ICH Q7a原料药的GMP指南(中英对照)

Q7a

Intermediates

17.20 Agents, brokers, traders, distributors, repackers, and relabelers should maintain complete traceability of APIs and intermediates that they distribute. Documents that should be retained and available include:

● Identity of original manufacturer ● Address of original manufacturer ● Purchase orders

● Bills of lading (transportation documentation) ● Receipt documents

● Name or designation of API or intermediate ● Manufacturer’s batch number

● Transportation and distribution records

● All authentic Certificates of Analysis, including those of the original manufacturer ● Retest or expiry date

17.20 代理、经纪人、贸易商、经销商、重新包装者和重新贴签者应当保留完整的已分发原料药和中间体的可追溯性。应当保留和可得到的文件包括：

● 原生产商的身份 ● 原生产商的地址 ● 订单

● 装运帐单（运输文件）

● 接收文件

● 原料药或中间体的名称或命名

● 生产商的批号 ● 运输和分发记录

● 所有确认的分析报告单，包括原生产商的

● 复验期或失效期

17.3质量管理 17.3 Quality Management

17.30 Agents, brokers, traders, distributors, 17.30 代理、经纪人、贸易商、经销商、重新包repackers, or relabelers should establish, document 装者或重新贴签者应当按第2节的规定建立并and implement an effective system of managing 执行一个有效的质量管理系统。 quality, as specified in Section 2.

17.4 Repackaging, Relabeling, and Holding of 17.4原料药和中间体的重新包装、重新贴签和

待检 APIs and Intermediates

17.40 Repackaging, Relabeling, and holding APIs 17.40 原料药和中间体的重新包装、重新贴签和and intermediates should be performed under 待检应当在本指南中所制定的适当的GMP控制appropriate GMP controls, as stipulated in this 下进行，以防原料药或中间体的特性或纯度的混guidance, to avoid mix-ups and loss of API or 淆和损失。 intermediate identity or purity.

17.41 Repackaging should be conducted under 17.41 重新包装应当在合适的，能防止污染和交appropriate environmental conditions to avoid 叉污染的环境条件下进行。 contamination and cross-contamination.

17.5稳定性 17.5 Stability

17.50 Stability studies to justify assigned 17.50 如果原料药或中间体的重新包装所使用expiration or retest dates should be conducted if 的容器与原料药或中间体的生产商所使用的不the API or intermediate is repackaged in a different 同，就应当进行稳定性研究，以确认规定的失效type of container than that used by the API or 期或复验期。 intermediate manufacturer.

17.6 信息的传达 17.6 Transfer of Information

17.60 Agents, brokers, distributors, repackers, or 17.60 代理、经纪人、贸易商、经销商、重新包relabelers should transfer all quality or regulatory 装者或重新贴签者应当将从原料药或中间体生information received from an API or intermediate 产商和客户之间传递所有质量或药政的信息。

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manufacturer to the customer, and from the customer to the API or intermediate manufacturer.

17.61 The agent, broker, trader, distributor, repacker, or relabeler who supplies the API or intermediate to the customer should provide the name of the original API or intermediate manufacturer and the batch number(s) supplied.

17.62 The agent should also provide the identity of the original API or intermediate manufacturer to regulatory authorities upon request. The original manufacturer can respond to the regulatory authority directly or through its authorized agents, depending on the legal relationship between the authorized agents and the original API or intermediate manufacturer. (In this context authorized refers to authorized by the manufacturer.)

17.63 The specific guidance for certificate of analysis included in Section 11.4 should be met.

17.7 Handling of Complaints and Recalls

17.70 Agents, brokers, traders, distributors, repackers, or relabelers should maintain records of complaints and recalls, as specified in Section 15, for all complaints and recalls that come to their attention.

17.71 If the situation warrants, the agents, brokers, traders, distributors, repackers, or relabelers should review the complaint with the original API or intermediate manufacturer to determine whether any further action, either with other customers who may have received this API or intermediate or with the regulatory authority, or both, should be initiated. The investigation into the cause for the complaint or recall should be conducted and documented by the appropriate party.

17.72 Where a complaint is referred to the original API or intermediate manufacturer, the record maintained by the agents, brokers, traders, distributors, repackers, or relabelers should include any response received from the original API or intermediate manufacturer (including date and information provided).

17.8 Handling of Returns

17.61 将原料药或中间体提供给客户的代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当提供所供原料药或中间体的原生产商的名称和原批号。

17.62 需要时，代理还应当向药政当局提供原生产商的身份。按照原料药或中间体的原生产商和授权代理人之间的法律关系，原生产商可直接地或通过其授权代理向药政当局作回复。（此处“授权”是指由原生产商所给的授权）

17.63 应当遵循第11.4章所述有关报告单的指南。

17.7 投诉和召回的处理

17.70 参照第15章的要求，代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当保留他们收到的所有投诉和召回的记录。

17.71 如果情况允许，代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当与原料药或中间体的生产商一起审阅投诉，以确定是否应当与其它收到该原料药或中间体的客户，或者药政当局一起采取进一步的措施。对投诉和召回的原因应当由合适的一方进行调查，并记录备查。

17.72 如果投诉是针对原料药或中间体的原生产商，由代理、经纪人、贸易商、经销商、重新包装者或重新贴签者保存的记录应当包括从原料药或中间体原生产商处得到的任何反馈信息（包括提供的日期和内容）。

17.8 退货的处理

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17.80 Returns should be handled as specified in Section 14.5. The agents, brokers, traders, distributors, repackers, or relabelers should maintain documentation of returned APIs and intermediates.

