FDA行业指南草案：原料药批准后变更 201809 （译文仅供参考）

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Post-approval Changes to Drug Substances
Guidance for Industry
行业指南：原料药批准后变更

This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.
本指南草案（当定稿时）代表FDA当前对此主题的观点。它并不赋予任何人任何权力，对FDA和公众亦不形成强制。在满足本适用法律法规的要求时可以使用替代的方法。关于替代方法的讨论，请联系FDA办公室负责此本指南的人员，联系方式在标题页给出。

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 achange to the drug substance manufacturing process during the drug product application’s postapproval period . It does not address holders of biologics license 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 semisynthetic 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
• Changes in the source of the drug substance.
• 原料药来源变更
• Changes to the container closure system for the drug substance.
• 原料药容器密闭系统变更
This guidance does not address postapproval changes to peptides , oligonucleotides, radiopharmaceuticals; or drug substances isolated from natural sources or produced by procedures involving biotechnology; or nonsynthetic steps (such as fermentation) for semisynthetic drug substances. This guidance also does not address complex active ingredients as defined in the Generic Drug User Fee Act Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022, known as the GDUFA II CommitmentLetter .
本指南不针对多肽、寡核苷酸、放射药品以及从天然来源中分离的原料药和采用生物技术生产的原料药、半合成原料药的非合成步骤（例如发酵）的批准后变更。本指南亦不针对仿制药付费法案重新授权绩效目标和2018-2022财年强化计划（常称为GDUFA 承诺函）中所定义的复杂活性成分。
Ingeneral, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
一般来说，FDA的指南文件并不产生法律强制义务。相反，指南中所述的只是药监当局对某个主题当前的考虑，应仅作为是建议，其中引用了具体法规或法律要求者除外。SHOULD一词在药监机构的指南中出现时表示建议或推荐某事但并非强制要求。

II. BACKGROUND 背景

As part of the reauthorization of the Generic Drug User Fee Amendments (GDUFA II),FDA committed to issuing a guidance on postapproval changes to Type II API DMFs and submission mechanisms for ANDA holders who reference such DMFs . This guidance is intended to fulfill that commitment, and describes the recommended documentation for master file holders or drug substance manufacturers, as appropriate. The guidance also outlines the recommended documentation to be submitted by the approved application holder, as well as references the appropriate pathways for such submissions.
作为GDUFAII重新授权的一部分，FDA承诺要发布II类API DMF批准后变更以及引用此类DMF的ANDA持有人申报机制指南。本指南意在履行此承诺，阐述了建议主文件持有人和原料生产商（适当时）需提交的文件。本指南亦列出了已批准的制剂批文持有人所应提交的文件，以及对此类申报的适当引用方式。

A. Established Conditions and Reporting Categories 已订立的条件和报告分类

Under 21 CFR 314.70, 314.97, and 514.8, application holders must notify FDA about changes to conditions established in approved applications beyond the variations already provided for in their applications. FDA’s regulations identify three broad reporting categories: major changes (i.e., changes that require submission of a prior approval supplement (PAS)) ; moderate changes(i.e., changes that require submission of a changes being effected in 30 days(CBE-30) supplement or a changes being effected (CBE-0) supplement) ; and changes that must be reported in an annual report . The reporting category for a change is based on the potential risk for the change to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to its safety or effectiveness. This guidance provides recommendations on the information that should be provided to CDER, CBER, or CVM to ensure continued drug substance quality and drug product quality and performance characteristics. For the most up-to-date information on reporting categories for postapproval changes, see the referenced guidances insection XII, Reporting Category.
在21CFR 314.70, 314.97和 514.8中，申报持有人必须通知FDA其对已批准申报资料中既定条件超出原有变更范畴的变更。FDA的法规大致将变更分为三种报告类别：主要变更（即需要提交预先批准的增补PAS）、中等变更（即需要提交30日内生效的增补CBE-30或立即生效的增补CBE-0），以及必须在年报中报告的变更。变更的报告类别是根据该变更对药品的鉴别、剂量、质量、纯度或效价产生的不良影响确定的，因为这些因素可能与其安全性或有效性有关。本指南对于要向CDER、CBER或CVM提交的信息提供了建议，以确保原料药质量和制剂质量和性能特性的持续性。对于批准后变更报告类型的最新更新信息，参见第XII部分“报告类别”所引用的指南。

