This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs)

43 KB – 58 Pages

PAGE – 1 ============
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) September 2016 ICH Revision 1

PAGE – 2 ============
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients Guidance for Industry Additional copies are available from: Office of Communication s, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave. , Hillandale Bldg., 4 th Floor Silver Spring , MD 20993 -0002 Phone: 855-543-3784 or 301 -796-3400; Fax: 301-431-6353 Email: yInformation/Guidances/default.htm or Office of Communication, Outreach and Development Center for Biologics Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 71, Room 3128 Silver Spring, MD 20993 -0002 Phone : 800-835-4709 or 240 -402-8010 Email: uidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) September 2016 ICH Revision 1

PAGE – 3 ============
Contains Nonbinding Recommendations i Table Of Contents I. INTRODUCTION (1) .. 1 A. Objective (1.1) .. 1 B. Regulatory Applicability (1.2) 2 C. Scope (1.3) 2 II. QUALITY MANAGEMENT ( 2) .. 5 A. Principles (2.1) . 5 B. Responsibilities of the Quality Unit(s) (2.2) . 5 C. Responsibility for Production Activities (2.3) .. 6 D. Internal Audits (Self Inspection) (2.4) .. 7 E. Product Quality Review (2.5) . 7 III. PERSONNEL (3) . 8 A. Personnel Qualifications (3.1) . 8 B. Personnel Hygiene (3.2) .. 8 C. Consultants (3.3) . 9 IV. BUILDINGS AND FACILI TIES (4) .. 9 A. Design and Construction (4.1) 9 B. Utilities (4.2) 10 C. Water (4.3) 10 D. Containment (4.4) .. 11 E. Lighting (4.5) .. 11 F. Sewage and Refuse (4.6) .. 11 G. Sanitation and Maintenance (4.7) . 11 V. PROCESS EQUIPMENT (5 ) 12 A. Design and Construction (5.1) . 12 B. Equi pment Maintenance and Cleaning (5.2) .. 13 C. Calibration (5.3) 13 D. Computerized Systems (5.4) . 14 VI. DOCUMENTATION AND RE CORDS (6) . 15 A. Documentation System and Specifications (6.1) .. 15 B. Equipment Cleaning and Use Record (6.2) . 16

PAGE – 4 ============
Contains Nonbinding Recommendations ii C. Records of Raw Materials, Intermediates, API Labeling and Packaging Materials (6.3) 16 D. Master Production Instructions (Master Produ ction and Control Records) (6.4) . 16 E. Batch Production Records (Batch Production and Control Records) (6.5) 17 F. Laboratory Control Records (6.6) . 18 G. Batch Production Record Review (6.7) .. 19 VII. MATERIALS MANAGEMENT (7) .. 19 A. General Controls (7.1) .. 19 B. Receipt and Quarantine (7.2) 20 C. Sampling and Testing of Incoming Production Materials (7.3) . 20 D. Storage (7.4) . 21 E. Re-evaluation (7.5) .. 21 VIII. PRODUCTION AND IN -PROCESS CONTROLS (8) .. 21 A. Production Operations (8.1) . 22 B. Time Limits (8.2) .. 22 C. In-process Sampling and Controls (8.3) 23 D. Blending Batches of Intermediates or APIs (8.4) 23 E. Contamin ation Control (8.5) . 24 IX. PACKAGING AND IDENTI FICATION LABELING OF API s AND INTERMEDIATES (9) 24 A. General (9.1) . 25 B. Packaging Materials (9.2) .. 25 C. Label Issuance and Control (9.3) .. 25 D. Packaging and Labeling Operations (9.4) 26 X. STORAGE AND DISTRIBU TION (10) 26 A. Warehousing Procedures (10.1) . 26 B. Distribution Procedures (10.2) 27 XI. LABORATORY CONTROLS (11) .. 27 A. General Controls (11.1) 27 B. Testing of Intermediates and APIs (11.2) . 28 C. Validation of Analytical Procedures – See Section 12. (11.3) 29 D. Certificates of Analysis (11.4) .. 29 E. Stability Monitori ng of APIs (11.5) .. 30 F. Expiry and Retest Dating (11.6) . 30

