20100731 欧盟API GMP生效gmp_part2_en

Commission Européenne, B-1049 Bruxelles / Europese Commissie,B-1049 Brussel – Belgium, Telephone: (32-2) 299 11 11 1 EUROPEAN COMMISSION ENTERPRISE AND INDUSTRY DIRECTORATE-GENERAL Consumer goods Pharmaceuticals Brussels, 03 February 2010 ENTR/F/2/AM/an D(2010) 3374 EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Part II: Basic Requirements for Active Substances used as Starting Materials Document History An amendment is made to Part II of the GMP Guide to incorporate principles of Quality Risk Management in line with the ICH Q9 guideline on Quality Risk Management. Amendments correspond to similar changes made to Part I Chapter 1 of the Guide and published in February 2008. A new section on Quality Risk Management is introduced as section 2.19. The remaining sections of chapter 2 are renumbered. A minor change is made to section 2.21. No other changes have been made. September 2007 Public consultation April 2008 until October 2008 Adopted by the European Commission 31 January 2010 Deadline for coming into operation 31 July 2010 Commission Européenne, B-1049 Bruxelles / Europese Commissie,B-1049 Brussel – Belgium, Telephone: (32-2) 299 11 11 2 Table of Contents 1 Introduction 1.1 Objective 1.2 Regulatory Applicability 1.3 Scope 2 Quality Management 2.1 Principles 2.2 Quality Risk Management 2.3 Responsibilities of the Quality Unit(s) 2.4 Responsibility for Production Activities 2.5 Internal Audits (Self-Inspection) 2.6 Product Quality Review 3 Personnel 3.1 Personnel Qualifications 3.2 Personnel Hygiene 3.3 Consultants 4 Buildings and Facilities 4.1 Design and Construction 4.2 Utilities 4.3 Water 4.4 Containment 4.5 Lighting 4.6 Sewage and Refuse 4.7 Sanitation and Maintenance 5 Process Equipment 5.1 Design and Construction 5.2 Equipment Maintenance and Cleaning 5.3 Calibration 5.4 Computerized Systems 6 Documentation and Records 6.1 Documentation System and Specifications 6.2 Equipment Cleaning and Use Record 6.3 Records of Raw Materials, Intermediates, API Labelling and Packaging Materials 6.4 Master Production Instructions (Master Production and Control Records) 6.5 Batch Production Records (Batch Production and Control Records) 6.6 Laboratory Control Records 6.7 Batch Production Record Review 3 7 Materials Management 7.1 General Controls 7.2 Receipt and Quarantine 7.3 Sampling and Testing of Incoming Production Materials 7.4 Storage 7.5 Re-evaluation 8 Production and In-Process Controls 8.1 Production Operations 8.2 Time Limits 8.3 In-process Sampling and Controls 8.4 Blending Batches of Intermediates or APIs 8.5 Contamination Control 9 Packaging and Identification Labelling of APIs and Intermediates 9.1 General 9.2 Packaging Materials 9.3 Label Issuance and Control 9.4 Packaging and Labelling Operations 10 Storage and Distribution 10.1 Warehousing Procedures 10.2 Distribution Procedures 11 Laboratory Controls 11.1 General Controls 11.2 Testing of Intermediates and APIs 11.3 Validation of Analytical Procedures 11.4 Certificates of Analysis 11.5 Stability Monitoring of APIs 11.6 Expiry and Retest Dating 11.7 Reserve/Retention Samples 12 Validation 12.1 Validation Policy 12.2 Validation Documentation 12.3 Qualification 12.4 Approaches to Process Validation 12.5 Process Validation Program 12.6 Periodic Review of Validated Systems 12.7 Cleaning Validation 12.8 Validation of Analytical Methods 13 Change Control 14 Rejection and Reuse of Materials 14.1 Rejection 14.2 Reprocessing 14.3 Reworking 14.4 Recovery of Materials and Solvents 14.5 Returns 4 15 Complaints and Recalls 16 Contract Manufacturers (including Laboratories) 17 Agents, Brokers, Traders, Distributors, Repackers, and Relabellers 17.1 Applicability 17.2 Traceability of Distributed APIs and Intermediates 17.3 Quality Management 17.4 Repackaging, Relabelling and Holding of APIs and Intermediates 17.5 Stability 17.6 Transfer of Information 17.7 Handling of Complaints and Recalls 17.8 Handling of Returns 18 Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18.1 General 18.2 Cell Bank Maintenance and Recordkeeping 18.3 Cell Culture/Fermentation 18.4 Harvesting, Isolation, and Purification 18.5 Viral Removal/Inactivation Steps 19 APIs for Use in Clinical Trials 19.1 General 19.2 Quality 19.3 Equipment and Facilities 19.4 Control of Raw Materials 19.5 Production 19.6 Validation 19.7 Changes 19.8 Laboratory Controls 19.9 Documentation 20 Glossary 5 1 Introduction This guideline was published in November 2000 as Annex 18 to the GMP Guide reflecting the EU’s agreement to ICH Q7A and has been used by manufacturers and GMP inspectorates on a voluntary basis. Article 46 (f) of Directive 2001/83/EC and Article 50 (f) of Directive 2001/82/EC; as amended by Directives 2004/27/EC and 2004/28/EC respectively, place new obligations on manufacturing authorisation holders to use only active substances that have been manufactured in accordance with Good Manufacturing Practice for starting materials. The directives go on to say that the principles of Good Manufacturing Practice for active substances are to be adopted as detailed guidelines. Member States have agreed that the text of former Annex 18 should form the basis of the detailed guidelines to create Part II of the GMP Guide. 