling suite are present during the study, air returns are visible, filling activities are consistent with those performed during filling operations, and there is documentation to demonstrate that the studies are reviewed and evaluated. Selected FDA 483 Observations (January 2006) Sterile Product Manufacture [VIP ID: 179660] There should be assurance, such as video records of smoke tests, that gaps in strip curtains used to separate Class 100 areas from Class 10,000 areas do not disrupt airflow. Selected FDA 483 Observations (January 2006) Sterile Product Manufacture [VIP ID: 179680] Smoke studies should demonstrate the ability to maintain the integrity of laminar airflow within a critical area when Extracted from FDA Warning Letter 320-05-03 (July 2005) Extracted from FDA warning letter 320-05-03 Italy 21/07/2005 [VIP ID: 169310] 9. The [redacted] filling process was not adequately designed to permit unidirectional airflow protection of the bulk sterile drug.

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The smoke studies of your [redacted] filling operation indicated that unidirectional flow is not achieved in your current design. Documentation of the design of the [redacted] you propose to put in place, and information regarding the new layout of the filling area was not submitted. FDA-483 observations that dealt with this area remain a concern. Your response also does not address the dead air space inside the filling cabinet, and the turbulent airflow that can be created by repeatedly opening and closing the cabinet. We acknowledge your long-term goal of installing a [redacted] in this area, but you also need to address these short term manufacturing issues. Selected FDA 483 Observations (February 2005) Sterile Product Manufacture [VIP ID: 128740] Smoke studies should completely demonstrate that the air is moving away from the open product vials and work surfaces, during personnel manual interventions, to include: (1) When opening and closing access doors in front of fill nozzles. (2) When opening and closing access doors in front of stopper bowls. (3) During the manual transfer of stainless steel 'Bleeding Pans' when positioned over fill nozzles. (4) During manual interventions with the particle control shields and air filtration devices. Selected FDA 483 Observations (February 2005) Sterile Product Manufacture [VIP ID: 128750] Evaluations (smoke study) should be performed for the pass throughs when opening and closing the doors in order to assure that the manual process does not negatively impact the unidirectional flow of air within Class 100 fill areas. Selected FDA 483 Observations (February 2005) Sterile Product Manufacture [VIP ID: 128730] Where an aseptic filling process requires aseptic connections to be performed in a Class 100 area, evaluations (smoke study) should be performed to demonstrate that the HEPA filtered air provides adequate unidirectional air flow and that the manual process does not produce air turbulences that can have a negative impact on the aseptic connections. Selected FDA 483 Observations (August 2004) Sterile Product Manufacture [VIP ID: 122660] HVAC system qualification should include: a. the performance of smoke studies to determine air-flow patterns in aseptic processing areas. b. the testing of room particle counts, number of air changes, and air-flow velocities at multiple times to demonstrate adequate performance over time. Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121960] Smoke stick studies conducted to demonstrate air flow patterns in aseptic filling rooms should show: a. Air flow patterns when the doors of the area are closed. b. The effect the heat in the area has on the air patterns. c. Air flow patterns inside shrouds. d. How the movement of equipment affects the air flow patterns. Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 70930] Determination of filter laminarity and air flow in filling rooms should be performed with the employees who are normally present during routine operations to determine if the laminarity and air flow is affected by their presence. Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 70940] There should be evidence (e.g. video) to demonstrate that smoke tests are adequately executed.

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Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 72340] Smoke tests conducted in class 100 parenteral filling areas should be performed under dynamic conditions to determine how the laminar flow is affected by the presence of operators (as observed during regular production) and equipment. Selected FDA 483 Observations (November 2003) Product Manufacture [VIP ID: 70250] Videotaped smoke testing performed to determine air circulation patterns, air recovery, and to ascertain the positive air pressure environment within dispensing rooms should be reviewed and approved by the Quality Unit. Selected FDA 483 Observations (November 2003) Sterile Product Manufacture [VIP ID: 70280] Airflow patterns for the transfer to components (stoppers/plungers/etc.) from the Component Processor to bags and the sealing of filled bags should be adequately evaluated with smoke studies to assess turbulence, disruption of unidirectional airflow, and adequacy of aseptic technique. Selected FDA 483 Observations (March 2003) Sterile Product Manufacture [VIP ID: 52210] Smoke pattern studies (airflow pattern studies) should: (a) demonstrate that the air is moving away from open product vials, work surfaces and during manual interventions. (b) demonstrate that the movement of individuals who perform some of the manual operations during the filtration process does not produce air turbulence that could have a negative impact on the aseptic filling areas. (c) include a complete evaluation of the unidirectional flow of air during the manual transfer operations of the partially stoppered vials as the vials are transferred into the mobile transfer carts, used to transfer aseptically filled vials to the lyophilizer. (d) include simulations with transfer trays containing partially stoppered vials during the transfer process into the lyophilizer. Selected FDA 483 Observations (January 2002) Sterile Product Manufacture [VIP ID: 46210] Videotapes documenting the dynamic airflow assessments performed on filling lines should include simulation of operator interventions. Selected FDA 483 Observations (September 2001) Product Manufacture [VIP ID: 41120] The direction of air flow should be documented in weighing, blending and compression rooms. Selected FDA 483 Observations (August 2001) Sterile Product Manufacture [VIP ID: 40720] Airflow (smoke) studies should include: (1) personnel performing stipulated activities Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26520] Smoke tests used to determine air flow patterns in an aseptic core should be performed under dynamic conditions with video. The results should not be hand drawn.

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Selected FDA 483 Observations (August 2000) Sterile Product Manufacture [VIP ID: 19420] HEPA filter integrity testing should include: d) the measurement of the distance between smoke entry and exit planes during laminar airflow (smoke) studies to ensure the flow is laminar e) more than just a narrative report to fully and accurately assess airflow patterns Selected FDA 483 Observations (November 1999) Sterile Product Manufacture [VIP ID: 8790] Air flow studies to assess turbulence and laminarity should be performed with personnel performing aseptic activities and when personnel traverse the filling area. Extracted from FDA Warning Letter CHI-12-00 (February 2000) Extracted from FDA warning letter CHI-12-00 USA 07/02/2000 [VIP ID: 161610] Failure to establish and follow procedures, designed to prevent objectionable microorganisms in drug products purporting to be sterile [21 CFR 211.113]. For example: There is no established procedure or written test method for conducting smoke pattern testing of the HVAC systems. There is no written document that defines terms, establishes acceptance criteria, or describes how the tests should be done, recorded and reviewed. The smoke pattern tests reviewed during this inspection were not completely described and/or documented. Employees have not received training on how to do airflow pattern tests. Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7302] Isolator airflow smoke studies should include: 1) the lower limit pressure differential 2) confirmation of unidirectional airflow 3) dynamic conditions (gloves in place etc.) Extracted from FDA Warning Letter CBER-99-013 (March 1999) Extracted from FDA warning letter CBER-99-013 UK 17/03/1999 [VIP ID: 159560] 7. Failure to assure that air filtration systems are adequate [21 CFR 211.46(c) and 211.100(a)] in that smoke studies to evaluate laminar flow in the filling area have not been conducted since 1985, are not documented, and there are no written procedures for such studies. Selected FDA 483 Observations (December 1997) Sterile Product Manufacture [VIP ID: 136490] Clean room smoke studies should include dynamic conditions such as equipment in operation and typical interventions simulated such as stopper staging and doors opening and closing.

11. Determination has to be made of the air flow at the aseptic work surface.
FDA Warning Letter 2002-DT-21 (January 2002) Extracted from FDA warning letter 2002-DT-21 USA 30/01/2002 4 [VIP ID: 48290] 4) Failure to have separate or defined areas, or such other control systems as are necessary to prevent contamination during the course of aseptic processing operations, as required by 21 CFR 211.42(c)(10). For example: b. No determination has been made of the airflow at the aseptic work surface.

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12. A smoke stick is not always enough.


Selected FDA 483 Observations (August 2001) Sterile Product Manufacture [VIP ID: 40720] Airflow (smoke) studies should include: (2) the generation of sufficient volumes of smoke to adequately evaluate airflow patterns across filter faces and filling lines (a smoke stick is not always enough)

13. There should be documentation to demonstrate that Flo-Viz materials are equivalent to smoke.
Selected FDA 483 Observations (March 2001) Sterile Product Manufacture [VIP ID: 27300] Where Flo-Viz materials (non-shedding monofilament nylon multi-strain mesh streamer material) are used in the determination of the direction of airflow, there should be documentation to demonstrate that they are equivalent to smoke.

14. Laminar air flow protection may provide a suitable alternative to sterilisable systems.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS EQUIPMENT 23 [VIP ID: 186374] The introduction or removal of material should take place using a sterilizable closed system, or possibly in an appropriate laminar air flow. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS STARTING MATERIALS Operating principles 50 [VIP ID: 186426] When necessary, for instance when two or more fermentors are within a single area, sampling and addition ports, and connectors (after connection, before the flow of product, and again before disconnection) should be sterilized with steam. In other circumstances, chemical disinfection of ports and laminar air flow protection of connections may be acceptable. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Operating principles 50. [VIP ID: 1649] Where necessary, for instance when two or more fermentors are within a single area, sampling and addition ports, and connectors (after connection, before the flow of product, and again before disconnection) should be sterilized with steam. In other circumstances, chemical disinfection of ports and laminar air flow protection of connections may be acceptable. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 05 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS (July 1993) Equipment 23. (para 3) [VIP ID: 1615] The introduction or removal of material should take place using a sterilizable closed system, or possibly in an appropriate laminar air flow.

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7.6 Air Velocity 1. There should be specifications for the air velocity in an aseptic core and written procedures for determining and recording air flow velocities should require that all readings are within that specification prior to averaging the results.
Selected FDA 483 Observations (February 2002) Sterile Product Manufacture [VIP ID: 46010] Written procedures for determining airflow velocities from HEPA filter units should require that all readings are within specification prior to averaging the results. Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26440] There should be specifications for the air velocity in an aseptic core.

2.

In critical areas, HEPA filtered air should be supplied at a sufficient and justified velocity to sweep particles away from areas where product is exposed. A velocity of 0.45 metres/second (90 feet per minute) 20 percent is generally accepted as appropriate, with possibly higher velocities where operations generate high levels of particulates.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 6) [VIP ID: 110230] HEPA-filtered [4] air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area (Ref. 3) [5] [4] High Efficiency Particulate Air filter [5] A velocity of 0.45 meters/second (90 feet per minute) has generally been established, with a range of plus or minus 20 percent around the setpoint. Higher velocities may be appropriate in operations generating high levels of particulates. Selected FDA 483 Observations (April 1997) Sterile Product Manufacture [VIP ID: 136310] There should be a routine air velocity monitoring program to assure the maintenance of a 90 foot/minute +/- 20% speed at critical filling sites during the filling operation.

3.

There should be a written procedure describing the frequency and method of obtaining air velocity measurements from HEPA filters and air diffusion panels located above Class 100 aseptic filling areas, which should include the equipment to be used and re-installation of the air diffusers following testing.
Selected FDA 483 Observations (February 2002) Sterile Product Manufacture [VIP ID: 46020] Written procedures for determining airflow velocities from HEPA filter units should require uniformity of air velocities between measuring points. Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26290] There should be a written procedure describing how to obtain air velocity measurements from HEPA filters and air diffusion panels located above Class 100 aseptic filling areas. This procedure should include: (a) the equipment to be used.

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(b) re-installation of the air diffusers following testing. Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7201] Air velocity testing of HEPA filters used where parenteral product is exposed should be performed at the critical working level not at inches from the filter face. Measurements taken from the filters face only should be correlated against those at the critical working level under dynamic conditions. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 34. [VIP ID: 2186] How often are air flow velocities checked for each HEPA filter?

4.

Air velocities in Class 100 areas should be taken at work height, not from the filter face.
GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. Equipment 1. Production Equipment para 6 b. Aseptic Workstation para 3 [VIP ID: 187414] We recommend laminar airflow velocities be monitored periodically at the work surface as well as at the HEPA filter face to ensure adequate uniformity of flow throughout the critical area. We recommend that operators be trained on the importance of minimizing objects and equipment within the critical area so laminar airflow is not disrupted. We recommend that microbiological monitoring (e.g., using settle plate) in the LAFW be conducted during sterility testing and critical aseptic manipulation. Selected FDA 483 Observations (August 2002) Sterile Product Manufacture [VIP ID: 47720] Air flow velocity checks should be measured near the work surface area (where vial filling occurs) rather than at the filter surface. Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7201] Air velocity testing of HEPA filters used where parenteral product is exposed should be performed at the critical working level not at inches from the filter face. Measurements taken from the filters face only should be correlated against those at the critical working level under dynamic conditions. Selected FDA 483 Observations (June 1998) Sterile Product Manufacture [VIP ID: 6727] The air velocity should be recorded at the aseptic filling work surfaces in accordance with a written procedure. Selected FDA 483 Observations (December 1997) Product Manufacture [VIP ID: 6268] Air velocities in Class 100 areas should be taken at work height, not from the filter face.

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CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 28. [VIP ID: 2180] Is the air flow in critical areas laminar when delivered to the point of use? At what velocity? Is velocity determined at the critical area or at the filter face?

5.

Air velocities should be adequate to sweep over filling lines.


Selected FDA 483 Observations (February 2000) Sterile Product Manufacture [VIP ID: 136780] Air velocity measurements should be taken, or an evaluation performed, to assure that there is a sufficient velocity of air over the aseptic fill line. Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7560] Air velocities should be adequate to sweep over filling lines.

7.7 Pressure Difference 1. Differential pressure specifications should be documented for all aseptic processing and/or ancillary clean rooms between which air may flow.
Selected FDA 483 Observations (December 1997) Sterile Product Manufacture [VIP ID: 2485] Differential pressure specifications should be documented for all aseptic processing and / or ancillary clean rooms between which air may flow.

2.

Differential pressure specifications should be documented for sterility test clean rooms, gowning rooms and general microbiology laboratory.
Selected FDA 483 Observations (November 1997) Sterile Product Manufacture [VIP ID: 2506] Differential pressure specifications should be documented for sterility test clean rooms, gowning rooms and general microbiology laboratory.

3.

Adjacent rooms of different grades should have a pressure differential of 10 to 15 pascals (guidance values) but this recommendation may need to be modified for materials requiring containment, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 29 [ViP ID: 186056] Adjacent rooms of different grades should have a pressure differential of 10-15 pascals (guidance values). Particular attention should be paid to the protection of the zone of greatest risk, that is, the immediate environment to which a product and cleaned components which contact the product are exposed. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations.

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GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities C. Clean Area Separation (para 1) [VIP ID: 110280] An essential part of contamination prevention is the adequate separation of areas of operation. To maintain air quality, it is important to achieve a proper airflow from areas of higher cleanliness to adjacent less clean areas. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness. For example, a positive pressure differential of at least 10-15 Pascals (Pa) [6] should be maintained between adjacent rooms of differing classification (with doors closed). When doors are open, outward airflow should be sufficient to minimize ingress of contamination, and it is critical that the time a door can remain ajar be strictly controlled (Ref. 4). [6] Equal to 0.04-0.06 inches of water gauge. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities C. Clean Area Separation (para 2) [VIP ID: 110290] In some cases, the aseptic processing room and adjacent cleanrooms have the same classification. Maintaining a pressure differential (with doors closed) between the aseptic processing room and these adjacent rooms can provide beneficial separation. In any facility designed with an unclassified room adjacent to the aseptic processing room, a substantial overpressure (e.g., at least 12.5 Pa) from the aseptic processing room should be maintained at all times to prevent contamination. If this pressure differential drops below the minimum limit, it is important that the environmental quality of the aseptic processing room be restored and confirmed. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.1 CLEAN ROOM DESIGN 8.1.2 Air Supply 8.1.2.2 [VIP ID: 190256] There should be a pressure differential of not less than 10 to 15 Pascals (guidance value) between each of the areas, i.e. ambient/airlock and airlock/test room. Pressure readings should be taken and recorded from externally mounted gauges unless a validated continuous monitoring system is installed. As a minimum, readings should be taken prior to operator entry to the test suite. Pressure gauges should be labelled to indicate the area served, the acceptable specification, and whether or not the reading is absolute or differential. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 29 (para 2) [VIP ID: 63220] Adjacent rooms of different grades should have a pressure differential of 10 - 15 pascals (guidance values). Particular attention should be paid to the protection of the zone of greatest risk, that is, the immediate environment to which a product and cleaned components which contact the product are exposed. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations. Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7550] Room differential pressures should be adequate to protect the integrity of the cleaner room.

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4.

An appropriate positive differential air pressure, supported by qualification studies, should be maintained between the isolator and surrounding room and between different parts of the isolator system, as necessary.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) Appendix 1: Aseptic Processing Isolators B. Design 3. Pressure Differential (para 1) [VIP ID: 111960] Isolators that include an open portal should be designed to ensure complete physical separation from the external environment. A positive air pressure differential adequate to achieve this separation should be employed and supported by qualification studies. Positive air pressure differentials from the isolator to the surrounding environment have largely ranged from approximately 17.5 to 50 Pascals [22]. The appropriate minimum pressure differential established by a firm will depend on the systems design and, when applicable, its exit port. Air balance between the isolator and other direct interfaces (e.g., dry heat tunnel) should also be qualified. [22] 0.07" to 0.20" water gauge. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. 7.5 The prevention of recontamination 7.5.2 [VIP ID: 190492] The control of leaks between the isolator and surrounding room and between different parts of the isolator system as necessary, should be assured as far as possible. As a guide a minimum of 10 Pascal positive differential air pressure should be maintained to protect against unforeseen circumstances. The maintenance of positive pressure should be monitored and fitted with an alarm.

5.

Differential air pressures between aseptic processing areas and surrounding support areas of lower classification should be routinely monitored and recorded during dynamic operations.
Extracted from FDA warning letter VLN# 06200780 (January 2007) Extracted from FDA warning letter VLN# 06200780 USA 05-Jan-07 6. b) [VIP ID: 194676] Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed. [21 CFR 211.113(b)] For example, b) air pressure differentials are not continuously monitored nor frequently recorded during aseptic filling operations. No system is in place to adequately monitor or record pressure differentials to assure that the rooms are maintained at the correct air pressure differential at all times. We acknowledge receipt of your September 8th and October 20th 2006, letters in response to the Form FDA-483, Inspectional Observations. We have reviewed your responses and have the following comments: Observation 5 Your October 20, 2006, response states your firm now has a visual and audible alarm in the aseptic fill room to signal aberrant air pressure differentials. We agree an alarm is helpful; however, no validation of your alarm system or approach to data recording was noted in your response. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 5 - MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS PREMISES 31 [VIP ID: 186060] A warning system should be provided to indicate failure in the air supply. Indicators of pressure differences should be fitted between areas where these differences are important. These pressure differences should be recorded regularly or otherwise documented.

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Selected FDA 483 Observations (December 2004) Product Manufacture [VIP ID: 124720] Pressure differentials between manufacturing rooms (encapsulation, granulation, tableting) should be continually monitored to determine that the pressure specification is maintained during production. Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124770] Air pressure measurements should be taken and documented during dynamic filling processes to assure that the air pressures are maintained as required. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities C. Clean Area Separation (para 3) [VIP ID: 110300] The Agency recommends that pressure differentials between cleanrooms be monitored continuously throughout each shift and frequently recorded. All alarms should be documented and deviations from established limits should be investigated. Selected FDA 483 Observations (December 2003) Product Manufacture [VIP ID: 70530] Pressure differentials between the classified and non- classified areas should be monitored to assure that the requisite air pressure is appropriately maintained. Selected FDA 483 Observations (May 2002) Sterile Product Manufacture [VIP ID: 46560] Pressure differentials between fill rooms and adjacent uncontrolled room sealing and inspection rooms should be monitored and controlled directly to assure that a suitable pressure differential is maintained across these critical opening under all conditions, including system errors, calibration accuracy and doors opening. FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42790] 2. Failure to provide equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing or holding of a drug product [21 CFR 211.46(b)]. For example, the manufacturing and filling rooms of (a) ****, ****, and **** are not equipped with differential pressure monitors; [FDA-483 Item 4]. Selected FDA 483 Observations (June 2001) Sterile Product Manufacture [VIP ID: 27710] Differential pressures should be monitored continuously (not twice daily) between the aseptic fill area and its adjacent gowning area. Selected FDA 483 Observations (April 2001) Sterile Product Manufacture [VIP ID: 27720] Differential pressures should be monitored continuously (not twice daily) in the aseptic fill controlled environment areas. Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26280] Differential air pressures should be monitored between aseptic filling areas and surrounding support areas during dynamic aseptic filling operations.

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Selected FDA 483 Observations (September 2000) Product Manufacture [VIP ID: 19320] Production room pressure differentials should be recorded each day for every room in use. Selected FDA 483 Observations (August 1999) Sterile Product Manufacture [VIP ID: 7780] Differential pressure should be monitored between filling rooms and neighboring unclassified rooms. Selected FDA 483 Observations (February 1999) Sterile Product Manufacture [VIP ID: 7128] The pressure differentials for aseptic filling and compounding rooms should be documented more frequently than once a day. FDA Warning Letter CBER-99-007 (December 1998) Extracted from FDA Warning Letter CBER-99-007 Canada 07/12/1998 [VIP ID: 13010] Air pressure differential is not monitored in the manufacturing areas, including the Vialing Rooms and the Monoclonal Production Room. FDA Warning Letter CBER-99-002 (October 1998) Extracted from FDA warning letter CBER-99-002 UK 21/10/1999 [VIP ID: 13020] Failure to establish separate or defined areas or other control systems for manufacturing and processing operations to prevent contamination or mix-ups [21 CFR 211.42(c)] in that data is not available to demonstrate that adequate pressure differential is maintained during filling operations. Selected FDA 483 Observations (August 1998) Product Manufacture [VIP ID: 6797] Room differential pressures should be routinely monitored. Selected FDA 483 Observations (June 1998) Sterile Product Manufacture [VIP ID: 6729] Differential air pressure readings between filling rooms and support areas should be read during dynamic operations. Selected FDA 483 Observations (February 1997) Sterile Product Manufacture [VIP ID: 2473] Air pressure differentials should be monitored or documented on a continuous basis to ensure a positive air pressure from the aseptic filling rooms to adjacent areas and to the uncontrolled environment outside the aseptic suite. Selected FDA 483 Observations (January 1997) Medical Device Manufacture [VIP ID: 135790] Validation of positive air pressure in the manufacturing areas should take into account testing with various doors open to determine situations which may negate the positive air pressure.

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6.

Where plastic curtains are used to segregate areas of different classes, the differential pressure across the curtains should be measured.
Selected FDA 483 Observations (February 1998) Sterile Product Manufacture [VIP ID: 6312] Where plastic curtains are used to segregate areas of different classes, the differential pressure across the curtains should be measured.

7.

Facilities for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility, including pressure control.
GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) III. FACILITY (para 1) [VIP ID: 2017] Facility design for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. These would include temperature, humidity and pressure control. Because sterile bulk aseptic facilities are usually larger, problems with pressure differentials and sanitization have been encountered. For example, a manufacturer was found to have the gowning area under greater pressure than the adjacent aseptic areas. The need to remove solvent vapors may also impact on area pressurization.

8.

In order to contain radioactive particles, it may be necessary for the air pressure to be lower where products are exposed than in surrounding areas. However, it is still necessary to protect the product from environmental contamination.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 3 - MANUFACTURE OF RADIOPHARMACEUTICALS PREMISES AND EQUIPMENT 3 [VIP ID: 186284] In order to contain the radioactivity, it may be necessary for the air pressure to be lower where products are exposed than in surrounding areas. However, it is still necessary to protect the product from environmental contamination. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 03 - MANUFACTURE OF RADIOPHARMACEUTICALS (January 1993) Premises and equipment 3. [VIP ID: 1561] In order to contain the radioactive particles, it may be necessary for the air pressure to be lower where products are exposed than in surrounding areas. However, it is still necessary to protect the product from environmental contamination.

