美国FDA原料药生产质量管理规范翻译模板(最后部分 中英文）

　　13. CHANGE CONTROL 13.变更的控制

　　13.10 A formal change control system should be established to evaluate all changes that could affect the production and control of the intermediate or API.

　　13.10 应当建立正式的变更控制系统，以评估可能影响中间体或原料药生产和控制的所有变更。

　　13.11 Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labeling and packaging materials, and computer software.

　　13.11 对原料、质量标准、分析方法、设施、支持系统、设备(包括计算机硬件)、工艺步骤、标签和包装材料、计算机软件的变更进行认证、提供文件、适当的审核和批准，应当提供书面程序。

　　13.12 Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality unit(s). 13.12 与GMP有关的任何变更提案都应当由相应的部门进行拟定、审核和批准，并由质量部门审核和批准。

　　13.13 The potential impact of the proposed change on the quality of the intermediate or API should be evaluated. A classification procedure may help in determining the level of testing, validation, and documentation needed to justify changes to a validated process. Changes can be classified (e.g., as minor or major) depending on the nature and extent of the changes, and the effects these changes may impart on the process. Scientific judgment should determine what additional testing and validation studies are appropriate to justify a change in a validated process. 13.13 应当评估所提议的变更对中间体或原料药质量的潜在影响。一种分类方法可能有助于确定为了说明对一个已验证的工艺作变更所需的测试、验证和文件工作的程度。变更可以根据变更的性质和程度及其可能对工艺产生的影响来分类(如，次要的或主要的)。应当用科学的判断来决定，为证明对一个已验证工艺的变更可行，什么样的附加测试和验证研究是适当的。

　　13.14 When implementing approved changes, measures should be taken to ensure that all documents affected by the changes are revised.

　　13.14 实施已核准的变更时，应当采取措施确保所有变更影响的文件都已修订。

　　13.15 After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.

　　13.15 变更实施后，应当对变更之后生产或测试的的头几个批次进行评估。

　　13.16 The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program.

　　13.16 关键的变更对规定的复验期和有效期的影响可能性应当进行评估。如有必要，可以将用修改了的工艺生产的中间体或原料药的样品放入一个加速稳定性计划，并/或稳定性监测计划。

　　13.17 Current dosage form manufacturers should be notified of changes from established production and process control procedures that can affect the quality of the API.

　　13.17 应当将可能影响原料药质量的对已确定的生产及工艺控制步骤所作的变更通知目前制剂药制造商。

　　14. REJECTION AND RE-USE OF MATERIALS 14.拒收和物料的再利用

　　14.1 Rejection 14.1 拒收

　　14.10 Intermediates and APIs failing to meet established specifications should be identified as such and quarantined. These intermediates or APIs can be reprocessed or reworked as described below. The final disposition of rejected materials should be recorded.

　　14.10 不合格中间体和原料药应当做有标志，并隔离。这些中间体和原料药可以按下述方法进行返工或重新加工。应当记录不合格物料的最终处置情况。

　　14.2 Reprocessing 14.2 返工

　　14.20 Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and reprocessing by repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process is generally considered acceptable. However, if such reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process.

　　14.20 将不符合标准或规格的一个中间体或原料药返回工艺过程，重复规定的生产工艺中的某一结晶步骤或其它合适的化学或物理处理步骤(如，蒸馏、过滤、层析、磨粉)，这种做法通常是可以接受的。然而，如果这种返工用于大多数的批号，那么该返工就应当作为标准生产工艺的一部分。

　　14.21 Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing.

　　14.21 在中间控制的测试表明一工艺步骤没有完成，从而继续该步骤，是正常工艺的一部分，不属于返工。

　　14.22 Introducing unreacted material back into a process and repeating a chemical reaction is considered to be reprocessing unless it is part of the established process. Such reprocessing should be preceded by careful evaluation to ensure that the quality of the intermediate or API is not adversely affected due to the potential formation of by-products and over-reacted materials. 14.22 将未反应的物料返回某一工序，并重复化学反应，这是进行返工，除非它已被列入规定的工艺中。在进行这种返工前，要仔细评估，以确保不会由于可能形成的副产物和过度反应物而对中间体或原料药的质量产生不良影响。

　　14.3 Reworking 14.3 重新加工

　　14.30 Before a decision is taken to rework batches that do not conform to established standards or specifications, an investigation into the reason for nonconformance should be performed.

