Seminar on GMP

Presented by: PANKAJ SINGH M.Pharm-I

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Pool of contents:
Introduction Part I Part Ia, Ib, Ic, Id, Ie, If. Part II Common Problems in GMP Execution How do GMPs of different countries compared???

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TRAGEDIES DUE TO HUMAN NEGLIGENCE

107 people died because of diethylene glycol poisoning in liquid oral preparation and 15 of wrong libeling of an antidiabetic drug as an antihypertensive drug. 80 people lost their eye sight /went to coma because of contamination of glibenclamide with sulpha drugs. 1960:-major teratogenic problems with thalidomide Matter of one life in operation theater but millions lives for pharma industry.
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What is GMP???
GMP is the part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standard appropriate to their intended use and as required by the marketing authorization. Good Manufacturing Practices (GMPs) are regulations that describe the methods, equipment, facilities, and controls required for producing: Human and veterinary products Medical devices Processed food In short GMP makes the difference between nearly right and exactly right.
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What is cGMP???
The fact is that production is a very dynamic process--people change, machines wear down, deliveries come in that may or may not be what you ordered. This dynamic system poses some unknowns.
It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product.

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minimize contamination

consistent quality.

Why GMP?

To minimize the risks

To eliminate error.

Final testing problems

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Is GMP necessary if there is quality control lab?

Good quality must be built in during the manufacturing process. Testing of finished product is not enough. Though quality control laboratory are set up, it covers only the finished product, so WHO established GMP guidelines to cover whole process of production.

In a testing approach to establish manufacturing product quality, you must depend on some kind of measurement of selected attributes. Another problem with the testing approach is that only small samples of the products are tested and the results of those tests are extrapolated to the untested units. However, the connection may not be valid.

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EVOLUTION OF GMP
1963:- first GMP publication -USA 1971:-first revision 1978:- Major revision

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Code of Federal Regulations (CFR): The Code of Federal Regulations (CFR) is the codification of the general and permanent rules and regulations (sometimes called administrative law) published in the Federal Register by the executive departments and agencies of the Federal Government of the United States.

Current regulations of GMP appear in part 210 (title 21) of code of federal regulations published by USFDA.
21 Code of Federal Regulations Part 210. Current Good Manufacturing Practice in Manufacturing Processing, packing, or Holding of Drugs. 21 Code of Federal Regulations Part 211. Current Good Manufacturing Practice for Finished Pharmaceuticals.

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GOOD MANUFACTURING PRACTICE

Standards of Performance
Audit Personal Internal External
C O M M I T M E N T REINFORCE

Training Top Management Manager/Supervisor Operators/Technicians Support staff

Top Management Operators/Technicians

Manager/Supervisor Support staff

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PART - I

Good manufacturing practices for premises and materials

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Good manufacturing practices for premises and materials

1.General Requirements 1.1 Location & surroundings 1.2 Building & premises 1.3 Water system 1.4 Disposal of waste 2.Ware Housing area. 3.Production Area 4.Ancillary Area
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5. Quality Control Area

6. Personnel 7. Health, clothing & sanitation of workers 8. Manufacturing operations and controls. 9. Sanitation in manufacturing area.

10. Raw materials.

11. Equipments
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12. Quality Assurance

1.

2. 3. 4. 5. 6. 7. 8. 9.

Requirements for QA Systems Ensure products are developed correctly. Identify managerial responsibilities. Provide SOPs for production and control. Organize supply and use of correct starting materials. Define controls for all stages of manufacture and packaging. Ensure finished product correctly processed and checked before release Ensure products are released after review by authorized person Provide storage and distribution Organize self-inspection.
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13. Quality Control System

It is not only confined to laboratory operations but shall be involved in all decisions concerning the quality of the product. All the batches released after certification of QC department. Maintain reference/retained sample from each batch. Separate areas for chemical, instrumentation, microbiological and biological testing. The quality control department shall conduct stability studies of the products to ensure and assign their shelf life at the prescribed conditions of storage. All records of such studies shall be maintained. All instruments shall be calibrated and testing procedures validated before these are adopted for routine testing.
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15.SELF INSPECTION AND QUALITY AUDIT

Quality audit means a systematic, independent examination of a manufacturer's quality system that is performed at defined intervals and at sufficient frequency to determine whether both quality system activities and the results of such activities comply with quality system procedures.
Quality audits are typically performed at predefined time intervals and ensure that the institution has clearly-defined internal quality monitoring procedures linked to effective action.
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Ensures that companys operations are compliant to GMP

Recommends corrective action

Quality Audit
Detect short comings in implementati on of GMP

Continuous quality improvement

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It is an important part of organization's quality management system and is a key element in the ISO quality system standard, ISO 9001.