9.

Differential air pressure records and maintenance records for air pressure adjustments and repairs should be reviewed for completeness and accuracy by a second individual.
Selected FDA 483 Observations (January 2000) Sterile Product Manufacture [VIP ID: 14520] Differential air pressure records and maintenance records for air pressure adjustments and repairs should be reviewed for completeness and accuracy by a second individual. Selected FDA 483 Observations (February 1998) Product Manufacture [VIP ID: 6269] Room pressure differential calculations should be recorded and the daily reading reviewed by someone other than the person taking the readings.

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10. Unloading of centrifuges and loading of dryers should not be performed in close proximity (within 20ft) of reactor trains without physical separation or pressure differential control.
Selected FDA 483 Observations (November 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 19760] Unloading of centrifuges and loading of dryers should not be performed in close proximity (within 20ft) of reactor trains without physical separation or pressure differential control.

11. Air pressure alarm systems monitoring aseptic filling rooms should be tested periodically. There should be a rationale behind established alarm times and alarm logs should document the actual air pressure when the alarm is initiated and the actual value when the alarm is cleared.
Selected FDA 483 Observations (January 2004) Product Manufacture [VIP ID: 70840] HVAC pressure differential Alarm Logs should document the actual air pressure when the alarm was initiated and the actual value when the alarm is cleared. Selected FDA 483 Observations (April 2001) Sterile Product Manufacture [VIP ID: 26990] Air pressure alarm systems monitoring aseptic filling rooms should be tested periodically. FDA Warning Letter 01-NSV-09 (March 2001) Extracted from FDA warning letter 01-NSV-09 USA 02/03/2001 [VIP ID: 29080] 5. Failure to appropriately validate equipment. For example, B). Failure to document the rationale behind established alarm times to monitor the specified differential air pressures within the manufacturing areas. [21 CFR 211.68]" [FDA Investigators: Thomas Arista, Patricia Cochran and Jeffrey Sommers] Extracted from FDA Warning Letter 2001-DT-12 (March 2001) Extracted from FDA warning letter 2001-DT-12 USA 02/03/2001 [VIP ID: 165740] 5. Failure to appropriately validate equipment. For example, B). Failure to document the rationale behind established alarm times to monitor the specified differential air pressures within the manufacturing areas. [21 CFR 211.68)

12. Validation of pressure differential monitoring systems in sterile fill production areas should include the evaluation, testing and challenge of data retrieval functions, where used.
Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 72650] Validation of pressure differential monitoring systems in sterile fill production areas should include the evaluation, testing and challenge of data retrieval functions where used.

13. Pneumatic lines in interstitial spaces, between clean room pressure indicators and transmitters should be physically tagged.
Selected FDA 483 Observations (December 1997) Sterile Product Manufacture [VIP ID: 136500] Pneumatic lines in interstitial spaces, between clean room pressure indicators and transmitters should be physically tagged.

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7.8 Temperature and Humidity 1. Facility design for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. These would include temperature, humidity and pressure control.
GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) III. FACILITY (para 1) [VIP ID: 2017] Facility design for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. These would include temperature, humidity and pressure control. ...

2.

Aseptic processing should include systems for temperature and humidity control.
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -- Buildings and Facilities Sec. 211.42 Design and construction features (c) [VIP ID: 20] Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures: (10) Aseptic processing, which includes as appropriate: (ii) Temperature and humidity controls;

3.

A firm may repackage solid oral dosage forms into unit dose containers and utilise an expiration date of not more than six months from the date of repackaging without conducting stability studies, provided that the repackaging and storage of the drug product is documented as being accomplished in a humidity controlled environment and within the temperature specified in the USP monograph or the product labeling. If no temperature/humidity is specified, a controlled room temperature, as defined by the USP, with a relative humidity not exceeding 75 percent should be maintained.
CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002B DRUG REPACKAGERS AND RELABELERS (December 1993) PART III - INSPECTIONAL OPERATIONS 3. Full Inspectional Option *b. Unit Dose Repackagers - 1) [VIP ID: 4137] For this program the full inspectional option provides specific policies for Unit-Dose Repackagers. The following practices, if completely met, are adequate to allow Unit Dose repackagers to comply with current good manufacturing practices in the specific areas described below. For all other areas, follow guidance in 3a: Expiration Dating for Unit Dose Containers: A unit dose container is a non-reusable container designed to hold a quantity of drug intended for administration as a single dose, which is to be used promptly after the container is opened. A firm may repackage solid oral dosage forms into unit dose containers and utilize an expiration date of not more than six months from the date of repackaging without conducting stability studies, provided that all of the following conditions are met: d) The repackaging and storage of the drug product is accomplished in a humidity controlled environment and within the temperature specified in the USP monograph or the product labeling. If no temperature/humidity is specified, a controlled room temperature, as defined by the USP, with a relative humidity not exceeding 75 percent should be maintained. *Documentation must be on file to verify that all the conditions listed above are met.*

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4.

Manufacturing and filling rooms should be equipped with temperature and humidity control monitors.
FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42790] 2. Failure to provide equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing or holding of a drug product [21 CFR 211.46(b)]. For example, the manufacturing and filling rooms of (a) ****, ****, and **** are not equipped with differential pressure monitors; and (b) **** and **** are not equipped with temperature and humidity control monitors [FDA-483 Item 4].

5.

There should be appropriate procedures defined for controlling and monitoring environmental conditions in production and storage areas.
Extracted from FDA warning letter W/L 06-07 (February 2007) Extracted from FDA warning letter W/L 06-07 USA 02-Feb-07 5 [VIP ID: 194870] Appropriate procedures have not been defined for controlling environmental conditions. Specifically your devices are labeled for room temperature or refrigerated storage. Your current manufacturing and warehousing facilities do not have temperature controlling equipment and you have no assurance that devices are maintained below the labeled 86F. [21 CFR 820.70] FDA Warning Letter 02-BLT-13 (January 2002) Extracted from FDA warning letter 02-BLT-13 USA 03/01/2002 5 [VIP ID: 48040] 5. Failure to establish written procedures (21 CFR 211.22, 211.67, 211.80, 211.100, 211.122, 211.166, and 211.198) for the following: f. The monitoring of temperatures, humidity, and the air-handling system in the production area;

7.9 Training 1. The routine training of personnel, who work in a controlled environment, including operators and personnel responsible for monitoring, equipment maintenance, engineering, washing and preparation, needs special emphasis as people are potentially one of the main sources of microorganisms in the environment.
21 CFR PART 820 - QUALITY SYSTEM REGULATION (April 2006) Subpart G--Production and Process Controls 21 CFR 820.70 Production and process controls. (d) Personnel. [VIP ID: 5807] Each manufacturer shall establish and maintain requirements for the health, cleanliness, personal practices, and clothing of personnel if contact between such personnel and product or environment could reasonably be expected to have an adverse effect on product quality. The manufacturer shall ensure that maintenance and other personnel who are required to work temporarily under special environmental conditions are appropriately trained or supervised by a trained individual.

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PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 8. STAFF TRAINING 8.1 [VIP ID: 188990] The routine training of personnel who work in a controlled environment needs special emphasis as people are potentially one of the main sources of microorganisms in the environment. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 8. STAFF TRAINING 8.2 [VIP ID: 188992] Included are not only operators but also other personnel working in a controlled environment as staff responsible for monitoring, equipment maintenance, engineering, washing and preparation.

2.

A formal personnel training programme is needed for all activities in each clean room. This means the programme has to be planned, documented and repeated at adequate intervals to ensure that the once trained individual meets the ongoing requirements for the work in a controlled environment.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 8. STAFF TRAINING 8.3 [VIP ID: 188994] A formal personnel training programme is needed for all activities in each clean room. This means the programme has to be planned, documented and repeated at adequate intervals to ensure that the once trained individual meets the ongoing requirements for the work in a controlled environment.

3.

Employees working in a sterile manufacturing area should have appropriate training in aseptic techniques and aseptic conduct.
FDA Warning Letter RAN 2004-06 (March 2004) Extracted from FDA warning letter RAN 2004-06 USA 31/03/2004 [VIP ID: 126710] 2. Employees working in the sterile manufacturing area and sterility suite lack appropriate training in aseptic techniques and aseptic conduct. In addition, these employees have failed to follow established SOPS designed to prevent microbiological contamination of drug products purported to be sterile as evidenced by FDAs numerous inspectional observations. The inspectional observations include an employee entering the Class [redacted] filling suite with exposed skin between the hood and mask. This same employee was observed to be wearing safety glasses when the Gowning Procedures for the Parenteral Sterile Filling Area SOP 14-011-12 specifically states in bold letters that safety goggles are to be worn. Forceps used to remove fallen vials were brought out of the Class [redacted] room area into the Class [redacted] area and back into the Class [redacted] area. Employees in room [redacted] aseptic filling room exhibited inappropriate aseptic conduct as evidenced by the observation of rapid movement throughout the Class [redacted] filling room. An operator was observed to reach over uncovered vials being loaded onto the turntable while he was removing vials that had fallen over. The plastic curtains that surround the Class [redacted] area, which are intended to protect the product from contamination, were displaced leaving gaps which could affect air flow in the Class [redacted] area. An operator in the sterile filling suite was observed spraying her fingertips with isopropyl alcohol before collecting personnel environmental monitoring samples from her fingertips. The above-referenced observations reveal significant problems in the training of the employees who perform activities in the sterile core. [21 CFR 211.25(a), 21 CFR 211.28(a), and 21 CFR 211.113(b)]

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4.

Environmental monitoring personnel need a thorough understanding of the sources of contamination risks (e.g. inadequately disinfected/sterilised sampling equipment) that are involved with the sampling methods.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 8. STAFF TRAINING 8.5 [VIP ID: 188998] Environmental monitoring personnel need a thorough understanding of the sources of contamination risks (e.g. inadequately disinfected/sterilised sampling equipment) that are involved with the sampling methods.

5.

Supervisors should ensure that all personnel are monitored and follow SOPs, and that they undergo periodic recertification, particularly when problems are detected during the course of routine environmental and negative control monitoring, or when operators perform the test infrequently.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 7. TRAINING 7.2 [VIP ID: 190242] Supervisors should ensure that all personnel are monitored and follow Standard Operating Procedures (SOPs). Personnel should undergo periodic re-certification, particularly when problems are detected during the course of routine environmental and negative control monitoring, or when operators perform the test infrequently.

6.

Each operator should be trained and certified in gowning procedures with training records maintained.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.2 AIRLOCK AND ASEPTIC GOWNING 8.2.2 Aseptic gowning 8.2.2.4 [VIP ID: 190270] Each operator should be trained and certified in gowning procedures with training records maintained.

7.

The training of clean room personnel associated with out-of-specification particle counts and contact plates should be documented.
Selected FDA 483 Observations (May 2004) Medical Device Manufacture [VIP ID: 121870] The training of clean room personnel associated with out-of-specification particle counts and contact plates should be documented.

8.

There should be documented evidence that outside contractors performing HEPA filter testing have been trained to follow the established written procedure.
Selected FDA 483 Observations (May 2001) Sterile Product Manufacture [VIP ID: 27160] There should be documented evidence that outside contractors performing HEPA Filter testing have been trained to follow the established written procedure.

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9.

Personnel in clean rooms should be instructed to move slowly and carefully, as rapid movements can create unacceptable turbulence in a critical area, disrupting the unidirectional air flow, and presenting a challenge beyond intended cleanroom design and control parameters.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. Personnel Training, Qualification and Monitoring A. Personnel (para 3) [VIP ID: 110590] - Move slowly and deliberately Rapid movements can create unacceptable turbulence in a critical area. Such movements disrupt the unidirectional airflow, presenting a challenge beyond intended cleanroom design and control parameters. The principle of slow, careful movement should be followed throughout the cleanroom.

10. Personnel involved in aseptic processing should be instructed that a proper aseptic manipulation should be approached from the side and not above the product in vertical unidirectional flow operations. They should also be instructed to refrain from speaking when in direct proximity to the critical area.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. Personnel Training, Qualification and Monitoring A. Personnel (para 3) [VIP ID: 110610] - Approach a necessary manipulation in a manner that does not compromise sterility of the product To maintain sterility of nearby sterile materials, a proper aseptic manipulation should be approached from the side and not above the product (in vertical unidirectional flow operations). Also, operators should refrain from speaking when in direct proximity to the critical area.

7.10 Calibration and Maintenance 1. A preventative maintenance programme should be established for a building HVAC system.
FDA Warning Letter 2002-DT-18 (January 2001) Extracted from FDA warning letter 2002-DT-18 USA 09/01/2001 [VIP ID: 42990] Failure to evaluate and establish specifications for the building HVAC system, to provide for periodic checks to assure the system provides proper air flow, humidity, and temperature, and to establish a preventative maintenance program for the HVAC system as required by 21 CFR 211.46, and 21 CFR 211.58. For examples, see 483 observations 9, 10 and 11.

2.

A comprehensive preventative maintenance programme is essential in ensuring buildings used in the manufacture of injectable drug products are maintained in a good state of repair.
Extracted from FDA Warning Letter 320-06-02 (April 2006) Extracted from FDA warning letter 320-06-02 Croatia 28-Apr-06 1 [VIP ID: 191894] Buildings used in the manufacture of injectable drug products are not always maintained in a good state of repair. 21 CFR 211.58.

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The flexible piping from the exhaust of the [redacted] was also ripped and observed to be taped in the same location from a previous tear. We are concerned that maintenance personnel did not notice the ripped exhaust when they had placed buckets in the same area. The investigator states she was informed that production would cease until cleaning was performed, samples were taken, and results were received. She later found out that production continued. Information supplied to the FDA inspection team must be reliable and you should take immediate action to prevent this from recurring. Your responses state that you have revised procedures, provided training, replaced the flexible piping, and will develop a comprehensive preventative maintenance program. Please explain what you have done to prevent the condensate from dripping through the ceiling to the production area.

3.

There should be a system for maintaining equipment used to control aseptic conditions.
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -- Buildings and Facilities Sec. 211.42 Design and construction features (c) [VIP ID: 20] Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures: (10) Aseptic processing, which includes as appropriate: (vi) A system for maintaining any equipment used to control the aseptic conditions.

4.

Equipment and fittings in Class 100,000 processing rooms should be maintained free from damage, rust and mould.
(Class 100,000)Extracted from FDA warning letter VLN# 06200780 (January 2007) Extracted from FDA warning letter VLN# 06200780 USA 05-Jan-07 3. c. [VIP ID: 194666] Failure to maintain any building used in manufacture, processing, packing, or holding of a drug product in a good state of repair. [21 CFR 211.58] For example, c. Rust-like substance was observed on the metal frame surrounding the ceiling tiles and HEPA filters in the processing room (Class 100,000). FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 3 [VIP ID: 49890] 3. Failure to avert contamination in separate or defined areas designed to prevent contamination from occurring during manufacturing and processing operations [21 CFR 211.42(c)(5)]. For example - The following is a summary list of the areas in **** rooms with rust build up: Manual Fill Station **** and recirculating air unit **** FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 5 [VIP ID: 49910] 5. Failure to have adequate systems to control contaminants in areas where air contamination occurs during production [21 CFR 211.46(c)]. For example, - There are numerous HEPA filter metal grills that have a build up of rust-like material and discoloration (e.g. Rotary **** Irrigation Filling, Part Fill Filling, and Manual Filling). Two HEPA filter grills are bent and reveal a buildup of moldlike and other unknown material and these grills are located immediately above the **** filling zone

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5.

Air handling and filtration systems should be subject to validation and planned maintenance, and their return to use should be approved.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS EQUIPMENT 36 [VIP ID: 186070] All equipment such as sterilisers, air handling and filtration systems, air vent and gas filters, water treatment, generation, storage and distribution systems should be subject to validation and planned maintenance; their return to use should be approved. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Equipment 36. [VIP ID: 1449] All equipment such as sterilisers, air handling and filtration systems, air vent and gas filters, water treatment, generation, storage and distribution systems should be subject to validation and planned maintenance; their return to use should be approved.

6.

Planned maintenance procedures for clean room air handling units should require cleaning of the units.
Selected FDA 483 Observations (November 2002) Sterile Product Manufacture [VIP ID: 47810] Planned maintenance procedures for cleanroom Air Handling Units (AHU) should require cleaning of the units.

7.

Cleaning procedures should include air conditioning grilles in solution preparation areas.
Selected FDA 483 Observations (November 2002) Sterile Product Manufacture [VIP ID: 47840] Cleaning procedures should include air conditioning grills in solution preparation areas.

8.

There should be calibration and maintenance procedures for HVAC equipment to include relative humidity and temperature sensors, and system sanitisation.
Selected FDA 483 Observations (December 1999) Product Manufacture [VIP ID: 8620] There should be calibration and maintenance procedures for HVAC equipment to include relative humidity and temperature sensors, and system sanitization.

9.

Gauges used to measure the differential pressure across clean room prefilters and HEPA filters should be subject to periodic calibration.
FDA Warning Letter [Reference Obliterated] (July 2003) Extracted from FDA warning letter UK 07/11/2002 [VIP ID: 57380] 10. Failure to establish and maintain adequate procedures to ensure that equipment is routinely calibrated, as required by 21 CFR 820.72(a). For example, the gauges used to measure the differential pressure across the cleanroom prefilter and HEPA filter are not subject to periodic calibrations. Selected FDA 483 Observations (January 2003) Sterile Product Manufacture [VIP ID: 51910] Differential pressure gauges monitoring the pressure across prefilters in Air Handling Units (AHU) supplying sterile areas should be calibrated.

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Selected FDA 483 Observations (October 2002) Sterile Product Manufacture [VIP ID: 51210] Differential pressure gauges monitoring the pressure across prefilters in Air Handling Units (AHU) supplying sterile areas should be calibrated. Selected FDA 483 Observations (March 2001) Sterile Product Manufacture [VIP ID: 26880] Magnehelic gauges used to monitor pressure differentials across pre-filters should be calibrated. Selected FDA 483 Observations (September 2000) Product Manufacture [VIP ID: 19330] There should be written procedures describing the calibration / certification methods and tolerance limits for all instruments used during production operations to include: (2) magnehelic gauges

10. Records should be maintained of the equipment used to calibrate magnehelic gauges in tablet compression suites.
Selected FDA 483 Observations (September 2002) Product Manufacture [VIP ID: 47470] Records should be maintained of the equipment used to calibrate magnehelic gauges in tablet compression suites.

11. Where instrumentation, such as magnehelic gauges and balances, are calibrated by outside contractors, a responsible individual should review the calibration data provided.
Selected FDA 483 Observations (September 2002) Product Manufacture [VIP ID: 47480] Where instrumentation such as magnehelic gauges and balances are calibrated by outside contractors a responsible individual from the firm should review the calibration data provided.

12. Laminar air flow hood prefilters, and prefilters and filters for air handling units, which supply air to classified areas, should be maintained or replaced as per SOPs.
FDA Warning Letter CBER-98-024 (August 1998) Extracted from FDA warning letter CBER-98-024 USA 14/08/1998 [VIP ID: 12170] Failure to clean, maintain, and sanitize equipment, utensils, and supplies at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength quality or purity of the drug product, to establish or maintain written procedures for cleaning and maintenance of equipment, and to maintain records [21 CFR 211.67 and 600.12], in that: a. equipment has not been maintained or replaced as per SOP entitled "---" For example: ii. the pre filters and filters for the air handling units, which supply air to the classified areas, have not been replaced every - months. iii. the laminar air flow hood pre-filters have not been replaced.

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13. Manufacturers should ensure that active air monitoring devices for assessing the microbial quality of air are calibrated.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 4. Monitoring Methods b. Active Air Monitoring [VIP ID: 111570] b. Active Air Monitoring Assessing microbial quality of air should involve the use of active devices including but not limited to impaction, centrifugal, and membrane (or gelatin) samplers. Each device has certain advantages and disadvantages, although all allow testing of the number of organisms per volume of air sampled. We recommend that such devices be used during each production shift to evaluate aseptic processing areas at carefully chosen locations. Manufacturers should be aware of a device's air monitoring capabilities, and the air sampler should be evaluated for its suitability for use in an aseptic environment based on collection efficiency, cleanability, ability to be sterilized, and disruption of unidirectional airflow. [20] Because devices vary, the user should assess the overall suitability of a monitoring device before it is placed into service. Manufacturers should ensure that such devices are calibrated and used according to appropriate procedures. [20] For example, the volume of air sampled should be sufficient to yield meaningful measurements of air quality in a given environment.

14. The movement and ingress of maintenance personnel, and the tools and materials necessary for equipment repairs/adjustments, into filling areas should be controlled and monitored to prevent contamination from occurring during manufacturing and processing operations.
FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 3 [VIP ID: 49890] 3. Failure to avert contamination in separate or defined areas designed to prevent contamination from occurring during manufacturing and processing operations [21 CFR 211.42(c)(5)]. For example The controlling and monitoring of the movement and ingress of personnel, including maintenance personnel, components, and ancillary materials, such as tools necessary for equipment repairs / adjustments into the **** filling areas is not being performed.

15. Where HVAC system preventive maintenance is not performed, due to the lack of personnel available or production taking place, reference should be made in the documents to any actions taken in response to the skipped work.
Selected FDA 483 Observations (August 2007) Sterile Product Manufacture [VIP ID: 193770] Where Heating, Ventilation, Air Conditioning (HVAC) System preventive maintenance is not performed due to the lack of personnel available or production taking place, reference should be made in the documents to any actions taken in response to the skipped work.

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7.11 Change Control 1. The definition of what constitutes a change to a process environment needs to be agreed.
PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 6. NON-STERILE PROCESS VALIDATION 6.6 Re-validation 6.6.4 [VIP ID: 188616] The definition of what constitutes a change to a process or process environment needs to be agreed. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN, DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 3. NON-STERILE PROCESS VALIDATION 3.6. Re-validation 3.6.4. [VIP ID: 68800] The definition of what constitutes a change to a process or process environment needs to be agreed. ...

2.

Written procedures should be in place to describe the actions to be taken if a change is proposed to the process environment.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION CHANGE CONTROL 43 [VIP ID: 187116] Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 6. NON-STERILE PROCESS VALIDATION 6.7 Change Control 6.7.1 [VIP ID: 188620] Change control is an important element in any Quality Assurance system. Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or support system operation. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) CHANGE CONTROL 43. [VIP ID: 21430] Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications.

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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN, DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 3. NON-STERILE PROCESS VALIDATION 3.7. Change Control 3.7.1. [VIP ID: 68820] Change control is an important element in any Quality Assurance system. Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or support system operation.

3.

Media fills should be performed after any significant modification to the HVAC system.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS SANITATION 42 [VIP ID: 186082] Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill). Selection of the nutrient medium should be made based on dosage form of the product and selectivity, clarity, concentration and suitability for sterilisation of the nutrient medium. The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. It should also take into account various interventions known to occur during normal production as well as worst case situations. Process simulation tests should be performed as initial validation with three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modification to the HVAC-system, equipment, process and number of shifts. Normally process simulation tests should be repeated twice a year per shift and process. The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth but a contamination rate of less than 0.1% with 95% confidence limit is acceptable. The manufacturer should establish alert and action limits. Any contamination should be investigated.[2] [2] For further details on the validation of aseptic processing, please refer to the PIC/S Recommendation on the Validation of Aseptic Processing (PI 007) PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 5. PROCESS SIMULATION TEST CONDITIONS 5.5 Test Frequency 5.5.4 [VIP ID: 188932] Start-up" simulation tests are performed for example for new processes, new equipment or after critical changes of processes, equipment or environment as for example significant personnel changes (a new shift), modifications in equipment directly in contact with the product or modifications in the HVAC system. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 5. PROCESS SIMULATION TEST CONDITIONS 5.5 Test Frequency 5.5.5 [VIP ID: 188934] An "on-going" simulation test consists of one satisfactory simulation test per shift and is mainly performed for the periodic monitoring of aseptic conditions during routine manufacturing but also for example after less critical changes of processes, equipment or environment or if processing lines stand idle for more than 6 months.