　　14.30 在决定对不符合规定的标准或规格的批号进行重新加工前，应当对不符合的原因进行调查。

　　14.31 Batches that have been reworked should be subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality to that produced by the original process. Concurrent validation is often the appropriate validation approach for reworked procedures. This allows a protocol to define the rework procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, a report can be written and the batch released once it is found to be acceptable. 14.31 重新加工的批号应当接受适当的评估、测试，如有理由还要做稳定性测试，并成文备查，以表明重新加工后的产品与原工艺生产的产品质量相等。同步验证常常是重新加工程序的合适的验证方法。允许用一方案来规定重新加工程序、如何进行和预期结果。如果只有一批产品重新加工，利用写一份报告，一旦认为该批可接受，即可放行。

　　14.32 Procedures should provide for comparing the impurity profile of each reworked batch against batches manufactured by the established process. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used.

　　14.32 应当有程序对每一重新加工过的批号与用规定的工艺生产的批号进行杂质概况的比较。如果常规分析方法不足以描绘重新加工批号的特征，应当采用另外的方法。

　　14.4 Recovery of Materials and Solvents 14.4 物料与溶剂的回收

　　14.40 Recovery (e.g., from mother liquor or filtrates) of reactants, intermediates, or the API is considered acceptable, provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use.

　　14.40 只要有核准的回收方法，并且回收的物料符合其使用标准，反应物、中间体或原料药的回收(例如，从母液或滤液中)是可以接受的。

　　14.41 Solvents can be recovered and reused in the same processes or in different processes, provided that the recovery procedures are controlled and monitored to ensure that solvents meet appropriate standards before reuse or commingling with other approved materials.

　　14.41 溶剂可以回收，并在同一工序或不同工序重新使用，只要回收过程得到了控制和监测，确保在重新使用或与其它核准的物料混合前，这种溶剂符合一定的标准。

　　14.42 Fresh and recovered solvents and reagents can be combined if adequate testing has shown their suitability for all manufacturing processes in which they may be used.

　　14.42 新鲜的和回收溶剂和试剂可以混合，如果有足够的测试表明它们适用于所参与的生产工序。

　　14.43 The use of recovered solvents, mother liquors, and other recovered materials should be adequately documented.

　　14.43 回收溶剂、母液和其它回收的物料的使用应当有足够的文件作证。

　　14.5 Returns 14.5 退货

　　14.50 Returned intermediates or APIs should be identified as such and quarantined. 14.50 退回的原料药和中间体应当作有标志，并隔离。

　　14.51 If the conditions under which returned intermediates or APIs have been stored or shipped before or during their return or the condition of their containers casts doubt on their quality, the returned intermediates or APIs should be reprocessed, reworked, or destroyed, as appropriate.

　　14.51 如果在中间体或原料药退货之前或退货期间的储存或运输条件，或者其包装容器的状况可能对其质量产生影响，退回的中间体或原料药应当根据情况进行返工、重新加工或销毁。

　　14.52 Records of returned intermediates or APIs should be maintained. For each return, documentation should be include:

　　14.52 退回的中间体或原料药应当存有记录。每次退货的记录内容应当包括：

　　15. COMPLAINTS AND RECALLS 15.投诉与召回

　　15.10 All quality-related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure.

　　15.10 所有与质量有关的投诉，无论以口头或书面方式收到，都应当根据书面程序进行记录和调查。

　　15.12 Records of complaints should be retained to evaluate trends, product-related frequencies, and severity with a view to taking additional, and if appropriate, immediate corrective action.15.12投诉记录应当保存，旨在评估其变化趋势、涉及产品的发生频率及其严重性，以便采取额外的，有时是即时的纠正措施。

　　15.13 There should be a written procedure that defines the circumstances under which a recall of an intermediate or API should be considered.

　　15.13 应当有书面程序规定在何种情况下应当考虑召回中间体或原料药。

　　15.14 The recall procedure should designate who should be involved in evaluating the information, how a recall should be initiated, who should be informed about the recall, and how the recalled material should be treated.

　　15.14 召回程序应当规定参与评估情况的人员、启动召回的方法、召回应当通知到的对象、以及召回后物料的处理方法。

　　15.15 In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities should be informed and their advice sought.

　　15.15 如果情况严重或可能威胁生命，则应当通知地方、国家或国际当局，并征求其建议。

　　16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)

　　16.协议生产商(包括实验室)

　　16.10 All contract manufacturers (including laboratories) should comply with the GMP defined in this guidance. Special consideration should be given to the prevention of cross-contamination and to maintaining traceability.

