EU and FDA GMP Regulations: Overview and Comparison

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1 THE QUALITY ASSURANCE JOURNAL, VOL. 2, (1997) EU and FDA GMP Regulations: Overview and Comparison The increasing emphasis on global supply of drug products, as well as starting materials and investigational materials, along with international agreements between regulatory authorities, requires Quality Professionals to be versed in the GMP requirements of other nations. In particular, knowledge of both EU and US GMPs is becoming a necessary aspect of doing business in today s market. The foundations of the EU and US GMP systems, an overview comparison of drug product GMP regulations and a summary of the status of regulations is presented. INTRODUCTION John G. Grazal Specialist Microbiologist (American Academy of Microbiology), Senior Manager, International Compliance Group, Zeneca Pharmaceuticals, Zeneca Inc., Wilmington, Delaware, USA David S. Earl Qualified Person (as defined by Article 23 of EC Directive 75/319), Quality Assurance Manager, Quality Assurance Dept., Zeneca Pharmaceuticals, Macclesfield, UK In 1989, the European Council delegated to the Commission the task of adopting measures to strengthen the control of manufacture of medicinal products by means of a directive and guidelines on good manufacturing practice. The Commission used the Community Guide to Good Manufacturing Practice, prepared by a working party of Community pharmaceutical inspectors, as the basis for the Directives 91/356 and 91/412/EEC which established the principles and guidelines for good manufacturing practice for medicinal products for human and veterinary use, respectively. There is no difference in GMPs between the two directives and subsequent reference will be to 91/356/EEC. The GMP principles are interpreted with reference to detailed guidelines published by the European Commission in the Guide to Good Manufacturing Practice for Medicinal Products (GMP Guide), contained within Volume IV of the Rules Governing Medicinal Products in the European Community (1). The US first promulgated GMP regulations in These were updated in 1971, and a major revision was written in 1978 which, notwithstanding several clarifying revisions, remains in effect today. The GMP requirements for human drugs are contained in regulations 21 Code of Federal Regulations (CFR) Parts 210 and 211 (2). These laws are binding regulations which are to be considered minimum standards below which products are deemed adulterated. The regulations apply to both human and veterinary drug products. FDA enforces current good manufacturing practices (CGMP) based on the CGMP provision in the Food Drug and Cosmetic (FD & C) Act. This provision states that a drug is deemed adulterated if the methods used in, or the facilities used for drug product manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with CGMP. If a practice is not specified in the regulations, FDA must prove that the practice is CGMP. EC GMP DIRECTIVES AND US REGULATIONS The EC GMP Directives contain the principles and guidelines for medicinal drug manufacture. These laws are made up of 16 articles which lay down the legal framework that member states and manufacturers must comply with. EC Directive 91/356/EEC contains three chapters. Chapter 1 (Articles 1 5) General Provisions, requires repeat CCC/ /97/ $ John Wiley & Sons, Ltd.

2 56 John G. Grazal and David S. Earl Table 1. EU Principles and Guidelines of GMP Quality management Personnel Premises and equipment Documentation Production Quality control Work contracted out Complaints and product recall Self inspection inspections by member states, establishes the GMP Guide as the means of interpretation of the principles and guidelines, requires importers of product from third countries to ensure equivalent standards of manufacture to those in EC Rules Volume IV, and states that manufacturers shall ensure compliance with the marketing authorization. Chapter 2 (Articles 6 14) promulgates the principles and guidelines of GMP for medicinal products for human use (Table 1). Chapter 3 (Articles 15 and 16) The Final Provisions, directs member states to implement the directives into national law. It is the principles outlined in EC Directive 91/356 which provide the legal basis for GMP in the EU. EC member states were expected to bring into force the laws, regulations and necessary administrative provisions to comply with the Directive no later than 1 January The UK Medicines Act was updated by Statutory Instrument 2846 on 11 December Other member states followed later and made compliance with the principles of GMP statutory. The difference in timings can be attributed to the definition of an EC Directive which is a mechanism for providing a framework for national legislation by setting out broad principles and criteria for regulating a particular subject. Directives are binding but leave the method of achieving the outcome, within specified time limits, to the individual states. The US GMP regulations are contained in the CFR Title 21, Food and Drugs, Parts 210 and 211. Part 210 provides the framework for the regulations along with some definitions. Part 211 states the requirements (Table 2). These GMP regulations are Federal Law. The CFR contains the rules published in the Federal Register by the Executive departments and agencies of the US Federal Government. The document is divided into 50 titles representing broad areas subject to Federal regulation. Title 21, covering food and drugs, is updated annually in April. By law, all proposed regulations must be published in the Federal Register