PAGE – 5 ============
Contains Nonbinding Recommendations iii G. Reserve/Retention Samples (11.7) . 31 XII. VALIDATION (12) 31 A. Valida tion Policy (12.1) 31 B. Validation Documentation (12.2) .. 32 C. Qualification (12.3) . 32 D. Approaches to Process Validation (12.4) .. 32 E. Process Validation Program (12.5) .. 33 F. Periodic Review of Validated Systems (12.6) . 34 G. Cleaning Validation (12.7) . 34 H. Validation of Analytical Methods (12 .8) 35 XIII. CHANGE CONTROL (13) .. 35 XIV. REJECTION AND RE -USE OF MATE RIALS (14) .. 36 A. Rejection (14.1) . 36 B. Reprocessing (14.2) . 36 C. Reworking (14.3) .. 37 D. Recovery of Materials and Solvents (14.4) .. 37 E. Returns (14.5) . 37 XV. COMPLAINTS AND RECAL LS (15) .. 38 XVI. CONTRACT MANUFACTURE RS (INCLUDING LABORA TORIES) (16) . 39 XVII. AGENTS, BROKERS, TRA DERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS (17) .. 39 A. Applicability (17.1) . 39 B. Traceability of Distributed APIs and Intermediates (17.2) .. 39 C. Quality Management (17.3) .. 40 D. Repackaging, Relabeling, and Holding of APIs and Intermediates (17.4) .. 40 E. Stability (17.5) 40 F. Transfer of Information (17.6) 40 G. Handling of Complaints and Recalls (17.7) . 41 H. Handling of Returns (17.8) 41 XVIII. SPECIFIC GUIDANCE FO R API s MANUFACTURED BY CELL CULTURE/FERMENTATION (18) .. 41 A. General (18.1) . 41 B. Cell Bank Maintenance and Record Keeping (18.2) . 43

PAGE – 6 ============
Contains Nonbinding Recommendations iv C. Cell Culture/Fermentation (18.3) .. 43 D. Harvesting, Isolation and Purification (18.4) . 44 E. Viral Removal/Inactivation steps (18.5) 44 XIX. API s FOR USE IN CL INICAL TRIALS (19) .. 45 A. General (19.1) . 45 B. Quality (19.2) .. 45 C. Equipment and Facilities (19.3) .. 46 D. Control of Raw Materials (19.4) . 46 E. Production (19.5) .. 46 F. Validation (19.6) 46 G. Changes (19.7) 46 H. Laboratory Controls (19.8) 47 I. Documentation (19.9) 47 GLOSSARY (20) . 48

PAGE – 8 ============
Contains Nonbinding Recommendations 2 This guidance is not intended to define registration and/or filing requirements or modify pharmacopoeial requirements. This guidance does not affect the ability of the responsible regulatory agency to establish specific registration/filing requirements re garding APIs within the context of marketing/manufacturing authorizations or drug applications. All commitments in registration/filing documents should be met. This guidance revises and replaces the guidance Q7A Good Manufacturi ng Practice Guidance for Active Pharmaceutical Ingredient s. This revision change s the ICH codification from Q7A to Q7 . This revision also adds the ICH section numbers in parentheses at the end of each paragraph in Sections II (2) through XIX (19) of the guidance. B. Regulatory A pplicability (1.2) Within the world community, materials may vary as to their 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 manufacture d according to this guidance. C. Scope (1.3) This guidance 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 ster ile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but should be performed in accordance with GMP guidances for drug (medicinal) products as defined by local authorities. This guidance covers APIs that are man ufactured by chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any combination of these processes. Specific guidance for APIs manufactured by cell culture/fermentation is described in Section XVIII (18). This g uidance excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs. However, it does include APIs that are produced using blood or plasma as raw materials. Note that cell substrat es (mammalian, plant, insect or microbial cells, tissue or animal sources including transgenic animals) and early process steps may be subject to GMP but are not covered by this guidance. In addition, the guidance does not apply to medical gases, bulk -pac kaged drug (medicinal) products (e.g., tablets or capsules in bulk containers), or radiopharmaceuticals. Section XIX (19) contains guidance that only applies to the manufacture of APIs used in the production of drug (medicinal) products specifically for clinical trials (investigational medicinal products). An API starting material is a raw material, an intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the A PI. An API starting material can be an article of commerce, a material

