澳大利亚TGA指南11：DMF和CEP（2/3）-未完待续-Julia

巴西木

11.3 Sponsor's obligations regarding Drug Master Files申请人在DMF方面的义务

Sponsors: 申请人

l         have an obligation under the standard conditions of registration, imposed under s. 28(3) of theTherapeutic Goods Act 1989 (the Act), to ensure no changes are made to the product, including the drug substance, without their knowledge and TGA approval (if required).

l         具有“治疗用品法案1989”S.28(3)下所赋予的义务，在标准注册条件下，保证在未获得TGA批准的前提下，不得对其产品，包括对原料药做出变更。

l         need a formal agreement with the manufacturer of the drug substance that ensures they will be notified before any changes are made to the drug substance.

l         需要与原料药生产商有正式协议，保证在对原料药做出任何变更前均会收到变更通知

l         are responsible for determining whether:

l         有义务决定是否

—       the proposed changes require data to be submitted to the TGA

—       拟提交变更需要向TGA提交数据

—       the variation can be made as a self-assessable request.

—       变更可以通过自评实施

11.3.1 Updating drug master files 更新DMF

DMFs should be updated periodically to reflect any changes, and ensure that one of the following is forwarded to the TGA before the changes are implemented:

DMF应周期进行更新，以反映所有变更，保证在实施变更前将以下之一资料提交TGA

l         the updated DMF (together with a detailed list of changes made), or

l         更新后的DMF（与详细的变更清单一起），或

l         details of any changes made.

l         所有实施的变更详细内容

Related information and guidance 相关资料和指南 l         Minor variations to registered prescription medicines: Chemical entities l         已注册处方药轻微变更：化学实体 l         Minor variations to registered prescription medicines: Biological medicines l         已注册处方药轻微变更：生物药品

11.4 Additional information in Drug Master Files for some drug substances: guidance for manufacturers 某些原料药DMF中的附加资料：生产商指南

The TGA has adopted the European Medicines Agency (EMA) Guideline on active substance master file procedure (CPMP/QWP/227/02 Rev 1), adopted with annotation. In addition to the requirements of the above EMA guideline; further information is required in the DMF for the following types of drug substances:

TGA已采用EMA的“活性物质主文件（ASMF）程序指南”，并增加了注释。除上述EMA指南要求外，以下类型原料药DMF需要更多资料：

l         drug substances with a default standard monograph

l         有默认标准各论的原料药

l         sterile drug substances

l         无菌原料药

l         products of human or animal origin

l         人或动物来源产品

l         substances produced wholly or in part by fermentation

l         全部或部分发酵生产物质

11.4.1 Drug substances with a default standard monograph 具有默认标准各论的原料药

For drug substances that are the subject of a pharmacopoeial monograph in a default standard(British Pharmacopoeia [BP], European Pharmacopoeia [Ph. Eur.] or United States Pharmacopeia–National Formulary [USP–NF]):

对于在默认标准中具有药典各论的原料药（欧洲药典、英国药典、美国药典）：

Include the following in the DMF:

DMF中应包括以下内容

l         a discussion of the potential impurities that are most likely to arise during synthesis using the manufacturing process described in the DMF

l         对在DMF中描述的生产工艺的合成中最可能生成的潜在杂质的讨论

l         evidence that these impurities are adequately controlled by the test procedures described in the pharmacopoeial monograph.

l         采用药典各论中的检测方法可以充分控制这些杂质的证据

Alternative test procedures may be used if it can be demonstrated that both:

如果可以证明以下两点，也可以采用其它检测方法替代药典方法

l         the results obtained are equivalent to, or more stringent than, the pharmacopoeial requirements, and

l         替代方法所得到的检测结果与药典要求等同，或更严格

l         the method has been appropriately validated.

l         替代方法已经过适当的验证

Provide justification (including toxicological data, if appropriate) if:

如果是以下情况，则需要提供论证（适当时应包括毒性数据）

l         impurities in the drug substance are not listed in the monograph but,

l         原料药中的杂质未列入各论，但

l         are proposed to be allowed at levels above the Committee for Medicinal Products for Human Use (CHMP)/International Congress on Harmonisation (ICH) limits for qualification.

l         拟定标准高于CHMP/ICH识别限

11.4.2 What to include in a Drug Master File for sterile drug substances 无菌原料药DMF中要包括什么

For drug substances (and/or excipients) that are terminally sterilised and do not undergo further sterilisation during manufacture of the drug product, ensure the DMF includes:

