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Facility Requirements for Biotech Plants

Donald Hill and Michael Beatrice

PDA J Pharm Sci and Tech 1991, 45 132-137

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COMMENTARY

Facility Requirements for Biotech Plants

DONALD HILL and MICHAEL BEATRICE Food and Drug Administration, Rockvffle, Maryland

[EDITOR'S NOTE: This document [provided to us by Ms. Jeanne Devers White) represents one of the presentations at the First Conference on "Compliance and Regulatory Affairs" sponsored by the Parenteral Drug Association in cooperation with the FDA on September 5-6, 1990inRockvilie,MD.]
Introduction

Characteristics of Biological Products

Facility requirements for the manufacture of biotechnology-derived products are a significant topic of discussion since the importance of the clinical applications of genetically engineered drugs and biologicals is becoming well-established within the medical community. Attention is currently focusing on the transfer of these new technologies from a laboratory research setting to a commercial production environment. Complicating this transfer is the fact that the field of biotechnology is itself in an evolutionary state. One has only to look back over the last five years and see how rapidly commercial biotechnology has advanced in product development, manufacturing, and testing, as well as the degree of sophistication in plant layout and equipment design. Thus, it is difficult to keep abreast of the latest advancements in determining the state of the art as it exists today for the manufacture of biotech-derived products, and, more importantly, to predict what it will be in the future. If a biotech plant is built today, will it meet facility requirements five or ten years down the road? This overview of major facility requirements for biotech plants is intended to provide scientists, regulatory affairs specialists, engineers, and others, who may not be totally familiar with the FDA regulatory review process, with a general understanding of how the regulatory standards and regulations are interpreted and applied to manufacturing plants for the production of biotechnology-derived products. Since there is no single plant layout or manufacturing process arrangement that can be used interchangeably for the production of the many different kinds of biotech products, this discussion will focus on regulatoryconcepts rather than specific regulatory requirements. Additionally, some of the primary questions and concerns that arise during our review of biotech facility plans will be presented.

Received October. 1990. Correspondence address: Ms. Jeanne Devers White. Assistant Director, Office of Small Business, Scientific and Trade Affairs. Office of the Commissioner. FDA. HFC-50. 5600 Fishers Lane. Rockville. MD 20857. 132

It is important to keep in mind that certain characteristics of biological products are in some aspects quite different from pure chemical drugs. These differences impact on the overall design considerations for a biotech plant. On too many occasions, a biotech manufacturer has submitted floor plans of a new facility only to be informed that the plant layout is totally inadequate for the production of biological products. What are the characteristics that make a biological product different from a pure chemical drug product? /) Biological products are derived from a living source, either human, animal, plant, or microorganism. This also holds true for new biotech-derived products such as recombinant DNA Interferon, where Escherichia coli may serve as the host microorganism, or the production of monoclonal antibodies obtained from the ascites fluid of mice. 2) Biological products are complex mixtures of proteins and other substances that are not easily identified or characterized in the final product. Components in the final container of most biological products cannot be identified or quantified to the same extent as pure chemical drugs. However, one of the exciting aspects of biotechderived products is the degree of identification and characterization that can be employed during all phases of manufacturing of these products when compared to the earlier biologies manufactured by traditional methods. 3) Biological products are often heat sensitive (heat labile). For this reason, most biological products are stored continuously at 2-8C, and some are not only stored cold or frozen but are also shipped in a frozen state, such as live oral polio vaccine. Therefore, during biological manufacturing, certain operations may need to be performed under controlled temperatures (below 10C in some cases) depending on the nature of the product being manufactured and the length of time required to complete the manufacturing procedure(s). 4) Biological products are also highly susceptible to microbial contamination. As mixtures of proteins, the products may be excellent vehicles for supporting microbial growth. Thus, concern for microbial contamination must be considered at every step during the manufacture of a biological product, from the time the seed cell or culture arrives in the plant to preparation of the culture media, the propagation of the product by fermentation or by a continuous cell culture system, the harvesting, concentration, and purification procedures, as well as the sterile filtration of the final bulk and aseptic filling of the bulk intofinalcontainers. Good manufacturing practices must be employed even during the
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earliest steps in biological manufacturing operations to assure freedom from contamination.