　　16.10 所有协议生产商(包括实验室)应当遵循本指南所规定的GMP。特别应当注意防止交叉污染，并保持可追溯性。

　　16.11 Companies should evaluate any contractors (including laboratories) to ensure GMP compliance of the specific operations occurring at the contractor sites.

　　16.11 合同委托方应当对协议生产商(包括实验室)进行评估，以确保在合同地点发生的特定操作符合GMP。

　　16.12 There should be a written and approved contract or formal agreement between a company and its contractors that defines in detail the GMP responsibilities, including the quality measures, of each party.

　　16.12 合同委托方与合同接受方之间应当有经过认定的书面合同或正式协议书，详细规定各方的GMP责任，包括质量措施。

　　16.13 A contract should permit a company to audit its contractor’s facilities for compliance with GMP.

　　16.13 合同应当允许合同委托方对合同接受方的设施进行GMP审计。

　　16.14 When subcontracting is allowed, a contractor should not pass to a third party any of the work entrusted to it under the contract without the company’s prior evaluation and approval of the arrangements.

　　16.14 在允许分包的情况下，未经合同委托方事先的评估和核准，合同接受方不应当将合同中委托给他的工作转交给第三方。

　　16.15 Manufacturing and laboratory records should be kept at the site where the activity occurs and be readily available.

　　16.15 生产和分析记录应当保存在操作现场，并随时可得。

　　16.16 Changes in the process, equipment, test methods, specifications, or other contractual requirements should not be made unless the contract giver is informed and approves the changes. 16.16 应当在通知合同委托方，并得到批准后，才可以对工艺、设备、测试方法、规格标准或其它合同要求进行变更。

　　17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 17.代理商、经纪人、贸易商、经销商、重新包装者和重新贴签者

　　17.1 Applicability 17.1适用性

　　17.10 This section applied to any party other than the original manufacturer who may trade and/or take possession, repack, relabel, manipulate, distribute, or store an API or intermediate.

　　17.10 本章内容适用于除原生产商以外，参与贸易和/或持有、处理、重新包装、重新贴签、运作和储存原料药或中间体的任何一方。

　　17.11 All agents, brokers, traders, distributors, repackers, and relabelers should comply with GMP as defined in this guidance.

　　17.11 所有的代理、经纪人、贸易商、经销商、重新包装者和重新贴签者都必须遵循本指南的GMP。

　　17.2 Traceability of Distributed APIs and Intermediates

　　17.2已分发的原料药和中间体的可追溯性

　　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:

　　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：

　　17.3 Quality Management 17.3质量管理

　　17.30 Agents, brokers, traders, distributors, repackers, or relabelers should establish, document and implement an effective system of managing quality, as specified in Section 2.

　　17.30 代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当按第2节的规定建立并执行一个有效的质量管理系统。

　　17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates

　　17.4原料药和中间体的重新包装、重新贴签和待检

　　17.40 Repackaging, Relabeling, and holding APIs and intermediates should be performed under appropriate GMP controls, as stipulated in this guidance, to avoid mix-ups and loss of API or intermediate identity or purity.

　　17.40 原料药和中间体的重新包装、重新贴签和待检应当在本指南中所制定的适当的GMP控制下进行，以防原料药或中间体的特性或纯度的混淆和损失。

　　17.41 Repackaging should be conducted under appropriate environmental conditions to avoid contamination and cross-contamination.

　　17.41 重新包装应当在合适的，能防止污染和交叉污染的环境条件下进行。

　　17.5 Stability 17.5稳定性

　　17.50 Stability studies to justify assigned expiration or retest dates should be conducted if the API or intermediate is repackaged in a different type of container than that used by the API or intermediate manufacturer.

　　17.50 如果原料药或中间体的重新包装所使用的容器与原料药或中间体的生产商所使用的不同，就应当进行稳定性研究，以确认规定的失效期或复验期。

　　17.6 Transfer of Information 17.6 信息的传达

　　17.60 Agents, brokers, distributors, repackers, or relabelers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.

　　17.60 代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当将从原料药或中间体生产商和客户之间传递所有质量或药政的信息。

　　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.

　　17.61 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 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.)

　　17.62 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 The specific guidance for certificate of analysis included in Section 11.4 should be met. 17.63 应当遵循第11.4章所述有关报告单的指南。

　　17.7 Handling of Complaints and Recalls 17.7 投诉和召回的处理

　　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.

　　17.70 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 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. 17.71 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 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).

　　17.72 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 Handling of Returns 17.8 退货的处理

　　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.

　　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. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18. 用细胞繁殖/发酵生产的原料药的特殊指南

　　18.1 General 18.1 总则

　　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.