对于终端灭菌，且在制剂生产中不再灭菌的原料药（和/或辅料），应保证DMF包括

l         information on bioburden

l         生物负载的资料

l         details of physical and microbiological validation that show a sterility assurance level (SAL) of 10–6.

l         物理和微生物验证详细内容，显示无菌保证水平（SAL）为10-6

For drug substances (and/or excipients) that are aseptically manufactured and do not undergo further sterilisation during manufacture of the drug product, ensure the DMF includes:

对于无菌工艺生产，且在制剂生产中不再灭菌的原料药（和/或辅料），应保证DMF包括

l         pre-sterilisation bioburden information for the drug substance and any solvents that may be used after the drug substance has been passed through the sterilising filter for further processing

l         原料药在过滤前的生物负载情况，以及所有在原料药通过无菌过滤器后，且不再有进一步处理时所用的溶剂在过滤前的生物负载情况

l         ?details of pre-use and post-use filter integrity testing for sterilising filters used with the drug substance and any solvents

l         原料药和所有溶剂用无菌过滤器在使用前和使用后的完整性测试详细资料

l         validation of the bacterial retention properties of the sterilising filters used with the drug substance and any solvents, conducted in the presence of each of the substances/solvents to be filtered

l         原料药和所有溶剂所用的无菌滤器的微生物截留特性验证，该验证应采用实际的原料药或溶剂实施。

l         details of the media fills used to validate the aseptic manufacturing process, including processing times and duration of campaign (if campaign manufacturing is used)

l         用于无菌生产工艺验证的培养基灌装详细信息，包括处理次数和一个周期的时长（如果采用了周期生产方式）

l         details of the container/closure system used to contain the sterile drug substance after manufacture. This should include the parameters of the sterilisation processes applied to the container/closure system and confirmation that these have been physically and microbiologically validated to a SAL of 10–6

l         用于盛装生产出的无菌原料药的容器、密闭系统的详细信息。要包括容器、密闭系统所用的无菌工艺参数，以及确认其经过物理和微生物至SAL10-6。

l         validation of container/closure integrity

l         容器/密闭系统完整性验证

l         results of finished drug substance sterility testing

l         原料药成品无菌测试的结果

l         results of transport validation.

l         运输验证结果

11.4.3 Products of human or animal origin 人或动物来源产品

The TGA guidance Adventitious agent safety of medicines details the information to be included in the DMF for materials of animal or human origin.

TGA指南“药品外源性试剂安全性”中详细说明了要包括在人或动物来源物料DMF中的资料

11.4.3.1 Heparin products 肝素产品

Manufacturers that use heparin products should strictly control all the starting materials and intermediates used in the manufacture of the product.

使用肝素产品的生产商要严格控制所有用于制剂生产的起始物料和中间体。

Hence the information that is included in the DMF for heparin should form part of Module 3 of theCTD information provided in support of the drug product.

因此，在肝素DMF中的资料应包括在制剂CTD文件模块3中。

11.4.3.2 Human albumin 人血清蛋白

Collection and control of the starting material for human albumin will be described in the plasma master file (PMF). The DMF for human albumin should describe the manufacturing processes used, which is essential to assess the safety of the final product.

人血清蛋白的起始物料收集和控制要在血清主文件（PMF）中进行描述。人血清DMF应描述所用的生产工艺，这是评估制剂产品安全性所必需的资料。

Related information and guidance 相关资料和指南 l         Therapeutic goods that contain or are produced from human blood or plasma l         含有或采用人血液或血浆生产的治疗用品 l         Adventitious agent safety of medicines l         药品的外源性试剂安全

11.4.4 Substances produced wholly or in part by fermentation 全部或部分由发酵生产的物质

Guidance on fermentation and nomenclature of substances of natural or semisynthetic origin can be found in the relevant pharmacopoeial monograph of the default standard, such as:

在相关的药典各论中可以找到自然或半合成来源的物质发酵和命名指南，例如：

l         SC II C, 'Structures and nomenclature of substances of natural or semi-synthetic origin' of the BP.

l         SC II C，BP“自然或半合成来源物质结构和命名”

Related information and guidance 有关资料和指南

? Note for guidance on quality of biotechnological products: derivation and characterisation of cell substrates used for production of biotechnological/biological products (CPMP/ICH/294/95). This guideline outlines information relating to the manufacture and stability of drug substances produced by fermentation.