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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Processing 42 (para 1) [VIP ID: 63350] Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill). Selection of the nutrient medium should be made based on dosage form of the product and selectivity, clarity, concentration and suitability for sterilisation of the nutrient medium. The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. It should also take into account various interventions known to occur during normal production as well as worst case situations. Process simulation tests should be performed as initial validation with three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modification to the HVAC-system, equipment, process and number of shifts.

4.

Change control should be carefully reviewed as it is often involved in loss of control of bioburden.
PI 005-2 RECOMMENDATION ON GUIDANCE ON PARAMETRIC RELEASE (July 2004) APPENDIX I RECOMMENDATIONS FOR A GENERAL STERILITY ASSURANCE SYSTEM FOR TERMINALLY STERILISED PRODUCTS AND PROVISIONS FOR PARAMETRIC RELEASE 5. CONTROL OF PRESTERILIZATION BIOBURDEN 5.9 [VIP ID: 188288] The following elements should be carefully reviewed as they are often involved in loss of control of bioburden: (g) Change control and validation. ...

5.

Deviation or change control systems should address atypical conditions posed by shutdown of air handling systems.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities E. Design (para 12) [VIP ID: 110540] Deviation or change control systems should address atypical conditions posed by shutdown of air handling systems or other utilities, and the impact of construction activities on facility control. Written procedures should address returning a facility to operating conditions following a shutdown.

8.

ENVIRONMENT MONITORING REGULATORY GUIDANCE 8.1 General 1. A clean area environmental monitoring programme should include personnel monitoring and regular sampling and testing of the manufacturing environment, including air, floors, walls, and equipment surfaces, using validated test methods. It should address issues such as sample location, appropriate sampling frequency, timing of sample collection, duration of sampling, size of sample, specific sampling equipment and techniques, limits, identification of microorganisms, trending systems, and procedures to promptly address out of limit results or adverse trends.
Selected FDA 483 Observations (January 2007) Sterile Product Manufacture [VIP ID: 194246] The airborne particulate monitoring program should adequately monitor locations in the aseptic processing zone that pose a contamination risk to the product, e.g. stopper hopper, filling heads and accumulating table (empty vials). Extracted from FDA Warning Letter 2006-NOL-04 (February 2006)

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Extracted from FDA warning letter 2006-NOL-04 USA 15/02/2006 [VIP ID: 176710] 2. You do not have control systems to prevent contamination, as required under 21 CFR 211.42(c)(10)(i). For example, you do not perform environmental monitoring for viable and non viable organisms in your aseptic areas. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 1. General Written Program (para 1) [VIP ID: 111440] In aseptic processing, one of the most important laboratory controls is the environmental monitoring program. This program provides meaningful information on the quality of the aseptic processing environment (e.g., when a given batch is being manufactured) as well as environmental trends of ancillary clean areas. Environmental monitoring should promptly identify potential routes of contamination, allowing for implementation of corrections before product contamination occurs (211.42 and 211.113). GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 1. General Written Program (para 2) [VIP ID: 111450] Evaluating the quality of air and surfaces in the cleanroom environment should start with a well-defined written program and scientifically sound methods. The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces that come in contact with the product, container, and closures. Written procedures should include a list of locations to be sampled. Sample timing, frequency, and location should be carefully selected based upon their relationship to the operation performed. Samples should be taken throughout the classified areas of the aseptic processing facility (e.g., aseptic corridors, gowning rooms) using scientifically sound sampling procedures. Sample sizes should be sufficient to optimize detection of environmental contaminants at levels that might be expected in a given clean area. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) XII. Batch Record Review: Process Control Documentation (para 1) [VIP ID: 111860] Manufacturers should build process and environmental control activities into their aseptic processing operation. It is critical that these activities be maintained and strictly implemented on a daily basis. The requirement for review of all batch records and data for conformance with written procedures, operating parameters, and product specifications prior to arriving at the final release decision for an aseptically processed product calls for an overall review of process and system performance for that given cycle of manufacture. All in-process and laboratory control results must be included with the batch record documentation in accordance with section 211.188. Review of environmental and personnel monitoring data, as well as other data relating to acceptability of output from support systems (e.g., HEPA/HVAC, WFI, steam generator) and proper functioning of equipment (e.g., batch alarms report; integrity of various filters) are considered essential elements of the batch release decision. FDA Warning Letter 2004-NOL-36 (September 2004) Extracted from FDA warning letter 2004-NOL-36 USA 17/09/2004 [VIP ID: 130040] 2. Your firm failed to establish a system for monitoring environmental conditions in the aseptic, processing area as required by 21 CFR 211.42(c)(10)(iv). Specifically, routine environmental monitoring of the aseptic filling area for viable and non-viable particulates is not done. Routine microbiological monitoring of the gowns and gloves of the employees working in the class 100 area is not done. [Reference: Form FDA 483, Observation 4]

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PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 2. INTRODUCTION 2.3 General information 2.3.1 [VIP ID: 188786] ... Annex 1 to the EU/PIC/S Guide to GMP provides the basic requirements for the manufacture of sterile products including those aseptically processed. The Annex includes requirements, standards and recommendations, for example, for monitoring of the environment and of personnel. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING [VIP ID: 188970] - Annex 1 of the EU/PIC/S Guide to GMP provides the basis for environmental and personnel monitoring requirements and recommendations. - Some specific additional guidance is given below on air borne microbial and non-viable particle monitoring, intervention monitoring and staff training. FDA Warning Letter RAN 2004-06 (March 2004) Extracted from FDA warning letter RAN 2004-06 USA 31/03/2004 [VIP ID: 126720] 3. The environmental monitoring systems in the small volume parenteral manufacturing and filling areas are deficient in that your firm has not performed a scientific assessment to identify appropriate environmental monitoring sampling sites during the actual manufacturing and sterile filling operations that could pose the most microbiological risk to the products manufactured. Inspectional observations include failure to perform air sampling in the area near the vial turntable to assess the condition of the air during manual loading of vials. Environmental monitoring of personnel was not performed immediately after a significant intervention into the Class [redacted] area. Equipment such as forceps, carts, and tools used during the filling operation are not routinely monitored. Ispropyl alcohol was observed being sprayed directly over the [redacted] air samplers located in the Class [redacted] area during the media fill. This occurred after intervention through the plastic curtains that surround the Class [redacted] area and after Rodac sampling of the plastic curtains was performed. Environmental monitoring for viable organisms in the manufacturing area is done in the center of the room at times when there is no activity in the room. [21 CFR 211.113(b)] Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 72670] There should be a documented rationale and data to support the statistical validity of sampling frequencies for non-viable and viable particulates in critical filling zones. FDA Warning Letter WL 09-04 (November 2003) Extracted from FDA warning letter WL 09-04 USA 24/11/2003 [VIP ID: 125200] 4. Environmental control systems have not been inspected periodically to verify that the system including necessary equipment is adequate and functioning properly [21 CFR 820.70(c)]. Specifically, the Class 100,000 cleanroom was not recertified between 3/97 to 9/2003 and no documented evidence that demonstrates that any environmental monitoring is conducted by the firm. Selected FDA 483 Observations (November 2003) Sterile Product Manufacture [VIP ID: 70260] The environmental monitoring program should insure that batch related environmental data is generated for each aseptic stopper bagging and sealing activity.

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CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III - Inspectional B. Inspection 5. Environmental controls/monitoring (para 1) [VIP ID: 77130] There should be a comprehensive environmental monitoring program, which includes monitoring for non-viable and viable air particulates, surface viables and, in the aseptic filling areas, personnel. Procedures should address frequencies and locations for monitoring, alert, and action limits for each area, and corrective actions to be taken when limits are exceeded. Actions taken when limits are exceeded should include adequate investigation into the source of the problem, potential impact on the product, and measures taken to prevent recurrence. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III - Inspectional B. Inspection 5. Environmental controls/monitoring (para 2) [VIP ID: 77140] Generally, less frequent monitoring is acceptable in areas in which upstream steps are performed. There, steps may be performed in unclassified, but "controlled" environments (ones with some level of particulate controls). As the process moves further downstream, more frequent monitoring is expected. Monitoring should be performed during production. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART V - REGULATORY/ADMINISTRATIVE STRATEGY Regulatory/Administrative Follow-Up Significant Deviations 2. Buildings and Facilities [VIP ID: 78050] [211.42 - 211.58 and 600.11] Non-viable particulate monitoring is not performed in critical or controlled production areas. Surface monitoring for microbial in critical areas is not performed. Microbial and particulate counts are not performed during periods of activity.

EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Principle Note: [VIP ID: 62310] This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Reference should be made to other documents such as the EN/ISO Standards. Selected FDA 483 Observations (October 2002) Sterile Product Manufacture [VIP ID: 47560] Airborne particulate monitoring programs should adequately monitor all locations in the aseptic processing zone which pose a contamination risk to the product. (For example, for a fill room this may include the stopper hopper, filling heads and the accumulating table.) FDA Warning Letter 2001-DAL-WL-35 (September 2001) Extracted from FDA warning letter 2001-DAL-WL-35 USA 07/09/2001 [VIP ID: 42520] Failure to establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications [21 CFR 820.70]. For example, your firm: b. has not performed routine monitoring of the environmental controlled room for product bioburden, room temperature, and room humidity [FDA-483 Item 1].

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FDA Warning Letter 01-NWJ-26 (June 2001) Extracted from FDA warning letter 01-NWJ-26 USA 08/06/2001 [VIP ID: 42000] Failure to establish and monitor environmental conditions. For example, the inspection revealed that your employees used the manufacturing area as a lunchroom. In addition, you have not established or monitored product bioburden levels. HUMAN DRUG CGMP NOTES, VOLUME 07, NUMBER 01 (March 1999) Motise's Notebook Policy Questions On: Question 7 [VIP ID: 6009] What is the purpose of an environmental monitoring program in aseptic processing? What are some major factors that ensure the environment does not contaminate product throughout a batch's manufacture? Reference: 21 CFR 211.42, Design and construction features [Subpart C-Buildings and Facilities]; 211.113, Control of microbiological contamination; 211.22, Responsibilities of quality control unit; 211.46, Ventilation, air filtration, air heating and cooling; 1987 Guideline on Sterile Drug Products Produced by Aseptic Processing; July 1994 Guide to Inspections of Sterile Drug Substance Manufacturers The environmental monitoring program is a vital part of a quality control unit's CGMP responsibility to monitor and ensure ongoing control of an aseptic process. The CGMP regulations, at section 211.113 require firms to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. This section is particularly applicable to sterile drug products made by aseptic processing, and the aseptic guideline addressed at length various aspects of environmental monitoring. An environmental monitoring program is vital for aseptic processing operations because it: 1) provides crucial information on the quality of the aseptic processing environment during manufacturing; 2) prevents release of a potentially contaminated batch if appropriate quality standards (defined by a firm's written procedures) are not fulfilled; and, 3) prevents future contamination by detecting adverse trends. In addressing the environmental monitoring program, the aseptic guideline discussed regular sampling and testing of the manufacturing environment, including air, floors, walls, and equipment surfaces. Evaluating the quality of air and surfaces in cleanrooms should start with a well-defined and specific written program, including validated test methods. As explained in the guideline, among issues normally addressed by an environmental monitoring program are: sample location, appropriate sampling frequency, timing of sample collection, duration of sampling, size of sample, specific sampling equipment and techniques, limits, identification of microorganisms, trending systems, and procedures to promptly address out of limit results or adverse trends. A number of major variables influence environmental control, all of which need to be addressed by appropriate written SOPs, in accordance with section 211.113. It is important that a personnel qualification and monitoring program address operator practices, critical in maintaining environmental control of the aseptic processing area. In addition, the CGMPs at section 211.46 require equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product. In this context, the Heating, Ventilation, and Air Conditioning (HVAC) system design and controls play a key role in providing an adequate environment (e.g., particulate cleanliness, air pressure, and airflow) for aseptic processing. Adequate cleaning and sanitizing procedures, facility design, equipment design, personnel flow, and material flow are among other key variables which significantly impact on the suitability of the environment in which aseptic processing operations are conducted. Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 35. [VIP ID: 2187] Does the firm have a written monitoring program for classified areas that includes a scientifically sound sampling schedule that describes sampling locations, their relation to the working level, and frequency? Describe the basis for the sampling program. (21 CFR, 211.160)

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CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 41. [VIP ID: 2193] Report the actual volume of air sampled per location. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 49. [VIP ID: 2201] What sampling device is used? What volume of air is sampled? CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 50. [VIP ID: 2202] How many samples are collected per location? Are results averaged? CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 51. [VIP ID: 2203] When was sampling equipment last calibrated? CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 52. [VIP ID: 2204] Were environmental sampling results within specifications during the manufacture of the batches of the selected drug product? (Describe any deviations and firm's response.) CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 55. [VIP ID: 2207] What type of monitoring is done? CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) STERILIZATION SYSTEMS Filtration Sterilization II. Aseptic Filling 245. [VIP ID: 2397]

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Briefly describe the aseptic filling processes from preparation of bulk liquid product to filling and sealing of final dosage form, including the environmental monitoring performed in critical areas during actual production (e.g., how are Class 100 conditions maintained; where are the sampling sites; is bioburden testing performed on the bulk product?) CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) LABORATORY Environment 286. [VIP ID: 2438] What type of environmental monitoring is performed in the laboratory (e.g., type and location of sampling; sampling equipment; frequency)? BIOTECHNOLOGY INSPECTION GUIDE (November 1991) PROCESSING AND FILLING C. Filling (para 3) [VIP ID: 1098] Problems that have been identified during filling include inadequate attire; deficient environmental monitoring programs; hand-stoppering of vials, particularly those that are to be lyophilized; and failure to validate some of the basic sterilization processes. Because of the active involvement of people in filling and aseptic manipulations, the number of persons involved in these operations should be minimized, and an environmental program should include an evaluation of microbiological samples taken from people working in aseptic processing areas. This program along with data should be reviewed during the inspection.

2.

Environmental monitoring personnel need a thorough understanding of the sources of contamination risks (e.g. inadequately disinfected/sterilised sampling equipment) that are involved with the sampling methods.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 8. STAFF TRAINING 8.5 [VIP ID: 188998] Environmental monitoring personnel need a thorough understanding of the sources of contamination risks (e.g. inadequately disinfected/sterilised sampling equipment) that are involved with the sampling methods.

3.

Environmental monitoring should be performed under operational (dynamic) conditions.


PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. ENVIRONMENTAL MONITORING 10.2 [VIP ID: 190296] Environmental monitoring should be performed under operational (dynamic) conditions either within the isolator or in the laminar airflow and associated background areas. Selected FDA 483 Observations (July 2004) Sterile Product Manufacture [VIP ID: 122400] Viable and non-viable particulate monitoring should be performed during operations for all processing areas. HUMAN DRUG CGMP NOTES, VOLUME 05, NUMBER 02 (June 1997) Motise's Notebook Active Pharmaceutical Ingredients (APIs) 3) [VIP ID: 3505] Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routine monitoring of aseptic processing areas?

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References: 21 CFR 211.160(b), General requirements (Subpart I Laboratory Controls); 211.113, Control of microbiological contamination; 1987 Guideline on Sterile Drug Products Produced by Aseptic Processing. No. Sampling an environment for particulates during static (at rest) times is of minimal utility in assessing actual processing conditions. On the other hand, operational (dynamic) monitoring performed throughout aseptic processing is needed. Here's why. Aseptic processing operations are designed to exclude living microorganisms, end toxins, and particulates from the finished product. It is generally accepted that monitoring of particulate concentration in classified (environmentally controlled) areas during operations serves as a direct indicator of changes in local air quality while indirectly indicating the increased potential for the introduction of microorganisms to the monitored area. Occasional static monitoring during periods of no operation to ensure particulate levels remain well below an area's classification level would be useful as a facility maintenance parameter. However, firms should obtain data from dynamic monitoring (during operations) as a routine batch control. Firms should monitor frequently throughout manufacturing, and in proximity to the work surfaces and exposed product or container/closures. For example, in class 100 areas, samples should be taken about one foot away from the work surface. Many firms now have the capability to monitor nonviables continuously; however, failure to monitor continuously is not objectionable. High levels of particulates generally represent a departure from processing norms, indicating, for example, unusual personnel activity which challenges the intended cleanroom design parameters. It is therefore important that the Quality Control unit investigate such "particulate excursions." Finally, when qualifying a cleanroom, firms conduct studies to establish the room's air classification. Although the classification studies include assessment of particulate levels under static conditions, the final classification should be derived from data generated while equipment is in place and operations are ongoing. Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 36. [VIP ID: 2188] Are both viable and non-viable particulate samplings performed in all classified areas during production? CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 38. [VIP ID: 2190] Report the limits used, length of sampling period, and if sampling is done during production or at rest. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) FREEZE-DRYING (LYOPHILIZATION) Lyophilization Validation 80. [VIP ID: 2232] Is environmental monitoring performed during loading of the lyophilizer both during production as well as during validation? CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) FREEZE-DRYING (LYOPHILIZATION) Lyophilization Validation 82. [VIP ID: 2234] Is environmental monitoring performed during unloading of the chamber during production as well as during validation?

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CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) STERILIZATION SYSTEMS Aseptic Sterilization Systems Dry Powder Filling 217. [VIP ID: 2369] Briefly describe the environmental monitoring performed by the firm in critical areas during actual production. (e.g., how are Class 100 conditions maintained? Where are the sampling sites? Is non-viable particulate monitoring performed?)

4.

Because some cleanroom operators may be shedders or practice poor aseptic technique, it is important to monitor and qualify cleanroom operations on each production shift.
HUMAN DRUG CGMP NOTES, VOLUME 06, NUMBER 03 (September 1998) Motise's Notebook POLICY QUESTIONS: Question 1 [VIP ID: 5959] How would the CGMPs address the problem of cleanroom operators who are shedders or practice poor aseptic technique? References: See 21 CFR 211.42(c)(10), Design and construction features; 211.25, Personnel qualifications; 211.28, Personnel responsibilities; 211.113 Control of microbiological contamination; Guideline on Sterile Drug Products Produced by Aseptic Processing, June 1987 Cleanrooms are defined by their low levels of both viable and nonviable particulates and these levels need to be monitored and kept under control. Humans are a chief source of particulate contamination in the cleanroom, although these contaminants may originate from a number of other sources. Note that because some people are found to be shedders, not everyone will be suitable for cleanroom duty. Ultimately, it is such differences among cleanroom personnel which underscore the need to monitor and qualify cleanroom operations on each production shift. Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov

5.

Active and excipient raw materials used in the manufacture of parenteral drugs should be sampled in a suitable, environmentally monitored area.
Selected FDA 483 Observations (February 1999) Sterile Product Manufacture [VIP ID: 7074] Active and excipient raw materials used in the manufacture of parenteral drugs should be sampled in a suitable, environmentally monitored area.

6.

Environmental monitoring should be performed in areas where parenteral grade APIs are milled, blended, isolated, dried and/or packed.
Selected FDA 483 Observations (November 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 19770] Environmental monitoring should be performed in milling, blending and drying areas where APIs intended for parenteral use are exposed. Selected FDA 483 Observations (March 1999) Active Pharmaceutical Ingredient Manufacture [VIP ID: 7087] Environmental monitoring should be performed in areas where parenteral grade APIs are isolated, dried and packed. Selected FDA 483 Observations (May 1999) Active Pharmaceutical Ingredient Manufacture [VIP ID: 7154] Environmental monitoring should be performed in areas where parenteral grade APIs are isolated, dried or packed.

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7.

HVAC systems that could impact on product quality should be qualified and appropriately monitored, and action should be taken when limits are exceeded.
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 4. BUILDINGS AND FACILITIES 4.2 Utilities 4.20 [VIP ID: 24539] All utilities that could impact on product quality (e.g. steam, gases, compressed air, and heating, ventilation and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. Drawings for these utility systems should be available. ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. BUILDINGS AND FACILITIES 4.2 Utilities 4.20 [VIP ID: 153710] All utilities that could impact on product quality (e.g. steam, gases, compressed air, and heating, ventilation and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. Drawings for these utility systems should be available.

8.

The heads of Production and Quality Control may be jointly responsible for the monitoring and control of the manufacturing environment.
EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 2 - PERSONNEL Key Personnel 2.7. [VIP ID: 333] The heads of Production and Quality Control generally have some shared, or jointly exercised, responsibilities relating to quality. These may include, subject to any national regulations: - the monitoring and control of the manufacturing environment;

9.

Routine environmental monitoring of filling areas should be performed by individuals from QC, not by filling room operators.
Selected FDA 483 Observations (March 2000) Sterile Product Manufacture [VIP ID: 14560] Routine environmental monitoring of filling areas should be performed by individuals from QC, not by filling room operators.

10. QA should review environmental monitoring data for excursions occurring during lot production to determine the potential impact on product quality.
Selected FDA 483 Observations (November 2003) Sterile Product Manufacture [VIP ID: 70300] QA should review environmental monitoring data for excursions occurring during lot production to determine the potential impact on product quality.

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11. Monitoring of the environment assumes particular importance, in cases where it is necessary to take the decision to release or reject a batch or a product before all tests are completed.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 3 - MANUFACTURE OF RADIOPHARMACEUTICALS PRODUCTION 7 [VIP ID: 186292] Process validation, in-process controls and monitoring of process parameters and environment assume particular importance in cases where it is necessary to take the decision to release or reject a batch or a product before all tests are completed. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 03 - MANUFACTURE OF RADIOPHARMACEUTICALS (January 1993) Production 7. [VIP ID: 1565] Process validation, in-process controls and monitoring of process parameters and environment assume particular importance in cases where it is necessary to take the decision to release or reject a batch or a product before all tests are completed.