Regulating Biological Products

Plant Design Considerations

Biological products are regulated in this country either as licensed products, NDA products, or medical devices. Examples of licensed products include bacterial and viral vaccines (diphtheria, tetanus, measles, rubella, mumps, polio, etc.) and human blood and derivatives (albumin, immune globulin, antihemophilic factor, etc.). Authority to license both the product and the manufacturing establishment is promulgated under the licensing provisions of Section 351 of the Public Health Service Act. Interferon, hepatitis vaccine, tissue plasminogen activator, and Muromonab-CD3 are examples of biotech-derived products with therapeutic applications which have been licensed recently by the FDA. NDA regulated biologicals include antibiotics, hormones, and enzymes. NDA products are regulated under the applicable provisions of the Federal Food, Drug and Cosmetic Act as are certain biological medical device products. Examples of biotech-engineered NDA products include recombinant human insulin and human growth hormone. Most biological products intended for in vitro diagnostic use are regulated as medical devices, except for some of those utilized in the testing of licensed biologicals such as human blood and blood products. These "biological device products" include blood grouping and typing reagents as well as reagents used to test for presence in the blood of the hepatitis virus or the antibody to HIV (AIDS) virus. Diagnostic monoclonal antibody and recombinant products intended for such uses are regulated as biological products subject to licensure.