to allow a minimum of 30 days for public review and comment before becoming final. The publication of a Table 2. US CMP Regulations for Finished Pharmaceuticals General provisions Organization and personnel Buildings and facilities Equipment Control of components and drug product containers and closures Production and process controls Packaging and labelling control Holding and distribution Laboratory controls Records and reports Returned and salvaged drug products final food or drug regulation in the Federal Register is accompanied by a summary of each type of comment submitted on the proposal along with the FDA Commissioner s conclusions. The Commissioner s rationale (preamble) for accepting or rejecting a comment represents FDA s position on specific GMP requirements and serves as an invaluable reference when interpreting Title 21 Parts 210 and 211. Failure to comply with any of the GMP regulations in 21 CFR renders the drug adulterated under the FD & C Act. With that, the drug and the individuals responsible for the failure to comply shall be subject to regulatory action. EC AND US GMP GUIDELINES The stated purpose of guideline information for both the EU and the US is very similar. Both represent current acceptable practice by providing detailed guidance which interprets and expands on the principles or regulations. Guideline requirements are used by the regulatory authorities in both the EU and the US when assessing applications (Manufacturing and Marketing Authorizations, New Drug Applications (NDAs), Abbreviated new Drug Applications (ANDAs)) as well as a basis for inspections of manufacturers. The regulatory authorities allow implementation of alternate methods to those stated in guideline documents providing equivalent assurance is established. The risk in adopting alternate methods lies in justifying and documenting equivalence to the authorities. In short, guidelines list principles and practices which are acceptable; they do not list the principles and practices that must, in all instances, be used to comply with law. Neither the EC Guide or the FDA guidance documents carry the legal sanction of the principles or regulations. Volume IV of The Rules and Guidance Governing Medicinal Products In The

3 EU and FDA GMP Regulations 57 Table 3. EU GMP Guide Chapters and Annexes Chapters Annexes 1. Quality management 1. Sterile medicinal products 2. Personnel 2. Biological medicinal products for human use 3. Premises and equipment 3. Radiopharmaceuticals 4. Documentation 4. Veterinary medicinal products other than immunologicals 5. Production 5. Immunological veterinary medicinal products 6. Quality Control 6. Medicinal gasses 7. Contract manufacture and analysis 7. Herbal medicinal products 8. Complaints/product recall 8. Sampling of starting and packaging materials 9. Self-inspection 9. Liquids, creams and ointments 10. Pressurized metered dose aerosol preparations for inhalation 11. Computerized systems 12. Ionizing radiation in the manufacture of medicinal products 13. Investigational medicinal products 14. Products derived from human blood or human plasma Table 4. Examples of FDA Guidance Documents Guidelines Inspection guides Validation Pharmaceutical QC laboratories Bacterial endotoxin testing using LAL Lyophilization of parenterals Stability High purity water systems Aseptic processing Validation of cleaning processes Clinical Supplies Microbiological QC laboratories Repackaging Bulk pharmaceutical chemicals European Community titled Good Manufacturing Practice for Medicinal Products contains the nine Chapters and 13 Annexes which make up the GMP Guide. The chapter titles and the annexes are listed in Table 3. Examples of FDA GMP guidance documents are listed in Table 4. Additional sources of current GMPs (CGMPs) can be found in international guidelines such as the World Health Organization (WHO) GMP Guidelines, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, International Organization for Standards (ISO) standards, and Pharmaceutical Inspection Cooperation Scheme (PICS) Guidelines. Common practices within the industry, license reviews, and crisis management control are also sources of CGMPs. REGULATION OVERVIEW AND COMPARISON The subject areas of both the US and EU GMP regulations are very similar. The US regulations are lengthier and more prescriptive by incorporating detail which, in the EU scheme, is included in the Guide to GMP. An overview comparison keying on the EU GMP Principles and Guidelines is presented. Article 6 of the EU Principles requires an effective quality assurance system involving management s active participation. Article 11 outlines the responsibilities of the quality control department. It is useful to review both Articles together. The terms quality control department (EU), and quality control unit (US) do not discriminate between laboratory control and the responsibilities of the group most often referred to in industry as Quality Assurance (QA). Nevertheless, concepts such as batch record review, ensuring conformity to specifications, adequate laboratory facilities, and a reserve sample programme are common to both sets of regulations. EU regulations require a reserve (retained) sample of starting materials be held for at least 2 years after the release of the product. The US require a reserve sample of the active ingredient to be retained for 1 year after the expiration date of the last lot of drug product containing the active ingredient. The US regulations emphasize written procedures, in many cases detailing minimum requirements. The EU regulations leave the detail of written procedures to the GMP Guide.