12. Written procedures should be established and followed for the routine environmental monitoring of surfaces, personnel and airborne particulates, and following HVAC system failures, defining the specifications, test methods, equipment to be used and records to be maintained.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 1 QUALITY MANAGEMENT QUALITY CONTROL 1.4 [VIP ID: 185508] Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organisation, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. The basic requirements of Quality Control are that: i. adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 4 DOCUMENTATION GENERAL 4.1 [VIP ID: 185644] Procedures give directions for performing certain operations e.g. cleaning, clothing, environmental control, sampling, testing, equipment operations. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 4 DOCUMENTATION DOCUMENTS REQUIRED PROCEDURES AND RECORDS (Other) 4.26 [VIP ID: 185694] There should be written procedures and the associated records of actions taken or conclusions reached, where appropriate, for: - environmental monitoring;

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PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 5 PRODUCTION PROCESSING OPERATIONS - INTERMEDIATE AND BULK PRODUCTS 5.38 [VIP ID: 185778] Any necessary in-process controls and environmental controls should be carried out and recorded. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 6 QUALITY CONTROL DOCUMENTATION 6.7 [VIP ID: 185848] Laboratory documentation should follow the principles given in Chapter 4. An important part of this documentation deals with Quality Control and the following details should be readily available to the Quality Control Department: - data from environmental monitoring, where required; ... 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -- Buildings and Facilities Sec. 211.42 Design and construction features (c) [VIP ID: 20] Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures: (10) Aseptic processing, which includes as appropriate: (iv) A system for monitoring environmental conditions; Extracted from FDA Warning Letter WL: 320-06-01 (February 2006) Extracted from FDA warning letter WL: 320-06-01 India 21-Feb-06 2 [VIP ID: 191620] Control records do not include complete and accurate information relating to the production and control of each batch. 21 CFR 211.188 A. The [redacted] preparation record did not include documentation to confirm the addition of [redacted] to the [redacted] used for environmental monitoring. (Observation #4 on the FDA-483) Your response states that the SOP for "Storage, preparation and sterilization of the [redacted] has been revised. Although the revision of the SOP addresses this problem going forward, revision response does not explain how your firm knows whether [redacted] was added to the [redacted] prior to the revision. The lack of documentation supporting the addition of [redacted] during the environmental monitoring calls into question whether or not this addition did indeed occur, especially since other additions to the [redacted] were documented. Documentation reviewed during this inspection as well as the last inspection showed extremely low counts on your environmental monitoring. Without the [redacted] addition to the [redacted] the [redacted] nature of the drug may not have been inhibited. Please demonstrate that the environmental monitoring of your [redacted] products is representative and accurate, and includes accurate documentation for these products prior to shipment. Extracted from FDA Warning Letter WL: 320-06-01 (February 2006) Extracted from FDA warning letter WL: 320-06-01 India 21-Feb-06 1 [VIP ID: 191622] Written production and process control procedures were not always followed and documented at the time of performance. 21 CFR 211.100 (b) B. The locations of [redacted] used for environmental monitoring during the execution of Protocol [redacted] were not documented until eight months after the execution of the record. (Observation #3 on the FDA-483)

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Your response states that a drawing of the locations of the [redacted] during the [redacted] effectiveness study was prepared for the investigator; however, this drawing was prepared from memory. The observation is citing failure to define or document the location of the [redacted] prior to or during the study. Your response also did not address the issue of preparing and approving validation protocols which lacked this important information. Relying on the recollection of an employee eight months after the protocol was executed is not good practice. Further, no preventative actions were submitted for future protocols and studies. FDA Warning Letter [NO REFERENCE] (September 2005) FDA Warning Letter [NO REFERENCE] USA 30/09/2005 [VIP ID: 173180] 9. Failure to establish and maintain procedures to adequately control environmental conditions that could adversely effect product quality, as required by 21 CFR 820.70(c). For example: a. Filling room operators have exposed facial skin surfaces. b. Product contact surfaces are only sanitized, not sterilized. c. Sterile forceps used to manipulate sterile container components were placed on exposed surge tank surface when not in use. d. Smoke studies were performed only under static conditions. e. Differential pressure between filling room and adjacent controlled environment is only monitored once daily. f. No documented action was taken when out of specification pressure differentials occurred. g. Surface monitoring procedures fail to provide quantitative assessment of the Class 100 and controlled environment surfaces. h. Action levels for the RCS air sampling and the purified water bioburden allow for multiple days of air sampling or multiple unlimited bioburden counts before corrective action is taken. i. There are no established personnel environmental monitoring specifications or limits for filling room operators. j. Four out of five Alert/Action Level Notifications issued from January 31, 2001, until the present were identified as alert notifications, although the results indicate all five met the criteria for action level notifications. Extracted from FDA Warning Letter 2005-DAL-WL-21 (August 2005) Extracted from FDA warning letter 2005-DAL-WL-21 USA 03/08/2005 [VIP ID: 170400] 1. Failure of the management with executive responsibility to ensure that an adequate and effective quality system has been fully implemented and maintained at all levels of the organization, as required by 21 CFR 820.20 [FDA-483 Items 1 through 37]. For example, your firm's corporate management and local management failed to (a) conduct management reviews at defined intervals; (b) follow procedures for conducting quality audits; and (c) establish and maintain procedures for complaint handling, design controls, corrective and preventive actions, validating manufacturing processes, acceptance activities, environmental monitoring, purchasing controls, and document controls. Extracted from FDA Warning Letter 2005-DAL-WL-22 (August 2005) Extracted from FDA warning letter 2005-DAL-WL-22 USA 04/08/2005 [VIP ID: 170680] 9. Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70(c) [FDA-483 Item 26]. For example: a) Procedures outlining environmental monitoring of the clean room where the Heparin concentrate solutions were diluted and filled and Sodium Chloride solutions are filled into syringes have not been established. b) Your firm has not monitored the temperature, humidity, and pressure of the clean room, and has not conducted routine bioburden testing to monitor and identify viable and non-viable particulates in the clean room. Extracted from FDA Warning Letter 05-ATL-21 (August 2005) Extracted from FDA warning letter 05-ATL-21 USA 11/08/2005 [VIP ID: 171010] 2. Your firm failed to establish and maintain procedures to adequately control environmental conditions which could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(c) [FDA 483, Item 4]. You have failed to establish formal parameters for temperature, humidity, and pressure. A review of Filling Room temperature records revealed several instances where the temperature range limits (on the form) were exceeded.

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FDA Warning Letter SEA 05-16 (March 2005) Extracted from FDA warning letter SEA 05-16 USA 17/03/2005 [VIP ID: 135310] 3. Failure to have control systems for your firm's operations necessary to prevent contamination of drug product during aseptic processing [21 CFR 211.42(c)(10)]." . "Furthermore, our investigators noted that you do not perform environmental monitoring of your manufacturing area. You have also not established any written procedures for environmental monitoring that specifically address issues such as sample location, sample frequency, sampling technique, sample size, analytical techniques, interpretation of results, acceptance criteria, and corrective actions in the event of failures. FDA Warning Letter 2005-DAL-WL-13 (February 2005) Extracted from FDA warning letter 2005-DAL-WL-13 USA 10/02/2005 [VIP ID: 134660] 8. Failure to establish and maintain procedures to adequately control environmental conditions to prevent their adverse effects on product quality, as required by 21 CFR.820.70(c) and to prevent contamination of equipment, or product as required by 21 CFR 820.70(e) [FDA-483, item 7]. For example; your firm failed to conduct environmental testing on a [redacted] schedule as required by your firm's environmental testing procedures. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 1. General Written Program (para 5) [VIP ID: 111480] All environmental monitoring locations should be described in SOPs with sufficient detail to allow for reproducible sampling of a given location surveyed. Written SOPs should also address elements such as (1) frequency of sampling, (2) when the samples are taken (i.e., during or at the conclusion of operations), (3) duration of sampling, (4) sample size (e.g., surface area, air volume), (5) specific sampling equipment and techniques, (6) alert and action levels, and (7) appropriate response to deviations from alert or action levels. PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 7. PREMISES Environmental Control 7.12 [VIP ID: 185052] Access to temperature and pressure controlled areas should be restricted and controlled. Environmental monitoring should be performed to demonstrate that the appropriate classification is consistently achieved. Records of the monitoring should be maintained. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III - Inspectional B. Inspection 5. Environmental controls/monitoring (para 3) [VIP ID: 77150] Determine whether the firm has procedures in place for adequate environmental monitoring and if the procedures are followed and if the procedures describe what to do with any affected product. Determine. what steps the firm takes if action or alert limits are exceeded and review any investigations performed. If the limits were exceeded during any production runs, determine the disposition of the product.

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FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42760] With regard to the air filtration system, your firm was cited for not providing HEPA-filtered air into the **** clean rooms as required by 21 CFR 211.46(c) Ventilation, Air Filtration, Air Heating and Cooling [FDA-483 Item 3]. You disagreed with the investigators observation in that HEPA-filtered air is not necessary for each of the **** clean rooms (Class **** because the aseptic processing is being performed under the biological hoods that are equipped with HEPA filters. Your justification is not adequate because you have not provided supporting documentation of (1) air cleanliness qualification data; (2) data from a routine environmental monitoring program; (3) the specific ratings of each of the successive filters found in the HVAC system that serve the Class **** clean room; and (4) diagrams/charts of the HVAC system. FDA Warning Letter CBER-01-023 (July 2001) Extracted from FDA warning letter CBER-01-023 USA 24/07/2001 [VIP ID: 43310] Failure to maintain and/or follow written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to posses and to assure that such procedures, including any changes, are drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by quality control [21 CFR 211.100]. For example: d. The SOP entitled Environmental Monitoring Sampling/Handling/Reporting, was not followed in that monthly excursion status reports have not been generated since April 4, 2000. In addition, no other procedures for tracking excursions have been implemented. FDA Warning Letter 2001-DT-07 (January 2001) Extracted from FDA warning letter 2001-DT-07 USA 16/01/2001 [VIP ID: 28420] 3. 211.160 Laboratory Controls-General Requirements. Your firm failed to have in place written procedures for many of the operations performed by your laboratory, that were drafted by an appropriate organizational unit and reviewed and approved by a quality control unit. These procedures should include scientifically sound specifications and test procedures. Some examples from the FDA483 are: d. Item 7. There are no written procedures in place for, nor is there any testing performed, for environmental monitoring for airborne contaminants or surfaces of laboratory equipment and benches. 211.160(b)(1) [FDA Investigators: Renee L. Rice and Miah I. Schneider] Selected FDA 483 Observations (February 2000) Sterile Product Manufacture [VIP ID: 136790] Records documenting air sampling during media fills should include the individual times at which the samples are taken. Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 7305] There should be SOPs for environmental monitoring in manufacturing and product filling areas. Selected FDA 483 Observations (February 1999) Sterile Product Manufacture [VIP ID: 7130] HVAC failure during filling emergency procedures should include: 1) clearing filling lines of all product and open container closure systems 2) additional environmental testing after air flow is restored and prior to resuming operations (surface, personnel, non-viable and viable particulate)

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Selected FDA 483 Observations (December 1998) Sterile Product Manufacture [VIP ID: 6842] Complaint investigations should include: 3) investigations into environmental records and other manufacturing records Extracted from FDA Warning Letter CBER-99-005 (November 1998) Extracted from FDA warning letter CBER-99-005 Ireland 23/11/1998 [VIP ID: 158920] 3. Failure to establish and/or follow adequate written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess and to assure that such procedures, including any changes, are reviewed and approved by the appropriate organizational units and reviewed and approved by quality control [21 CFR 211.100] in that: b. Written procedures which describe steps to be taken when personnel exceed the action limits for environmental monitoring are not always followed. For example, there was no evidence of retraining of aseptic operators in seven out of eight excursions occurring between August 1997 and June 1998. EU GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 1 - QUALITY MANAGEMENT Quality Control 1.4 [VIP ID: 297] Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organisation, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. The basic requirements of Quality Control are that: i. adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 4 - DOCUMENTATION General 4.1. [VIP ID: 406] Procedures give directions for performing certain operations eg cleaning, clothing, environmental control, sampling, testing, equipment operation. EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 4 - DOCUMENTATION Documents required - Procedures and records (Other) 4.26. [VIP ID: 497] There should be written procedures and the associated records of actions taken or conclusions reached, where appropriate, for: - environmental monitoring; EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 - PRODUCTION Processing operations: intermediate and bulk products 5.38. [VIP ID: 560] Any necessary in-process controls and environmental controls should be carried out and recorded.

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EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 6 - QUALITY CONTROL Documentation 6.7. [VIP ID: 601] Laboratory documentation should follow the principles given in Chapter 4. An important part of this documentation deals with Quality Control and the following details should be readily available to the Quality Control Department: - data from environmental monitoring, where required; GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) I. INTRODUCTION (para 2) [VIP ID: 2012] As with other inspections, any rejected batches, along with the various reasons for rejection, should be identified early in the inspection to provide direction for the investigator. For example, lists of batches rejected and/or retested over a period of time should be obtained from the manufacturer to provide direction for coverage to be given to specific processes or systems. Because some of the actual sterile bulk operations may not be seen, and because of the complexity of the process, it is particularly important to review reports and summaries, such as validation studies, reject lists, Environmental Monitoring Summary Reports, QA Investigation Logs, etc. These systems and others are discussed in the Basic Inspection Guide. This is particularly important for the foreign sterile bulk drug substance manufacturer where time is limited. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) III. FACILITY (para 2) [VIP ID: 2018] Unnecessary equipment and/or equipment that cannot be adequately sanitized, such as wooden skids and forklift trucks, should be identified. Inquire about the movement of large quantities of sterile drug substance and the location of pass-through areas between the sterile core and non-sterile areas. Observe these areas, review environmental monitoring results and sanitization procedures. GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS - CGMPR'S (October 1993) 2. Environmental Controls (para 1) [VIP ID: 2669] Specifications for viable and non-viable particulates must be established. Specifications for viable particulates must include provisions for both air and surface sampling of aseptic processing areas and equipment. Review the firm's environmental control program, specifications, and test data. Determine if the firm follows its procedure for reviewing out-of-limit test results. Also, determine if review of environmental test data is included as a part of the firm's release procedures. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002C RADIOACTIVE DRUGS (September 1993) PART III - INSPECTIONAL INVESTIGATIONAL C. Manufacturing Controls Report: 7. [VIP ID: 4403] Firm's procedures for monitoring the environment, personnel, glassware, equipment, and various stages in processing for evidence of contamination by radioactive materials. GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROL LABORATORIES (July 1993) 11. MICROBIOLOGICAL (para 2) [VIP ID: 118580] Review bioburden (before filtration and/or sterilization) from both an endotoxin and sterility perspective. For drug substance labs evaluate methods validation and raw data for sterility, endotoxin testing, environmental monitoring, and filter and filtration validation. Also, evaluate the methods used to test and establish bioburdens.

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13. Environmental monitoring procedures for aseptic processing rooms should require the routine checking of air velocities in Class 100 areas at work height, monitoring of all frequently touched surfaces (e.g. pens, seats, etc. used by operators, and complete investigation of personnel monitoring test results that exceed microbiological action limits.
Selected FDA 483 Observations (August 2003) Sterile Product Manufacture [VIP ID: 53070] Environmental monitoring procedures for aseptic processing rooms should require: (a) the routine checking of air velocities in Class 100 areas of the rooms at work height. (b) monitoring of all frequently touched surfaces (e.g. pens and seats etc. used by operators.). (c) complete investigation of personnel monitoring test results that exceed microbiological action limits.

14. There should be a procedure for routine environmental monitoring of manufacturing areas during times when the area has been idle.
Selected FDA 483 Observations (March 1998) Sterile Product Manufacture [VIP ID: 6299] There should be a procedure for routine environmental monitoring of manufacturing areas during times when the area has been idle.

15. Where a proposed construction project may affect ongoing production, a protocol should be developed to identify baseline viable microbial counts in the manufacturing areas adjacent to the construction, so that action limits can be established, and to include increased environmental sampling and additional sampling sites during construction.
Selected FDA 483 Observations (April 2005) Sterile Product Manufacture [VIP ID: 138140] Where a proposed construction project may affect ongoing production, a protocol should be developed to include: b. The identification of baseline viable microbial counts in the manufacturing areas adjacent to the construction so that action limits can be established c. Increased environmental sampling and additional sampling sites during construction

16. Alert and action limits, based on validation studies, should be assigned for environmental monitoring of both classified areas and of controlled, non classified areas.
Selected FDA 483 Observations (December 2005) Sterile Product Manufacture [VIP ID: 179170] Environmental monitoring action and alert limits for clean rooms should be based on historical data and/or statistical rationale Selected FDA 483 Observations (September 2004) Medical Device Manufacture [VIP ID: 123400] Environmental monitoring should include: a. data and validation to support sampling sites and frequencies. b. evidence to justify alert levels. Selected FDA 483 Observations (July 2004) Sterile Product Manufacture [VIP ID: 122410] Alert and action limits should be assigned for viable and non-viable particulate monitoring of controlled, nonclassified areas

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FDA Warning Letter DEN-03-11 (February 2003) Extracted from FDA warning letter DEN-03-11 USA 21/02/2003 [VIP ID: 59960] 7. Failure to establish and maintain procedures to adequately control environmental conditions as required by 21 CFR 820.70(c). For example, SOP 10-003-02, Monitoring of Bioburden on Lenses, dated September 10, 2001, does not identify action or alert limits for aerobic and anaerobic bioburden." [Investigators: Lori A. Medina and Elaine G. Stewart]. Selected FDA 483 Observations (March 1999) Sterile Product Manufacture [VIP ID: 7089] Environmental monitoring warning and action limits should be established through validation. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) III. FACILITY (para 4) [VIP ID: 2020] Facilities used for the charge or addition of non-sterile components, such as the non-sterile drug substance, should be similar to those used for the compounding of parenteral solutions prior to sterilization. The concern is soluble extraneous contaminants, including endotoxins, that may be carried through the process. Observe this area and review the environmental controls and specifications to determine the viable and non-viable particulate levels allowed in this area. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VII. VALIDATION (para 7) [VIP ID: 2047] Environmental and personnel monitoring must be performed during validation, in a manner and amount sufficient to establish appropriate monitoring limits for routine production.

17. Excursions beyond alert/action limits should be evaluated at the time they occur to determine if the process is still being performed and if there is any threat to the product.
Extracted from FDA Warning Letter 320-05-03 (July 2005) Extracted from FDA warning letter 320-05-03 Italy 21/07/2005 [VIP ID: 169320] 10. [redacted] processing areas were deficient regarding the system for monitoring environmental conditions. Your response regarding monitoring the environmental conditions does not address the issue of failing to acknowledge and evaluate alert and action limits at the time they occur. It is important to assess an observation at or above established limits to determine if the process is still being performed under [redacted] conditions. Also, non-viable monitoring before and after a campaign run does not give an accurate measure of the levels during the multi-week campaign. The "closed" system used to manufacture [redacted] is open at the time [redacted] is performed, and it is necessary to monitor and control the environment in which this [redacted] is performed to ensure [redacted].

18. Corrective and preventative action procedures should include requirements for identifying, investigating and tracking environmental monitoring failures.
Selected FDA 483 Observations (October 2004) Sterile Product Manufacture [VIP ID: 123480] There should be a system in place for tracking open environmental and water monitoring excursions.

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GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 2. Establishing Levels and a Trending Program (para 2) [VIP ID: 111500] Environmental monitoring data will provide information on the quality of the manufacturing environment. Each individual sample result should be evaluated for its significance by comparison to the alert or action levels. Averaging of results can mask unacceptable localized conditions. A result at the alert level urges attention to the approaching action conditions. A result at the action level should prompt a more thorough investigation. Written procedures should be established, detailing data review frequency and actions to be taken. The quality control unit should provide routine oversight of near-term (e.g., daily, weekly, monthly, quarterly) and long-term trends in environmental and personnel monitoring data. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 2. Establishing Levels and a Trending Program (para 3) [VIP ID: 111510] Trend reports should include data generated by location, shift, room, operator, or other parameters. The quality control unit should be responsible for producing specialized data reports (e.g., a search on a particular isolate over a year period) with the goal of investigating results beyond established levels and identifying any appropriate followup actions. Significant changes in microbial flora should be considered in the review of the ongoing environmental monitoring data. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) XI. Sterility Testing C. Investigation of Sterility Positives (para 3) 6. [VIP ID: 111830] 6. Production Record Review Complete batch and production control records should be reviewed to detect any signs of failures or anomalies that could have a bearing on product sterility. For example, the investigation should include elements such as: Events that could have impacted on the critical zone. Batch and trending data that indicate whether utility and/or support systems are functioning properly. For instance, records of air quality monitoring for filling could show a time at which there was improper air balance or an unusually high particle count. Whether construction or maintenance activities could have had an adverse impact.

Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121950] Corrective and preventative action procedures should include requirements for identifying and investigating all nonconformities, including in-process sterility and environmental monitoring failures. Selected FDA 483 Observations (March 2004) Sterile Product Manufacture [VIP ID: 71220] There should be systems in place for tracking open environmental and water monitoring excursions describing responsibilities regarding timely review and closure of investigations.

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CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART III - Inspectional B. Inspection 9. GMP b. Buildings (para 6) [VIP ID: 77580] Review procedures for controlling and monitoring pressure differentials, humidity, and temperature. Procedures should include actions to be taken when results are not within established limits. Ensure that the impact of out-oflimit results on the product is adequately addressed. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002M INSPECTIONS OF LICENSED BIOLOGICAL THERAPEUTIC DRUG PRODUCTS (October 2003) PART V - REGULATORY/ADMINISTRATIVE STRATEGY Regulatory /Administrative Follow-Up Significant Deviations 5. Production and Process Controls [VIP ID: 78080] [211.100 - 211.115] There were no records of investigations to determine sources of contamination associated with environmental monitoring excursions.

FDA Warning Letter W/L 08-03 (November 2002) Extracted from FDA warning letter W/L 08-03 USA 19/11/2002 [VIP ID: 54380] 5. Aseptic processing areas are deficient regarding the system for monitoring environmental conditions [21 CFR 211.42(c) (10)(iv)] and [21 CFR 820.70(c)]. Specifically, the investigation process used to investigate environmental monitoring excursions and to determine release of product is based partly on results from "in house challenge studies", but there is no approved procedure to define this test method. Selected FDA 483 Observations (September 2000) Sterile Product Manufacture [VIP ID: 19240] When aseptic environmental monitoring results exceed action limits, an evaluation of what personnel were doing at the time of the excursion should be performed, together with an investigation in to the possible effect on product sterility. Selected FDA 483 Observations (September 2000) Sterile Product Manufacture [VIP ID: 19250] Procedures detailing the action to take when environmental monitoring limits in critical and non-critical areas are exceeded during aseptic fills should require comparing all environmental monitoring results (to include personnel monitoring). Selected FDA 483 Observations (April 1997) Sterile Product Manufacture [VIP ID: 2471] The SOP for environmental monitoring should provide for additional sampling of critical sites where action limits are exceeded. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. ENVIRONMENTAL MONITORING (para 6) [VIP ID: 2040] In the management of a sterile bulk operation, periodic (weekly/monthly/quarterly) summary reports of environmental monitoring are generated. Review these reports to obtain those situations in which alert/action limits were exceeded. Review the firm's investigation report and the disposition of batches processed when objectionable environmental conditions existed.

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CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) LABORATORY Environment 287. [VIP ID: 2439] Compare the firm's written environmental specifications for the laboratory with sampling data for the previous three months. Are results within specifications? If not, what action was taken by the firm with reference to: (a) environmental specifications; (b) product undergoing testing at the time of the out-of-spec results?

19. The monitoring activity itself should not compromise the product quality. Worst case scenarios of simulations tests should also include monitoring activities.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING 7.1 Air Borne Microbial and Non-Viable Particle Monitoring 7.1.1 [VIP ID: 188972] It is important to state that the monitoring activity itself should not compromise the product quality. Worst case scenarios of simulations tests should also include monitoring activities.

20. It is recommended that environmental control records be kept in a manner permitting trend evaluation and that environmental data is trended from year to year.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 6 QUALITY CONTROL DOCUMENTATION 6.9 [VIP ID: 185852] For some kinds of data (e.g. analytical tests results, yields, environmental controls, ...) it is recommended that records in a manner permitting trend evaluation be kept. Selected FDA 483 Observations (February 2000) Sterile Product Manufacture [VIP ID: 14240] Environmental monitoring data should be highlighted to indicate if it was obtained during static or dynamic conditions to enable meaningful trend analysis. Selected FDA 483 Observations (December 1999) Sterile Product Manufacture [VIP ID: 8720] Environmental monitoring results during dynamic and static conditions should be trended. EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 6 - QUALITY CONTROL Documentation 6.9. [VIP ID: 610] For some kinds of data (e.g. analytical tests results, yields, environmental controls etc.) it is recommended that records be kept in a manner permitting trend evaluation. Selected FDA 483 Observations (January 1997) Sterile Product Manufacture [VIP ID: 135610] Air pressure differential data throughout the clean room monitoring locations should be trended, and there should be comparison or trending of environmental data from year to year.

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21. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems).
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.1 General 18.15 [VIP ID: 24835] Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems). ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION 18.1 General 18.15 [VIP ID: 156400] Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems).

22. Where potent or highly sensitising drugs are processed and air is recirculated, there should be data demonstrating the efficiency of air filtration including include surface and/or air sampling.
GUIDE TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS II. FACILITIES (para 3) [VIP ID: 3208] The firm's HVAC (Heating Ventilation and Air Conditioning) system may also warrant coverage particularly where potent or highly sensitizing drugs are processed. Some manufacturers recirculate air without adequate filtration. Where air is recirculated, review the firm's data which demonstrates the efficiency of air filtration such should include surface and/or air sampling.

