Drugs: From Discovery to Approval, Second Edition, By Rick NgCopyright 2009 John Wiley & Sons, Inc.
GOOD MANUFACTURING PRACTICE: REGULATORY REQUIREMENTS
9.1 Introduction 279 9.2 United States 279 9.3 Europe 283 9.4 International Conference on Harmonization 283 9.5 Core Elements of GMP 287 9.6 Selected GMP Systems 297 9.7 The FDA s New cGMP Initiative 310
9.8 Case Study #9 313 9.9 Summary of Important Points 315 9.10 Review Questions 316 9.11 Brief Answers and Explanations 316 9.12 Further Reading 317
In the earlier chapters, we discussed how a drug is discovered, followed by research on pharmacodynamics and pharmacokinetics, then through clinical trials on humans, leading fi nally to fi ling the application and approval being given for the drug to be marketed. This is a long journey of some 10 12 years, with many risks of failure along the way. Now, after having been granted the marketing approval, a pharmaceutical fi rm is ready to manufacture the drug for sale, but it must do so in accordance with Good Manufacturing Practice (GMP).
GMP is a quality concept and consists of a set of policies and procedures for manufacturers of drug products. These policies and procedures describe the facilities, equipment, methods, and controls for producing drugs with the intended quality. The guiding principle for GMP is that quality cannot be tested into a product, but must be designed and built into each batch of the drug product throughout all aspects of its manufacturing processes. Manufac-turers are required to abide by the GMP regulatory guidelines to ensure drugs are pure, consistent, safe, and effective. Regulatory guidelines are dynamic; they are revised and updated from time to time to implement new research, data, or information. Therefore, manufacturers have to keep abreast with regu-latory developments by following current Good Manufacturing Practice (cGMP).
On a global level, GMP regulations are very similar for various countries. There are, however, differences in emphasis and implementation in specifi c areas. We will explain the GMP regulations from the United States, Europe, and the International Conference on Harmonization (ICH) in this chapter. In Chapter 10 , we will discuss the manufacturing processes for small molecule synthetic and large molecule protein - based drugs.
9.2 UNITED STATES
GMP regulations came into effect in the United States in 1963. They have since undergone several major revisions. The implementation of GMP is the result of a number of tragedies to ensure that drugs are safe for the patients and effective for treatment. Some of these tragedies are described in Exhibit 9.1 .
The Food and Drug Administration (FDA) is charged with the responsibil-ity for ensuring drug manufacturers comply with GMP regulations in the
UNITED STATES 279
280 GOOD MANUFACTURING PRACTICE: REGULATORY REQUIREMENTS
United States. GMP is defi ned by the FDA as a federal regulation setting minimum quality requirements that drug, biologics and device manufacturers must meet. It describes in general terms known and accepted quality assurance principles for producing these products. Its components are scientifi c under-standing, documentation, analysis and measurements and personnel matters. Its intended result is total quality assurance and product control.
The US FDA GMP is codifi ed in the following regulations:
21 CFR Part 210: Current Good Manufacturing Practice in Manufactur-ing, Processing, Packing, or Holding of Drugs; General
21 CFR Part 211: Current Good Manufacturing Practice for Finished Pharmaceuticals
21 CFR Part 600: Biological Products: General 21 CFR Part 610: General Biological Products Standards
Further details for each of these sets of regulations are presented in Exhibit 9.2 . Selected items of these regulations (as part of ICH Q7) are discussed in later sections. It should be noted that the applicable regulations for small molecule drugs are 21 CFR Parts 210 and 211, and for biopharmaceuticals the regulations are 21 CFR Parts 210, 211, 600, and 610. The reason is that protein - based biopharmaceuticals are less well - defi ned chemically and they are sensi-tive to the storage and manufacturing environment as well as the manufacturing processes. Biopharmaceuticals are normally prepared under aseptic condi-tions, as they are sensitive to degradation under normal sterilization processes. Special techniques and analytical methods are required for the production and testing of biopharmaceuticals.
According to 21 CFR 210.1(a), the regulations contain the minimum current good manufacturing practice for methods to be used in, and the facili-ties or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements.