4 58 John G. Grazal and David S. Earl Both sets of regulations allow the use of outside laboratories to carry out the quality control functions necessary for examination and testing of materials. The thrust of the regulations is that adequate laboratory facilities be available to the quality function, not that the facilities be owned and operated by the drug product manufacturer. However, the drug product manufacturer is ultimately responsible for ensuring the contract laboratory operates to GMP. In the EU legal action can be taken against the Heads of Production and Quality Control and the Qualified Persons... The regulations in both the EU and the US assign the responsibility for quality manufacturing practices to senior management. In the US, products are deemed adulterated based on either laboratory examination of drug products or on the basis of objectionable conditions observed during manufacturing or holding of the drug products. The latter means of determining product adulteration results from an FDA conclusion that the product(s) were not manufactured in accordance with CGMP. When products have been found to be adulterated, FDA has both administrative and legal options it can exercise. Administrative actions include issuing Warning Letters and withholding approval of applications. The legal actions in the US include product seizure, debarment of individuals from working in the pharmaceutical industry, court injunctions and prosecution. Where product is manufactured outside the US and been found to be adulterated, FDA has taken administrative actions and in some cases barred import of the drug products into the US. In the EU, besides the powers European inspectors have to seize and detain medicinal products from the manufacturing facility, legal action can be taken against the persons named on the Manufacturers License. These are the Heads of Production and Quality Control and the Qualified Persons (QP). Article 7 of the EU Principles discusses personnel requirements. Organizational charts and job descriptions are required. There are no similar requirements for these documents in the US regulations. Education, experience, and training as the foundation for qualified personnel is integral to both sets of regulations, although the detail in the EU is again covered in the Guide. There is a statutory requirement for initial and ongoing training, including GMP training, in both sets of regulations. Health, hygiene, and clothing for personnel is also addressed in the regulations. Uniquely, CFR Part addresses the use of consultants requiring them to be qualified and mandating the drug product manufacturer to maintain records containing the name, address, qualifications and the type of service performed by these individuals. Article 8 addresses premises and equipment. Chapter 3 of the Guide provides the detail. The CFR Part 211 Subparts C and D cover facilities and equipment in similar detail to the Principles and Guide. The design, construction and operation features of buildings and equipment must be such as to minimize the potential for contamination and quality problems. 211 CFR Subpart C goes into a fair amount of detail on requirements for separate or defined areas for various operations including aseptic processing. Both sets of regulations require buildings and equipment to be maintained. Equipment surfaces that come into contact with product must not be reactive, additive or absorptive (2). Maintenance and cleaning activities are detailed in the CFR while similar requirements are in the EU GMP Guide. Premises and equipment critical to product quality must be subject to appropriate qualification according to Article 8, Item 3. While the wording is less clear, FDA point to 21 CFR Part a, in particular the requirement that equipment be checked according to a written program designed to assure proper performance (2) as the regulation requiring equipment qualification or validation. Separate facilities for penicillin production are addressed in the US regulations and the EU GMP Guide. CFR on sterile filtration covers many of the same details outlined in Annex 1 of the GMP Guide. This section of the CFR should be read in conjunction with the FDA Guideline On Sterile Drug Products Produced By Aseptic Processing 1987, where specific good practices relating to sterile filtration are detailed. Article 9 on documentation coupled with Chapter 4 of the GMP Guide provides a comprehensive and detailed set of requirements related to documentation. CFR 211 Subpart J, Records and Reports, details the US requirements. The similarity in content and detail between the documentation requirements should provide firms on both sides of the Atlantic with adequate instruction to meet FDA s inspectional emphasis on documentation.