23. Where an aseptic process involves hand filling and sealing, enhanced attention should be given to environmental monitoring.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 13 - MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS (1997) - SUPERSEDED! (December 1996) Premises and equipment 7. [VIP ID: 4591] Validation of aseptic processes presents special problems when the batch size is small; in these cases the number of units filled may be the maximum number filled in production. Filling and sealing is often a hand operation presenting great challenges to sterility so enhanced attention should be given to environmental monitoring.

24. Environmental control and its associated monitoring play a part in product bioburden control, but it is often a relatively small part. Hence, the primary focus of attention should be on the details of determining and controlling presterilisation bioburden.
PI 005-2 RECOMMENDATION ON GUIDANCE ON PARAMETRIC RELEASE (July 2004) APPENDIX I RECOMMENDATIONS FOR A GENERAL STERILITY ASSURANCE SYSTEM FOR TERMINALLY STERILISED PRODUCTS AND PROVISIONS FOR PARAMETRIC RELEASE 5. CONTROL OF PRESTERILIZATION BIOBURDEN 5.2 [VIP ID: 188274] Environmental control and its associated monitoring play a part in product bioburden control, but it is often a relatively small part. Hence, the primary focus of attention should be on the details of determining and controlling presterilization bioburden.

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25. Facilities used to conduct sterility tests should have the same environmental monitoring and gowning standards as those used in aseptic processing production facilities.
REG 07/01/93 GUIDE TO INSPECTIONS OF MICROBIOLOGICAL PHARMACEUTICAL QUALITY LABORATORIES (July 1993) IV. Sterility Testing (para 2) [VIP ID: 2909] CONTROL

The USP points out that the facilities used to conduct sterility tests should be similar to those used for manufacturing product. The USP states, "The facility for sterility testing should be such as to offer no greater a microbial challenge to the articles being tested than that of an aseptic processing production facility". Proper design would, therefore, include a gowning area and pass-through airlock. Environmental monitoring and gowning should be equivalent to that used for manufacturing product.

8.2 Physical 1. Room particle counts, the number of air changes, and air flow velocities should be tested at multiple times to demonstrate adequate performance over time.
Selected FDA 483 Observations (August 2004) Sterile Product Manufacture [VIP ID: 122660] HVAC system qualification should include: b. the testing of room particle counts, number of air changes, and air-flow velocities at multiple times to demonstrate adequate performance over time. Selected FDA 483 Observations (February 2006) Sterile Product Manufacture [VIP ID: 179930] Room particle counts, number of air changes and airflow velocities should be tested multiple times, rather than at a single time point, to demonstrate adequate performance over time.

2.

Actual particle count and air velocity results should be recorded, not just a check mark to indicate that they are acceptable.
Selected FDA 483 Observations (March 2001) Medical Device Manufacture [VIP ID: 27430] Actual particle count and air velocity results should be recorded not just a check mark to indicate that they are acceptable.

3.

Air velocities/volumes and the exact placement of primary barriers should be recorded to support environmental monitoring smoke studies.
Selected FDA 483 Observations (September 2000) Sterile Product Manufacture [VIP ID: 19830] Environmental monitoring should require the following information to be recorded to support smoke studies: a) air velocities/volumes b) the exact placement of primary barriers

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4.

There should be scientific justification for the frequency assigned to the testing of filters in sterile areas and procedures should include a specification for the required distance for taking test measurements, and for monitoring of pressure differentials between various operational areas.
Extracted from FDA Warning Letter 320-05-02 (August 2005) Extracted from FDA warning letter 320-05-02 Switzerland 16/08/2005 [VIP ID: 171110] 2. There was insufficient evidence that ventilation and air filtration systems provided adequate control over microorganisms for the manufacture, processing, packing, or holding of a drug product. 21 CFR 211.46 The following deviations were noted regarding ventilation and air filtration systems: There was no scientific justification for testing of [redacted] filters in the Class A (ISO 5) area and sterile [redacted] only once annually, the procedures did not include a specification for the required distance for taking [redacted] test measurements, or for monitoring of pressure differentials between various operational areas.

5.

For Class 100 areas, it is recommended that measurements to confirm air cleanliness be taken at sites where there is most operator activity and most potential risk to the exposed sterilised product, containers, and closures. The particle counting probe should be placed in an orientation demonstrated to obtain a meaningful sample, and not compromise the laminarity of the air flow. Regular monitoring should be performed during each production shift. It is also recommended to conduct non viable particle monitoring with a remote counting system as these systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters.
Selected FDA 483 Observations (July 2006) Sterile Product Manufacture [VIP ID: 193732] Non-viable monitoring probes for sterile connections for filtration and filling should be located to assure the connection areas are in control when connections are performed. Selected FDA 483 Observations (June 2005) Sterile Product Manufacture [VIP ID: 140120] The location of particle counters in rooms should be demonstrated to provide an accurate representation of particle activity. Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124780] There should be data to support the selected sampling points for environmental surface counts, viable airborne microorganisms and non viable particulate matter in the areas used in the filling of sterile diluents. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 4) [VIP ID: 110210] We recommend that measurements to confirm air cleanliness in critical areas be taken at sites where there is most potential risk to the exposed sterilized product, containers, and closures. The particle counting probe should be placed in an orientation demonstrated to obtain a meaningful sample. Regular monitoring should be performed during each production shift. We recommend conducting nonviable particle monitoring with a remote counting system. These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters. See Section X.E. for additional guidance on particle monitoring.

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PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING 7.2 Non-viable monitoring 7.2.1 [VIP ID: 188974] The location chosen for monitoring should be checked to ensure that the positions reflect the worst case. For room monitoring, the counts should be performed in locations where there is most operator activity. For the filling environment the counts should be performed adjacent to the filling zone and where components are exposed in such way as to detect operator activity within these areas. Monitoring with sampling probes located in such a way that they monitor the air from the HEPA filter rather than the air immediately surrounding the critical zones should be avoided. However the location of the sample device should not compromise the laminarity of the air flow in the critical zone. Initial validation should be checked to confirm that worst case positions have been adequately identified. These may be reconfirmed during process simulation tests.

6.

Some operations can generate high levels of product (e.g. powder) particles that, by their nature, do not pose a risk of product contamination. It may not, in these cases, be feasible to measure air quality within the one foot distance and still differentiate background levels of particles from air contaminants. In these instances, air can be sampled in a manner that, to the extent possible, characterises the true level of extrinsic particle contamination to which the product is exposed. Initial qualification of the area under dynamic conditions, without the actual filling function, provides some baseline information on the non product particle generation of the operation.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 5) [VIP ID: 110220] Some operations can generate high levels of product (e.g., powder) particles that, by their nature, do not pose a risk of product contamination. It may not, in these cases, be feasible to measure air quality within the one-foot distance and still differentiate background levels of particles from air contaminants. In these instances, air can be sampled in a manner that, to the extent possible, characterizes the true level of extrinsic particle contamination to which the product is exposed. Initial qualification of the area under dynamic conditions without the actual filling function provides some baseline information on the non-product particle generation of the operation.

7.

Environmental monitoring systems (temperature and humidity) should be validated (IQ/OQ/PQ).


Extracted from FDA Warning Letter 2001-DAL-WL-04 (November 2000) Extracted from FDA warning letter 2001-DAL-WL-04 USA 17/11/2000 [VIP ID: 164920] 3) Failure to assure and document that automated equipment used in manufacturing, processing, packaging, and holding of drug products will perform its intended function satisfactorily [21 CFR Part 211.68]. Similarly, failure to establish and document procedures to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 CFR Part 211.100], as well as failure to verify and document that equipment used for monitoring processing equipment and environmental conditions is adequate and functioning properly [21 CFR Part 820.70]. As examples, a) Necessary actions have not been predetermined and documented when responding to alarms from the [redacted]. Also, this alarm system is unable to store more than [redacted] transgressions, and these transgressions are not recorded. There is also no secondary review of such alarm events, and any corrective actions taken are not documented. ... Selected FDA 483 Observations (July 1999) Product Manufacture [VIP ID: 7207] Environmental monitoring systems (temperature and humidity) should be validated (IQ/OQ/PQ).

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8.

A suitable facility monitoring system will rapidly detect atypical changes that can compromise the facilitys environment. An effective system facilitates restoration of operating conditions to established, qualified levels before reaching action levels. For example, pressure differential specifications should enable prompt detection (i.e. alarms) of an emerging low pressure problem to preclude ingress of unclassified air into a classified room.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities C. Clean Area Separation (para 5) [VIP ID: 110320] A suitable facility monitoring system will rapidly detect atypical changes that can compromise the facilitys environment. An effective system facilitates restoration of operating conditions to established, qualified levels before reaching action levels. For example, pressure differential specifications should enable prompt detection (i.e., alarms) of an emerging low pressure problem to preclude ingress of unclassified air into a classified room.

9.

Non viable particle counts should be routinely performed during sterile fill set-up operations for media fill runs and during aseptic filling operations and include all areas where there are open containers and closures.
Selected FDA 483 Observations (September 2004) Sterile Product Manufacture [VIP ID: 123290] Environmental monitoring programs in aseptic filling areas should include: c. non-viable particulate monitoring of all areas where there are open containers and closures. Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 72640] Non-viable particulate monitoring should be performed during sterile fill set-up operations for media fill runs and routine manufacturing to demonstrate the maintenance of [sterile] conditions. (NOTE: Set up operations are generally personnel intensive operations that can be representative of worse case conditions.) Selected FDA 483 Observations (April 2000) Sterile Product Manufacture [VIP ID: 14810] The following activities should be routinely performed during aseptic filling operations: (1) non-viable particle counts ... Selected FDA 483 Observations (April 1997) Sterile Product Manufacture [VIP ID: 136330] Non-viable particle counts should be continuously monitored at critical sites in the aseptic filling rooms to assure the maintenance of Class 100 conditions at these sites during the aseptic processing of parenteral drug products.

10. Data collected from particle counters on aseptic filling lines should be archived.
Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121980] Data collected from particle counters on aseptic filling lines should be archived.

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11. There should be a written procedure that defines the method of establishing alert limits for airborne non viable particulate levels in classified areas and an established schedule calling for a periodic reevaluation of the alert limits based on historical data.
Selected FDA 483 Observations (January 2007) Sterile Product Manufacture [VIP ID: 194248] There should be a written procedure that defines the method of establishing alert limits for airborne non-viable particulate levels in classified areas and an established schedule calling for a periodic re-evaluation of the alert limits based on historical data.

12. There should be written procedures for reviewing particle count data, and specifying the action to be taken when non viable action limits are exceeded.
Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121970] There should be written procedures for reviewing particle count data. Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 19960] Environmental monitoring SOPs should specify the action to be taken when non-viable action limits are exceeded.

13. Instances of alert or action levels being exceeded for non viable particulates, should result in deviation reports, investigations and corrective measures being undertaken in response to these events.
Selected FDA 483 Observations (February 2007) Sterile Product Manufacture [VIP ID: 194290] Attributions of over action limit particulate levels in a Class 100 area to air disturbance caused by a cart in the Class 100 area are unfounded if no smoke studies have been performed with these carts in place. Selected FDA 483 Observations (July 2006) Sterile Product Manufacture [VIP ID: 193664] For all lots of product, potentially affected by repeated action level excursions for foreign matter in vials, there should be an investigation of the finished product lots manufactured between the two excursion events, including lots with particle counts elevated above trend averages. Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 128300] lnvestigations should be conducted when alarms occur for non-viable particulate (NVP) monitoring in Class 100 fill areas. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls E. Particle Monitoring [VIP ID: 111650] Routine particle monitoring is useful in rapidly detecting significant deviations in air cleanliness from qualified processing norms (e.g., clean area classification). A result outside the established classification level at a given location should be investigated as to its cause. The extent of investigation should be consistent with the severity of the excursion and include an evaluation of trending data. Appropriate corrective action should be implemented, as necessary, to prevent future deviations. See Section IV.A for additional guidance on particle monitoring.

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FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 11 [VIP ID: 49970] 11. Failure to maintain records so that data therein could be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications, manufacturing, or control procedures [21 CFR 211.180(e)]. For example, - Monitoring for non-viable particulates performed 10/26/01 in room 2217 (Part Fill filling area) recorded counts over the action limit in the **** area. There was no deviation report, investigation, or corrective measure undertaken in response to this event. FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 8 [VIP ID: 49940] 8. Failure to thoroughly review the failure of a batch or any of its components to meet any of its specifications [21 CFR 211.192]. For example, - BQAOO14, "Handling of Product Complaints and WIP Shipment Complaints" *, does not describe the level of investigation to be performed when product complaints describing particulate matter in injectable products are received. - Environmental monitoring results are not routinely evaluated when complaints for metallic particles or other particulates are confirmed by analysis. FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 9 [VIP ID: 49950] 9. Failure to establish and follow adequate procedures describing the handling of complaints related to drug products [21 CFR 211.198]. For example, - BQA0014 "Handling of Product Complaints and WIP Shipment Complaints" does not describe the level of investigation to perform when product complaints describing particulate matter in injectable products are received. - The investigation of PER #100361029, lot #74087-JT determined and / or confirmed metallic particles and synthetic fibers near the port. However, there was no attempt to determine the source of the particulates at the manufacturing site, there was no review of environmental monitoring data that was obtained during manufacturing and filling operations for the referenced lot, nor was any batch record review conducted. Extracted from FDA Warning Letter CHI-12-00 (February 2000) Extracted from FDA warning letter CHI-12-00 USA 07/02/2000 [VIP ID: 161520] Failure of the quality control unit to assure that all unexplained discrepancies or failures of batches to meet specifications are thoroughly investigated and that the records of the investigations are complete, including conclusions and follow-ups [21 CFR 211.192]. For example: The written investigation [#032-99I] of the OAL (over-action-limit) non-viable particle counts in Fill Room 1 does not include justification for releasing lots 190365, 190362, 190374, 190383 and 190389. These lots were aseptically filled on the [redacted] Filler, which the investigation report identifies as the source of the high particle counts. Four other lots made on the same equipment during the same time period were rejected. In addition, four of the lots were released for distribution before the investigation was completed on 7/12/99. For example, Lot 190389 was released for distribution on 6/4/99; Lot 19383 was released on 6/2/99; Lot 190374 was released on 6/1/99; and Lot 190365 was released on 5/25/99.

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14. The frequency for non viable particulate sampling in classified areas should be defined.
FDA Warning Letter 2002-DAL-WL-04 (November 2001) Extracted from FDA warning letter 2002-DAL-WL-04 USA 08/11/2001 [VIP ID: 42800] 1. Failure to follow appropriate written procedures and conduct adequate validation of the sterilization process designed to prevent microbial contamination in drug products purporting to be sterile [21 CFR 211.113(b)]. For example, your firm: (b) fails to follow the environmental control procedure (SOP# 3001, dated 4/20/00) in that monitoring of non-viable particulate has not been performed in the manufacturing and filling rooms for ****, ****, and ****[FDA-483 Item 2]. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 48. [VIP ID: 2200] How often is non-viable particulate sampling performed in classified areas: a. Exposed product areas b. Filling areas c. Surrounding areas

15. There should be assurance that the volume of air sampled for non viable particulates is adequate in relation to the time required to perform operations.
Selected FDA 483 Observations (September 2005) Sterile Product Manufacture [VIP ID: 177960] There should be assurance that the volume of air sampled for non-viable particulates is adequate in relation to the time required to perform operations.

16. Pressure differential and particle count trend reports included as part of a batch record should be documented as reviewed by quality assurance or production personnel.
Selected FDA 483 Observations (February 2006) Sterile Product Manufacture [VIP ID: 179920] Pressure differential and particle count trend reports included as part of the batch record should be documented as reviewed by quality assurance or production personnel.

17. The differential air pressure for aseptic filling areas and surrounding support areas should be monitored under dynamic conditions rather than at rest (static).
Extracted from FDA warning letter 06-NWJ-14 (July 2006) Extracted from FDA warning letter 06-NWJ-14 USA 11-Jul-06 6) [VIP ID: 192240] Failure to maintain separate or defined areas or other such control systems as are necessary to prevent contamination and mix-ups in the course of manufacturing and processing operations [21 CFR 211.42(c)(5)]. Specifically, no monitoring of the system is conducted to demonstrate that the volume of air supplied is sufficient to maintain appropriate air pressure differentials between manufacturing rooms, corridors, and pharmacy rooms. Selected FDA 483 Observations (June 2006) Active Pharmaceutical Ingredient Manufacture [VIP ID: 193574] The routine monitoring of the differential air pressures between rooms should be documented.

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Extracted from FDA Warning Letter 320-99-04 (June 1999) Extracted from FDA warning letter 320-99-04 Netherlands 23/06/1999 [VIP ID: 159820] 3. The differential air pressure for the aseptic filling areas and surrounding support areas is monitored at rest (static) rather than under dynamic conditions.

18. The HEPA filters of vacuum cleaners, used to clean production area floors, should be evaluated to ensure that airborne particulates are not dispersed into the production areas.
Extracted from FDA warning letter OEWL-06-01 (June 2006) Extracted from FDA warning letter OEWL-06-01 USA 30-Jun-06 6 [VIP ID: 192180] Additionally, significant deviations in the manufacture of your monovalent concentrate that is used to formulate Influenza Virus Vaccine, Fluzone were observed during the inspection. These deviations violate Section 501(a)(2)(B) of the FD&C Act and Section 351(a) of the PHS Act. Specific areas of concern include, but are not limited to: 6. The wet/dry vacuum is used to clean the floors of your production areas. However, the vacuum's HEPA filter has not been evaluated to ensure that airborne particulates are not dispersed into the production areas.

19. Systems used to monitor temperature, pressure, humidity and alarm conditions for environmentally classified areas, used for aseptic manufacturing should be able to produce alarm reports for critical and sub-critical areas, which should be adequately documented to assure that evaluation of the impact on product quality and trending can be conducted.
Selected FDA 483 Observations (March 2007) Sterile Product Manufacture [VIP ID: 194384] Building Monitoring SCADA Systems used to monitor temperature, pressure, humidity and alarm conditions for environmentally classified areas, used for aseptic manufacturing should be able to produce alarm reports for critical and sub-critical areas. Alarms should be adequately documented to assure that evaluation of the impact on product quality and trending can be conducted.

20. Aseptic processing area temperature conditions should be documented to ensure they are consistently within established specifications.
Extracted from FDA warning letter 07-ATL-01 (October 2006) Extracted from FDA warning letter 07-ATL-01 USA 31-Oct-06 9 [VIP ID: 192634] Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70(c). Specifically, temperature conditions within the aseptic processing area are not being documented to ensure such conditions are consistently within established specifications of [redacted] degrees Celsius. Your firm's response to observation 8 is inadequate. Your firm has stated that it has updated the Preventative Maintenance Task List to include space to record specific temperature readings on April 27, 2006. Your company has stated that it will conduct an audit to identify and enhance other temperature documentation practices and will install a continuous temperature and humidity recording system. Your firm has not provided the updated task list to FDA and the temperature audit has not been completed.

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8.3 Microbiological 1. Microbiological monitoring is the responsibility of the pharmaceutical manufacturer and the heads of Production and Quality Control have shared responsibility for the monitoring and control of the manufacturing environment.
PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 2 PERSONNEL KEY PERSONNEL 2.7 [VIP ID: 185524] The heads of Production and Quality Control generally have some shared, or jointly exercised, responsibilities relating to quality. These may include, subject to any national regulations: the authorisation of written procedures and other documents, including amendments; the monitoring and control of the manufacturing environment; training; the designation and monitoring of storage conditions for materials and products; the monitoring of compliance with the requirements of GMP; the inspection, investigation, and taking of samples, in order to monitor factors which may affect product quality.

PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 12 - USE OF IONISING RADIATION IN THE MANUFACTURE OF MEDICINAL PRODUCTS INTRODUCTION MICROBIOLOGICAL MONITORING 46 [VIP ID: 186814] Microbiological monitoring is the responsibility of the pharmaceutical manufacturer. It may include environmental monitoring where product is manufactured and pre-irradiation monitoring of the product as specified in the marketing authorisation. FDA Warning Letter 02-PHI-03 (February 2002) Extracted from FDA warning letter 02-PHI-03 USA 22/02/2002 [VIP ID: 48520] The Quality Unit failed to adequately investigate the impact of the presence of **** in **** drug products when environmental monitoring samples taken in the **** facility were found positive for **** [21 CFR 211.22]. For example, your firm possessed no validated analytical method to determine if **** drug products were crosscontaminated with ****.

2.

There should be procedures for the review and/or approval of major quality decisions by Senior Quality Management, including justification for continued operations when microbial action limits are exceeded in the environment.
Selected FDA 483 Observations (May 2005) Sterile Product Manufacture [VIP ID: 138850] There should be procedures for the review and/or approval of major quality decisions by Senior Quality Management, including justification for continued operations when microbial action limits are exceeded in the environment.

Manufacturing processes for products intended to be sterile, should include environmental monitoring to assess the microbial contamination in the manufacturing area during typical operating conditions.

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HEALTH CANADA - GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.4 SANITATION - C.02.007 & C.02.008 2.4.8 [VIP ID: 65760] CAN THE SAMPLING FOR THE MICROBIAL MONITORING OF AIR IN NON-STERILE AREAS WHERE SUSCEPTIBLE PRODUCTS ARE PRODUCED BE CONDUCTED WHEN THERE ARE NO MANUFACTURING OR PACKAGING ACTIVITIES? The sampling should occur during actual manufacturing or packaging in order to reflect the conditions to which the products being produced are really exposed. Monitoring between production runs is also advisable in order to detect potential problems before they arise. FDA Warning Letter CHI-10-01 (January 2001) Extracted from FDA warning letter CHI-10-01 USA 11/01/2001 [VIP ID: 28240] Airborne bioburden sampling of class 100 filling areas does not assure that results obtained reflect environmental conditions present during routine manufacture. For example, our investigators cited several examples of months where approximately **** of the airborne bioburden samples collected were taken with no operators in the class 100 filling area. Also, only **** cubic meters of air are taken for each airborne bioburden sample in class 100 filling areas and adjacent class 10,000 areas." [FDA Investigators: Bruce McCullough, Alicia Mozzachio and Jason Chancey] Selected FDA 483 Observations (May 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 15020] Manufacturing processes for API's which are pyrogen tested and intended for use in the manufacture of intravenous solutions and injectable finished products should include: (3) environmental monitoring to assess the microbial contamination in the manufacturing area Selected FDA 483 Observations (June 1999) Sterile Product Manufacture [VIP ID: 7165] Sterile manufacturing process validation should include microbiological evaluation of: 4) environment FDA Warning Letter M2329n (January 1999) Extracted from FDA warning letter M2329n Canada 08/01/1999 [VIP ID: 12570] A single filling room contains multiple filling lines and is used for additional ancillary processing facility functions. As a result, there is unnecessary equipment and extra personnel load in the room in which injectable products are produced. At least **** filling machines are located and run simultaneously in the same room. In addition, this **** filling room is used for other functions such as storage. Environmental monitoring has shown this section of the room to be a persistent source of microbiological contamination over the last 18 months. processing operations must be performed within separate, defined areas to prevent microbiological contamination, cross-contamination, or mix-ups (e.g., containers, closures, labeling), Each **** processing room should be designed to minimize personnel load and activity adjacent to its filling line. ... EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 12 - USE OF IONIZING RADIATION IN THE MANUFACTURE OF MEDICINAL PRODUCTS (January 1993) Microbiological monitoring 46. [VIP ID: 1815] Microbiological monitoring is the responsibility of the pharmaceutical manufacturer. It may include environmental monitoring where product is manufactured ...

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4.