　　18.10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 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.

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

　　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。

　　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.

　　18.13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 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.

　　18.14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 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).

　　18.15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。

　　18.17 Where appropriate, the removal of media components, host cell proteins, other process-related impurities, product-related impurities and contaminants should be demonstrated. 18.17应当根据情况证明培养基、宿主细胞蛋白、其它与工艺有关的杂质、与产品相关的杂质和污染物的去除效果。

　　18.2 Cell Bank Maintenance and Record Keeping 18.2细胞库的维护和记录的保存

　　18.20 Access to cell banks should be limited to authorized personnel.

　　18.20应当只有授权的人员才能进入细胞库。

　　18.21 Cell banks should be maintained under storage conditions designed to maintain viability and prevent contamination.

　　18.21细胞库应当维持在保持细胞活力、防止污染的储存条件下。

　　18.22 Records of the use of the vials from the cell banks and storage conditions should be maintained.

　　18.22细胞库中小瓶细胞的使用和储存条件应当有记录。

　　18.23 Where appropriate, cell banks should be periodically monitored to determine suitability for use.

　　18.23细胞库应当根据情况进行周期性的监测，以确定其适用性。

　　18.24 See ICH Guideline Q5D Quality of Biotechnological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products for a more complete discussion of cell banking.

　　18.24有关细胞库的详细论述请参见ICH 指南Q5D生物制品的质量：用于生物技术/生物制品生产的细胞质的诱导和特性描述。

　　18.3 Cell Culture/Fermentation 18.3细胞繁殖/发酵

　　18.30 Where aseptic addition of cell substrates, media, buffers, and gases is needed, closed or contained systems should be used where possible. If the inoculation of the initial vessel or subsequent transfers or additions (media, buffers) are performed in open vessels, there should be controls and procedures in place to minimize the risk of contamination.

　　18.30在需要进行来进行细胞质、培养基、缓冲液和气体的无菌添加的场合，如果可能的话，应当采用闭口或密闭系统。如果接种或转种或加料(培养基，缓冲液)是在敞口容器中操作的，就应当有控制措施和程序将污染的风险减少到最低限度。

　　18.31 Where the quality of the API can be affected by microbial contamination, manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment.

　　18.31在原料药的质量会受微生物污染的影响的情况下，使用敞口容器的操作应当在生物安全橱中，或相似的控制环境下进行。

　　18.32 Personnel should be appropriately gowned and take special precautions handling the cultures.

　　18.32操作人员应当着装适宜，并采取特殊的处理培养物的措施。

　　18.33 Critical operating parameters (for example temperature, pH, agitation rates, addition of gases, pressure) should be monitored to ensure consistency with the established process. Cell growth, viability (for most cell culture processes), and, where appropriate, productivity should also be monitored. Critical parameters will vary from one process to another, and for classical fermentation, certain parameters (cell viability, for example) may not need to be monitored.

　　18.33应当监测关键的操作参数(如温度，pH，搅拌速度，通气，压力)，确保与工艺规定一致。对细胞生长，活性(大多数生物技术工艺)， 必要时对生产能力也应当进行监测。不同工艺的关键操作参数是不同的，对经典发酵的某些参数可以不必监测。

　　18.34 Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should be cleaned, and sanitized or sterilized.

　　18.34细胞培养物的设备，使用后应当清洗和灭菌。发酵设备必要时应当清洗和消毒或灭菌。

　　18.35 Culture media should be sterilized before use when appropriate to protect the quality of the API.

　　18.35为了保证原料药的质量，细胞培养基必要时在使用前应当灭菌。

　　18.36 There should be appropriate procedures in place to detect contamination and determine the course of action to be taken. This should include procedures to determine the impact of the contamination on the product and those to decontaminate the equipment and return it to a condition to be used in subsequent batches. Foreign organisms observed during fermentation processes should be identified as appropriate and the effect of their presence on product quality should be assessed, if necessary. The results of such assessments should be taken into consideration in the disposition of the material produced.

　　18.36应当有合适的程序来检测是否染菌，并决定所采取的措施。该程序应当包括确定染菌对产品质量的影响，设备去污染，和恢复到用于以后批号的程序。适当情况下，发酵工艺中发现的外来有机物应当根据需要进行鉴别，必要时应当就其存在对产品质量的影响进行评估。在处理生产出来的物料时应当考虑该评估的结果。

　　18.37 Records of contamination events should be maintained. 18.37应当保存染菌记录。

　　18.38 Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of cross-contamination.