INTERNAL

EXTERNAL

REGULATORY
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Cont
personal, whereby every individual does a self-check to make sure that he/she is complying with all appropriate standards; internal audit, which should be performed by the quality assurance department as required by GMP, external audits, which can consist of an FDA audit, a consultant checking your compliance status

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16.SITE MASTER FILE:

Containing specific and factual GMP about the production and /or control of pharmaceutical manufacturing preparations carried out at the licensed premises. It shall contain the following General information Personnel Premises Equipment Sanitation Documentation Production Quality control: -Description of the quality system and of the activities of the quality control department. Procedure for the release of the finished products. Loan licence manufacture and licensee:-Description of the way in which compliance of GMP by the loan licensee shall be assessed. Distribution, complaints and product recall Self-inspection Export of drugs: - it may be Products exported to different countries. Complaints and product recall, if any.
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17. Product Recalls

A prompt and effective recall system of defective products shall be devised for timely information of all concerned stockists, wholesalers, suppliers, up to the retail level within the shortest period. The distribution records shall be readily made available to the persons designated for recalls. The effectiveness of the arrangements for recalls shall be evaluated from time to time. The recalled products shall be stored separately in a secured segregated area pending final decision on them.
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18.COMPLAINTS & ADVERSE REACTIONS: -

All complaints thereof concerning product quality shall be carefully reviewed and recorded according to written procedures. Each complaint shall be investigated /evaluated by the designated personnel of the company and records of investigation and remedial action taken thereof shall be maintained. Reports of serious adverse drug reactions resulting from the use of a drug along with comments and documents shall be forthwith reported to the concerned Licensing Authority. There shall be written procedures describing the action to be taken, recall to be made of the defective product.

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19. SOPs regarding,

Receipt of material. Sampling. Batch numbering. Testing.

20. Reference samples:

Each lot of every active ingredient, in a quantity sufficient to carry out all the tests, except sterility and pyrogens/Bacterial Endotoxin test shall be retained for a period of 3 months after the date of expiry of the last batch produced from that active ingredient. Samples of finished formulations shall be stored in the same or simulated containers in which the drug has been actually marketed.

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21. Distribution Records: Records for distribution shall be maintained in a such manner that finished batch of a drug can be traced to the retail level to facilitate prompt and complete recall of the batch, if and when necessary.
22. Validation: periodic validation to ensure that they remain capable of achieving the intended results. Critical process shall be validated, prospectively or retrospectively. When any new master formula or method of preparation is adopted, steps shall be taken to demonstrate its suitability for routine processing.

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23. Master Formula Records:

24. Packaging Records: 25. Batch Processing Records:

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DIFFERENT

SUBPARTS

OF

PART I

PART IA: Specific requirements for manufacture of sterile products, parenteral preparations (small volume injectables and large volume parenteral) and sterile ophthalmic preparations. PART IB: Specific requirements for manufacture of oral solid dosage forms (Tablets and capsules) The general requirements as given in part-I

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PART IC: Specific requirements for manufacture of oral liquids (syrups, elixirs, emulsion, suspension) PART ID: Specific requirements for manufacture of topical products i.e. external preparation (creams. Ointments, pastes, emulsions, lotions, solutions, dusting powders and identical product.

