Post-approval Changes to Drug Substances
Guidance for Industry
行业指南：原料药批准后变更
DRAFT GUIDANCE
指南草案
This guidance document is being distributed for comment purpos only.
本指南文件仅供公开征求意见
Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments v. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact (CDER) Carolyn Cohran 240-402-8612; (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010; or (CVM) Dennis Bensley 240-402-0696.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
Center for Biologics Evaluation and Rearch (CBER)
Center for Veterinary Medicine (CVM)
September 2018
Pharmaceutical Quality/CMC
Post-approval Changes to Drug Substances
Guidance for Industry
行业指南：原料药批准后变更
Additional copies are available from:
Office of Communications, Division of Drug Information Center for Drug
Evaluation and Rearch
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD
ppt用什么做20993-0002
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Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
怎样省钱Email: druginfo@v
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庞大的近义词Office of Communication, Outreach and Development Center for
Biologics Evaluation and Rearch
Food and Drug Administration
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MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@v
v/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or
Policy and Regulations Staff, HFV-6Center for
Veterinary Medicine Food and Drug
Administration
7519 Standish Place, Rockville, MD 20855
v/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
Center for Biologics Evaluation and Rearch (CBER)
Center for Veterinary Medicine (CVM)
September 2018
Pharmaceutical Quality/CMC
TABLE OF CONTENTS 目录
I.INTRODUCTION 概述 (5)
II.BACKGROUND 背景 (6)
A.Established Conditions and Reporting Categories 已订立的条件和报告分类 (7)
B.Reporting Responsibilities 报告义务 (7)
III.GENERAL CONSIDERATIONS 一般考量 (8)
A.Asssment of Risk 风险评估 (8)
B.Other Relevant Guidances 其它相关指南 (11)
IV.ASSESSMENT OF CHANGE 变更评估 (11)
A.Drug Substance 原料药 (11)
Table 1: Relevance of Physical Properties to Dosage Form Performance (18)
表1：物理特性与剂型性能的相关性 (18)
Table 2: Potential for Postapproval Changes To Adverly Affect the Physical Properties of a Drug Substance (19)
表2：批准后变更对原料药物理属性产生不良影响的可能性 (19)
B.Drug Product 制剂 (20)
V.TYPES OF CHANGES AND DOCUMENTATION 变更类型与文件要求 (22)
VI.FACILITY, SCALE, AND EQUIPMENT CHANGES 设施、生产规模和设备变更 (22)
A.Facility Changes 设施变更 (23)
B.Scale Changes 生产规模变更 (24)
C.Equipment Changes 设备变更 (25)
D.Recommended Documentation for the Drug Substance in a Master File or an Approved
Application 主文件或已批准申报中原料药文件建议 (25)
E.Recommended Documentation for the Drug Product in an Approved Application 批准后申
报资料中制剂文件建议 (27)
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VII.SPECIFICATION CHANGES 质量标准变更 (28)
A.Specification Changes to Raw Materials and Intermediates 原料和中间体质量标准变更 (28)
B.Specification Changes to Drug Substances 原料药质量标准变更 (30)
C.Recommended Documentation for the Drug Substance in a Master File or an Approved
Application DMF或已批准的制剂申报中原料药文件的建议 (30)
D.Recommended Documentation for the Drug Product in an Approved Application 已批准申
报资料中的制剂文件建议 (33)
VIII.M ANUFACTURING PROCESS CHANGES 生产工艺变更 (34)
A.Changes That Do Not Involve the Route of Synthesis 不涉及合成路线的变更 (34)
B.Changes in Route of Synthesis in One or More Steps 一个或多个步骤合成路线变更 (35)
C.Establishing a Reprocessing Procedure as Part of the Established Manufacturing Process 建
立返工程序作为已有生产工艺的一部分 (35)
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D.Recommended Documentation for the Drug Substance in a Master File or an Approved
Application 主文件或已批准申报中原料药文件建议 (35)
E.Recommended Documentation for the Drug Product in an Approved Application 已批准申
报中制剂的文件建议 (37)
IX.STARTING MATERIAL CHANGES 起始物料变更 (38)
A.Recommended Documentation for the Drug Substance in a Master File or an Approved
Application 主文件或已批准申报中原料药文件建议 (39)
B.Recommended Documentation for the Drug Product in an Approved Application 已批准申
报中原料药文件建议 (41)
X.CONTAINER CLOSURE SYSTEM CHANGES 容器密闭器系统变更 (41)
XI.MULTIPLE CHANGES 多重变更 (42)
XII.REPORTING CATEGORY 报告类别 (42)
XIII.G LOSSARY 术语 (43)
APPENDIX A. CHANGES TO DRUG SUBSTANCE MANUFACTURE (48)
附录A：原料药生产变更 (49)
APPENDIX B: REPORTING CATEGORIES FOR ADDITIONAL EXAMPLES OF CHANGES (50)
西游记原著简介附录B：报告类别变更附加举例 (50)
Reporting Categories for Equipment Changes 设备变更报告类别 (50)
Reporting Category for Manufacturing Process Changes 生产工艺变更报告类别 (51)
Post-approval Changes to Drug Substances
Guidance for Industry1
I. INTRODUCTION 概述
This guidance provides recommendations to holders of approved new drug applications (NDAs), abbreviated new drug applications (ANDAs), new animal drug applications (NADAs), and abbreviated new animal drug applications (ANADAs) and holders of drug master files (DMFs) and veterinary master files (VMFs) who want to make a change to the drug substance manufacturing process during the drug product application’s postapproval period2.It does not address holders of biologics licen applications (BLAs) or holders of any master files cross-referenced in BLAs.
本指南为已批准的NDA、ANDA、NADA、ANADA、DMF和VMF持有人变更其制剂声明批准之后的原料药生产工艺提供建议。本指南不适用于生物许可申报（BLA）持有人和BLA中交叉引用的任何主文件的持有人。
The guidance applies to synthetic drug substances and the synthetic steps involved in preparing misynthetic drug substances. The guidance covers the following changes:
本指南适用于合成原料药和半合成原料药中的合成步骤。指南覆盖以下变更：∙Facility, scale, and equipment changes associated with all steps of drug substance manufacturing.
∙与原料药生产所有步骤有关的设施、生产规模和设备变更
∙Specification changes to starting materials, raw materials, intermediates, and the unfinished and final drug substance.
∙起始物料、原料、中间体和原料药成品半成品质量标准变更
∙Synthetic manufacturing process changes.
∙合成生产工艺变更
1This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and Rearch in cooperation with the Center for Biologics Evaluation and Rearch and the Center for Veterinary Medicine at the Food and Drug Administration. 本指南由FDA的CDER的药品质量办公室联合CBER和兽药中心起草。
2In general, when this guidance refers to NDAs, ANDAs, and DMFs, we are also referring to NADAs, ANADAs,and VMFs, respectively. Further, the u of the term “master files” includes both DMFs and VMFs. 一般来说，当本指南提到NDA、ANDA和DMF时，我们亦分别指NADA、ANADA和VMF。另外，使用术语“主文件”时包括DMF和VMF。
FDA 行业指南草案：原料药批准后变更 201809 翻译：JULIA 页 5 / 51