Regulatory Requirements for a Biotech Manufacturing Plant

General facility requirements for the manufacture of biological products are found in the biologic establishment standards, Part 600 (1) and the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals, and Part 211 (2) of Title 21, Code of Federal Regulations. Although these FDA regulatory requirements do not directly refer to the manufacture of biotechderived products, they are considered broad enough in scope to be applicable to all biologies and drugs. In addition, the agency's "Points to Consider" in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology, in the Manufacture and Testing of Monoclonal Antibody Products for Human Use, and in the Characterization of Cell Lines Used to Produce Biologicals (3) provide current knowledge gained from recent research and experience with such products and cell lines. FDA Guidelines on Sterile Drug Products Produced by Aseptic Processing (4) and the NIH Guidelines for Research Involving Recombinant DNA Molecules (5) may serve as useful documents in designing an appropriate biotech-manufacturing facility.
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Proper design of a facility intended to produce biotechderived products by such procedures as fermentation or continuous cell culture should include the following considerations: /) identification of work areas where physical containment of the manufacturing processes are required for protection of the product, environment, and/or worker; 2) location of areas where containment is not required, such as glassware washing areas; 3) the flow or direction of the air in controlled and non-controlled areas; 4) the flow of materials, equipment, products, and biohazardous waste and; 5) the flow and control of personnel, particularly in the critical work areas. Each of these design considerations merit further discussion, beginning with the containment areas. Why is it necessary to have containment areas? There are three primary reasons for containment: to protect the workers as well as personnel in adjacent areas of the plant from unnecessary exposure to hazardous agents (primary containment), to prevent the release of such agents into the outside environment (secondary containment), and to protect the product itself from the introduction of contaminating organisms or the possible transfer of unknown or undesired genetic material into the product. In many instances, protecting the product may be the most important reason for requiring containment, because containment incorporates many of the features required for aseptic processing, such as environmental controls, systems validation, sterile technique, etc. The level of physical containment required is really dependent on the potential hazard of the organisms/ agents being used in the production processes. Such hazards would include the potential for causing disease in man or possible toxic, allergenic, or other biological effects of the organism on the workers. The level of isolation required for microorganisms derived by recombinant techniques can usually be evaluated by examining the known properties of the components used in the recombinant DNA process. For example, when DNA coding for a highly potent toxin is to be used, special care and attention is warranted. Thus, the level of biosafety containment required must match the assessment of the risks involved in the production of biotechnology-derived products. The descriptions of biosafety levels (BL) 1 through 4 appearing in the NIH Guidelines for Research Involving Recombinant DNA Molecules (5) parallel those of the earlier designated P 1 through 4 categories with the BL-4 or P-4 level requiring the highest degree of containment. Although these designated biosafety levels are intended for use in a laboratory research setting, they are being used and considered good laboratory practice standards today for biotech production operations. In general, the levels for large scale (LS) production operations (greater than 10 liters) are based upon the recombinant organism which is being employed in production as specified in the NIH guidelines. For certain organisms for large-scale fermentation production, the appropriate physical containment conditions need be no greater than those for the host organism unmodified by recombinant DNA techniques. Examples of such organisms would include E. coli
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K-12 and Saccharomyces cerevisiae. However, it may be advisabie for product protection to incorporate certain features of a validated ciosed-system arrangement for those organisms which are grown in facilities maintained at less than a BL1-LS. Fermentation processes are usually performed in closed vessels, however, the area around the fermentor often cannot be of clean-room quality due to the nature and scale of the operation. Frequently, fermentors for large scale production are capable of holding many thousands of liters and may extend through two or three floors of a facility. In those instances, inoculation of the production fermentors and harvesting should be performed in closed systems or in an aseptic manner to protect workers and the integrity of the product being produced. Many companies elect to build a dedicated facility for the manufacture of a biotech product. However, due to economic constraints and to maximize full utilization of the biotech plant, it may be permissible to "campaign" product manufacturing, provided validated cleaning and sanitizing procedures are employed between each product manufacturing run. The organism or particular cell line used in each production run should also be propagated in premises in which no other organisms or cells are handled or in contained closed systems, to minimize the chances of cross-contamination. The recovery and purification processes (unless the material has been completely inactivated at this stage), should also be performed in self-contained areas of the plant. Dedicated equipment should be employed in each of these areas and if product campaigning is utilized, dedicated equipment for each product may be necessary for certain operations. No person who has been in contact with transmissible agents or experimental animals should enter the premises on the same day that any such contact has been made unless they undergo a validated regowning procedure. Depending on the nature of the product or organism being grown, controlled temperatures in certain production and purification areas (such as 2-10C) may also be required. As described in the biological establishment standards [Title 21, Code of Federal Regulations, Section 600.11(e) (3)] all work with spore-bearing microorganisms should be done either in an entirely separate building or in a completely walled-off area of the same building which does not share air systems, equipment, or entrance with other manufacturing or testing areas. In the containment areas, the ceilings, walls, and floors should be constructed of non-shedding material that will provide non-porous, smooth, and easily cleanable surfaces. All joints should be sealed and all corners coved to prevent air leakage. Ceiling lights and utility outlets should be flush mounted and sealed. There should be no exposed piping except at points of use. Only necessary equipment and supplies should be brought into the containment areas. In addition, particular consideration should be given to cleaning and decontaminating procedures in cases of spills or accidents involving potentially hazardous agents. For example, there may be provisions incorporated in the design of the ventilation ducts, particularly the exhaust
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ducts which would permit the actuai mechanical cleaning and decontaminating of the ducts. :f the ievei of contamination should warrant such action. Another example would be that a collection and treatment area should be located below large scale fermentors in case of spills or leaks (i.e.. containment well). The treatment system should be validated as capable of immediate start-up and should be able to handle twice the capacity of production. Written procedures should be established for handling spills and should describe all actions to be initiated prior to re-use of the area and equipment. These written procedures and action levels become an important consideration in the environmental assessment of manufacturing facilities. The requirements for submission of applications for establishment and product licensure (21 CFR 601.2) direct the applicant to submit an environmental assessment under Section 25.31 (21 CFR 25.31) o r a claim for categorial exclusion under 25.24 (21 CFR 25.24). This requirement has its origin from the President's Council on Environmental Quality regulations (40 CFR 1500-1508) which govern federal implementation of the National Environmental Policy Act of 1969 (NEPA). Under the above regulations. FDA's NEPA-implementing procedures (21 CFR Part 25) were revised in a rule which became effective on July 25. 