B. Reporting Responsibilities 报告义务

Where drug substance information is provided in a DMF, a letter(s) of authorization must be provided to allow the applicant to reference the DMF . Any addition, change, or deletion of information in the master file must be submitted to the master file in the form of an amendment. Further, the master file holder must notify each person authorized to reference the DMF of the nature of the changes , and should provide as much detail as is consistent with the confidentiality agreement between the master file holder and the authorized person, so that the authorized person can determine how to report the changes in the approved application. In turn, application holders must notify FDA of each change in each condition established in an approved application, excluding the variations already provided for in the application .
如果原料药信息是在DMF里提供的，则必须提交一份授权信允许申请人引用该DMF。对DMF中信息的任何增加、变更或删除均必须以修订方式为DMF提交。另外，DMF持有人必须通知所有授权引用该DMF者其变更情况，并根据DMF持有人与被授权人之间的保密协议提交足够的详细信息，使得被授权人可以决定应如何在报告其已批准的申报变更。
When drug substance information is contained in an application, rather than in a referenced DMF, such changes must be submitted to FDA in the form of asupplement to the approved application or in an annual report, whichever is appropriate for the change being made .
如果原料药信息是放在制剂申报资料中而不是引用DMF，则必须采用对已批准申报资料增补的方式向FDA提交此变更，或在年报中提交（根据所做变更决定恰当方式）。
The responsibility for reporting the types of changes described in this guidance could lie with a single party or with several parties, depending on whether the drug substance synthesis or processing is described in an application or in one or more master files. The notification to FDA should include reference to the section of this guidance under which the change is made and all pertinent information to ensure the quality of the drug substance and drug product. For example, when a master file holder makes a manufacturing process change, the change should be described in an amendment to the master file, and the application holder should provide notification of the change (citing section VIII of this guidance) in a supplement or annual report, as appropriate. The data to support the process change should be provided in an amendment to the masterfile or supplement to the approved NDA or ANDA when no master file is referenced.
报告本指南中所述类别变更的义务可能是单一方的，也可能是多方的，这取决于原料药合成或加工是在制剂申报中描述还是在一个或多个DMF中描述。向FDA提交的通知应包括对本指南与所做变更相关部分的引用以及所有相关信息，以确保原料药和制剂质量。例如，当DMF持有人变更其生产工艺时，可在DMF修订中描述该变更，而制剂申报人则应在增补或年报（适当时）中提交变更通知（引用本指南第VIII部分）。支持工艺变更的数据应在DMF修订中提交，或在已批准NDA或ANDA增补中提交（如未引用DMF）。

III. GENERAL CONSIDERATIONS 一般考量
A. Assessment of Risk 风险评估

Any modification to drug substance manufacturing carries some risk of causing anadverse impact on quality, either in the physical properties of the drug substance or in the level or nature of impurities present, and, in some cases, to the bioequivalence or safety profile of the drug.
对原料药生产的任何改动均有可能对原料药质量产生不良影响的风险，要么是物理属性，要么是杂质在质与量方面，有时候是制剂的生物等效性或安全概况。
Certain kinds of modifications (e.g., equipment or facility changes) are viewed as less likely to result in an adverse impact than others (e.g., changes in the synthetic route). However, each drug substance manufacturer will need to assess the particular modification for their drug substance to determine the risk associated with the change . This guidance applies to changes made throughout the drug substance manufacturing process, i.e., from the starting material through the final drug substance. Late-stage changes in the drug substance manufacturing process are generally viewed as more likely to have an adverse impact on the quality of the drug substance and, consequently, on the drug product. Some late-stage changes should be evaluated not only by comparing pre-and post-modification drug substance, but also by comparing drug product prepared from pre- and post-modification drug substance. Finished drug product manufacturers should ensure that drug substances used in their products meet established specifications and, for compendial drug substances, meet United States Pharmacopeia (USP) standards.
某些种类的修改（例如设备或设施变更）被认为相比其它变更（例如合成路线变更）导致的不良影响会更小。但是，每个原料药生产商都需要评估其原料药的特定变更以确定该变更所带来的风险。本指南适用于对原料药整个生产工艺所做的变更，即从起始物料到原料药成品。对原料药生产工艺较后的阶段变更一般会认为更加有可能对原料药质量产生不良影响，从而对制剂产生影响。一些较后阶段的变更不仅应通过比较变更前后原料药，还应通过比较原料药变更前后的制剂来进行评估。凡是生产商应确保其制剂生产所用原料药符合既定标准，如果是药典原料药，则应符合USP标准。

Risk assessment principles are outlined in International Council for Harmonisation (ICH) guidance for industry Q9 Quality Risk Management (ICH Q9 ). As noted in ICH Q9, the level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk. A risk assessment should be performed by the drug substance manufacturer to assess the effect of the change, as well as by the drug product manufacturer to evaluate the risks associated with drug substance manufacturing modifications. A reduction in the number of drug substance and/or drug product batches from the recommendations provided in this guidance (see sections VI – XI) may also beacceptable if an adequate justification is provided based on the risk assessment.
ICH行业指南Q9“质量风险管理”（ICH Q9）中列出了风险评估原则。正如ICH Q9中所言，质量风险管理流程的工作水平、正式程度以及文件化应与风险水平相当。风险评估应由原料药生产商执行，以评估变更的影响，同时亦应由制剂生产商评估原料药生产变更所关联的风险。如果根据风险评估提交了足够的论证，则减少本指南中（参见第VI-XI部分）所建议的原料药和/或制剂批次亦可接受。