Exhibit 9.1 Some Drug Tragedies
In 1902, several children died after being administered contaminated diphtheria antitoxin.
In 1937, 107 people died when the drug sulfanilamide was wrongly formulated.
In 1955, 10 children died after being given improperly inactivated polio vaccine.
In the 1960s, untold physical damage was caused by thalidomide (see Chapter 6 ).
Exhibit 9.2 FDA Current Good Manufacturing Practice
21 CFR Part 210: Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General
210.1 Status of current good manufacturing practice regulations 210.2 Applicability of current good manufacturing practice regulations 210.3 Defi nitions
21 CFR Part 211: Current Good Manufacturing Practice for Finished Pharmaceuticals
subpart a: general provisions 211.1 Scope 211.3 Defi nitions
subpart b: organization and personnel 211.22 Responsibilities of quality control unit 211.25 Personnel qualifi cations 211.28 Personnel responsibilities 211.34 Consultants
subpart c: building and facilities 211.42 Design and construction features 211.44 Lighting 211.45 Ventilation, air fi ltration, air heating and cooling 211.48 Plumbing 211.50 Sewerage and refuse 211.52 Washing and toilet facilities 211.56 Sanitation 211.58 Maintenance
subpart d: equipment 211.63 Equipment design, size, and location 211.65 Equipment construction 211.67 Equipment cleaning and maintenance 211.68 Automatic, mechanical, and electronic equipment 211.72 Filters
subpart e: control of components and drug product containers and closures 211.80 General requirements 211.82 Receipt and storage of untested components, drug product containers,
and closures 211.84 Testing and approval or rejection of components, drug product
containers, and closures 211.86 Use of approved components, drug product containers, and closures 211.89.1 Rejected components, drug product containers, and closures 211.94 Drug product containers and closures
subpart f: production and process controls 211.100 Written procedures; deviations 211.101 Charge - in of components 211.103 Calculation of yield 211.105 Equipment identifi cation 211.110 Sampling and testing of in - process materials and drug products 211.111 Time limitation on production
211.113 Control of microbiological contamination 211.115 Reprocessing
subpart g: packaging and labeling control 211.122 Materials examination and usage criteria 211.125 Labeling issuance 211.130 Packaging and labeling operations 211.132 Tamper - resistant packaging requirement for over - the counter human
drug products 211.134 Drug product inspection 211.137 Expiration dating
subpart h: holding and distribution 211.142 Warehousing procedures 211.150 Distribution procedures
subpart i: laboratory controls 211.160 General requirements 211.165 Testing and release for distribution 211.166 Stability testing 211.72 Filters
21 CFR Part 610: General Biological Products Standards
610.1 Test prior to release required for each lot 610.2 Requests for samples and protocols; offi cial release 610.9 Equivalent methods and processes 610.10 Potency 610.11 General safety 610.11a Inactivated infl uenza vaccine, general safety test 610.12 Sterility 610.13 Purity 610.14 Identity 610.15 Constituent materials 610.16 Total solids in serums 610.17 Permissible combinations 610.18 Cultures 610.19 Status of specifi c products; Group A streptococcus 610.20 Standard preparations 610.21 Limits of potency 610.30 Test for mycoplasma 610.40 Test for hepatitis B surface antigen 610.41 History of hepatitis B surface antigen 610.45 Human immunodefi ciency virus (HIV) requirements 610.46 Lookback requirements 610.47 Lookback notifi cation requirements for transfusion services 610.50 Date of manufacture 610.53 Dating periods for licensed biological products 610.60 Container label 610.61 Package label 610.62 Proper name; package label; legible type 610.63 Divided manufacturing responsibility to be shown 610.64 Name and address of distributor 610.65 Product for export
In addition to the regulations under 21 CFR, the FDA publishes Guidance for Industry and documents called Points to Consider (PTCs) as guidelines and recommendations to industry to adopt as part of the compliance program.
