WHO新发布指南：试验用药品GMP，生产和QC有何要求？

11 月 5 日，世界卫生组织（WHO）发布了“试验用药品GMP” 指南（Good manufacturing practices for investigational products）的征求意见稿。

该文件是对WHO GMP附录7的修订，目前正处于收集意见期，截止日期为2021年1月。此后，将于2021年2-3月份提交专家工作组，进行讨论，完善后进行第2轮意见收集。最终修订稿计划于2021年10月份，提交第56药物制剂专家委员会（ECSPP）批准。

本指南主体部分分为18个章节，内容如下：

1.背景
2.简介
3.范围
4.质量管理
5.质量风险管理
6.人员
7.文件
8.设施
9.设备和公用系统
10.物料
11.生产
12.质量控制
13.确认和验证
14.投诉
15.召回
16.退货
17.运输
18.销毁

PharmLink计划进行翻译连载，供参考。

本次的内容为11-12章。

11. 生产
Production 

11.1.Products intended for use in clinical trials (late Phase II and Phase III studies) should, as far as possible, be manufactured at a licensed facility. The batch size for investigational products manufactured in a pilot plant or small-scale facility, as opposed to the commercial batch size, may vary widely.

对于计划用于临床试验（II期和III期后期）的产品，应尽可能在许可的工厂生产。在中试工厂或小型工厂中生产的试验用药品，在批量大小与商业批量大小不同。

11.2.The guidelines in this document are applicable to the following licensed facilities:

本文件中的准则适用于以下许可的设施：

•a pilot plant, primarily designed and used for process development; and

•a small-scale facility (sometimes called a "pharmacy"), separate both from the company pilot plant and from routine production.

•中试工厂，主要设计用于工艺开发；

•小型工厂（有时称为“药房”），与公司的中试工厂和常规生产是分开的。

11.3.Facilities, as listed below, should be subject to all GMP requirements for pharmaceutical products;

下表列出的设施应符合药品的所有GMP要求；

•a large-scale production line assembled to manufacture materials in larger batches (e.g. for late Phase III trials and first commercial batches); and

•the normal production line used for licensed commercial batches, and sometimes for the production of investigational products if the number of, for example, ordered ampoules, tablets or other dosage forms, is large enough.

•装配了大规模生产线，以大批量生产物料（例如，用于III期后期试验和第一批商业生产）；

•用于许可用于商业批次的正常生产线，如果订购的安瓿、片剂或其它剂型的数量足够大，有时用于生产试验用药品。

11.4.Where activities are outsourced to contract facilities, the contract must then clearly state, inter alia, the responsibilities of each party, compliance with GMP or of this guideline, and that the product(s) to be manufactured or controlled are intended for use in clinical trials. Close cooperation between the contracting parties is essential.

如果将活动外包给合同设施，则合同必须明确说明各方的责任，遵守GMP或本指南，保证生产或控制的产品可以用于临床试验目的。合同双方之间的密切合作至关重要。

生产操作
Manufacturing operations 

11.5.As process validation may not always be complete during the development phase of products, provisional quality attributes, process parameters and in-process controls should be identified, based on risk management principles and experience with analogous products.

由于在产品开发阶段工艺验证可能并不总是完整的，因此应基于风险管理原则和类似产品的经验，来识别临时质量属性、工艺参数和过程控制。

11.6.The necessary instructions should be identified and may be adapted based on the experience gained in production.

应该确定必要的指导，并可以根据在生产中获得的经验进行调整。

11.7.Where processes such as mixing have not been validated, additional quality control testing may be necessary.

如果未验证混合等过程，则可能需要进行其它QC检验。

11.8.For sterile investigational products, the assurance of sterility should be no less than for licensed products (see GMP for sterile products (6)).

对于无菌试验用药品，无菌保证应不低于许可产品的无菌水平（无菌产品参见GMP（6））。

包装和贴标
Packaging and labelling

11.9.The packaging and labelling of investigational products are likely to be more complex and more liable to errors (which are also harder to detect) when "blinded" labels are used than for licensed products. Supervisory procedures such as label reconciliation, line clearance, and so on, and the independent checks by quality unit personnel, should be intensified accordingly.

与使用许可产品相比，使用“盲”标签时，试验用药品的包装和贴标可能会更复杂，并且更容易出错（也更难以发现）。相应地应加强诸如标签衡算、生产线清场等的监督程序，以及质量部门人员的独立检查。

11.10. The packaging must ensure that the investigational product remains in good condition during transport and storage. Any opening of, or tampering with, the outer packaging during transport should be readily discernible.

包装必须确保试验用药品在运输和储存期间保持良好状态。在运输过程中任何打开或篡改外包装的情况，都应易于辨认。

盲操作
Blinding operations

11.11. In the preparation of "blinded" products, the blind should be maintained until it is required to allow for the identification of the “blinded” product. In-process control should include a check on the similarity in appearance and any other required characteristics of the different products being compared.

在准备“盲”产品时，应保持盲状态，直到需要识别“盲”产品为止。过程控制应包括检查外观的相似性，以及所比较的不同产品的任何其它所需特性。

11.12. A coding system should be introduced to permit the proper identification of "blinded" products. The code, together with the randomization list, must permit the proper identification of the product, including any necessary traceability to the codes and batch number of the product before the blinding operation.

应该引入编码系统，以正确识别“盲”产品。该代码以及随机列表必须允许正确识别产品，包括在盲操作之前对代码和产品批号的任何必要的可追溯性。

12.  质量控制
Quality control

12.1.Quality control should cover, for example, the sampling and testing of materials and products, ensuring that these are not released for use, sale or supply until their quality has been judged to be compliant with the specifications.