The following are examples of factors to consider when conducting a risk assessment on a change to the drug substance:
对原料药变更执行风险评估时要考虑的因素举例如下：
• Experience of the manufacturing facility and/or personnel involved in the portion of the process that encompasses the proposed change.
• 所提议变更涉及工艺部分中相关生产场所和/或人员的经验
o Changes implemented at the same facility with experienced personnel may pose less risk than a change implemented at a new facility with inexperienced personnel or involvement of a third-party vendor.
O 在相同设施内由富有经验的人员执行变更相比于在新设施由无经验的人员执行变更或涉及第三方供应商时风险会更小。
• Complexity of the manufacturing steps involved in the change.
• 变更所涉及生产步骤的复杂性
o Changes implemented to homogeneous reactions using common chemistry and reaction conditions may pose less risk than a change implemented to heterogeneous reaction steps involving unusually complex or sensitive chemistry, and/or unusual equipment or reaction conditions.
o 对采用一般化学和反应条件的均一反应执行变更相比对涉及非常规复杂或敏感化学和/或不常用设备或反应条件的成分混杂的反应执行变更风险更低
• Physical and chemical stability of the material (intermediate or drug substance) involved in the change.
• 变更涉及物料（中间体或原料药）的理化稳定性
o Changes implemented for a molecule that is physically and chemically stable may pose less risk than a change implemented for a molecule that degrades easily or has multiple or unstable physical forms.
o 对理化特性较稳定的分子执行变更相比对易于降解或具有多个或不稳定物理形态的分子执行变更风险更低
• Complexity of the molecule.
• 分子复杂性
o Changes implemented for a small molecule with minimal structural or stereochemical isomerism may pose less risk than a change implemented for a large molecule with multiple structural or stereochemical isomers.
o 对具有较少同分异构或化学立体异构体的小分子执行变更相比对具有多个同分异构或化学立体异构体的大分子执行变更风险更低
• Equivalence of the entire impurity profile.
• 整体杂质概况的等同性
o Batches of post-modification material that have levels of identified impurities comparable to historical data may pose less risk than batches with higher levels of identified impurities and/or new identified impurities.
o 变更后物料批次已知杂质水平与历史数据可比的情况相比于变更后物料批次中已知杂质和/或新已知杂质水平高于历史数据风险更低
o Batches of post-modification material that have a number and level of unidentified impurities comparable to historical data may pose less risk than batches with a larger number and/or levels of unidentified impurities.
o 变更后物料批次中未知杂质数量和水平与历史数据可比的情况相比于变更后物料批次中未知杂质数量和水平高于历史数据风险更低
• Comparability of physical properties when they may impact drug product performance or manufacturability (typically changes made to the drug substance at or after the final solution step would bethe most likely to impact physical properties).
• 可能影响制剂性能或可加工性（原料药最终溶液步骤或其后的变更一般最有可能影响物理特性）的物理特性的可比性
o Post-modification material that has the same physical properties may pose less risk than post-modification material with different physical properties (e.g., solid state form, particle size, solubility,bulk/tapped density).
o 变更后物料具有相同物理特性的相比于变更后物料具有不同物理特性（例如，固体形态、粒径、溶解度、堆密度/击拍密度）的风险更低

B. Other Relevant Guidances 其它相关指南

This guidance aligns with existing FDA guidance, including the ICH guidances for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients Questions and Answers, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, Q10 Pharmaceutical Quality System, Q11 Development and Manufacture of Drug Substances, Q11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)—Questions and Answers, and M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.In addition to ICH Q10, which describes key systems that help establish and maintain a state of control for process performance and product quality, the FDA guidances for industry Quality Systems Approach to Pharmaceutical CGMP Regulations and Process Validation: General Principles and Practices address the current good manufacturing practice (CGMP) requirement for change control.Change control is generally understood to be the responsibility of the quality control unit . Effective change control activities are key components of any quality system. Although this guidance does not repeat the concepts and principles explained in those guidances, FDA encourages the use of modern pharmaceutical development concepts, quality risk management, and an effective pharmaceutical quality system at all stages of the manufacturing process lifecycle.
本指南与已有FDA指南保持一致，包括ICH行业指南Q7“API的GMP”，Q7问答、Q8（R2）“药物研发”、Q9“质量风险管理”、Q10“药物质量体系”、Q11“原料药开发与生产”、Q11原料药（化学实体和生物制品实体）开发与生产问答，以及M7“药物中DNA反应活性（诱变性）杂质的评估与控制以限制潜在致癌风险”。除了ICH Q10阐述关键系统用于帮助建立和维护工艺性能与产品质量受控外，FDA行业指南“药物CGMP法规的质量体系实现”和“工艺验证：通则与规范”阐述了变更控制的CGMP要求。变更控制通常被理解为质量部门的职责。有效的变更控制活动是所有质量体系的关键要素，尽管本指南并未重复这些指南中所解释的概念和原则，但FDA鼓励在生产工艺生命周期的所有阶段使用现代化药物开发概念、质量风险管理以及有效的药物质量体系。