18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18.1 General

18.10 Section 18 is intended to address specific controls for APIs or intermediates manufactured by cell culture or fermentation using natural or recombinant organisms and that have not been covered adequately in the previous sections. It is not intended to be a stand-alone Section. In general, the GMP principles in the other sections of this document apply. Note that the principles of fermentation for “classical” processes for production of small molecules and for processes using recombinant and nonrecombinant organisms for production of proteins and/or polypeptides are the same, although the degree of control will differ. Where practical, this section will address these differences. In general, the degree of control for biotechnological processes used to produce proteins and polypeptides is greater than that for classical fermentation processes.

18.11 The term “biotechnological process” (biotech) refers to the use of cells or organisms that have been generated or modified by recombinant DNA, hybridoma or other technology to produce APIs. The APIs produced by biotechnological processes normally consist of high molecular weight substances, such as proteins and polypeptides, for which specific guidance is given in this Section. Certain APIs of low molecular weight, such as antibiotics, amino acids, vitamins, and carbohydrates, can also be produced by recombinant DNA technology. The level of control for these types of APIs is similar to that employed for classical fermentation.

18.12 The term “classical fermentation” refers to processes that use microorganisms existing in nature and/or modified by conventional methods (e.g. irradiation or chemical mutagenesis) to produce APIs. APIs produced by “classical fermentation” are normally low molecular weight

17.80 退货应当按照14.5章进行处理。代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当保留原料药或中间体退货的文档。

18. 用细胞繁殖/发酵生产的原料药的特殊指南

18.1 总则

18.10第18节旨在描述对通过细胞繁殖或用天然或重组组织发酵生产的原料药或中间体的一些在前面的章节中没有充分阐明的特殊控制。它不是一个独立的章节。通常，本文件中其他章节的GMP 原则也适用。值得注意的是尽管生产小分子的“经典”工艺的发酵原理和用重组或非重组组织生产蛋白质和/或多肽类的发酵原理是一样的，但是，它们的控制程度不同。本章节将在适当的地方阐述这些不同点。总的来说，用于生产蛋白质和多肽的生物技术工艺的控制要严于经典的发酵工艺。

18.11 “生物技术”是指用重组DNA、杂交瘤或其它技术产生或修饰的细胞或组织来生产原料药。用生物技术生产的原料药通常由蛋白质和多肽这类高分子量的物质组成，本节介绍其特殊指南。有些低分子量的原料药，如抗生素、氨基酸、维生素和糖类也可以用重组DNA来生产。这几类原料药的控制程度与经典发酵的相似。

18.12 “经典发酵”是指用天然的和/或以传统方法(如，辐照或化学诱变)修改的微生物来生产原料药的工艺。用“经典发酵”生产的原料药通常是低分子量的产品，如，抗生素、氨基酸、维生素和糖类。

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products such as antibiotics, amino acids, vitamins, and carbohydrates.

18.13 Production of APIs or intermediates from cell culture or fermentation involves biological processes such as cultivation of cells or extraction and purification of material from living organisms. Note that there may be additional process steps, such as physicochemical modification, that are part of the manufacturing process. The raw materials used (media, buffer components) may provide the potential for growth of microbiological contaminants. Depending on the source, method of preparation, and the intended use of the API or intermediate, control of bioburden, viral contamination, and/or endotoxins during manufacturing and monitoring of the process at appropriate stages may be necessary.

18.14 Appropriate controls should be established at all stages of manufacturing to assure intermediate and/or API quality. While this Guide starts at the cell culture/fermentation step, prior steps (e.g. cell banking) should be performed under appropriate process controls. This Guide covers cell culture/fermentation from the point at which a vial of the cell bank is retrieved for use in manufacturing.

18.15 Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems).

18.16 In general, process controls should take into account:

● Maintenance of the Working Cell Bank (where appropriate);

● Proper inoculation and expansion of the culture;

● Control of the critical operating parameters during fermentation/cell culture;

● Monitoring of the process for cell growth, viability (for most cell culture processes) and productivity where appropriate;

● Harvest and purification procedures that remove cells, cellular debris and media

18.13用细胞培养或发酵来生产原料药或中间体涉及到诸如细胞培养，或从活体组织提取和纯化物料等生物过程。值得注意的是，还有一些附加的隶属于生产工艺一部分的物理化学修饰。使用的原材料(培养基、缓冲成分)可能为微生物污染提供了可能性。根据物料来源、制备方法和原料药或中间体的预期用途，可能有必要在制造和工艺监测的适当阶段控制微生物、病毒污染和/或内毒素。

18.14制造过程的所有阶段都应当建立必要的控制，以保证中间体和/或原料药的质量。尽管本指南从细胞培养/发酵步骤开始，但是前期步骤(如细胞库) 应当在必要的控制下进行。本指南含盖了从细胞库取得用于生产的细胞开始的细胞培养/发酵过程。

18.15应当采取适当的设备和环境控制来将污染的风险降低到最低程度。环境质量的认可标准和监控的频率应当根据生产步骤和生产条件(开口，闭口，或封闭系统)而定。

18.16通常，应当考虑的工艺控制有：

● 工作细胞库的维护(视情况而定)；

● 恰当的接种和培养；

● 发酵/细胞培养过程中关键操作参数的控制； ● 细胞生长、活性(大多数生物技术工艺)和生产能力的监控；

● 为保护中间体和原料药不受污染(特别是微生物学特征)和不损害质量而作的去除细胞、细胞碎片和培养基组分的收集和纯化过程；

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