“生物技术产品质量指南解释：用于生物技术/生物产品的细胞基质的衍生物和特性”（CPMP/ICH/294/95）。本指南列出了与发酵生产原料药的生产和稳定性有关的信息。

In addition to the requirements of the above European Union guideline, further information is required for substances produced wholly or in part by fermentation:

除上述欧盟指南的要求外，全部或部分由发酵生产的物质还需要以下资料

l         manufacturing facilities

l         生产场所

l         manufacturing process and controls

l         生产工艺和控制

—       pharmaceutical development reports

—       药品研发报告

—       cell growth (propagation) and harvest

—       细胞生长（繁殖）和提取

—       purification and downstream processing

—       精制和后续处理

l         control of materials

l         原料控制

—       microorganism

—       微生物

—       cell bank system – master cell bank (MCB)

—       细胞库系统---母细胞库（MCB）

—       cell bank system – working cell bank (WCB)

—       细胞库系统---工作细胞库（WCB）

—       media components

—       培养基成分

—       solvents, reagents and auxiliary materials

—       溶剂、试剂和辅助物料

l         control of critical steps and intermediates

l         关键步骤和中间体控制

l         noncritical in-process controls

l         非关键中控

l         process validation and/or evaluation

l         工艺验证和/或评估

l         characterisation

l         特性描述

—       structural characterisation

—       结构确证

—       physicochemical characterisation

—       理化性质

—       biological activity

—       生物活性

—       impurities

—       杂质

—       degradation products

—       降解产物

l         control of intermediates and drug substances

l         中间体和原料药控制

—       specifications

—       质量标准

—       analytical procedures

—       分析方法

—       validation of analytical procedures

—       分析方法验证

—       reference standards or materials

—       对照品或标准物质

—       batch analyses

—       批分析

l         container/closure system

l         容器密闭系统

l         labelling

l         标签

l         stability summary and conclusions

l         稳定性试验总结和结论

—       batch selection for stability studies for fermentation-derived substances

—       发酵衍生物质稳定性研究批次的选择

—       expiration date or retest date.

—       有效期或复验期

11.4.4.1 Manufacturing facilities 生产场所

For each facility involved in the manufacture and/or testing of the drug substance (including contract manufacturers and testing laboratories):

每个涉及原料药生产和/或检测场所（包括合同生产商和合同化验室）

l         provide the name, address and manufacturing responsibility for the operations or processes performed.

l         提供名称、地址和其在所承担的生产或操作方面的责任

11.4.4.2 Manufacturing process and controls 生产工艺和控制

l         Provide a detailed description of the manufacturing process and controls for intermediates and drug substances.

l         提供中间体和原料药的生产工艺和控制详细描述

l         Describe the entire process, including original inoculum, propagation, harvest, isolation/purification and any modification reactions.

l         描述整个工艺，包括初始接种、繁殖、提取、分离/纯化和所有修饰反应

Pharmaceutical development reports 药物研发报告

Provide pharmaceutical development reports that describe the scientific rationale for the chosen manufacturing process(es) and controls for fermentation-derived drug substances.

提供药物研发报告，说明发酵衍生原料药的生产工艺和控制选择科学理由

Related information and guidance 有关资料和指南 l         Note for guidance on pharmaceutical development (EMEA/CHMP/167068/2004) l         药物研发指南解释

Cell growth (propagation) and harvest 细胞生产（繁殖）和提取

Provide a flow diagram illustrating each step in propagation from the original inoculum (e.g. cells from one or more vials of the WCB) through to the final harvesting operation.

提交流程图，画出从原始接种培养的每个步骤（例如，接种一个或多个WCB小瓶中的细胞），直到最后提取操作。

Include relevant information such as: 包括相关资料，例如

l         the growth conditions

l         生长条件

l         in-process controls and tests performed (e.g. cell concentrations, volumes, pH, cultivation times, temperatures)

l         中控和中控检测（例如，细胞浓度、体积、pH值、培养时长、温度）

Identify critical steps and intermediates for which specifications are established, along with sampling plans and testing time points.

识别出关键步骤和中间体，建立其质量标准，以及取样计划和检测时间点。

Include a narrative describing each manufacturing step in the process which identifies and describes:

包括识别出的工艺中每个生产步骤的描述，描述应包括以下内容：

l         all process controls (including critical process controls) and their associated ranges, limits or acceptance criteria

l         所有工艺控制（包括关键工艺控制）和其相关范围、限度和可接受标准

l         ?the intended scale of the process, including the maximum size for a production batch, and seed train expansion, if applicable

l         工艺的拟定规模，包括最大生产批量，适用时包括菌种扩大步骤

l         the major equipment involved in each step

l         每步所涉及的主要设备

l         the process for inoculation and each step in propagation, specifying growth conditions

l         繁殖过程中每一步的接种过程，详细说明生长条件

l         the media composition at each step of the fermentation process, including water quality, additives used and selection used (i.e. antibiotics, other factors)