5 EU and FDA GMP Regulations 59 Based on the number of FDA 483 observations related to documentation deficiencies, this does not appear to be the case. Both EU and US regulations require that documents be available for inspection purposes. The use of electronic storage for documents is recognized provided the system has been validated. Article 10 on production covers process validation and revalidation requirements. CFR Part 211 is scant in the area of process validation. This appears at odds with both the US industry and FDA s emphasis on validation. Clearly, process validation CGMPs have evolved without benefit of detailed regulation in this area. It must be remembered that the last major revision of 21 CFR was in Validation GMPs have progressed significantly since that time. A draft revision to 21CFR Parts 210 and 211, published by FDA in 1996 includes more specific validation requirements which have drawn negative comment from industry. Whilst time limits are discussed in Part and apply to all drug products, the European approach to this process control is reserved for the GMP Guide Sterile Products Annex. Article 11 was discussed in the context of QA/QC. Article 12 is devoted to work contracted out. The requirement for a written contract defining responsibilities between each party is unique to the European regulations. The EU provisions around inspections and subcontracting are GMP practices in the US. However, these requirements along with QP responsibilities (not recognized in the US) are not part of the GMP regulations. It is noteworthy that in the US, the quality control unit of a contract facility is required to approve or reject drug products produced by the contractor but the final release to market is to be performed by the owner of the drug product. In the EU, this distinction is not made provided the release is done by a QP. All holders of Manufacturers Licenses within the EU are required to have the services of a QP as defined in EC Directive 75/319. No batch of medicinal product may be released to the market within the EU unless a nominated QP has certified that it has been manufactured and checked in compliance with the laws in force. Article 13 on complaints and product recall outlines the requirements in these areas. Written procedures, investigations, and alerting the regulatory authorities are common to both systems. Recalls are voluntary in both the US and the EU. Both sets of regulations refer the reader to further guidance/regulation on the conduct of recalls. Firms have been cited on FDA Form 483 for not having an internal audit plan... Article 14 on Self Inspections does not have an equivalent in the US GMP regulations. While it is certainly CGMP to perform internal auditing, and the FDA expectation is that firms do so, there is no legal requirement in the US regulations. Firms have been cited on FDA Form 483 observations for not having an internal audit plan or for failing to carry out scheduled audits. STATUS OF GMP REGULATIONS IN THE EU AND US The draft revision of CFR Parts 210 and 211 mentioned above was published in a 6 May 1996 submission to the Federal Register. The Agency has stated that the reason for the proposed revisions to the regulations is to clarify requirements in certain areas of GMP that have been the subject of recent enforcement actions. Industry has commented that the proposed regulations impose substantial new requirements that do not contribute to the quality or safety of drug products. FDA is reviewing the industry comments and is expected to issue a final revision in Currently there are no statutory GMP regulations for active pharmaceutical ingredients (APIs) in either the EU or the US. While the FDA has an active inspection programme for APIs and uses CFR Parts 210 and 211, these regulations are used as guidelines only. APIs manufactured for use in drug products for the US market are required to conform to GMP since the Food, Drug and Cosmetic Act makes no distinction between drug substances and drug products, but there are no formal regulations. A similar situation exists in the EU, although there is no formal inspection programme for APIs. FDA released a draft guidance Manufacture, Processing, or Holding of Active Pharmaceutical Ingredients in October FDA is reviewing industry comment to this proposal and the final revision is expected in A legal GMP framework (regulations and guidelines) has been proposed in the EU for starting materials. This would establish both routine and

6 60 John G. Grazal and David S. Earl for cause inspections for selected starting materials including all active agents and certain excipients. These listed starting materials would be required to be manufactured in accordance with the regulations and guidelines. Inspections of third country starting material manufacturers is also called for. Investigational materials or clinical supplies must conform with the drug product CFRs for manufacture and/or distribution in the US. In the EU, these materials are not currently subject to statutory requirements. While the EU principles and guidelines, along with the detailed guidelines are relevant to the manufacture of investigational materials, it is Annex 13 in the GMP Guide which provides the framework for common standards in the area of investigational materials. CONCLUSIONS Pharmaceutical manufacture and regulation is clearly an international business. With the increasing emphasis on harmonization efforts and standard setting along with mutual recognition agreements, knowledge of foreign regulations is a necessity for both understanding the future direction of these efforts as well as for international supply of drug products. This paper presented some background information and an overview of drug GMP regulations and guidelines in the EU and the US. The laws and principles relating to GMP are fundamentally similar between the EU and the US. It is the detailed guidelines and their application where the differences arise, and even here there is much that is similar. As with any overview, there is much detail which is not covered. The intent of this article is to introduce the reader to the regulations and provide a starting point for further investigations. REFERENCES 1. Commission of the European Communities. The Rules Governing Medicinal Products in the EC. Vol. IV. Good Manufacturing Practice for Medicinal Products. Luxembourg: Office for Official Publications of the EC, ISBN X. 2. Food and Drug Administration, Department of Health and Human Services. 21CFR 210, 211. Washington: Office of the Federal Register National Archives and Records Administration, 1997.