　　18.38共用(多产品)设备在换产品的清洁后，根据情况可以进行额外测试，以便将交叉污染的风险减少到最低限度。

　　18.4 Harvesting, Isolation and Purification 18.4收取、分离和精制

　　18.40 Harvesting steps, either to remove cells or cellular components or to collect cellular components after disruption, should be performed in equipment and areas designed to minimize the risk of contamination.

　　18.40收取步骤，不管去除细胞或细胞组分，还是收集破坏后的细胞组分，都应当在按尽可能减少污染的要求而设计的设备和区域内进行。

　　18.41 Harvest and purification procedures that remove or inactivate the producing organism, cellular debris and media components (while minimizing degradation, contamination, and loss of quality) should be adequate to ensure that the intermediate or API is recovered with consistent quality.

　　18.41将生产有机物、细胞碎片或培养基组分去除或灭活(同时减少降解、污染、质量损失)的收取和精制工艺，应当充分保证回收到的中间体或原料药是均质的。

　　18.42 All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching without cleaning can be used if intermediate or API quality is not compromised.

　　18.42所有的设备使用后应当适当地清洗，根据情况还应当消毒。如果对中间体和原料药的质量没有危害，可以连续生产几批后清洗。

　　18.43 If open systems are used, purification should be performed under environmental conditions appropriate for the preservation of product quality.

　　18.43如果使用开口系统，应当在适合于保持产品质量的环境下进行精制。

　　18.44 Additional controls, such as the use of dedicated chromatography resins or additional testing, may be appropriate if equipment is to be used for multiple products.

　　18.44如果设备用于多个产品，可能有必要作诸如使用专用的层析树脂的额外精制控制，或额外的测试。

　　18.5 Viral Removal/Inactivation steps 18.5 病毒的去除/灭活步骤

　　18.50 See the ICH Guideline Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin for more specific information.

　　18.50更具体的资料参见ICH 指南Q5A生物制品的质量：从人体或动物组织细胞族得到的生物制品的病毒安全性评估。

　　18.51 Viral removal and viral inactivation steps are critical processing steps for some processes and should be performed within their validated parameters.

　　18.51对于某些工艺来说，病毒的去除和灭活是关键的工艺步骤，并按其验证过的参数进行。

　　18.52 Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.

　　18.52应当采取合适的预防措施来防止病毒去除/灭活前的步骤对病毒去除/灭活后的步骤的潜在病毒污染。因此，开口工艺应当在与其它操作活动分开的，有独立的空气处理装置的区域内进行。

　　18.53 The same equipment is not normally used for different purification steps. However, if the same equipment is to be used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be taken to prevent potential virus carry-over (e.g. through equipment or environment) from previous steps.

　　18.53不同的精制步骤通常不使用同一台设备。如果使用同一台设备，在再使用之前应当进行适当的清洁和消毒。应当采取合适的预防措施来防止病毒从前面的步骤带入(例如，通过设备或环境)。

　　19. APIs for Use in Clinical Trials 19. 用于临床研究的原料药

　　19.1 General 19.1 总则

　　19.10 Not all the controls in the previous sections of this Guide are appropriate for the manufacture of a new API for investigational use during its development. Section 19 provides specific guidance unique to these circumstances.

　　19.10不是本指南前面章节中所有的控制都适合于开发阶段用于研究的新原料药的制造。第19章提供了针对此种情况的特殊指南。

　　19.11 The controls used in the manufacture of APIs for use in clinical trials should be consistent with the stage of development of the drug product incorporating the API. Process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses from pre-clinical stages through clinical stages. Once drug development reaches the stage where the API is produced for use in drug products intended for clinical trials, manufacturers should ensure that APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API.

　　19.11用于生产临床试验用原料药的生产控制应当与含有该原料药的药品的开发阶段一致。工艺和检验程序应当随着工艺知识的积累，从前期临床阶段到临床阶段的药品临床测试的发展，提供变更的可能性。一旦药物的开发到了为用于临床试验的药品生产原料药的阶段，生产者应当确原料药是在适当的设施中，采用保证原料药质量的适当生产和控制程序生产的。

　　19.2 Quality 19.2 质量

　　19.20 Appropriate GMP concepts should be applied in the production of APIs for use in clinical trials with a suitable mechanism of approval of each batch.

　　19.20在对每批有合适的批准机制的临床试验用原料药的生产中应当采用适当的GMP观念。

　　19.21 A quality unit(s) independent from production should be established for the approval or rejection of each batch of API for use in clinical trials.