Where operations requiring high degrees of cleanliness are performed, microbiological monitoring of the environment, surfaces and personnel should be performed frequently according to a programme using methods, which do not interfere with zone protection. Such methods should include, as appropriate, swabs, contact plates, settle plates, dynamic air samplers.
Extracted from FDA warning letter CHI-3-07 (December 2006) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 1) b. [VIP ID: 194568] Failure to establish and follow written procedures designed to prevent microbiological contamination of drug products purporting to be sterile and failure to validate sterilization processes as required by 21 CFR 211.113(b). b) the stopper hopper is not a site selected for environmental monitoring. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS GENERAL 5 [VIP ID: 185994] Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods used in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation. Recommended limits for microbiological monitoring of clean areas during operation: Recommended limits for microbial contamination (a) Grade Air sample cfu/m A B C D Notes: (a) These are average values (b) Individual settle plates may be exposed for less than 4 hours. Selected FDA 483 Observations (July 2006) Sterile Product Manufacture [VIP ID: 193730] In the case of aseptic processing, viable monitoring should be performed during set-up of the sterile connections for filtration and filling. Selected FDA 483 Observations (September 2005) Sterile Product Manufacture [VIP ID: 177930] Active air sampling should be routinely monitored while critical operations are taking place, such as operators making aseptic connections at pre and post filtration sites. <1 10 100 200
3

Settle plates (diam. 90 mm) cfu/4 hours (b) <1 5 50 100

Contact plates (diam. 55 mm), cfu/plate <1 5 25 50

Glove print 5 fingers, cfu/glove <1 5 -

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Selected FDA 483 Observations (September 2005) Sterile Product Manufacture [VIP ID: 177940] Viable active air sampling should be performed at the area where most critical operations occur, rather than the air sampler being placed on a table in the corner of the room. GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VIII. PRODUCTION AND PROCESS CONTROLS C. Microbiological Control on Aseptic Processing and Sterilizing Filtration 8. Environmental and personnel monitoring [VIP ID: 187516] Environmental monitoring is crucial to maintaining aseptic conditions. We recommend that microbiological testing of aseptic workstations be performed during sterility testing and critical aseptic manipulation. Methods can include using swabs or contact plates for surfaces and settling plates or dynamic air samplers for air quality. Extracted from FDA Warning Letter 320-05-02 (August 2005) Extracted from FDA warning letter 320-05-02 Switzerland 16/08/2005 [VIP ID: 171120] 3. Control procedures were inadequate to prevent microbiological contamination of sterile eye drops. 21 CFR 211.113 (b) There were several deviations in aseptic practices and technique. An operator was observed spraying [redacted] near a [redacted] intended for environmental monitoring, chairs positioned in front of three exhaust vents were obstructing air flow in the Class A/B (ISO 5) room, three individuals were observed in the Class A/B (ISO 5) room with exposed eye and partial forehead areas, there was no assurance that irradiated caps were exposed to [redacted] for [redacted] minutes as required by the batch production record and environmental monitoring did not include the area where duct tape surrounds the hole where bottles exit the Class A (ISO 5) filling area. We acknowledge that you have updated standard operating procedures and batch production records, re-trained personnel and provided face covering and eye protection to those working in the [redacted] area. However, due to the limited amount of time the inspection team had available to observe aseptic practices and the number and significance of the deviations, we have no assurance that all control procedures are adequate and suggest that a more comprehensive assessment of aseptic practices and techniques at your firm is needed to provide greater assurance of microbiological control. Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 124990] Sampling procedures for environmental surface sampling in the filling and packaging suites should be representative of the entire work areas to include: a. all portions of the rooms. b. critical areas that are most often in contact with personnel (e.g. vinyl curtains, dry heat oven doors, autoclave doors etc.) GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 1. General Written Program (para 3) [VIP ID: 111460] It is important that locations posing the most microbiological risk to the product be a key part of the program. It is especially important to monitor the microbiological quality of the critical area to determine whether or not aseptic conditions are maintained during filling and closing activities. Air and surface samples should be taken at the locations where significant activity or product exposure occurs during production. Critical surfaces that come in contact with the sterile product should remain sterile throughout an operation. When identifying critical sites to be sampled, consideration should be given to the points of contamination risk in a process, including factors such as difficulty of setup, length of processing time, and impact of interventions. Critical surface sampling should be performed at the conclusion of the aseptic processing operation to avoid direct contact with sterile surfaces during processing. Detection of microbial contamination on a critical site would not necessarily result in batch rejection. The contaminated critical site sample should prompt an investigation of operational information and data that includes an awareness of the potential for a low incidence of false positives.

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Selected FDA 483 Observations (March 2005) Sterile Product Manufacture [VIP ID: 128950] Environmental Monitoring (EM) programs for aseptic filling areas should include obtaining EM samples from the following locations to demonstrate that there are no microbial contaminants present: a. The fill equipment access door handles. b. The interior surface of the rubber stopper access door that comes into contact with the back of the operator's upper right side shoulder. c. The back of the operator's upper right side shoulder. d. The surfaces of the stainless steel writing bench. e. The stainless steel "bleed pan:' f. The writing pens.

g. Viewing light buttons located on the top of tanks. h. The areas of the rubber stopper transfer equipment that are handled by the operators. i. j. The air hose touching the black tubing that connected the SMA outlets. The wall phone that is used in the aseptic fill room.

FDA Warning Letter CBER-05-006 (December 2004) Extracted from FDA warning letter CBER-05-006 USA 09/12/2004 [VIP ID: 133210] 6. Your firm failed to establish an adequate system for monitoring environmental, conditions of aseptic processing areas. [21 CFR 211.42(c)(10)(iv)] For example, routine viable air sampling does not encompass aseptic activities including the times and locations where the critical operations are performed. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 4. Monitoring Methods a. Surface Monitoring [VIP ID: 111560] Acceptable methods for monitoring the microbiological quality of the environment include: a. Surface Monitoring Environmental monitoring involves sampling various surfaces for microbiological quality. For example, product contact surfaces, floors, walls, and equipment should be tested on a regular basis. Touch plates, swabs, and contact plates can be used for such tests. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 4. Monitoring Methods b. Active Air Monitoring [VIP ID: 111570] b. Active Air Monitoring Assessing microbial quality of air should involve the use of active devices including but not limited to impaction, centrifugal, and membrane (or gelatin) samplers. Each device has certain advantages and disadvantages, although all allow testing of the number of organisms per volume of air sampled. We recommend that such devices be used during each production shift to evaluate aseptic processing areas at carefully chosen locations. Manufacturers should be aware of a device's air monitoring capabilities, and the air sampler should be evaluated for its suitability for use in an aseptic environment based on collection efficiency, cleanability, ability to be sterilized, and disruption of unidirectional airflow. [20] Because devices vary, the user should assess the overall suitability of a monitoring device before it is placed into service. Manufacturers should ensure that such devices are calibrated and used according to appropriate procedures. [20] For example, the volume of air sampled should be sufficient to yield meaningful measurements of air quality in a given environment.

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GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 4. Monitoring Methods c. Passive Air Monitoring (Settling Plates) [VIP ID: 111580] c. Passive Air Monitoring (Settling Plates) Another method is the use of passive air samplers, such as settling plates (petri dishes containing nutrient growth medium exposed to the environment). Because only microorganisms that settle onto the agar surface are detected, settling plates can be used as qualitative, or semi-quantitative, air monitors. Their value in critical areas will be enhanced by ensuring that plates are positioned in locations posing the greatest risk of product contamination. As part of methods validation, the quality control laboratory should evaluate what media exposure conditions optimize recovery of low levels of environmental isolates. Exposure conditions should preclude desiccation (e.g., caused by lengthy sampling periods and / or high airflows), which inhibits recovery of microorganisms. The data generated by passive air sampling can be useful when considered in combination with results from other types of air samples. Selected FDA 483 Observations (September 2004) Sterile Product Manufacture [VIP ID: 123290] Environmental monitoring programs in aseptic filling areas should include: a. routine, active environmental viable monitoring (slit-to-agar) at multiple points, not just at filling needles. b. slit-to-agar monitoring during setup line adjustment and fill weight check operations. d. glove monitoring of operators performing aseptic weighing of bulk product before the operators have changed gloves or sanitized their hands. e. microbiological monitoring of all surfaces that have direct contact with stoppers. f. routine monitoring of sterilized, and sanitized utensils used for aseptic manipulations.

Selected FDA 483 Observations (September 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 123340] Products manufactured or repackaged which are labeled as being pyrogen tested and are intended for use in injectable drug formulations should be validated from an endotoxin perspective to include: c. environmental monitoring of the manufacturing and packaging area.

Selected FDA 483 Observations (August 2004) Sterile Product Manufacture [VIP ID: 122650] Environmental monitoring of aseptic processing areas should include: e. monitoring for anaerobic organisms.

PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 11. COMPONENT PREPARATION Preparation of Components 11.6 [VIP ID: 185162] The premises used for the preparation of blood components in a closed-system should be kept in a clean and hygienic condition and the microbial contamination load on critical equipment, surfaces and the environment of the preparation areas should be monitored. (As closed-system processing involves the use of pre-configured multiple bag systems, the only breach of the integrity of the system is during the act of blood collection and does not require to be carried out in a classified clean room).

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PI 005-2 RECOMMENDATION ON GUIDANCE ON PARAMETRIC RELEASE (July 2004) APPENDIX I RECOMMENDATIONS FOR A GENERAL STERILITY ASSURANCE SYSTEM FOR TERMINALLY STERILISED PRODUCTS AND PROVISIONS FOR PARAMETRIC RELEASE 5. CONTROL OF PRESTERILIZATION BIOBURDEN 5.9 [VIP ID: 188288] The following elements should be carefully reviewed as they are often involved in loss of control of bioburden: (d) Microbiological monitoring. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING 7.3 Microbial Monitoring 7.3.1 [VIP ID: 188976] It is usually expected that a combination of the methods identified in the Annex 1 of the EU/PIC/S GMP guide for monitoring microbial levels is used in environmental monitoring programmes where appropriate. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. ENVIRONMENTAL MONITORING 10.1 [VIP ID: 190294] Environmental microbiological monitoring should include a combination of air and surface sampling methods, such as: active air sampling; settle (exposure) plates; surface contact (RODAC) plates, swabs or flexible films; operators' gloved hand plates.

EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) General 5 [Table and Notes] [VIP ID: 62680] Recommended limits for microbiological monitoring of clean areas during operation are provided in the table below. Recommended limits for microbial contamination (a) Grade Air sample cfu/m A B C D Notes (a) These are average values. (b) Individual settle plates may be exposed for less than 4 hours. <1 10 100 200
3

Settle plates (diam. 90 mm) cfu/4 hours (b) <1 5 50 100

Contact plates (diam. 55 mm), cfu/plate <1 5 25 50

Glove print 5 fingers, cfu/glove <1 5 -

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FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 6 [VIP ID: 49920] 6. Failure to follow written production and process control procedures [21 CFR 211.100(b)]. For example, - BMFG1413, "General Good Employee Practices", states: do not "bring in or use rusty racks, tools, furniture etc. in the clean areas";..."helps control particulate counts". However, Rust and corrosion was observed on the base and impeller blades on active air sampler, equipment no., which was observed in use in the critical manufacturing areas. Selected FDA 483 Observations (November 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 19770] Environmental monitoring should be performed in milling, blending and drying areas where APIs intended for parenteral use are exposed. FDA Warning Letter CBER-00-017 (March 2000) Extracted from FDA warning letter CBER-00-017 USA 16/03/2000 [VIP ID: 12690] Failure to establish separate or defined areas or other control systems for manufacturing and processing operations to prevent contamination or mix-up [21 CFR 211.42(c)(10)(iv)] in that surface environmental monitoring was not performed in the **** hoods where aseptic filling occurs. Selected FDA 483 Observations (January 2000) Sterile Product Manufacture [VIP ID: 137550] Environmental monitoring sampling should include curtains at locations where personnel move through to perform activities along a fill line. Extracted from FDA Warning Letter CHI-27-99 (July 1999) Extracted from FDA warning letter CHI-27-99 USA 09/07/1999 [VIP ID: 159920] Failure to have sufficient production and process controls or to establish procedures to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess as required by 21 CFR 211.100 and/or failure to establish procedures designed to prevent microbiological contamination as required by 21 CFR 211.113. For example: j. No microbial monitoring of air is done in the Class 100 area in the Smeja unloading rooms. Extracted from FDA Warning Letter CBER-99-013 (March 1999) Extracted from FDA warning letter CBER-99-013 UK 17/03/1999 [VIP ID: 159510] 2. Failure to establish an adequate system for monitoring environmental conditions of aseptic processing areas [21 CFR 211.42(c)(10)(iv) and 600.11(a)] in that active air sampling is not performed during aseptic filling but rather immediately after every filling operation. HUMAN DRUG CGMP NOTES, VOLUME 05, NUMBER 04 (December 1997) Motise's Notebook POLICY QUESTIONS: 4) [VIP ID: 4054] Has FDA identified an appropriate microbiological specification for monitoring critical surfaces in an aseptic area used to make sterile drug products? Reference: June, 1987 "Guideline on Sterile Drugs Produced by Aseptic Processing" Yes.

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Product, container, and closure contact surfaces are known as "critical surfaces." Microbiological monitoring of critical surfaces should yield zero colony forming units (CFUs). Firms often express this action limit as <1 CFU. FDA's 1987 "Guideline on Sterile Products Produced by Aseptic Processing" states: "Equipment surfaces which contact sterilized drug product or sterilized container/closure surfaces should, of course, be sterile. It is just as important in aseptic processing to properly validate sterilization processes applied to these equipment surfaces as it is to validate such processes for the drug product and container/closures." This standard can also be found in international publications such as the European Union's "Manufacture of Sterile Medicinal Products" (Annex I to the European Union Guide to Good Manufacturing Practice). Contact for further information: Richard L. Friedman, HFD- 322, 301-594-0095; e-mail: friedmanr@cder.fda.gov Selected FDA 483 Observations (January 1997) Sterile Product Manufacture [VIP ID: 135620] Environmental monitoring samples of critical aseptic filling areas should be collected at worst case locations and times, e.g.: a. Viable air samples and settling plate samples should be collected at locations where personnel are actively loading bottles onto the turntable and making adjustments to filling nozzles b. Viable air samples should be collected during aseptic connections c. Surface samples should be collected from areas where activity is performed. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) General Microbiological Monitoring Of Graded Areas [VIP ID: 1393] 5. Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods used in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation. GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. D. Procedures and Specifications for Media Fills 11. [VIP ID: 17430] 11. Microbiological monitoring The microbiological monitoring data obtained during the media fill runs should be provided (see section IV.F. of this guidance). GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. F. Microbiological Monitoring of the Environment. [VIP ID: 17470] 1. Microbiological Methods The microbiological materials and methods used in the environmental monitoring program should be described. Methods may include sample collection, transport, neutralization of sanitizers, incubation, and calculation of results. The following are sources of microbial contamination and their monitoring that should be addressed, including specifications: a. Airbourne microorganisms b. Microorganisms on inanimate surfaces c. Microorganisms on personnel d. Water systems

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e. Product component bioburden GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. F. Microbiological Monitoring of the Environment. [VIP ID: 17480] 2. Yeasts, Molds, and Anaerobic Microorganisms A description of periodic or routine monitoring methods used for yeasts, molds, and anaerobes should be provided. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 37. [VIP ID: 2189] Report the frequency of viable sampling using "active" sampling methods for: 1. exposed product areas 2. filling areas 3. surrounding areas CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 39. [VIP ID: 2191] Report the type of viable sampling equipment used (STA, Centrifugal sampler, etc.). CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 40. [VIP ID: 2192] Does the firm have data on the ability of these samplers to recover organisms without deleterious effect on survivability such as through impact or dessication of organisms or media? CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 57. [VIP ID: 2209] What type of contact surface monitoring devices are used (RODAC, swabs, etc.)?

5.

The exteriors of environmental monitoring plates should be sanitised before being set out in the aseptic areas.
Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 19930] The exteriors of environmental monitoring plates should be sanitized before being set out in the aseptic areas.

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6.

There should be incoming checks of Petri dishes to be utilised in preparation of environmental monitoring plates.
Selected FDA 483 Observations (October 2006) Sterile Product Manufacture [VIP ID: 193928] There should be incoming checks or specifications for filters used in sterile filtration and tubing used in the manufacturing of product, and for Petri dishes utilized in preparation of environmental monitoring plates.

7.

Suppliers of environmental monitoring plates should be audited.


Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 19940] Suppliers of environmental monitoring plates should be audited.

8.

Laboratory records should include a description of the sample received for testing, the source or location from where the sample was obtained, a unique identifier for the sample, the date and time the sample was taken and verification that the samples are incubated within the established period of time.
Selected FDA 483 Observations (August 2006) Laboratories [VIP ID: 193804] Laboratory records should include a description of the sample received for testing, the source or location from where the sample was obtained, the lot number or other distinctive code of the sample, and the date the sample was taken. For example, incubator logbooks should include sample identification to assure that the incubated samples, such as environmental and media fill samples, are incubated within the established period of time, and the laboratory should have an accurate inventory of the samples incubated in each incubator. Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124750] Read times and dates should be documented for environmental monitoring viable surface count plates and viable active air count plates to assure incubation times have been met.

9.

Active air samplers should be evaluated for their suitability for use in an aseptic environment based on collection efficiency, cleanability, ability to be sterilised, and disruption of unidirectional airflow.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 4. Monitoring Methods b. Active Air Monitoring [VIP ID: 111570] b. Active Air Monitoring ... Manufacturers should be aware of a device's air monitoring capabilities, and the air sampler should be evaluated for its suitability for use in an aseptic environment based on collection efficiency, cleanability, ability to be sterilized, and disruption of unidirectional airflow. [20] Because devices vary, the user should assess the overall suitability of a monitoring device before it is placed into service. Manufacturers should ensure that such devices are calibrated and used according to appropriate procedures. [20] For example, the volume of air sampled should be sufficient to yield meaningful measurements of air quality in a given environment.

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FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 6 [VIP ID: 49920] 6. Failure to follow written production and process control procedures [21 CFR 211.100(b)]. For example, - BMFG1413, "General Good Employee Practices", states: do not "bring in or use rusty racks, tools, furniture etc. in the clean areas";..."helps control particulate counts". However, Rust and corrosion was observed on the base and impeller blades on active air sampler, equipment no., which was observed in use in the critical manufacturing areas.

10. Other suitable microbiological test methods, such as USP, can be considered for environmental monitoring, if it is demonstrated that the methods are equivalent or better than traditional methods.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls D. Alternate Microbiological Test Methods [VIP ID: 111640] Other suitable microbiological test methods (e.g., rapid test methods) can be considered for environmental monitoring, in-process control testing, and finished product release testing after it is demonstrated that the methods are equivalent or better than traditional methods (e.g., USP).

11. An environmental monitoring programme should include alert/action limits and appropriate follow-up actions to be taken when they are reached.
GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. F. Microbiological Monitoring of the Environment. [VIP ID: 17490] 3. Exceeded Limits A description of the actions taken when specifications are exceeded should be provided. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. ENVIRONMENTAL MONITORING (para 1) [VIP ID: 2035] The environmental monitoring program for the sterile bulk drug substance manufacturer should be similar to the programs employed by the SVP industry. This includes the daily use of surface plates and the monitoring of personnel. As with the SVP industry, alert or action limits should be established and appropriate follow-up action taken when they are reached.

12. Environmental microbiological monitoring should include details of the testing locations and the identification of all isolated organisms in a format that facilitates early detection of trends.
Selected FDA 483 Observations (October 2004) Sterile Product Manufacture [VIP ID: 123790] SOPs for the viable sampling of Glove Boxes and Laminar Flow Hoods should provide for the collection of surface samples at the conclusion of aseptic activity.

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GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls B. Microbiological Media and Identification (para 1) [VIP ID: 111590] Characterization of recovered microorganisms provides vital information for the environmental monitoring program. Environmental isolates often correlate with the contaminants found in a media fill or product sterility testing failure, and the overall environmental picture provides valuable information for an investigation. Monitoring critical and immediately surrounding clean areas as well as personnel should include routine identification of microorganisms to the species (or, where appropriate, genus) level. In some cases, environmental trending data have revealed migration of microorganisms into the aseptic processing room from either uncontrolled or lesser controlled areas. Establishing an adequate program for differentiating microorganisms in the lesser-controlled environments, such as Class 100,000 (ISO 8), can often be instrumental in detecting such trends. At minimum, the program should require species (or, where appropriate, genus) identification of microorganisms in these ancillary environments at frequent intervals to establish a valid, current database of contaminants present in the facility during processing (and to demonstrate that cleaning and sanitization procedures continue to be effective). Selected FDA 483 Observations (August 2004) Sterile Product Manufacture [VIP ID: 122650] Environmental monitoring of aseptic processing areas should include: d. identification of organisms isolated from Class 100 locations, colony morphology is not enough. ... PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. ENVIRONMENTAL MONITORING 10.6 [VIP ID: 190304] Records should be maintained of the numbers and type of organisms isolated and results presented in a format that facilitates early detection of trends. Routine identification of environmental micro-organisms to at least the genus level should assist in detecting trends. Sensitive techniques such as molecular typing techniques will be required for identification of micro-organisms if equivalence of identity of environmental and test isolates is the sole rationale used to invalidate the original sterility test (refer to clause 13.1). Selected FDA 483 Observations (December 2003) Sterile Product Manufacture [VIP ID: 70670] Surfaces in aseptic processing rooms that are frequently contacted by filling operators during production, such as curtains, chairs, and plexiglass doors, should be included in the environmental monitoring program. Selected FDA 483 Observations (June 2000) Sterile Product Manufacture [VIP ID: 15660] Environmental monitoring should include: (1) trending of isolates Selected FDA 483 Observations (April 2000) Sterile Product Manufacture [VIP ID: 14670] Organisms isolated during personnel bioburden monitoring, gowning validation and routing gowning monitoring should be identified. Selected FDA 483 Observations (March 2000) Sterile Product Manufacture [VIP ID: 14540] Environmental monitoring of filling areas should include: (1) class 100 plastic curtains (2) entry ways for the filling area (3) product filling nozzles

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(4) rubber stopper bowl Selected FDA 483 Observations (June 1999) Sterile Product Manufacture [VIP ID: 7179] Plastic curtains enclosing class 100 laminar air flow areas should be included in environmental monitoring during filling. FDA Warning Letter CBER-99-002 (October 1998) Extracted from FDA warning letter CBER-99-002 USA 06/10/1998 [VIP ID: 12160] Failure to establish an adequate system for maintaining equipment used to control the aseptic process [21 CFR 211.42(c) (10)(vi) and 600.11(b)] in that there is no cleaning / sanitization validation for the non sterilizable vibratory bowl (stopper hopper) in the aseptic filling suite. In addition, the vibratory bowl is not included in the routine environmental monitoring program. Selected FDA 483 Observations (January 1998) Sterile Product Manufacture [VIP ID: 6248] Environmental monitoring of production areas and systems should include routine speciation of all organisms, not just those at or above alert/action levels. Selected FDA 483 Observations (July 1997) Medical Device Manufacture [VIP ID: 2535] Airborne and Surface Bioburden Monitoring of production areas should include: (1) a documented schedule and frequency for the monitoring and testing of the controlled environment (2) identification of the location and specific areas in which microbial sampling is performed (3) identification of isolated microorganisms CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 43. [VIP ID: 2195] Are recovered microorganisms routinely identified? To what level (genus, species)?

13. There should be written procedures covering the microbiological monitoring of the environment and surfaces in manufacturing areas, which specify the frequency of all types of monitoring, recording requirements, test location maps, exposure durations and the test media to be used, including inactivating agents, where required. These should be based on a scientific rationale.
Extracted from FDA warning letter CHI-3-07 (December 2006) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 5) [VIP ID: 194586] Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area as required by 21 CFR 211.42(c)(10)(iv). There is no documented explanation or justification for the selection of the surfaces defined in SOP [redacted] Monitoring of Surfaces," dated May 23, 2006, as "Class 100 Critical Sites." The four sites described as critical are surfaces on the in-feed turntable, two equipment platforms and the conveyor motor cover. The critical sites listed in the SOP do not include any surfaces that come in direct contact with the sterile product or sterile components. Your response indicates that you will continue to monitor the same sites until at least February 2007, and makes no commitment to monitor equipment surfaces that come in direct contact with the sterile product or sterile.