1985. These regulations require that the FDA consider the environmental impact of proposed actions prior to any final action and that any decision regarding environmental impact be publicly disclosed. For practical purposes, a manufacturer is requested to submit an environmental assessment (EA) as a part of their application for licensure. The assessment should include a description of the procedures employed for containment to protect the worker, environment, or product, particularly in the event of a spill or accident, as well as the procedures for disposal of solid, liquid, and gaseous waste. Agency review of the adequacy of a submitted EA includes examining the information provided with that contained in the manufacturer's iicense applications and the implementation of such procedures during the preiicensing inspection of the establishment. Results of this review are summarized in the agency's Summary of Basis for Approval (SBA) which is a part of the final approval action documentation. The air flow and air pressure boundaries are extremelycritical to the performance of an effective containment barrier. To achieve adequate containment, it may be necessary to reverse the now of air from adjacent rooms to move into the contained areas. The areas with the highest potential to emit the production vector should be maintained at a lower pressure than less potentially contaminated areas including the public or uncontrolled areas. This effectively provides a negative pressure system during product manufacturing as compared to a clean room operation for aseptic filling of final containers where a positive pressure system should be maintained. It is important to stress that within a "negative pressure" production area, biological safety cabinets of proper classification and design may be necessary for certain open operations involving the production of the biotech product. For
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example, inoculation of genetically engineered microorganisms should be performed under a validated biosafety cabinet providing Class 100 (per cubic foot particle count of no more than 100 in size range of 0.5 micrometers and larger) laminar now air (7). A question that arises is under what, if any, conditions can an aseptic filling operation take place in the same facility that houses a biohazard containment area for the production-of biotech products? Ideally, such functions should be performed in entirely separate buildings. However, due to cost constraints or space limitations, it is not always feasible or practical to operate separate buildings. In such cases, a plant layout may be designed in a manner that isolates a separate wing of the building for the containment area with no common hallway or direct access to the aseptic filling areas. Other practical considerations should include dedicated equipment and glassware for each function. Separate air handling systems supplying positive pressure directional air in the filling suites must also be provided. Strict adherence to the plant's standard operating procedures for entry into either the containment area or the final formulation/filling area must be observed by all employees and visitors. Thus, the plant layout may be thought of as two separate facilities within a facility, each functioning independently of the other. Particular consideration should also be given to the flow of components, equipment, and product in any biotech plant design. Such considerations should include the receipt and proper storage of incoming cells; storage of seed cultures, master cell banks, working cell banks and other raw materials, such as chemicals and process gases; adequate areas for equipment washing and preparation; media production; inoculations; fermentation; harvesting; extraction; and purification. In general, the flow should be unidirectional where feasible, so that materials and equipment enter the contained area by means of an airlock and leave the contained area through either a double-door autoclave (for sterilization of contaminated materials) or by an airlock. Product, as well as materials and equipment used during the fermentation and harvesting processes in the containment rooms, should not return in the same direction that clean materials enter the containment areas. Clean equipment and supplies should not, if at all possible, cross the patch of dirty equipment and supplies. "Dirty" equipment in this context refers not only to possible contaminated equiptent but to all equipment that has been used in the reduction process. Improper flow of clean components nd the product as well as the flow of personnel crossing le path of "dirty" components, supplies, and equipment re examples which are frequently seen in a plant design. The facility design should also take into consideration le flow of personnel from the time a person enters the uilding to his or her place of final destination. For examle, only persons actually involved in the fermentation, arvesting, and purification procedures should be allowed i the specific areas when active work is in progress. All ther personnel and visitors should be restricted from ntering any containment or controlled areas. Limited ccess to these areas may be accomplished by use of an
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electronic card or similar device to gain entry into the restricted areas. Complete sterile gowning of the personnel may be required for working in the containment area to protect the product or worker from contamination. Special care should be given to the design of the gowning and degowning areas including appropriate air locks with a dirty/clean side. The use of showers may be necessary prior to exiting the degowning area for certain biohazard materials. The environmental monitoring program for the biotech plant should include monitoring at frequency intervals of all personnel working in critical areas of manufacturing, including formulation and filling. Establishment of appropriate bioburden specifications for the personnel should provide valuable information in determining the environmental conditions of the work areas during actual operation, as well as determining the adequacy of the employee's gowning procedures. Appropriate training and supervision of personnel is another essential element in assuring that the necessary containment and aseptic conditions required for the manufacture of biotech-derived products are being maintained. Personnel should be made aware of potential safety hazards and should be trained in the proper techniques for safe handling of such materials and in the operations that they are responsible for. Enforcement of strict adherence to the company's standard operating procedures is an absolute must. The SOPs should be available to employees within each work area and all personnel should be trained on the precise steps to be taken in case of accidents or spills in the containment areas. Summary of such training of personnel should be documented in writing. Plant SystemsHVAC System Control of viable and non-viable air-borne particulates in the production and purification areas is normally required. Particulates may enter a production process and contaminate it physically or, by acting as a vehicle for carrying microorganisms. It is, therefore, important to minimize the particle content of the air and to effectively reduce the size and number of particles which are present. The air supply should be filtered through high efficiency particulate air (HEPA) filters, with the air having a velocity sufficient to sweep particulate matter away, thereby reducing potential air-borne contaminants by rapid dilution. In this regard, an air flow sufficient to achieve at least 20 air changes per hour is normally acceptable. However, if the production process involves potentially hazardous substances or when the operations generate high levels of particulates or when equipment configuration disrupts laminar flow it may be necessary to increase the number to 30, 40, or even 50 air changes per hour. Rooms used for inoculum preparation, fermentation, harvesting, and purification should normally be on separate air handling systems and may require negative air pressure in relation to adjacent areas of the production facility as previously discussed. All rooms in strict containment areas should have single pass HEPA-filtered inlet and outlet (exhaust) air. Filtered exhaust air is necessary in
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order to minimize the risk of potential contaminants being discharged to the outside environment. If any portion of the production and/or purification processes is conducted in an open system (exposing the product to the plant environmental air), such procedures should be performed under Class 100 air (7). Thus, air purity, air pressure differentials, air changes, relative humidity, and temperature control are all key elements in the design of an effective and efficient heating, ventilation, and air conditioning (HVAC) system. Since the HVAC system represents one of the most expensive costs in the construction of a manufacturing plant, it is extremely important that the system be properly designed and balanced. The establishment license application should include specific drawings of the HVAC system with air flow and pressure differentials for each area designated on the layout.
Water System