　　19.21应当建立独立于生产部的质量部门，来确定每批用于临床试验的原料药合格或不合格。

　　19.22 Some of the testing functions commonly performed by the quality unit(s) can be performed within other organizational units.

　　19.22某些通常由质量部门执行的测试功能可以在其它部门进行。

　　19.23 Quality measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs.

　　19.23质量措施应当包括一个测试原料、包装材料、中间体和原料药的系统。

　　19.24 Process and quality problems should be evaluated.

　　19.24对工艺和质量问题应当进行评估。

　　19.25 Labelling for APIs intended for use in clinical trials should be appropriately controlled and should identify the material as being for investigational use.

　　19.25临床实验用原料药的贴签应当有适当的控制，并将物料标明用于研究。

　　19.3 Equipment and Facilities 19.3 设备和设施

　　19.30 During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean and suitable for its intended use.

　　19.30在临床开发的所有阶段，包括使用小型设备或实验室进行临床试验用原料药的生产，应当提供确保设备经过校验、清洁并适于其预定用途的程序。

　　19.31 Procedures for the use of facilities should ensure that materials are handled in a manner that minimizes the risk of contamination and cross-contamination.

　　19.31设施的使用程序应当确保原料以将污染和交叉污染减少到最低限度的方式操作。

　　19.4 Control of Raw Materials 19.4 原料的控制

　　19.40 Raw materials used in production of APIs for use in clinical trials should be evaluated by testing, or received with a supplier’s analysis and subjected to identity testing. When a material is considered hazardous, a supplier's analysis should suffice.

　　19.40用于临床试验用原料药生产的原料应当通过测试来评估，或者凭供应商的分析报告单接收，并进行鉴别测试。如果原材料有毒性，一份供应商的分析报告单应当够了。

　　19.41 In some instances, the suitability of a raw material can be determined before use based on acceptability in small-scale reactions (i.e., use testing) rather than on analytical testing alone. 19.41有时，原料的适用性可以在使用前根据其在小规模反应(如使用测试)中的可接受程度而定，而不单凭分析测试。

　　19.5 Production 19.5 生产

　　19.50 The production of APIs for use in clinical trials should be documented in laboratory notebooks, batch records, or by other appropriate means. These documents should include information on the use of production materials, equipment, processing, and scientific observations.

　　19.50临床试验用原料药的生产应当在实验室记录本、批记录中，或以其它适合的方式成文备查。这些文件应当包括所用的生产原料、设备、工艺，和科学观察。

　　19.51 Expected yields can be more variable and less defined than the expected yields used in commercial processes. Investigations into yield variations are not expected.

　　19.51预期产量同正式生产的预期产量相比可能更具变异性、更不确定。无需对产量变化进行调查。

　　19.6 Validation 19.6 验证

　　19.60 Process validation for the production of APIs for use in clinical trials is normally inappropriate, where a single API batch is produced or where process changes during API development make batch replication difficult or inexact. The combination of controls, calibration, and, where appropriate, equipment qualification assures API quality during this development phase.

　　19.60在临床试验用原料药只生产一批，或者有由于原料药开发中工艺的变更使批次的重现困难或不精确的场合，不适合作原料药的工艺验证。控制、校验和必要的设备确认的结合会保证开发阶段的原料药质量。

　　19.61 Process validation should be conducted in accordance with Section 12 when batches are produced for commercial use, even when such batches are produced on a pilot or small scale.19.61在生产商业用批号，甚至是中试或小规模生产批号时，应当按照第12章进行工艺验证。

　　19.7 Changes 19.7 变更

　　19.70 Changes are expected during development, as knowledge is gained and the production is scaled up. Every change in the production, specifications, or test procedures should be adequately recorded

　　19.70随着知识的积累和生产规模的扩大，在开发阶段会有变更。生产、规格或检验方法的每一个变更都应当适当地记录。

　　19.8 Laboratory Controls 19.8 实验室控制

　　19.80 While analytical methods performed to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound.

　　19.80虽然评估一批临床试验用原料药的分析方法可能还没有验证，但是，它们应当是科学，合理的。

　　19.81 A system for retaining reserve samples of all batches should be in place. This system should ensure that a sufficient quantity of each reserve sample is retained for an appropriate length of time after approval, termination, or discontinuation of an application.

　　19.81应当有一套保存所有批号留样的系统。该系统应当确保在申请批准、终止或中断后能将足够量的每一个留样保存一段适当的时间。

　　19.82 Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For new APIs, Section 11.6 does not normally apply in early stages of clinical trials.