l         发酵工艺每步所用培养基成分，包括水质量，所用的添加剂和所用的选择方法（即，抗生素，其它因素）

l         the sterilisation procedures for the equipment (e.g. fermentation vessel), feeds, and other materials used in the fermentation process (dedicated versus general)

l         设备的灭菌工艺（例如，发酵罐）、接种器和发酵工艺中所用的其它物料（专用的和通用的）

l         process parameters monitored, and controls for critical steps and intermediates

l         受监控的工艺参数，关键步骤和中间体的控制

l         procedures used to transfer material between steps

l         步骤间物料转移所用的程序

l         procedures used to minimise contamination by adventitious agents

l         用于减小外源性试剂到最小程度的方法

l         process controls to confirm the effectiveness of the specific manufacturing steps used to inactivate and/or remove adventitious agents

l         确认用于灭活和/或去除外源性试剂的特定生产步骤有效性的工艺控制

l         the criteria for harvesting, including:

l         提取的标准，包括在发生污染时接受和拒绝一个发酵批次的标准

—       criteria for rejecting or accepting a fermentation batch if contamination occurs

—       一个发酵批发生污染时，接受或拒绝的标准

—       the determination of yields

—       收率的计算

—       criteria for pooling more than one harvest, if applicable

—       适当时，选择合并而不是一次性提取的标准

—       storage conditions and time limits if the harvested crude fermentation product is held before further processing.

—       提取的发酵物粗品会在进一步处理前保存时，保存的存贮条件和时间限度

Purification and downstream processing 纯化和后续加工

Include a flow diagram and a narrative to describe all the steps involved in isolating the crude fermentation product and purifying it to its final form, along with any relevant information (e.g. volumes, pH, temperatures, holding times).

包括对发酵粗品进行分离及纯化得到最终形态时所涉及的所有步骤的流程图和描述，以及所有相关的资料（例如，体积、pH值、温度、保存时长）。

Identify critical steps and intermediates for which specifications are established, along with testing time points.

识别出关键步骤和中间体，建立质量标准，以及其检测时间点。

Identify all process controls and their associated numeric ranges, limits or acceptance criteria, and include the following:

识别出所有工艺控制及其相关数字范围、限度或可接受标准，并包括以下内容：

l         methods used in purification or separation of the crude fermentation product (e.g. precipitation, centrifugation, filtration), including major equipment used (e.g. columns, membranes, dedicated/general)

l         用于发酵产品粗品纯化或分离的方法（例如，结晶、离心、过滤），包括所用的主要设备（如，柱、膜、专用还是通用）

l         in-process controls and analytical tests used to characterise the fermentation product (identity, purity and concentration), including levels of process-related and product-related impurities)

l         用于检测发酵产品特性的中控和分析方法（鉴别、纯定和浓度），包括工艺相关杂质和产品相关杂质的水平

l         control measures to avoid microbial contamination during purification

l         纯化过程中避免微生物污染的控制措施

l         conditions for reuse, and/or procedures for regeneration, of columns, membranes and adsorbents

l         柱、膜和吸附剂重复使用条件和/或再生程序

l         storage conditions and time limits if the purified fermentation product is held before further processing.

l         纯化后发酵产物在用于后续工艺前存贮的条件及可存贮时限

Describe modification reactions as follows:

修饰反应描述的要求如下：

Chemical modifications 化学修饰

When a fermentation product is subjected to further molecular change through chemical means:

如果发酵产品要经过化学方法对分子进行进一步变更

l         include a description of the synthetic steps in the procedural narrative.

l         在流程描述中包括合成步骤描述

l         provide a flow diagram of the synthetic process.

l         提供化学工艺流程图

Enzymatic modifications 酶修饰

When the fermentation product is further modified using enzymes:

如果发酵产品要采用酶法进一步修饰

l         include the steps in the flow diagram and in the procedural narrative. Additionally, because enzymatic functionality requires carefully controlled conditions (e.g. pH, temperature, osmolarity).

l         包括流程图和流程叙述中的所有步骤。另外，由于酶的功能要求小心地控制条件（例如，pH值，温度和渗透压）【译者：此处原文如此，似为误句】

l         include detailed information on:

l         包括以下详细资料

l         reaction controls and the optimum range of operation

l         反应控制和操作最优范围

l         the biological source of the enzyme

l         酶的生物来源

l         how the enzyme is prepared and its purity.

l         酶的制备方法及其纯度

l         describe, when appropriate, the operations for reprocessing, reworking, recycling, regeneration and salvaging.

l         适当时，对再加工、返工、回收、再生和废物利用进行描述

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