tion areas of the plant by means of a hot loop circulation system in which the water is maintained at 80 C in both the loop and storage tanks. For those production procedures requiring ambient temperature water, the water can be passed through suitable heat exchangers that cool the WFI as itflowsthrough or by the use of a wellcontrolled secondary cold (ambient temperature) loop. 316L or similar quality polished stainless steel should be used for all piping and holding tanks to minimize potential corrosive problems. Frequent monitoring of all WFI points of use for microorganisms and endotoxins is essential, especially on days of use.
Sterilization System

The quality of water required for manufacturing use and for glassware and equipment washing is also important in designing a water system for the plant. USP Water for Injection (WFI) (6) should be used when the water comes in direct contact with the product including during purification procedures (e.g., rinsing of the resin columns), buffer preparation, product formulation and for the final rinsing of glassware, stoppers, and equipment used in the purification and formulation/filling operations. It may be appropriate to utilize WFI or an alternate, high pharmaceutical quality water for preparation of the growth media depending upon the nature of the product and its subsequent handling. The use of an uncontrolled water source (i.e., city or well water) without subsequent treatment for media preparation is not acceptable. It should be noted that the USP monograph for Water for Injection specifies "water purified by distillation or by reverse osmosis" (6). However, recognizing that water production techniques such as reverse osmosis are difficult to maintain, the section on Water for Pharmaceutical Purposes further states: "Purified water produced by distillation is sterile, provided the production apparatus is suitable and is sterile. On the other hand, ion exchange columns and reverse osmosis units require special attention in that they afford sites for microorganisms to lodge, to multiply, and to enter the effluent. Thus, frequent monitoring may be called for, particularly with the use of these units following periods of shutdown for more than a few hours." The Water for Injection system should be designed so that it can be easily sanitized both after construction and following routine maintenance. The system is usually designed in a manner that allows incoming potable water into the plant to be pretreated by use of carbon filters and deionization (cation and anion) beds. After purification by reverse osmosis or by distillation using an appropriate still capable of producing the quality and quantity of WFI required for plant utilization, the WFI water is usually stored and supplied to the produc136

A plant facility layout should include adequate provisions for the sterilization of equipment and supplies entering the containment and aseptic processing areas. Autoclaves and dry heat ovens should be double doored to permit the direct access of the sterilized goods into either the containment or aseptic processing areas. The cooldown phase for sterilized materials should be carried out under controlled air, in order to further reduce the change of microbial contamination. Class 100 air may be required for this process and if the sterilized materials are cooled down in the autoclave or oven, the chamber air should be HEPA filtered. Provisions should also be made for the disposal and sterilization of all contaminated liquid and solid waste, as well as the sterilization of equipment and other materials generated from the biotech production process, prior to leaving the containment area. Disposed liquid waste should include a large enough treatment reservoir to accommodate adequately all possible loads. Provisions should also be made for the cleaning and decontamination of the work areas between operations. Such validated procedures should be detailed in written standard operating procedure manuals with appropriate cleaning logs being maintained. In order to establish baseline data to support the effectiveness of cleaning procedures and reagents, initial bioburden of all areas and equipment should be performed after qualification and should be recertified at regular intervals. Separate autoclaves for decontamination and sterilization are recommended based upon the principle that clean and dirty component pathways should never cross.
Qualification/Validation Program