PART IE: Specific requirements for manufacture of metered dose inhalers (MDI).
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PART IF: Specific requirements of premises, plant and materials for manufacture of active pharmaceutical ingredients (BULK DRUGS). The general requirements as given in part-I Additional requirements are as following: 1. Building and civil works 2. Utility cervices 3. Equipment design, size and location 4. In-process controls 5. Product containers and closures
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PART-2

Requirement of plant & equipments

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Requirements of plant and equipment

Area requirements
1. External preparations 2. Oral liquid preparations 3. Tablets Coating section 4. Powders 5. Capsules 6. Surgical dressings 7. Ophthalmic preparations 8. Pessaries & suppositories 9. Inhalers & vitrellae 10. Repacking of drug & pharmaceutical chemicals 11. Parenteral preparations 11.1 In glass containers 11.2 In plastic containers
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Basic installation
30 sq. m 30 sq. m 80 sq. m 30 sq. m 30 sq. m 25 sq. m 30 sq. m 25 sq. m 20 sq. m 20 sq. m 30 sq. m

Ancillary Area
10 sq. m 10 sq. m 20 sq. m 10 sq. m 10 sq. m 10 sq. m 100 sq. m(svp) 150 sq. m (lvp) 150 sq. m 100 sq. m (lvp Packaging)
AMISH GANDHI

150 sq. m 250 sq. m

M.PHARM-I (2007-08)

Common Problems in GMP Execution

1.Organization
Lack of commitment Lack of resources for execution

2. Layout & Construction

No quarantine area Insufficient environmental monitoring Cracked floor
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3. Equipment:
No calibration No performance check of balance before use Rusty Parts not kept improperly

4. Laboratory Testing:
Poor reference standard keeping Poor data recording Reagent with no label
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5. Documentation & Recording:

No signature; no countercheck Improper correction made No written procedure Incomplete complaint record No up-to-date training record No document review

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6. Labelling:
Status not defined clearly Poor labelling control Release label not kept securely Inadequate reconciliation of batch label Defective equipment with no label

7. Validation:
Insufficient validation Insufficient raw data No validation programme
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How do GMPs change???

GMPs change formally and informally.

GMPs are currently undergoing significant changes.

Example of formal change:

The U.S. medical device GMPs have been completely rewritten, making them more compatible with the ISO-9001 quality document . In fact device GMPs were renamed - FDA now calls them the

Quality System Regulation (QSR)

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Example of Informal change:

In the U.S., these changes are communicated by seminars and papers presented by FDA personnel and through agency Guides and Guidelines.

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How do GMPs of different countries compared???

At a high level, GMPs of various nations are very similar most require things like -Equipment and facilities being properly designed, maintained, and cleaned. Standard Operating Procedures (SOPs) be written and approved. An independent Quality unit (like Quality Control and/or Quality Assurance). Well trained personnel and management.

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Cont.
The World Health Organization (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in over one hundred countries worldwide, primarily in the developing world. The European Union's GMP (EU-GMP) enforces more compliance requirements than the WHO GMP, as does the Food and Drug Administration's version in the US. Similar GMPs are used in other countries, with Australia, Canada, Japan, Singapore and others having highly developed/sophisticated GMP requirements. In the United Kingdom, the Medicines Act (1968) covers most aspects of GMP in what is commonly referred to as "The Orange Guide", because of the colour of its cover, is officially known as The Rules and Guidance for Pharmaceutical Manufacturers and Distributors.

Enforcement of GMP in Different countries:

GMPs are enforced in the United States by the FDA; within the European Union, GMP inspections are performed by National Regulatory Agencies (e.g., GMP inspections are performed in the United Kingdom by the Medicines and Healthcare products Regulatory Agency (MHRA); in Australia by the Therapeutical Goods Administration (TGA); in India and Pakistan by the Ministry of Health

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References :Good manufacturing practices for pharmaceutical. A plan for total quality control by willig. The Gazette of India .Sch M. The Theory and practice of industrial pharmacy by Lachman. Pg:- 804 www.fda.gov

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Q??? From Exam..

1. Write a note on comparison of GMPs of different countries. (Uni. 2007) 2. Discuss the self inspection & Quality audit proposed by FDA regarding maintenance of pharma. Mfg. unit. (Uni. 2006) 3. Give prototype sample of site master file and discuss each component of it in detail. (Uni.2006)

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THE HARDEST THING ABOUT ANY TASK IS JUST GETTING STARTED.

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