质量控制应包括，例如，物料和产品的取样和检验，确保在判定其质量符合质量标准之前，不放行这些物料以供使用、销售或供应。

12.2.Each batch of product should be tested in accordance with a Product Specification File and should meet its specification. Product release is often carried out in two stages; that is, before final packaging (bulk product testing) and after final packaging (finished product testing). 

每批产品应按照产品质量标准文件进行检验，并应符合其质量标准。产品通常分为两个阶段：也就是说，在最终包装之前（半产品检验）和最终包装之后（成品检验）。

12.3.Bulk product testing should cover all relevant factors including production conditions, the results of in-process testing, a review of manufacturing documentation and compliance with the Product Specification File and the order. Finished product testing should cover, in addition to the bulk product assessment, all relevant factors including packaging conditions, the results of in-process testing, a review of packaging documentation and compliance with the Product Specification File and the order.

半产品检验应涵盖所有相关因素，包括生产条件、过程检验结果、生产文件审查，以及对产品质量标准文件和订单的符合情况。成品检验除对半成品的评估外，还应包括所有相关因素，包括包装条件、过程检验结果、包装文件审查，以及对产品质量标准文件和订单的符合情况。

12.4.When necessary, quality control should also be used to verify the similarity in appearance and other physical characteristics such as the odour of "blinded" investigational products.

必要时，还应通过质量控制来验证外观和其它物理特性（例如“盲”试验用药品的气味）是否相似。

12.5.End-product testing should be carried out in order to ensure that each batch meets its specification.

应当进行最终产品检验，以确保每个批次都符合其质量标准。

12.6 Reference and retention samples of each batch of product should be retained.

每批产品的参比样品和留样应保留。

12.7 Samples should be retained in the primary container used for the study or in a suitable bulk container for at least two years after the termination or completion of the relevant clinical trial. If the sample is not stored in the pack used for the study, stability data should be available to justify the shelf life in the pack used.

在相关临床试验终止或完成后，样品应保存在用于研究的主要容器中或合适的散装容器中，时间为至少两年。如果样品未保存在用于研究的包装中，则应提供稳定性数据以证明所用包装的有效期。

12.8 Retention samples should be kept until the clinical report has been prepared in order to enable the confirmation of product identity in the event of, and as part of an investigation into, inconsistent trial results.

留样应一直保存，直到准备好临床报告为止，以便在试验结果不一致时，作为调查的一部分，能够确认产品的鉴别。

12.9 The storage location of reference and retention samples should be defined in a technical agreement between the sponsor and manufacturer(s) and should allow for timely access by the competent authorities.

参比样品和留样的存放位置应在发起人与生产商之间的技术协议中规定，并应允许主管当局及时取用。

12.10The reference sample should be of sufficient size to permit the carrying out on, at least, two occasions of the full analytical controls on the batch in accordance with the Investigational Product dossier submitted for authorization in order to conduct the clinical trial.

参比样品应有足够的数量，以至少允许两次对批次进行全面的分析控制，该分析控制基于为获得临床试验许可而提交的试验用药品档案。

12.11 In the case of retention samples, it is acceptable to store information related to the final packaging as written or electronic records if such records provide sufficient information. In the case of reference samples, the system should comply with the requirements of WHO guidelines for computerized systems (7).

对于留样，如果能够提供了足够的信息，则可以书面或电子记录形式储存有关最终包装的信息。对于参比样品，系统应符合WHO对计算机系统指南的要求（7）。

12.12 The release of a batch of an investigational product should only occur after the designated responsible person has certified that the product meets the relevant requirements. These requirements include the assessment of, as appropriate:

仅在指定负责人证明产品符合相关要求后，才能放行该批试验用药品。这些要求包括对以下方面的评估：

•batch records, including control reports, in-process test reports, changes, deviations and release reports demonstrating compliance with the product specification file, the order, protocol and randomization code;

•批记录，包括控制报告、过程检验报告、变更、偏差和放行报告，证明它们符合产品质量标准文件、订单、草案和随机编码；

•production conditions;

•生产条件；

•the validation status of facilities, processes and methods, as appropriate;

•设施、工艺和方法的验证状态（如适用）；

•the examination of finished packs;

•成品包装的检查；

•where relevant, the results of any analyses or tests performed after importation;

•在相关的情况下，进口后进行的任何分析或检验的结果；

•stability reports;

•稳定性报告；

•the source and verification of conditions of storage and shipment;

•储存和运输条件的来源和确认；

•audit reports concerning the quality system of the manufacturer, where applicable;

•有关生产商质量体系的审计报告（如适用）；

•documents certifying that the manufacturer is authorized to manufacture investigational medicinal products or comparators for export by the appropriate authorities in the country of export; and

•就生产商已获得出口国有关当局授权生产试验用药品或参比品，其出口相关的证明文件； 

•where relevant, regulatory requirements for marketing authorization, GMP standards applicable and any official verification of GMP compliance.

•适当时，有关上市许可的法规要求，适用的GMP标准，以及对GMP合规性的任何官方确认。

Note: The relevance of the above elements is affected by the country of origin of the product, the manufacturer and the marketed status of the product

注意：以上要素的相关性受产品原产国、生产商和产品市场状况的影响

Ref.: [WHO][2020-11-07]DRAFT WORKING DOCUMENT FOR COMMENTS: Good manufacturing practices for investigational products

       文章来源：PharmLink

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