发布时间 : 星期三 文章ICH-Q7a原料药的GMP指南(中英对照)更新完毕开始阅读
Q7a
such and quarantined. These intermediates or APIs can be reprocessed or reworked as described below. The final disposition of rejected materials should be recorded.
14.2 Reprocessing
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.
14.21 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.
14.22 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.
14.3 Reworking
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.
14.31 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
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 返工
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 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 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 重新加工
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 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。
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found to be acceptable.
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.
14.4 Recovery of Materials and Solvents
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.
14.41 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.
14.42 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.
14.43 The use of recovered solvents, mother liquors, and other recovered materials should be adequately documented.
14.5 Returns
14.50 Returned intermediates or APIs should be identified as such and quarantined.
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.
14.52 Records of returned intermediates or APIs should be maintained. For each return, documentation should be include:
● Name and address of the consignee
● Intermediate or API, batch number, and
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 物料与溶剂的回收
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 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 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 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 退货
14.50 退回的原料药和中间体应当作有标志，并隔离。
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 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：
● 收货人姓名和地址；
● 退回的中间体或原料药、批号和数量；
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quantity returned ● Reason for return
● Use or disposal of the returned intermediate or
API
15. COMPLAINTS AND RECALLS
15.10 All quality-related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure.
15.11 Complaint records should include: ● Name and address of complainant
● Name (and, where appropriate, title) and phone
number of person submitting the complaint ● Complaint nature (including name and batch
number of the API)
● Date complaint is received
● Action initially taken (including dates and
identity of person taking the action) ● Any follow-up action taken
● Response provided to the originator of
complaint (including date response sent)
● Final decision on intermediate or API batch or
lot
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.
15.13 There should be a written procedure that defines the circumstances under which a recall of an intermediate or API should be considered.
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.
15.15 In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities should be informed and their advice sought. 16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)
16.10 All contract manufacturers (including
● 退货原因；
● 退回中间体或原料药的用途或处置。
15.投诉与召回
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。
15.11 投诉记录应当包括： ● 投诉人姓名地址
● 递交投诉者的姓名（必要时包括头衔）和电
话
● 投诉性质（包括原料药名称和批号）
● 收到投诉的日期 ● 最初采取的措施（包括日期和执行者的身份） ● 随后采取的任何措施
● 对投诉人的回复（包括发出回复的日期）
● 对该批中间体或原料药的最终处置
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 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 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 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.协议生产商（包括实验室）
16.10 所有协议生产商（包括实验室）应当遵循
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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.
16.11 Companies should evaluate any contractors (including laboratories) to ensure GMP compliance of the specific operations occurring at the contractor sites.
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.
16.13 A contract should permit a company to audit its contractor’s facilities for compliance with GMP.
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.
16.15 Manufacturing and laboratory records should be kept at the site where the activity occurs and be readily available.
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.
17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 17.1 Applicability
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.
17.11 All agents, brokers, traders, distributors, repackers, and relabelers should comply with GMP as defined in this guidance.
17.2 Traceability of Distributed APIs and
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 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 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 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 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 生产和分析记录应当保存在操作现场，并随时可得。
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.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适用性
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 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已分发的原料药和中间体的可追溯性
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