1.1 Objective These guidelines are intended to provide guidance regarding Good Manufacturing Practice (GMP) for the manufacture of active substances under an appropriate system for managing quality. It is also intended to help ensure that active substances meet the requirements for quality and purity that they purport or are represented to possess. In these guidelines “manufacturing” includes all operations of receipt of materials, production, packaging, repackaging, labeling, relabelling, quality control, release, storage and distribution of active substances and the related controls. The term “should” indicates recommendations that are expected to apply unless shown to be inapplicable, modified in any relevant annexes to the GMP Guide, or replaced by an alternative demonstrated to provide at least an equivalent level of quality assurance. The GMP Guide as a whole does not cover safety aspects for the personnel engaged in manufacture, nor aspects of protection of the environment. These controls are inherent responsibilities of the manufacturer and are governed by other parts of the legislation. These guidelines are not intended to define registration requirements or modify pharmacopoeial requirements and do not affect the ability of the responsible competent authority to establish specific registration requirements regarding active substances within the context of marketing/manufacturing authorisations. All commitments in registration documents must be met. 1.2 Scope These guidelines apply to the manufacture of active substances for medicinal products for both human and veterinary use. They apply to the manufacture of sterile active substances only up to the point immediately prior to the active substance being rendered sterile. The sterilisation and aseptic processing of sterile active substances are not covered, but should be performed in accordance with the principles and guidelines of GMP as laid down in Directive 2003/94/EC and interpreted in the GMP Guide including its Annex 1. In the case of ectoparasiticides for veterinary use, other standards than these guidelines, that ensure that the material is of appropriate quality, may be used. These guidelines exclude, whole blood and plasma, as Directive 2002/98/EC and the technical requirements supporting that directive lay down the detailed requirements for the collection and testing of blood, however, it does include active substances that are produced using blood or plasma as raw materials. Finally, these guidelines do not apply 6 to bulk-packaged medicinal products. They apply to all other active starting materials subject to any derogations described in the annexes to the GMP Guide, in particular Annexes 2 to 7 where supplementary guidance for certain types of active substance may be found. The annexes will consequently undergo a review but in the meantime and only until this review is complete, manufacturers may choose to continue to use Part I of the basic requirements and the relevant annexes for products covered by those annexes, or may already apply Part II. Section 19 contains guidance that only applies to the manufacture of active substances used in the production of investigational medicinal products although it should be noted that its application in this case, although recommended, is not required by Community legislation. An “Active Substance Starting Material” is a raw material, intermediate, or an active substance that is used in the production of an active substance and that is incorporated as a significant structural fragment into the structure of the active substance. An Active Substance Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. Active Substance Starting Materials normally have defined chemical properties and structure. The manufacturer should designate and document the rationale for the point at which production of the active substance begins. For synthetic processes, this is known as the point at which "Active Substance Starting Materials" are entered into the process. For other processes (e.g. fermentation, extraction, purification, etc), this rationale should be established on a case-by-case basis. Table 1 gives guidance on the point at which the Active Substance Starting Material is normally introduced into the process. From this point on, appropriate GMP as defined in these guidelines should be applied to these intermediate and/or active substance manufacturing steps. This would include the validation of critical process steps determined to impact the quality of the active substance. However, it should be noted that the fact that a manufacturer chooses to validate a process step does not necessarily define that step as critical. The guidance in this document would normally be applied to the steps shown in grey in Table 1. It does not imply that all steps shown should be completed. The stringency of GMP in active substance manufacturing should increase as the process proceeds from early steps to final steps, purification, and packaging. Physical processing of active substances, such as granulation, coating or physical manipulation of particle size (e.g. milling, micronising), should be conducted at least to the standards of these guidelines. These guidelines do not apply to steps prior to the first introduction of the defined "Active Substance Starting Material". In the remainder of this guideline the term Active Pharmaceutical Ingredient (API) is used repeatedly and should be considered interchangeable with the term “Active Substance”. The glossary in section 20 of Part II should only be applied in the context of Part II. Some of the same terms are already defined in Part I of the GMP guide and these therefore should only be applied in the context of Part I. 7 Table 1: Application of this Guide to API Manufacturing 8 2 Quality Management 2.1 Principles 2.10 Quality should be the responsibility of all persons involved in manufacturing. 