ICH HARMONISED TRIPARTITE GUIDELINE

1 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE good MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7 Current Step 4 version dated 10 November 2000 This GUIDELINE has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. Q7 Document History First Codification History Date New Codification November 2005 Q7A Approval by the Steering Committee under Step 2 and release for public consultation.

2 19 July 2000 Q7 Current Step 4 version Q7A Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies. 10 November 2000 Q7 i good MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS ICH HARMONISED TRIPARTITE GUIDELINE Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 10 November 2000, this GUIDELINE is recommended for adoption to the three regulatory parties to ICH TABLE OF CONTENTS 1. INTRODUCTION .. 1 Objective .. 1 Regulatory Applicability .. 1 Scope .. 1 2. QUALITY MANAGEMENT .. 4 Principles .. 4 Responsibilities of the Quality Unit(s) .. 4 Responsibility for Production Activities.

3 5 Internal Audits (Self Inspection) .. 5 Product Quality Review .. 6 3. PERSONNEL .. 6 Personnel Qualifications .. 6 Personnel Hygiene .. 6 Consultants .. 7 4. BUILDINGS AND FACILITIES .. 7 Design and Construction .. 7 Utilities .. 8 Water .. 8 Containment .. 8 Lighting .. 9 Sewage and Refuse .. 9 Sanitation and Maintenance .. 9 5. PROCESS EQUIPMENT .. 9 Design and Construction .. 9 Equipment Maintenance and Cleaning .. 10 Calibration .. 11 Computerized Systems .. 11 good Manufacturing Practice Guide for Active Pharmaceutical Ingredients ii 6. DOCUMENTATION AND RECORDS .. 12 Documentation System and Specifications .. 12 Equipment Cleaning and Use Record .. 12 Records of Raw Materials, Intermediates, API Labelling and Packaging Materials.

4 13 Master Production Instructions (Master Production and Control Records) .. 13 Batch Production Records (Batch Production and Control Records) .. 14 Laboratory Control Records .. 14 Batch Production Record Review .. 15 7. MATERIALS MANAGEMENT .. 16 General Controls .. 16 Receipt and Quarantine .. 16 Sampling and Testing of Incoming Production Materials .. 16 Storage .. 17 Re-evaluation .. 17 8. PRODUCTION AND IN-PROCESS CONTROLS .. 18 Production Operations .. 18 Time Limits .. 18 In-process Sampling and Controls .. 18 Blending Batches of Intermediates or APIs .. 19 Contamination Control .. 20 9. PACKAGING AND IDENTIFICATION LABELLING OF APIS AND INTERMEDIATES .. 20 General.

5 20 Packaging Materials .. 20 Label Issuance and Control .. 20 Packaging and Labelling Operations .. 21 10. STORAGE AND DISTRIBUTION .. 22 Warehousing Procedures .. 22 Distribution Procedures .. 22 11. LABORATORY CONTROLS .. 22 General Controls .. 22 Testing of Intermediates and APIs .. 23 Validation of Analytical Procedures - see Section 12.. 24 Certificates of Analysis .. 24 Stability Monitoring of APIs .. 24 Expiry and Retest Dating .. 25 good Manufacturing Practice Guide for Active Pharmaceutical Ingredients iii Reserve/Retention Samples .. 25 12. VALIDATION .. 25 Validation Policy .. 25 Validation Documentation .. 26 Qualification .. 26 Approaches to Process Validation.

6 26 Process Validation Program .. 27 Periodic Review of Validated Systems .. 27 Cleaning Validation .. 28 Validation of Analytical Methods .. 28 13. CHANGE CONTROL .. 29 14. REJECTION AND RE-USE OF MATERIALS .. 29 29 Reprocessing .. 30 Reworking .. 30 Recovery of Materials and Solvents .. 30 Returns .. 31 15. COMPLAINTS AND RECALLS .. 31 16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) .. 31 17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS .. 32 Applicability .. 32 Traceability of Distributed APIs and Intermediates .. 32 Quality Management .. 33 Repackaging, Relabelling and Holding of APIs and Intermediates .. 33 Stability .. 33 Transfer of Information.

7 33 Handling of Complaints and 33 Handling of Returns .. 34 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION .. 34 34 Cell Bank Maintenance and Record Keeping .. 35 Cell Culture/Fermentation .. 35 Harvesting, Isolation and Purification .. 36 Viral Removal/Inactivation steps .. 36 good Manufacturing Practice Guide for Active Pharmaceutical Ingredients iv 19. APIS FOR USE IN CLINICAL TRIALS .. 37 General .. 37 Quality .. 37 Equipment and Facilities .. 37 Control of Raw Materials .. 37 Production .. 38 Validation .. 38 Changes .. 38 Laboratory Controls .. 38 Documentation .. 38 20. GLOSSARY .. 39 1 good MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS 1.

8 INTRODUCTION Objective This document (Guide) is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the requirements for quality and purity that they purport or are represented to possess. In this Guide manufacturing is defined to include all operations of receipt of materials, production, packaging, repackaging, labelling, relabelling, quality control, release, storage and distribution of APIs and the related controls. In this Guide the term should indicates recommendations that are expected to apply unless shown to be inapplicable or replaced by an alternative demonstrated to provide at least an equivalent level of quality assurance.

9 For the purposes of this Guide, the terms current good manufacturing practices and good manufacturing practices are equivalent. The Guide as a whole does not cover safety aspects for the personnel engaged in the manufacture, nor aspects of protection of the environment. These controls are inherent responsibilities of the manufacturer and are governed by national laws. This Guide is not intended to define registration/filing requirements or modify pharmacopoeial requirements. This Guide does not affect the ability of the responsible regulatory agency to establish specific registration/filing requirements regarding APIs within the context of marketing/manufacturing authorizations or drug applications.

10 All commitments in registration/filing documents must be met. Regulatory Applicability Within the world community, materials may vary as to the legal classification as an API. When a material is classified as an API in the region or country in which it is manufactured or used in a drug product, it should be manufactured according to this Guide. Scope This Guide applies to the manufacture of APIs for use in human drug (medicinal) products. It applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but should be performed in accordance with GMP guidelines for drug (medicinal) products as defined by local authorities.