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GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS
1. INTRODUCTION
1.1 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. 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. All commitments in registration/filing documents must be met.
1.2 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.
1.3 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.
This Guide covers APIs that are manufactured by chemical synthesis, extraction, cell culture/fermentation, by recovery from natural sources, or by any combination of these processes. Specific guidance for APIs manufactured by cell culture/fermentation is described in Section 18.
This Guide 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 substrates (mammalian, plant, insect or microbial cells, tissue or animal sources including transgenic
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Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
animals) and early process steps may be subject to GMP but are not covered by this Guide. In addition, the Guide does not apply to medical gases, bulk-packaged drug (medicinal) products, and manufacturing/control aspects specific to radiopharmaceuticals.
Section 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, 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 API. An API 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. 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. 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 API Starting Material is normally introduced into the process.
From this point on, appropriate GMP as defined in this Guide 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 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 gray in Table 1. It does not imply that all steps shown should 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, micronizing), should be conducted at least to the standards of this Guide.
This GMP Guide does not apply to steps prior to the introduction of the defined "API Starting Material".
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Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
Table 1: Application of this Guide to API Manufacturing
Type of Manufacturing
Application of this Guide to steps (shown in grey) 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 plants
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
Establishment 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
“Classical” Fermentation to produce an API
Establishment of cell bank
Maintenance of the cell bank
Introduction of the cells into fermentation
Isolation and purification
Physical processing, and packaging
Increasing GMP requirements
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