　　19.82按第11.6节规定的设定有效期或复验期适用于现有的临床试验用原料药。对新的原料药，第11.6节通常不适于临床试验的前期阶段。

　　19.9 Documentation 19.9 文件

　　19.90 A system should be in place to ensure that information gained during the development and the manufacture of APIs for use in clinical trials is documented and available.

　　19.90应当有一个系统确保在临床试验用原料药的开发和生产过程中得到的信息均成文备查，并可获得。

　　19.91 The development and implementation of the analytical methods used to support the release of a batch of API for use in clinical trials should be appropriately documented.

　　19.91支持放行一批临床试验用原料药的分析方法的开发和实施应当适当地成文备查。

　　19.92 A system for retaining production and control records and documents should be used. This system should ensure that records and documents are retained for an appropriate length of time after the approval, termination, or discontinuation of an application.

　　19.92应当采用一套保存生产和控制的记录和文件的系统。该系统应当保证记录和文件在申请批准、终止或中断后能记录和文件保存一段适当的时间。

　　20. Glossary 20. 术语

　　Acceptance Criteria认可标准

　　Numerical limits, ranges, or other suitable measures for acceptance of test results.

　　接收测试结果的数字限度、范围或其它合适的量度标准。

　　Active Pharmaceutical Ingredient (API) (or Drug Substance)

　　Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

　　活性药用成分(原料药)旨在用于药品制造中的任何一种物质或物质的混合物，而且在用于制药时，成为药品的一种活性成分。此种物质在疾病的诊断，治疗，症状缓解，处理或疾病的预防中有药理活性或其它直接作用，或者能影响机体的功能和结构。

　　API Starting Material原料药的起始物料

　　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 are normally of defined chemical properties and structure.

　　用在原料药生产中的，以主要结构单元被并入该原料药的原料、中间体或原料药。原料药的起始物料可能是在市场上有售，能够根据合同或商业协议从一个或多个供应商处购得，或者自己生产。原料药的起始物料通常有特定的化学特性和结构。

　　Batch (or Lot) 批

　　A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.

　　由一个或一系列工艺过程生产的一定数量的物料，因此在规定的限度内是均一的。在连续生产中，一批可能对应于与生产的某一特定部分。其批量可规定为一个固定数量，或在固定时间间隔内生产的数量。

　　Batch Number (or Lot Number) 批号

　　A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined.

　　用于标识一批的一个数字、字母和/或符号的唯一组合，从中可确定生产和销售的历史。

　　Bioburden生物负载

　　The level and type (e.g. objectionable or not) of micro-organisms that can be present in raw materials, API starting materials, intermediates or APIs. Bioburden should not be considered contamination unless the levels have been exceeded or defined objectionable organisms have been detected.

　　可能存在于原料、原料药的起始物料、中间体或原料药中的微生物的水平和种类(例如，致病的或不致病的)。生物负载不应当当作污染，除非含量超标，或者测得致病生物。

　　Calibration校验

　　The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements. 证明某个仪器或装置在一适当的量程范围内所测得的结果与一参照物，或可追溯的标准相比在规定限度内。

　　Computer System计算机系统

　　A group of hardware components and associated software, designed and assembled to perform a specific function or group of functions.

　　设计安装用于执行某一项或一组功能的一组硬件元件和关联的软件。

　　Computerized System计算机化系统

　　A process or operation integrated with a computer system.

　　与计算机系统整合的一个工艺或操作。

　　Contamination污染

　　The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, sampling, packaging or repackaging, storage or transport.

　　在生产、取样、包装或重新包装、贮存或运输过程中，具化学或微生物性质的杂质或外来物质进入或沾染原料、中间体或原料药。

　　Contract Manufacturer协议制造商

　　A manufacturer performing some aspect of manufacturing on behalf of the original manufacturer. 代表原制造商进行部分制造的制造商。

　　Critical关键的

　　Describes a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.用来描述为了确保原料药符合规格标准，必须控制在预定范围内的工艺步骤、工艺条件、测试要求或其它有关参数或项目。

　　Cross-Contamination交叉污染

　　Contamination of a material or product with another material or product.

　　一种物料或产品对另一种物料或产品的污染。

　　Deviation偏差

　　Departure from an approved instruction or established standard.

　　对批准的指令或规定的标准的偏离。

　　Drug (Medicinal) Product药品

　　The dosage form in the final immediate packaging intended for marketing. (Reference Q1A) 经最后包装准备销售的制剂(参见Q1A)。

　　Drug Substance原料药

　　See Active Pharmaceutical Ingredient 见活性药物成分

　　Expiry Date (or Expiration Date) 有效期

　　The date placed on the container/labels of an API designating the time during which the API is expected to remain within established shelf life specifications if stored under defined conditions, and after which it should not be used.