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Selected FDA 483 Observations (December 2006) Sterile Product Manufacture [VIP ID: 194098] Procedures for monitoring environmental conditions within aseptic areas should address when viable air monitoring is to be conducted (i.e. during dynamic or static operations) and should provide a scientific rationale to support surface sampling sites. Selected FDA 483 Observations (January 2006) Sterile Product Manufacture [VIP ID: 179430] Aseptic processing areas are deficient regarding the system for monitoring environmental conditions if: a. The SOP only requires monthly monitoring of the Class 10,000 room directly adjacent to the fill room, which can result in instances when more than 30 days can elapse without monitoring. b. The SOP requires the initiation of an investigation and corrective action only after two consecutive action levels are exceeded as the schedule for sampling may result in long periods of time between consecutive samplings of the same area. c. Growth promotion is not performed on the media used for sampling. d. Organisms isolated from Class 100 locations are not identified. It is insufficient only to determine colony morphology. e. Monitoring for anaerobic organisms is not performed. Extracted from FDA Warning Letter 06-NWJ-09 (December 2005) Extracted from FDA warning letter 06-NWJ-09 USA 14/12/2005 [VIP ID: 175560] 7. Failure to establish and maintain procedures to adequately control the environmental conditions, which could reasonably be expected to have an adverse affect on product quality as required by 21 CFR 820.70(c). For example: a. Your firm's sampling of airborne and surface microbes procedure (Document #060018, dated August 2, 2002) failed to explain how and when environmental monitoring of the packaging room [redacted] would be performed. In addition, the procedure does not specify the number of air samples that need to be collected (the procedure does not specify the specific sampling sites in each location for manufacturing and final packaging operations). Selected FDA 483 Observations (September 2005) Medical Device Manufacture [VIP ID: 178230] Procedures should be defined and documented for controlling environmental conditions, e.g. the monitoring of bioburden levels throughout the production areas. Selected FDA 483 Observations (June 2005) Sterile Product Manufacture [VIP ID: 140130] There should be a scientific rationale for the locations of the placement of viable air samplers and settling plates in aseptic filling suites. Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124760] There should be SOPs requiring the recording of read times and dates for environmental monitoring viable surface count plates and viable active air count plates. Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124780] There should be data to support the selected sampling points for environmental surface counts, viable airborne microorganisms and non viable particulate matter in the areas used in the filling of sterile diluents.

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PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. ENVIRONMENTAL MONITORING 10.3 [VIP ID: 190298] Location maps, exposure duration, and frequency of all types of microbiological environmental monitoring should be specified in written procedures. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 10. ENVIRONMENTAL MONITORING 10.4 [VIP ID: 190300] The media used for each type of monitoring should be specified and the recovery of micro-organisms on the chosen media should be validated. Suitable inactivators of disinfectants and cleaning solutions may need to be incorporated into recovery media used for samples taken from surfaces. Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121920] Microbiological surface sampling procedures should provide instructions regarding the frequency of sampling and the sites for sampling. Selected FDA 483 Observations (July 2000) Product Manufacture [VIP ID: 16150] Environmental monitoring procedures should include monitoring compounding and other manufacturing areas for the presence of objectionable organisms. GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. F. Microbiological Monitoring of the Environment. [VIP ID: 17460] The microbiological monitoring program used during routine production and media fills should be described. The frequency of monitoring, type of monitoring, sites monitored, alert and action level specifications, and precise descriptions of the actions taken when specifications are exceeded should be included. GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS - CGMPR'S (October 1993) 2. Environmental Controls (para 2) [VIP ID: 2670] Note: In the preparation of media for environmental air and surface sampling, suitable inactivating agents should be added. For example, the addition of penicillinase to media used for monitoring sterile penicillin operations and cephalosporin products. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 42. [VIP ID: 2194] Are settling plates used? Describe the length of exposure period; sampling frequency; location (including proximity to critical operations); microbial limits.

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CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 45. [VIP ID: 2197] What media are used? CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 46. [VIP ID: 2198] Are deactivators (e.g., penicillinase) used for antibiotics or other bacteriocidal/bacteriostatic substances? Has the firm shown that these are effective? (Are records available? Are calculations correct?) CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 56. [VIP ID: 2208] Does the firm have written procedures for the monitoring of product contact surfaces? STERILIZATION PROCESS VALIDATION - SUPERSEDED! (January 1993) II. Information for Aseptic Fill Manufacturing Processes Which Should Be Included in Drug Applications The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. F. [VIP ID: 3035] Describe the microbiological monitoring program used during routine production (and media fills if the monitoring program for media fills differs from routine monitoring). Include the frequency of monitoring, type of monitoring, sites monitored, alert and action level specifications, and precise descriptions of the actions taken when specifications are exceeded. Include air, surfaces, personnel, and water monitoring programs. Descriptions of the bioburden monitoring program should also be provided, including specifications. 1. Exact descriptions of the microbiological methods used in the environmental monitoring program should be provided so that an assessment of the results can be made in relationship to the methods used in obtaining the results. 2. A description of periodic or routine monitoring methods used for yeasts, molds, anaerobes, or other microbes, should be provided. Include specifications as applicable. 3. A description of the actions taken when specifications are exceeded should be provided.

14. Incidents which may cause environmental monitoring plates to be compromised should be recorded at the time they occur.
Selected FDA 483 Observations (May 1999) Sterile Product Manufacture [VIP ID: 7157] Incidents which may cause environmental monitoring plates to be compromised should be recorded at the time they occur.

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15. For manufacturing processes using spore-forming micro-organisms, environmental monitoring specific for the spore-forming micro-organism(s) must be conducted in adjacent areas during manufacturing operations and in the manufacturing area after completion of cleaning and decontamination.
21 CFR PART 600 - BIOLOGICAL PRODUCTS: GENERAL (April 2006) Subpart B--Establishment Standards Sec. 600.11 Physical establishment, equipment, animals, and care. (e) [VIP ID: 1854] Restrictions on building and equipment use (3) Work with spore-forming microorganisms. (i) Manufacturing processes using spore-forming microorganisms conducted in multiproduct manufacturing site must be performed under appropriate controls to prevent contamination of other products and areas within the site. Prevention of spore contamination can be achieved by using a separate dedicated building or by using process containment if manufacturing is conducted in a multiproduct manufacturing building. All product and personnel movement between the area where the sporeforming microorganisms are manufactured and other manufacturing areas must be conducted under conditions that will prevent the introduction of spores into other areas of the facility. (ii) If process containment is employed in a multiproduct manufacturing area, procedures must be in place to demonstrate adequate removal of the sporeforming microorganism(s) from the manufacturing area for subsequent manufacture of other products. These procedures must provide for adequate removal or decontamination of the spore-forming microorganisms on and within manufacturing equipment, facilities, and ancillary room items as well as the removal of diposable or product dedicated items from the manufacturing area. Environmental monitoring specific for the spore-forming microorganism(s) must be conducted in adjacent areas during manufacturing operations and in the manufacturing area after completion of cleaning and decontamination.

16. The use of ultraviolet lights in operating areas may mask a contaminant on a settling or aerobic plate. They may even contribute to the generation of a resistant (flora) organism. Thus, the use of Rodac or surface plates will provide more information on levels of contamination.
GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. ENVIRONMENTAL MONITORING (para 2) [VIP ID: 2036] There are some bulk drug substance manufacturers that utilize UV lights in operating areas. Such lights are of limited value. They may mask a contaminant on a settling or aerobic plate. They may even contribute to the generation of a resistant (flora) organism. Thus, the use of Rodac or surface plates will provide more information on levels of contamination.

17. There should be validation data to establish surface sampling sites and frequencies.
Selected FDA 483 Observations (June 2004) Sterile Product Manufacture [VIP ID: 121930] There should be validation data to establish surface sampling sites and frequencies.

18. It is important to observe operator activity over a period of time and ensure that microbial monitoring sites are located in and around areas of high operator activity.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING 7.3 Microbial Monitoring 7.3.2 [VIP ID: 188978] Microbial monitoring should be performed in and around areas of high operator activity. It is not unusual to see settle plates and air sample locations well away from such areas. A typical example is where settle plates are located well to the rear of the filling machine where there is little or no operator activity. The same may be true for air sampling. It is important, therefore, to observe operator activity over a period of time and ensure that the monitoring sites are so located as to monitor operator activity.

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19. Environmental monitoring samples should be taken from the areas of the filling equipment most likely to be contaminated and contain bioburdens, such as sites prone to spillage.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING 7.3 Microbial Monitoring 7.3.4 [VIP ID: 188982] A useful monitoring technique is to monitor the filling needles at the end of the filling session. Selected FDA 483 Observations (June 2000) Sterile Product Manufacture [VIP ID: 15370] Environmental monitoring samples should be taken from the areas of the filling equipment most likely to be contaminated and contain bioburdens (i.e.. Sites prone to spillage). Selected FDA 483 Observations (February 2000) Sterile Product Manufacture [VIP ID: 14250] Routine personnel viable monitoring programs within environmentally controlled areas for aseptically processed and terminally sterilized products should include the routine sampling of: (2) contact surfaces (such as filling heads and the inside the stopper bowl)

20. Environmental monitoring of critical surfaces, including those in product contact, should be performed during or at the conclusion of operations, not at the beginning (before processing) or end of a shift (following sanitisation).
Selected FDA 483 Observations (August 2000) Sterile Product Manufacture [VIP ID: 16520] Environmental monitoring of critical surfaces (to include product contact) should be performed during or at the conclusion of operations, not at the beginning (before processing) or end of a shift (following sanitization). GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) V. EQUIPMENT (para 6) [VIP ID: 2033] Another potential problem with SIP systems is condensate removal from the environment. Condensate and excessive moisture can result in increased humidity and increases in levels of microorganisms on surfaces of equipment. Therefore, it is particularly important to review Environmental monitoring after sterilization of the system. GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. ENVIRONMENTAL MONITORING (para 4) [VIP ID: 2038] As previously discussed, it is not unusual to see the highest level of contamination on the surfaces of equipment shortly after systems are steamed. If this occurs, the cause is usually the inadequate removal of condensate.

21. It is important that alert and action levels for all microbiological contaminants found in monitoring samples are established and defined, based on validation studies and historical data, and that investigations are performed into the causes of contamination at the time of inspection.
Selected FDA 483 Observations (February 2007) Sterile Product Manufacture [VIP ID: 194332] If an out-of-specification environmental monitoring result is obtained for viable particulates during routine monitoring, it should be identified and investigated at the time of inspection.

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Extracted from FDA Warning Letter 320-05-02 (August 2005) Extracted from FDA warning letter 320-05-02 Switzerland 16/08/2005 [VIP ID: 171150] 6. Unexplained discrepancies were not adequately investigated by the quality control unit. 21 CFR 211.192 Microbiological test results for personnel and environmental monitoring that exceed your firm's action level were not investigated and were inadequately investigated, respectively. We acknowledge your statement that you will conduct an internal review of your deviation reporting and to investigate all OOS results. However, we want to emphasize the importance of good documentation in relation to investigating deviations. Selected FDA 483 Observations (February 2005) Sterile Product Manufacture [VIP ID: 128770] Microbial operational alert limits for Class 1,000 to 100,000 areas and the action limits for personnel gowning should be based on historical Environmental Monitoring (EM) data. FDA Warning Letter [NO REFERENCE] (February 2005) Extracted from FDA warning letter USA 25/02/2005 [VIP ID: 135000] 3. Failure to establish and maintain procedures to investigate the cause of nonconformities relating to product, processes, and the quality system, as required by 21 CFR 820.100(a)(2).For example, between [redacted] through [redacted] your firm took four corrective actions as a result of high microbial counts found in the controlled environment room but failed to investigate the root cause of the high counts. Also, during our review of 5 of your firm's 140 Quality Strategic Response (QSR) reports, the Investigator observed that your firm failed to investigate the root cause of high microbial counts noted during the monthly environmental monitoring program although corrective action was taken. Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 125000] Microbial "alert" and "action" levels should be based on historical environmental monitoring program data. Selected FDA 483 Observations (December 2004) Sterile Product Manufacture [VIP ID: 124540] Microbial action levels for manufacturing aseptic areas and surrounding support areas should be based on current historical Environmental Monitoring (EM) data. FDA Warning Letter CBER-05-006 (December 2004) Extracted from FDA warning letter CBER-05-006 USA 09/12/2004 [VIP ID: 133130] 1. Your facilitys quality control unit failed to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated; the quality control unit also failed to investigate thoroughly any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications [21 CFR 211.22 and 211.192] For example: a) The quality control units investigation of Fluvirin sterility failures (Fluvirin Sterility Failure Investigation Report #R/0198/04, October 9, 2004) concluded that [redacted] fumigation of your facilitys formulation areas on May 17, 2004 'was successful' as confirmed by your ongoing environmental monitoring program. Yet environmental data from April 2004 through September 2004 for formulation rooms [redacted] and [redacted] indicate continued alert and action level excursions for gram negative organisms, including but not limited to Serratia spp. FDA Warning Letter CBER-05-006 (December 2004) Extracted from FDA warning letter CBER-05-006 USA 09/12/2004 [VIP ID: 133150]

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1. Your facility's quality control unit failed to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated; the quality control unit also failed to investigate thoroughly any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications [21 CFR 211.22 and 211.192] For example: c) The Fluvirin sterility failure investigation conducted by the quality control unit failed to address the fact that numerous monovalent blend pools (over 50%) used from March 2004 through October 2004 exceeded your firms bioburden alert level ([redacted] cfu / ml). The quality control unit did not thoroughly investigate the environmental monitoring excursions during filling for Fluvirin lots [redacted] and [redacted]. The non-conformance reports were limited to review of the filling activity for each specified lot. There was no investigation in these non-conformance reports of aseptic filling area environmental monitoring excursions that occurred for other lots between September 2004 and October 2004, and which subsequently resulted in the rejection of the lots. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities A. Critical Area - Class 100 (ISO5) (para 8) [VIP ID: 110250] Air monitoring samples of critical areas should normally yield no microbiological contaminants. We recommend affording appropriate investigative attention to contamination occurrences in this environment. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 1. General Written Program (para 4) [VIP ID: 111470] Environmental monitoring methods do not always recover microorganisms present in the sampled area. In particular, low-level contamination can be particularly difficult to detect. Because false negatives can occur, consecutive growth results are only one type of adverse trend. Increased incidence of contamination over a given period is an equal or more significant trend to be tracked. In the absence of any adverse trend, a single result above an action level should trigger an evaluation and a determination about whether remedial measures may be appropriate. In all room classes, remedial measures should be taken in response to unfavorable trends. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 2. Establishing Levels and a Trending Program (para 1) [VIP ID: 111490] Microbiological monitoring levels should be established based on the relationship of the sampled location to the operation. The levels should be based on the need to maintain adequate microbiological control throughout the entire sterile manufacturing facility. One should also consider environmental monitoring data from historical databases, media fills, cleanroom qualification, and sanitization studies, in developing monitoring levels. Data from similar operations can also be helpful in setting action and alert levels, especially for a new operation. Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 70910] Warning and action limits for sampling plates used to monitor the bioburden on the floors, walls, and machinery surfaces in the manufacturing areas should be based on the results of validation studies.

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FDA Warning Letter DEN-03-16 (May 2003) Extracted from FDA warning letter DEN-03-16 USA 08/05/2003 [VIP ID: 56180] Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70(c). For example, the results of environmental testing performed in 2001 and 2002 as listed in the "Viable Air/ Surface Plate Survey Report," indicated several instances of "uncountable overgrown" and "lawn" plates. The procedure, "Validation of Limited Access Areas" states if the test results are over the maximum microbiological contaminant level [redacted], the [redacted] will complete a "White Room Discrepancy Notice" and forward it to the White Room Supervisor. However, this procedure does not define what is meant by "overgrown," "lawn," or "too numerous to count." The procedure also does not describe what corrective actions the White Room Supervisor is to take if the monitoring limits are exceeded." [Investigator: Lori A. Medina]. FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 9 [VIP ID: 49950] 9. Failure to establish and follow adequate procedures describing the handling of complaints related to drug products [21 CFR 211.198]. For example, BQA0014 "Handling of Product Complaints and WIP Shipment Complaints" does not describe the level of investigation to perform when product complaints describing particulate matter in injectable products are received. This appears to be a persistent problem. In a previous inspection, after a complaint was received regarding mold in the product, the presence of mold was confirmed by analysis. The investigation did not indicate any review or evaluation of environmental monitoring data as a result of the confirmation that there was mold growth on the caps or any attempt to ascertain the source of the mold.

Extracted from FDA Warning Letter 99-PHI-36 (September 1999) Extracted from FDA warning letter 99-PHI-36 USA 28/09/1999 [VIP ID: 160120] 3. Failure to thoroughly investigate exceeded environmental monitoring action levels in the sterile filling room in which meperidine HCI injection lot [redacted] was filled. The inspection revealed that your firms environmental monitoring found mold, [redacted] species, on the floor which exceeded your firms action levels for that surface. Post-inspectional correspondence from your firm states that the exceeded action levels were associated with environmental sampling conducted prior to filling the meperidine HCl and that floor samples taken during filling were negative for growth. However, documentation for samples taken during filling shows that the areas where positive growth was found prior to filling (south, east, west, and center floors) were not sampled. There is no documentation that additional disinfection was done between samplings. Although your firm believes that these floor counts did not impact the aseptic filling operations because of negative environmental monitoring results for critical surfaces, personnel, and air, such monitoring cannot provide a complete overview of the room conditions. Our review of the literature found that [redacted] spp. can contaminate water damaged, cellulose-containing building materials. The literature reports it can be an opportunistic pathogen in immunocompromised individuals and references a 1988 incident regarding [redacted] spp. contamination of the air system and the HEPA filters in a hospitals oncology-hematology special care unit. Four bone marrow transplant recipients were subsequently infected. We note that the West Chester facility has had water leaks above the ceilings in the sterile core, has had periodic breaks in sterile conditions (to change HEPA filters or otherwise access ceilings), and has identified the presence of [redacted] spp. as part of a trend in the sterile environment between [redacted] and [redacted]. Given that mold spores can become aerosolized, we have concerns regarding the source of the contamination. If it is above the sterile core ceilings, there is a potential for impact to the critical surfaces. Your firm maintains that a ceiling or HEPA filter route of contamination is not likely because air and surface monitoring, with the exception of the floors, have been negative for [redacted] spp. contamination. We have not, to date, received any information from your firm regarding any investigation into possible contamination in the ceilings and/or HEPA filters or other potential source of this mold. We believe that cGMP requires additional vigilance in this area.

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Selected FDA 483 Observations (April 1999) Sterile Product Manufacture [VIP ID: 7129] Microbial contaminant limits for surface counts should be based on historical trending of environmental monitoring data. FDA Warning Letter [NO REFERENCE] (January 1999) FDA Warning Letter [NO REFERENCE] USA 14/01/1999 [VIP ID: 159200] 1) Quality Control/Assurance has not consistently discharged their responsibilities for overseeing procedures impacting on quality and purity as follows: a) They failed to recognize and investigate significant environmental trends and out-of-specification microbial results in sterile areas. For example, environmental monitoring data identifies [redacted] instances of microbial contamination of critical equipment surfaces during the prior 9 months, [redacted] of which involved contamination of the filling needle area. On 8/28/98 microbial contamination was identified on five critical sites in fill room 3, including [redacted] CFU on one employees gloves, [redacted] CFU on the [redacted], [redacted] CFU on the filling needle area, [redacted] CFU on the turntable, [redacted] CFU on the alcohol container. ... Selected FDA 483 Observations (June 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6368] Gram staining should be routinely conducted when environmental limits are exceeded. GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) II. INFORMATION FOR TERMINAL MOIST HEAT STERILIZATION PROCESSES The following information should be submitted for each facility to be used in the manufacture of the proposed drug product: D. Microbiological Monitoring of the Environment (para 1) [VIP ID: 17030] Section 211.160 of the Code of Federal Regulations requires, in part, the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to ensure that components, drug product containers, closures, in-process materials, and drug products conform to appropriate quality standards. Therefore, a microbiological monitoring program for production areas along with a bioburden monitoring program for product components and process water should be established. Process water includes autoclave cooling water. Applicants should provide information concerning this program. Frequency, methods used, action levels, and data summaries should be included. A description of the actions taken when specifications are exceeded should be provided.

22. The adequacy of disinfection procedures should be evaluated using a routine environmental monitoring programme.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls A. Environmental Monitoring 3. Disinfection Efficacy (para 3) [VIP ID: 111550] Disinfection procedures should be described in sufficient detail (e.g., preparation, work sequence, contact time) to enable reproducibility. Once the procedures are established, their adequacy should be evaluated using a routine environmental monitoring program. If indicated, microorganisms associated with adverse trends can be investigated as to their sensitivity to the disinfectants employed in the cleanroom in which the organisms were isolated. Selected FDA 483 Observations (April 1997) Medical Device Manufacture [VIP ID: 136380] Surface bio-burden should be used to determine the effectiveness of cleaning and sanitization procedures in maintaining controlled environment conditions.

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23. Additional monitoring around the affected area prior to disinfection may provide useful information as to the cause.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING 7.3 Microbial Monitoring 7.3.5 [VIP ID: 188984] Additional monitoring around the affected area prior to disinfection may provide useful information as to the cause.

24. The process simulation test, which should include the various interventions that are known to occur during normal production runs, will provide an ideal opportunity to confirm that worst case locations have been identified, by the use of additional monitoring during the test.
PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING 7.3 Microbial Monitoring 7.3.3 [VIP ID: 188980] The process simulation test provides an ideal opportunity to confirm that worst case locations have been identified by the use of additional monitoring during the test. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 7. ENVIRONMENTAL AND PERSONNEL MONITORING 7.4 Intervention Monitoring 7.4.1 [VIP ID: 188986] It is essential to include in a simulation test the various interventions that are known to occur during normal production runs, e.g. repair or replacement of needles/tubes, replacement of on-line filters, microbial sampling by monitoring personnel and sampling device, duration of stops on the line, filling and handling of stoppers etc. GUIDANCE FOR INDUSTRY FOR THE SUBMISSION DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG PRODUCTS (November 1994) IV. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. D. Procedures and Specifications for Media Fills 11. [VIP ID: 17430] 11. Microbiological monitoring The microbiological monitoring data obtained during the media fill runs should be provided (see section IV.F. of this guidance). STERILIZATION PROCESS VALIDATION - SUPERSEDED! (January 1993) II. Information for Aseptic Fill Manufacturing Processes Which Should Be Included in Drug Applications The following types of information should be submitted in support of sterility assurance for products manufactured by aseptic processing. D. [VIP ID: 3033] Provide procedures and specifications used for media fills, and summaries of results for validations using the same container/closure system and filling process that is to be used for the product in question. Provide details of the microbiological testing method(s) used. Any procedural differences between the media fill and the production process should be indicated. A summary of recent media fill results, including failures, should be provided. These data should be obtained using the same filling line(s) that are to be used for the product in question. Briefly describe the routine media fill program for existing filling lines including acceptance specifications. The following details should be included with the data summary for each media fill run described: 11. Microbiological monitoring data obtained during the media fill run. See F below for further details.