The principles and guidelines for GMP for human medicinal products were laid down in EU Directive 91/356/EEC on June 13, 1991. The following are basic requirements:
Quality management Personnel Premises and equipment Documentation Production Quality control Contract manufacture and analysis Complaint and product recall Self - inspection Inclusion of annexes
Manufacture of sterile medicinal products Manufacture of biological medicinal products for human use Manufacture of radiopharmaceuticals Manufacture of veterinary medicinal products other than immunologicals
9.4 INTERNATIONAL CONFERENCE ON HARMONIZATION
We discussed in Section 7.11 the tripartite harmonization of guidelines by the United States, Europe, and Japan. The GMP Guidance is one of these guide-lines; it is described in the ICH Q7 document called GMP Guidance for Active Pharmaceutical Ingredients . Because of the wide implications of this guidance, the Steering Committee of the ICH invited experts from Australia, India, and China and industrial representatives from the generics industry, self - medication industry, and PIC/S (Pharmaceutical Inspection Cooperation Scheme, Section 7.13 ) to participate in the preparation of this document. Hence, the Q7 document has been endorsed as a truly international document for GMP.
The United States, the European Union, and Japan have implemented this GMP Guidance, and the details are presented in Exhibit 9.3 . The Q7 GMP Guidance sets out the requirements for GMP manufacturing. Details are sum-marized in Exhibit 9.4 . Most of the requirements of ICH Q7 are derived from
INTERNATIONAL CONFERENCE ON HARMONIZATION 283
284 GOOD MANUFACTURING PRACTICE: REGULATORY REQUIREMENTS
Exhibit 9.3 Implementation of ICH Q7 GMP Guide
European Union: Adopted by CPMP (a former committee, now changed to CHMP), November 2000; issued as CPMP/ICH/1935/00 http://dg3.eudra.org/ .
Ministry of Health, Labor and Welfare, Japan: Adopted November 2, 2001, PMSB Notifi cation No. 1200. http://www.nihs.go.jp/dig/ich/ichindex.htm .
Food and Drug Administration ( USA ): Published in the Federal Register , Vol. 66, No. 186, September 25, 2001, pp. 49028 49029.
CDER: http://www.fda.gov/cder/guidance/index.htm . CBER: http://www.fda.gov/cber/guidelines.htm .
Exhibit 9.4 ICH Q7 Guidance for Active Pharmaceutical Ingredients
Introduction Objective Regulatory Applicability Scope
Quality Management Principles Responsibilities of the Quality Unit(s) Responsibilities for Production Activities Internal Audits (Self Inspection) Product Quality Review
Personnel Personnel Qualifi cations Personnel Hygiene Consultants
Buildings and Facilities Design and Construction Utilities Water Containment
Lighting Sewerage and Refuse Sanitation and Maintenance
Process Equipment Design and Construction Equipment Maintenance and Cleaning Calibration Computerized System
Documentation and Records Documentation System and Specifi cations Equipment Cleaning and Use Record Records of Raw Materials, Intermediates, API Labeling and Packaging
Materials Master Production Instructions Batch Production Records Laboratory Control Records Batch Production Record Review
Materials Management General Controls Receipt and Quarantine Sampling and Testing of Incoming Production Materials Storage Reevaluation
Production and In - Process Controls Production Operations Time Limits In - Process Sampling and Controls Blending Batches of Intermediates or APIs Contamination Control
Packaging and Identifi cation Labeling of APIs and Intermediates General Packaging Materials Label Issuance and Control Packaging and Labeling Operations
Storage and Distribution Warehousing Procedures Distribution Procedures
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286 GOOD MANUFACTURING PRACTICE: REGULATORY REQUIREMENTS
Laboratory Controls General Controls Testing of Intermediates and APIs Validation of Analytical Procedures Certifi cate of Analysis Stability Monitoring of APIs Expiry and Retest Dating Reserve/Retention Samples
Validation Validation Policy Validation Documentation Qualifi cation Approaches to Process Validation Process Validation Program Periodic Review of Validated Systems Cleaning Validation Validation of Analytical methods
Change Control, Rejection, and Reuse of Materials Rejection Reprocessing Reworking Recovery of Materials and Solvents Returns
Complaints and Recalls Contract Manufacturers (Including Laboratories) Agents, Brokers, Traders, Distributors, Repackers, and Relabelers
Applicability Traceability and Distributed APIs and Intermediates Quality Management
Repackaging, Relabeling, and Ho...