PAGE – 9 ============
Contains Nonbinding Recommendations 3 purchased from one or more suppliers under contract or commercial agreement, or produced in -house. API starting materials normally have defined chemical properties and structure. The company should designate and document the rationale for the point at which production of the API begins. For synthetic processes, this is known as the point at which API starting materials are entered into the process. For other processes (e.g., ferme ntation, extraction, purification), this rationale should be established on a case -by-case basis. Table 1 gives guidance on the point at which the API starting material is normally introduced into the process. From this point on, appropriate GMP as define d in this guidance should be applied to these intermediate and/or API manufacturing steps. This would include the validation of critical process steps determined to impact the quality of the API. However, it should be noted that the fact that a company ch ooses 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 gray in Table 1. However, all steps shown may not need to be completed. The stringency of GMP in API manufacturing should increase as the process proceeds from early API steps to final steps, purification, and packaging. Physical processing of APIs, such as granulation, coating or physical manipulation of particle size (e.g., milling, microniz ing) should be conducted according to this guidance. This GMP guidance does not apply to steps prior to the introduction of the defined API starting material.

PAGE – 10 ============
Contains Nonbinding Recommendations 4 Table 1: Application of this Guidance to API Manufacturing Type of Manufacturing Application of this guidance to steps (shown in gray) used in this type of manufacturing Chemical Manufacturing Production of the API starting material Introduction of the API starting material into process Production of Intermediate(s) Isolation and purification Physical processing, and packaging API derived from animal sources Collection of organ, fluid, or tissue Cutting, mixing, and/or initial processing Introduction of the API starting material into process Isolation and purification Physical processing, and packaging API extracted from plant sources Collection of plant Cutting and initial extraction(s) Introduction of the API starting material into process Isolation and purification Physical processing, and packaging Herbal extracts used as API Collection of plants Cutting and initial extraction Further extraction Physical processing, and packaging API consisting of comminuted or powdered herbs Collection of plants and/or cultivation and harvesting Cutting/ comminuting Physical processing, and packaging Biotechnology: fermentation/ cell culture Establish -ment of master cell bank and working cell bank Maintenance of working cell bank Cell culture and/or fermentation Isolation and purification Physical processing, and packaging fiClassicalfl Fermentation to produce an API Establish -ment of cell bank Maintenance of the cell bank Introduction of the cells into fermentation Isolation and purification Physical processing, and packaging Increasing GMP requirements

PAGE – 11 ============
Contains Nonbinding Recommendations 5 II. QUALITY MANAGEMENT ( 2) A. Principles (2.1) Quality should be the responsibility of all persons involved in manufacturing. (2.10) Each manufacturer should establish, document, and implement an effective system for managing quality t hat involves the active participation of management and appropriate manufacturing personnel. (2.11) The system for managing quality should encompass the organizational structure, procedures, processes and resources, as well as activities to ensure confidence that the API will meet its intended specifications for quality and purity. All quality -related ac tivities should be defined and documented. (2.12) There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. The quality unit 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. (2.13) The persons authorized to release intermediates and APIs should be specified. (2.14) All quality -related activities should be recorded at the time they are performed. (2.15) Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented. (2.16) No materials should be re leased 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 X (10) or the use of raw materials or interme diates pending completion of evaluation). (2.17) 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, r ecalls, and regulatory actions). (2.18) B. Responsibilities of the Quality Unit(s) (2.2) The quality unit(s) should be involved in all quality -related matters. (2.20) The quality unit(s) should review and approve all appropriate quality -related docume nts. (2.21)

43 KB – 58 Pages