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25. Supervisors should ensure that all personnel are initially qualified in gowning procedures, that they are monitored to verify they follow Standard Operating Procedures (SOPs), that alert and action limits are established for personnel monitoring, that out-of-specification results are trended and that personnel undergo periodic recertification.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. Personnel Training, Qualification and Monitoring A. Personnel (para 5) [VIP ID: 110640] There should be an established program to regularly assess or audit conformance of personnel to relevant aseptic manufacturing requirements. An aseptic gowning qualification program should assess the ability of a cleanroom operator to maintain the quality of the gown after performance of gowning procedures. We recommend that this assessment include microbiological surface sampling of several locations on a gown (e.g., glove fingers, facemask, forearm, chest). Sampling sites should be justified. Following an initial assessment of gowning, periodic requalification will provide for the monitoring of various gowning locations over a suitable period to ensure consistent acceptability of aseptic gowning techniques. Annual requalification is normally sufficient for those automated operations where personnel involvement is minimized and monitoring data indicate environmental control. For any aseptic processing operation, if adverse conditions occur, additional or more frequent requalification could be indicated. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. Personnel Training, Qualification and Monitoring C. Monitoring Program (para 1) [VIP ID: 110670] Personnel can significantly affect the quality of the environment in which the sterile product is processed. A vigilant and responsive personnel monitoring program should be established. Monitoring should be accomplished by obtaining surface samples of each operator's gloves on a daily basis, or in association with each lot. This sampling should be accompanied by an appropriate sampling frequency for other strategically selected locations of the gown (Ref. 5). The quality control unit should establish a more comprehensive monitoring program for operators involved in operations which are especially labor intensive (i.e., those requiring repeated or complex aseptic manipulations). PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 7. TRAINING 7.2 [VIP ID: 190242] Supervisors should ensure that all personnel are monitored and follow Standard Operating Procedures (SOPs). Personnel should undergo periodic re-certification, particularly when problems are detected during the course of routine environmental and negative control monitoring, or when operators perform the test infrequently. Selected FDA 483 Observations (January 2004) Sterile Product Manufacture [VIP ID: 72330] Gowning Monitoring Programs for Parenteral Aseptic Areas should consider sampling the chest, palm (left and right) and fingertips (left and right) of personnel returning from lunch breaks. HEALTH CANADA - GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.4 SANITATION - C.02.007 & C.02.008 2.4.7 [VIP ID: 65750] CLOTHING: IS IT ACCEPTABLE TO HAVE TWO LEVELS OF CLOTHING IN THE NON-STERILE MANUFACTURING AREAS, i.e. ONE LEVEL FOR OPERATORS WITH FULL GOWNING AND COVERALLS AND ANOTHER LEVEL FOR QA AUDITORS AND VISITORS? WHAT ENVIRONMENTAL MONITORING DATA IS REQUIRED? Yes. There are basic clothing requirements for any person entering the manufacturing areas, such as hair, mustache and beard covering, as well as protective garments. However, a firm may decide to apply more stringent requirements for operators, such as dedicated shoes and garments providing a higher level of protection. There are no specific environmental monitoring requirements for clothing worn in the non-sterile manufacturing areas.

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Selected FDA 483 Observations (July 2000) Sterile Product Manufacture [VIP ID: 15800] Environmental monitoring of personnel should trend out-of-specification results between employee gloves and gowns. Selected FDA 483 Observations (February 2000) Sterile Product Manufacture [VIP ID: 14250] Routine personnel viable monitoring programs within environmentally controlled areas for aseptically processed and terminally sterilized products should include the routine sampling of: (1) operators gowns and masks. Selected FDA 483 Observations (January 2000) Sterile Product Manufacture [VIP ID: 137560] Finger dab samples should be collected from personnel performing aseptic connections on filling equipment immediately after the connections are made. Selected FDA 483 Observations (October 1999) Sterile Product Manufacture [VIP ID: 7750] Personnel monitoring SOPs should require an action condition for a single excessively high glove count or any adverse trend. Selected FDA 483 Observations (May 1999) Sterile Product Manufacture [VIP ID: 7158] Gloves used for aseptic addition of sterile powder should be tested prior to changing. FDA Warning Letter [NO REFERENCE] (January 1999) FDA Warning Letter [NO REFERENCE] USA 14/01/1999 [VIP ID: 159200] 1) Quality Control/Assurance has not consistently discharged their responsibilities for overseeing procedures impacting on quality and purity as follows: b) They failed to assure that SOPs are followed which prohibit employees who fail gown testing during media fills from working in the sterile core until they are retrained. For example, one employee failed gown testing on 7/22/98 and was not retrained until 10/9/98; another employee failed gown testing on 7/23/98 and was not retrained until 10/5/98. This employee also exceeded action limits for gloves during actual product filling on [redacted] other occasions in the 9 months before the date of retraining, including a microbial count of [redacted] on 9/14/98. This is the same employee mentioned in 1(a) above who had [redacted] CFU on gloves on 8/28. Both employees continued to work in the sterile core before retraining occurred. The failure to recognize serious environmental trends and make informed judgments is very clearly demonstrated when employees were permitted to work in the sterile core despite known problems with maintaining sterile technique. One of these employees repeatedly exceeded microbial action limits but was permitted to routinely operate in the sterile core without consideration of the potential impact on finished product. ... Selected FDA 483 Observations (December 1997) Sterile Product Manufacture [VIP ID: 136530] Environmental monitoring procedures should include periodic monitoring of the back and wrist areas of gloved hands. Selected FDA 483 Observations (December 1997) Sterile Product Manufacture [VIP ID: 136540] Environmental monitoring procedures should include periodic monitoring of personnel after performing aseptic connections.

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CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 53. [VIP ID: 2205] How often is monitoring performed on filling room personnel? CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 54. [VIP ID: 2206] What are the firm's alert and action limits for personnel monitoring? GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Filling (para 3) [VIP ID: 2755] Because of the active involvement of people in filling and aseptic manipulations, an environmental program should also include an evaluation of microbiological levels on people working in aseptic processing areas. One method of evaluation of the training of operators working in aseptic processing facilities includes the surface monitoring of gloves and / or gowns on a daily basis. Manufacturers are actively sampling the surfaces of personnel working in aseptic processing areas. A reference which provides for this type of monitoring is the USP XXII discussion of the Interpretation of Sterility Test Results. It states under the heading of "Interpretation of Quality Control Tests" that review consideration should be paid to environmental control data, including ... microbial monitoring, records of operators, gowns, gloves, and garbing practices. In those situations in which manufacturers have failed to perform some type of personnel monitoring, or monitoring has shown unacceptable levels of contamination, regulatory situations have resulted.

26. Systems should be in place to assure that all personnel are monitored at exit from an aseptic zone and, where self monitoring is performed, proper procedures are followed for monitoring of gloves and gowns.
Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 125010] Microbial environmental monitoring samples should be routinely taken from production personnel working in filling operations. Selected FDA 483 Observations (November 2003) Sterile Product Manufacture [VIP ID: 70270] All personnel entering aseptic processing areas should be monitored at least once each day, to include personnel who enter the aseptic processing areas but do not directly perform work in the filling area (examples included engineering and equipment preparation personnel). Selected FDA 483 Observations (November 2002) Sterile Product Manufacture [VIP ID: 50990] Systems should be in place to assure that all personnel are monitored at exit from the aseptic zone and where self monitoring is performed proper procedures are followed for monitoring of gloves and gowns. FDA Warning Letter 2003-DAL-WL-01 (October 2002) Extracted from FDA warning letter 2003-DAL-WL-01 USA 15/10/2002 3 [VIP ID: 49890] 3. Failure to avert contamination in separate or defined areas designed to prevent contamination from occurring during manufacturing and processing operations [21 CFR 211.42(c)(5)]. For example

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- The controlling and monitoring of the movement and ingress of personnel, including maintenance personnel, components, and ancillary materials, such as tools necessary for equipment repairs / adjustments into the **** filling areas is not being performed.

27. If processing of a sterile bulk drug substance occurs around the clock, microbiological monitoring of surfaces and personnel during the second and third shifts should be routine.
GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. ENVIRONMENTAL MONITORING (para 5) [VIP ID: 2039] Since processing of the sterile bulk drug substance usually occurs around the clock, monitoring surfaces and personnel during the second and third shifts should be routine.

28. Protective garments should be changed for each work session or at least once a day, if justified from the results of microbiological monitoring and validation studies.
FDA Warning Letter [NO REFERENCE] (February 2005) Extracted from FDA warning letter USA 25/02/2005 [VIP ID: 134960] 1. Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70(c). For example: b. Our Investigator observed employees who did not wear shoe covers and wore the same shoes as they wore outside the facility into the 'white area.' [redacted] does not require that employees working in the, 'white area' wear shoe covers. Your firm stated that [redacted] evaluated the effects of shoe covers on the environment in the clean room and on product bioburden and determined that eliminating the practice of wearing shoe covers appeared to have reduced the product's bioburden and recommended that this employee gowning practice be eliminated. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.2 AIRLOCK AND ASEPTIC GOWNING 8.2.2 Aseptic gowning 8.2.2.2 [VIP ID: 190266] Protective garments should be changed for each work session or at least once a day if justified from the results of microbiological monitoring and validation studies.

29. Environmental monitoring media residues should be removed from operator gowns prior to them returning to a production area.
Selected FDA 483 Observations (April 1999) Sterile Product Manufacture [VIP ID: 7117] Environmental monitoring media residues should be removed from operator gowns prior to them returning to a production area.

30. Environmental monitoring gowning failures should be evaluated against product sterility issues.
Selected FDA 483 Observations (June 2001) Sterile Product Manufacture [VIP ID: 27780] Environmental monitoring gowning failures should be evaluated against product sterility issues.

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31. Clean room personnel should not sanitise their hands immediately prior to touching finger touch plates used for personnel monitoring.
Selected FDA 483 Observations (October 2007) Sterile Product Manufacture [VIP ID: 193922] Clean room personnel should not sanitise their hands immediately prior to touching finger touch plates used for personnel monitoring.

32. For the sampling of critical surfaces, such as operators' gloves, the averaging of results on plates is unacceptable.
GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS (July 1994) VI. ENVIRONMENTAL MONITORING (para 3) [VIP ID: 2037] There are some manufacturers that set alert/action levels on averages of plates. For the sampling of critical surfaces, such as operators' gloves, the average of results on plates is unacceptable. The primary concern is any incidence of objectionable levels of contamination that may result in a non-sterile product.

33. Environmental monitoring procedures should address the actions to be taken when operators exceed specified levels of contamination, and the disqualification and subsequent requalification of aseptic operators, when repeated alert and action limits are reported for them over time.
Extracted from FDA Warning Letter 2005-DAL-WL-22 (August 2005) Extracted from FDA warning letter 2005-DAL-WL-22 USA 04/08/2005 [VIP ID: 170620] 3. Failure to establish and maintain adequate complaint handling procedures for receiving, reviewing, and evaluating complaints by a formally designated unit and to ensure that all the requirements of 21 CFR 820.198(a) through (e) are met [FDA-483 Items 4 and 5]. For example, prior to our current inspection, FDA and CDC notified your firm of a report of patient infections associated with your devices contaminated with fluorescens. Since the initial FDA and CDC notifications to your firm, additional cases of patient infections were reported. This information was communicated to your firm by our office and during the inspection and was communicated to the public in three FDA press releases, dated January 31, February 4, and February 8, 2005. At the conclusion of our inspection, your firm had not (b) conducted microbiological testing of the quarantined devices, including recalled devices, all device components and raw materials, and manufacturing environments to determine the extent of bacterial contamination in your devices and where and why the contamination occurred in your device manufacturing process or the compounding pharmacy's drug manufacturing process. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) V. Personnel Training, Qualification and Monitoring C. Monitoring Program (para 2) [VIP ID: 110680] Asepsis is fundamental to an aseptic processing operation. An ongoing goal for manufacturing personnel in the aseptic processing room is to maintain contamination-free gloves and gowns throughout operations. Sanitizing gloves just prior to sampling is inappropriate because it can prevent recovery of microorganisms that were present during an aseptic manipulation. When operators exceed established levels or show an adverse trend, an investigation should be conducted promptly. Follow-up actions can include increased sampling, increased observation, retraining, gowning requalification, and in certain instances, reassignment of the individual to operations outside of the aseptic manufacturing area. Microbiological trending systems, and assessment of the impact of atypical trends, are discussed in more detail under Section X. Laboratory Controls. Selected FDA 483 Observations (June 2000) Sterile Product Manufacture [VIP ID: 15640] Environmental monitoring procedures should address the disqualification and subsequent requalification of aseptic operators when repeated alert and action limits are reported for them over time.

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34. Microbiological monitoring should also include the aseptic area of the laboratory and personnel and any upward trends in its microbial load should be promptly investigated as to cause, and corrected.
GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) XI. Sterility Testing C. Investigation of Sterility Positives (para 3) 2. [VIP ID: 111790] 2. Record of Laboratory Tests and Deviations Microbial monitoring of the aseptic area of the laboratory and personnel can also reveal trends that are informative. Upward trends in the microbial load in the aseptic area of the laboratory should be promptly investigated as to cause, and corrected. In some instances, such trends can appear to be more indicative of laboratory error as a possible source of a sterility test failure.

35. The European Pharmacopoeia only permits a repeat sterility test if certain criteria are satisfied, including the data of the microbiological monitoring of the sterility testing facility showing a fault.
PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 13. INTERPRETATION AND REPEAT TESTS 13.1 [VIP ID: 190378] A test may be repeated only when it can be demonstrated that the test was invalid for causes unrelated to the product being examined. The European Pharmacopoeia[1] restricts criteria to one or more of the following conditions only: (a) the data of the microbiological monitoring of the sterility testing facility show a fault; [1]. European Pharmacopoeia, Third Edition. Supplement 1998, Council of Europe, Strasbourg.

36. Sterility Test Failure investigations should include, but not be limited to, a review of environmental monitoring results at the time of failure.
Extracted from FDA warning letter CHI-3-07 (December 2006) Extracted from FDA warning letter CHI-3-07 USA 18-Dec-06 2) a. ii) [VIP ID: 194572] Failure to thoroughly investigate or maintain a written record of the investigation of any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has been distributed, and the failure to extend the investigation to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy as required by 21 CFR 211.192. Examples of your failure to conduct adequate investigations, and notably, to properly extend failure investigations to all associated batches or product are discussed below. a) Investigations of two positive sterility tests did not determine conclusive or probable root causes for the contamination. Although root causes were not determined, both investigations conclude that "the impact of the sterility test positive was isolated to the affected batch" and all other batches placed on hold when the test failures were found were released for distribution. However, significant errors that impact directly on the determination of the potential scope of the sterility assurance problem were noted with each investigation as follows. ii) Progesterone Injection, USP, Lot [redacted]. The lot was aseptically filled on Line 4 on April 26, 2006. The contaminating organism was identified as Bacillus pumilus, which is one of the primary microbiological contaminants identified in the multiple media fill failures investigated under [redacted]. The investigation of this sterility failure fails to mention this correlation and does not discuss the impact of a new adverse trend with regard to the detection of this problematic organism. The organism was detected nine times in 2006, and seven of the nine samples were in the same month of manufactures as the failed lot, including a viable air sample in the aseptic core of an adjacent filling line the day after the manufacture of this batch. The investigation also also incorrectly associates this sample result with the detection sample. These deficiencies in the investigation, which also have a bearing on the scope of lots potentially implicated by the sterility failure, were not detected by those reviewing and approving the final report.

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Extracted from FDA Warning Letter 320-05-03 (July 2005) Extracted from FDA warning letter 320-05-03 Italy 21/07/2005 [VIP ID: 169250] 7. Sterility complaint investigation reports failed to identify and discuss any possible correlation of the sterility test isolate with microorganisms found in your firm's environmental and personal monitoring. 21 CFR 211.198 Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 128310] lnvestigations into initial sterility test failures should: (1) include an evaluation of environmental monitoring conducted at the time of the filling operation (2) include an attempt to associate the organisms isolated from the sterility failures to organisms isolated previously from the environment. (3) address corrective actions relating to personnel GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) XI. Sterility Testing C. Investigation of Sterility Positives (para 3) 3. [VIP ID: 111800] 3. Monitoring of Production Area Environment Trend analysis of microorganisms in the critical and immediately adjacent areas is especially helpful in determining the source of contamination in a sterility failure investigation. Consideration of environmental microbial data should not be limited to results of monitoring the production environment for the lot, day, or shift associated with the suspect lot. For example, results showing little or no recovery of microorganisms can be misleading, especially when preceded or followed by a finding of an adverse trend or atypically high microbial counts. It is therefore important to look at both short- and long-term environmental trend analyses. Selected FDA 483 Observations (October 1999) Sterile Product Manufacture [VIP ID: 7980] Sterility Test Failure investigations should include: (1) review of environmental monitoring results for the failing day (2) corrective actions (3) indication of probable causes and corrective action where no identifiable cause is determined

37. Quality control procedures for the control of media to be used in microbiological monitoring should be strictly followed.
FDA Warning Letter 2001-DT-07 (January 2001) Extracted from FDA warning letter 2001-DT-07 USA 16/01/2001 [VIP ID: 28430] 4. 211.194 Laboratory Controls-Laboratory Records The laboratory records fail to consistently and accurately include complete data derived from all tests necessary to assure compliance with specifications and standards. Examples from the FDA-483 are: d. Item 11. Procedure (CM 1) for the quality control of media was not always followed in that expired media was used, different test organisms than specified were used as positive controls, and negative and positive control testing was not performed. 211.194(a)(8) f. Item 16. Analysts notebooks failed to always document the following pertinent information: 1. person performing the analysis 211.194(a)(7) 2. analytical method used 211.194(a)(2) 3. media and inhibitory agents used including lot numbers and dates made 211.194(c) 4. sample amount used for analysis 211.194(a)(3)

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5. incubator used and its temperature 211.194(d) 6. the incubation start and end date 211.194(d) g. Item 17. Analysts notebooks fail to document individual plate results when an average of the two was reported as the test result. 211.194(4)&(5) [FDA Investigators: Renee L. Rice and Miah I. Schneider]

38. Data should be established to demonstrate the suitability of methods of transportation and incubation of environmental monitoring agar plates for surface and air monitoring.
Selected FDA 483 Observations (June 2005) Sterile Product Manufacture [VIP ID: 140110] Data should be established to demonstrate the suitability of using film wax sheets in the transportation / incubation of environmental monitoring agar plates for surface and air monitoring, or other wrap techniques (that completely seals the Petri dishes so to minimize the availability of oxygen to the growing microorganisms on the agar surface). Selected FDA 483 Observations (March 2005) Sterile Product Manufacture [VIP ID: 137990] Procedures specifying the submission of environmental samples to the laboratory for incubation within a set time period of collection, should be based on data supporting the upper time limit specified.

39. Tests should be performed on media to assure that it is capable of supporting microbial growth and details of media handling and incubation methods should be available.
Extracted from FDA Warning Letter 320-05-02 (August 2005) Extracted from FDA warning letter 320-05-02 Switzerland 16/08/2005 [VIP ID: 171160] 7. Laboratory controls did not include scientifically sound and appropriate test procedures designed to assure that components, in-process materials, and drug products conform to appropriate standards of identity, strength, quality, and purity. 21 CFR 211.160 Growth promotion testing was not performed on microbiological testing media, there was no assurance that yeast and mold will grow at the [redacted] incubation temperature used to detect bacteria growth, microorganisms found during environmental testing were not identified, and the [redacted] analytical method used on eye drops and nasal spray was not fully validated. Your proposed corrections appear acceptable pending our receipt and review of supporting documentation. It is important to note that failure to conduct growth promotion testing is another example where you are missing a large body of data that is important for microbiological investigations where environmental results exceeded your firm's action level. We acknowledge you have now committed to conducting growth promotion testing, but we would like to emphasize that this is an important body of information that is missing for all investigations in the past. As mentioned above, we encourage you to maintain the necessary documents and data to determine the root causes of failures. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls B. Microbiological Media and Identification (para 3) [VIP ID: 111610] The goal of microbiological monitoring is to reproducibly detect microorganisms for purposes of monitoring the state of environmental control. Consistent methods will yield a database that allows for sound data comparisons and interpretations. The microbiological culture media used in environmental monitoring should be validated as capable of detecting fungi (i.e., yeasts and molds) as well as bacteria and incubated at appropriate conditions of time and temperature. Total aerobic bacterial count can be obtained by incubating at 30 to 35 deg. C for 48 to 72 hours. Total combined yeast and mold count can generally be obtained by incubating at 20 to 25 deg C for 5 to 7 days.

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GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) X Laboratory Controls B. Microbiological Media and Identification (para 4) [VIP ID: 111620] Incoming lots of environmental monitoring media should be tested for their ability to reliably recover microorganisms. Growth promotion testing should be performed on all lots of prepared media. Where appropriate, inactivating agents should be used to prevent inhibition of growth by cleanroom disinfectants or product residuals (e.g., antibiotics). Selected FDA 483 Observations (August 2004) Sterile Product Manufacture [VIP ID: 122650] Environmental monitoring of aseptic processing areas should include: a. growth promotion testing of the media used for sampling. ... Selected FDA 483 Observations (December 2003) Sterile Product Manufacture [VIP ID: 70570] Environmental monitoring programs should include the use of microbial growth media that is optimum for the propagation of yeast or mold contaminates. Selected FDA 483 Observations (August 2000) Sterile Product Manufacture [VIP ID: 16480] TSA media used in environmental monitoring should be qualified to show it can support growth at the specified action levels. Selected FDA 483 Observations (April 2000) Sterile Product Manufacture [VIP ID: 14800] Validation studies should be completed to assure that the microbial settle plates are capable of supporting microbial growth after the exposure time in class 100 rooms. Selected FDA 483 Observations (April 2000) Sterile Product Manufacture [VIP ID: 14820] Growth promotion tests should be performed on sterility media to assure the media is capable of supporting microbial growth. Selected FDA 483 Observations (June 1999) Sterile Product Manufacture [VIP ID: 7176] Strains of factory isolates from firms controlled environments should be used in the performance of growth promotion testing of media used for media fills and environmental monitoring. CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 44. [VIP ID: 2196] Are the culture media used in the viable monitoring program shown to be capable of detecting molds and yeasts as well as bacteria by means of growth promotion tests? Is anaerobic monitoring performed?

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CPGM-DB CHAPTER 56 - DRUG QUALITY ASSURANCE 7356.002A STERILE DRUG PROCESS INSPECTIONS ATTACHMENT A (September 1993) MAJOR SYSTEMS AND PROCESSES Monitoring of Environment 47. [VIP ID: 2199] What incubation periods are used and at what temperature?

40. Environmental monitoring should include periodic challenging of sanitisers with new resistant isolates, such as Bacillus lichenformis and Bacillus thurigenesis.
Selected FDA 483 Observations (June 2000) Sterile Product Manufacture [VIP ID: 15660] Environmental monitoring should include: (2) periodic challenging of sanitizers with new resistant isolates such as Bacillus lichenformis and Bacillus thurigenesis

41. Of particular importance in evaluating the environment to be used for production of biological and biotechnological products is the susceptibility of biotechnology and biological products to contamination with biological substances including microbial adventitious agents, e.g. bacterial, viral, mycoplasm.
GUIDANCE FOR INDUSTRY INDS - APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) VI. SPECIAL PRODUCTION SITUATIONS C. Biological and Biotechnological Products 1. General Considerations para 4 [VIP ID: 183908] Of particular importance in evaluating the environment to be used for production (see section V) is the susceptibility of biotechnology and biological products to contamination with biological substances including microbial adventitious agents (e.g., bacterial, viral, mycoplasm) that may remain from previous research or production activities.

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VIP CONTACT DETAILS Bound copies of this guidance document can be purchased directly from Validation in Partnership Limited, if required. For details of price and delivery, or to find out more about us and the services we offer please visit the ViP Web Site: www.ViPltd.co.uk or contact us directly at the address below. Validation in Partnership Limited 34 Chester Road Maccesfield Cheshire SK11 8DG, UK Telephone : Facsimile : Email : Web Page : +44 (0)1625 660880 +44 (0)1625 660881 Kieran.Sides@ViPltd.co.uk www.ViPltd.co.uk

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