　　原料药容器/标签上注明的日期，在此规定时间内，该原料药在规定条件下贮存时，仍符合规格标准，超过这一期限则不应当使用。

　　In-Process Control (or Process Control) 过程控制

　　Checks performed during production in order to monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or API conforms to its specifications.

　　生产过程中为监测，在必要时调节工艺和/或保证中间体或原料药符合其规格而进行的检查。

　　Intermediate中间体

　　A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated. (Note: this Guide only addresses those intermediates produced after the point that the company has defined as the point at which the production of the API begins.)

　　原料药工艺步骤中产生的、必须经过进一步分子变化或精制才能成为原料药的一种物料。中间体可以分离或不分离。(注：本指南只涉及该公司定义为原料药生产起始点以后生产的中间体。)

　　Qualification确认

　　Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.

　　证明设备或辅助系统，安装正确、工作正常、确实产生预期的结果，并以文件佐证的行为。确认是验证的一部分，但单独的确认步骤不构成工艺验证。

　　Quality Assurance (QA) 质量保证

　　The sum total of the organised arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.

　　以确保所有原料药达到其应用所要求的质量，并维持质量体系为目的的全部组织安排的总和。

　　Quality Unit(s) 质量部门

　　An organizational unit independent of production which fulfills both Quality Assurance and Quality Control responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization. 独立于生产部门的履行质量保证和质量控制职责的组织机构。按照组织机构的大小和结构，可以是单独的QA 和QC部门，或个人，或小组。

　　Quarantine待验

　　The status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.

　　在实物上或以其它有效方式将物料隔离，等待对其随后的批准或拒收做出决定的状态。

　　Raw Material原料

　　A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs.

　　用来表示中间体或原料药的生产中要用的起始物料、试剂和溶剂的通用专业名词。

　　Reference Standard, Primary基准参考标准品

　　A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. This standard can be: (1) obtained from an officially recognised source, or (2) prepared by independent synthesis, or (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing production material. 经广泛分析测试表明具有可信的高纯度的物质。这类标准品可以：1)来源于法定的机构，2)独立合成，3)来自于高纯度的现有生产物料，或4)用进一步精制现有生产物料的方法来制备。

　　Reference Standard, Secondary二级参考标准品

　　A substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis.

　　与基准参考标准品比较显示具有规定的质量和纯度，并用作日常实验室分析的参考标准品。

　　Reprocessing返工

　　Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process, and not reprocessing.

　　将不符合标准或规格的一个中间体或原料药返回工艺过程，重复规定的生产工艺中的某一结晶步骤或其它合适的化学或物理处理步骤(如蒸馏，过滤，层析，磨粉)，这种做法通常是可以接受的。在中间控制的测试表明一工艺步骤没有完成，从而继续该步骤，是正常工艺的一部分，而不是返工。

　　Reworking重新加工

　　Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with a different solvent).

　　将不符合规格标准的中间体或原料药用不同于规定生产工艺的一个或几个步骤进行处理，以得到质量可接受的中间体或原料药(如：用不同溶剂的再结晶)。

　　Specification质量标准

　　A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. Conformance to specification means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.

　　一系列的测试项目、有关的分析程序和适当的认可标准，此标准可以是数值限度、范围或所述测试项目的其它标准。它规定一套标准，物料应当符合该标准，才被认为可以用作其预期的用途。符合规格表示物料按所列的分析程序测试时，会符合所列的接受标准。

　　Validation验证

　　A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria.

　　为某一特定的工艺、方法或系统能够持续地产生符合既定接受标准的结果提供充分保证的文件程序。

　　Validation Protocol验证方案

　　A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters/operating ranges, product characteristics, sampling, test data to be collected, number of validation runs, and acceptable test results.

　　说明如何进行验证和规定接受标准的书面计划。例如，生产工艺验证方案确定工艺设备、关键性工艺参数/操作范围、产品特性、取样、收集的测试数据、验证的次数，以及可接受的测试结果。

　　Yield, Expected预期产量

　　The quantity of material or the percentage of theoretical yield anticipated at any appropriate phase of production based on previous laboratory, pilot scale, or manufacturing data.

　　在以前实验室、中试规模或生产数据的基础上，预计任何适当的生产阶段的物料的量或理论产量的百分比。