2.11 Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel. 2.12 The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and documented. 2.13 There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization. 2.14 The persons authorised to release intermediates and APIs should be specified. 2.15 All quality related activities should be recorded at the time they are performed. 2.16 Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented. 2.17 No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g. release under quarantine as described in Section 10.20 or the use of raw materials or intermediates pending completion of evaluation). 2.18 Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g. quality related complaints, recalls, regulatory actions, etc.). 2.19 To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented quality system incorporating Good Manufacturing Practice, Quality Control and Quality Risk Management. 2.2 Quality Risk Management 2.20 Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the active substance. It can be applied both proactively and retrospectively. 2.21 The quality risk management system should ensure that: - the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient through communication with the user of the active substance - the level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk Examples of the processes and applications of quality risk management can be found, inter alia, in Annex 20. 9 2.3 Responsibilities of the Quality Unit(s) 2.30 The quality unit(s) should be involved in all quality-related matters. 2.31 The quality unit(s) should review and approve all appropriate quality-related documents. 2.32 The main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include but not necessarily be limited to: 1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing company; 2. Establishing a system to release or reject raw materials, intermediates, packaging and labelling materials; 3. Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution; 4. Making sure that critical deviations are investigated and resolved; 5. Approving all specifications and master production instructions; 6. Approving all procedures impacting the quality of intermediates or APIs; 7. Making sure that internal audits (self-inspections) are performed; 8. Approving intermediate and API contract manufacturers; 9. Approving changes that potentially impact intermediate or API quality; 10. Reviewing and approving validation protocols and reports; 11. Making sure that quality related complaints are investigated and resolved; 12. Making sure that effective systems are used for maintaining and calibrating critical equipment; 13. Making sure that materials are appropriately tested and the results are reported; 14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates where appropriate; and 15. Performing product quality reviews (as defined in Section 2.5) 2.4 Responsibility for Production Activities The responsibility for production activities should be described in writing, and should include but not necessarily be limited to: 1. Preparing, reviewing, approving and distributing the instructions for the production of intermediates or APIs according to written procedures; 2. Producing APIs and, when appropriate, intermediates according to pre- approved instructions; 3. Reviewing all production batch records and ensuring that these are completed and signed; 4. Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded; 10 5. Making sure that production facilities are clean and when appropriate disinfected; 6. Making sure that the necessary calibrations are performed and records kept; 7. Making sure that the premises and equipment are maintained and records kept; 8. Making sure that validation protocols and reports are reviewed and approved; 9. Evaluating proposed changes in product, process or equipment; and 10. Making sure that new and, when appropriate, modified facilities and equipment are qualified. 2.5 Internal Audits (Self Inspection) 2.50 In order to verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule. 2.51 Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner. 2.6 Product Quality Review 2.60 Regular quality reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least: - A review of critical in-process control and critical API test results; - A review of all batches that failed to meet established specification(s); - A review of all critical deviations or non-conformances and related investigations; - A review of any changes carried out to the processes or analytical methods; - A review of results of the stability monitoring program; - A review of all quality-related returns, complaints and recalls; and - A review of adequacy of corrective actions. 2.61 The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner. 3 Personnel 3.1 Personnel Qualifications 3.10 There should be an adequate number of personnel qualified by appropriate education, training and/or experience to perform and supervise the manufacture of intermediates and APIs. 3.11 The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing. 3.12 Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates 11