The qualification of facilities, equipment, plant systems (HVAC, WFI compressed air and gases, waste sterilization, etc.), and the validation of the actual processes (operations) should not be an afterthought in the design of a plant for producing biotech-derived products. Rather, plans for the qualification/validation programs should be an integral part of the preliminary plant concepts and specifications. It should not be looked upon solely as a burdensome requirement for complying with FDA regulations, but as a means of increasing productivity through consistently producing lots of products that meet all specifications for marketing, thereby reducing the number of
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lot rejects. Also, maintenance costs, equipment downtime, and utility costs may be reduced through a welldesigned qualification/validation program. The qualification/validation program can be divided into three major parts: (/) Installation Qualification, (2) Operational Qualification, and (3) Process Validation. Installation qualification is the first step taken and it relates to the proper installation of the equipment and systems. It includes checking the equipment and systems to see that they meet appropriate design specifications after installation. At this time, programs for maintaining the systems and equipment in good working condition may be identified, such as preventive maintenance and equipment calibration programs. It should be noted that complete reliance on outside contractors for validation of all systems and equipment removes an important internal quality control check. If outside contractors are utilized, the manufacturer's quality control unit should receive and evaluate the raw data rather than rely on a certificate of acceptance. In addition, written validation procedures utilized by outside contractors should be a part of the manufacturer's SOP manual. Operational qualification relates to the actual testing of the equipment and systems in order to determine the operational limits, including whether the equipment and systems are fully capable of repeatedly performing the production functions for which they were intended. Process validation should not begin until all equipment and systems have been satisfactorily tested and determined to meet established specifications. Process validation is intended to verify that the equipment and system can perform their intended functions within the established specifications during actual production conditions or operations. Test runs should be performed enough times to assure that the equipment, systems, and operations will consistently produce a product within acceptable established limits during all employee shifts. One of the most important aspects of any qualification/ validation program is the documentation of the tests performed and test results. Each piece of equipment and system that is to be qualified and validated must first have a written protocol describing the intended objective(s), a set of instructions for performing all required tests, established specifications, and acceptance criteria. The protocol and the written results of all tests performed must be maintained (including all raw data). Illustrations of placement of testing equipment should be incorporated into the protocol design where applicable. For example, diagrams of the placement of thermocouples in an autoclave during heat distribution and penetration studies

should be included in the protocol package for such equipment. All protocols should be as complete and detailed as necessary and all test results should be accurately recorded in order to serve as reliable references for subsequent revalidation of the equipment and systems validation. Such documentation should be on file when an outside contractor is employed for equipment and system validation. Final approval of the protocol and acceptance of test results and the system, equipment, or operation is usuallyobtained from responsible personnel of the production, quality control and/or quality assurance and engineering departments even if outside contractors are utilized. Once validated and accepted, no significant changes in the equipment, system or operating procedure should be made without written approval of authorized individuals responsible for plant operations. Major changes to the equipment or system may require revalidation and acceptance prior to resuming actual operations in the work area. In addition, periodic revalidation of some systems may also be required at appropriate intervals. Validation of systems and processes should also include any computer systems employed in the manufacture and testing of the biotech product. Validation of the computer hardware need not be elaborate but should be sufficient to show confidence that it can be consistently maintained at the level of operation demanded. Validation of computer software should include: {}) simulated "worst case" testing, (2) testing of ability to give consistently reliable results (usually three separate runs), and (3) documenting all test runs. If process changes are made, then revalidation of the software may be indicated. Validation of computer systems may also include verification of computer "security" and limited access to software programs controlling the process steps during production. References
1. Code of Federal Regulations, Title 21. Parts 600-680. Revised April 1.1988. 2. Code of Federal Regulations, Title 21, Parts 200-211. Revised April 1.1988. 3. "Points to Consider" in the Production and Testing of New Drugs and Biologicals Produced by DNA Technology (April 10, 1985), in the Manufacture and Testing of Monoclonal Antibody Products for Human Use (June 1987), and in the Characterization of Cell Lines Used to Produce Biologicals (Nov. 1987). 4. FDA Guidelines on Sterile Drug Products Produced by Aseptic Processing, June, 1987. 5. NIH Guidelines for Research Involving Recombinant DNA Molecules, May 7, 1986 and Aug. 24, 1987. 6. U.S. Pharmacopeia, 21st rev.. United States Pharmacopeia! Convention, Inc., 1985. 7. U.S. Federal Standard 209D, Clean Room and Work Station Requirements, Controlled Environment, June 15, 1988.

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