近日，瑞士药监局发布了关于《产品质量回顾的技术解释》，该文件描述了主管当局的检查员在检查药品制造商、API 制造商或上市许可持有人时，在评估是否符合要求时可以采用的最低要求以及建立和评估 PQR 的建议。翻译如下：

 

1. Purpose and scope

 

目的和范围

 

The importance and requirements for performing annual Product Quality Reviews (PQRs) are described and defined in the Guide to Good Manufacturing Practice for medicinal products, part I and part II, PIC/S document PE 009 respectively Eudralex volume 4. The PQR is considered a key document for verifying the consistency of the existing production process.

 

GMP第 I 部分和第II 部分、PIC/S文件PE 009 分别描述和定义了执行年度产品质量回顾（PQR）的重要性和要求。PQR被认为是确认现有生产工艺一致性的关键文件。

 

This technical interpretation describes the minimal expectations as well as recommendations for establishing and evaluating a PQR, that inspectors of the competent regulatory authority can have when assessing compliance with the guidance during an inspection of a manufacturer of medicinal products, a manufacturer of Active Pharmaceutical Ingredients (APIs) for medicinal products or a marketing authorisation holder, in order to assure a harmonized conduct of in-spections.

 

本技术文件描述了主管当局的检查员在检查药品制造商、活性药物成分 （API） 制造商或上市许可持有人时，在评估是否符合指南时可以采用的最低要求以及建立和评估 PQR 的建议。 以确保检查的协调进行。

 

2. Basics

 

参考文献

 

3. Definitions and abbreviations

 

定义和术语

 

4. Interpretation

 

解析

 

The PQR must be written in a defined language which can be understood by all involved parties (manufacturer, marketing authorisation holder, responsible person and competent regulatory authorities).

 

PQR 必须以所有相关方（制造商、上市许可持有人、负责人和主管监管机构）都能理解的既定语言编写。

 

4.1 Content of the PQR

 

PQR的内容

 

The Guide to GMP requires conducting PQRs for APIs and for all licensed medicinal products (including export only products) and lists the topics, which need to be taken into account (for fin-ished products in the Guide to GMP, part I and for APIs in the Guide to GMP, part II).

 

GMP要求对原料药和制剂（包括仅出口的产品）进行质量回顾，并列出了需要考虑的主题。

 

It is expected that all topics listed in the Guide to GMP are explicitly addressed in the PQR. The extent (i.e. selection of the parameters to be reviewed, e.g. critical in-process controls) and depth of data review for each of these topics should be defined in a risk based way and should be suitable to highlight any trends in relevant quality characteristics and enable to identify the necessity for product and/or process improvements. The justification for the chosen extent and depth should be science based and documented. The justification can be described in a sepa-rate document. In general, the PQR has to cover all products and all the batches of a product produced during the review period. Grouping of products is acceptable but a scientific justifica-tion for the grouping must be part of the PQR.

 

要求GMP 指南中列出的所有主题都在 PQR 中明确说明。每个主题的数据回顾的程度（例如，需要回顾的参数，例如关键的工艺控制）和深度应以基于风险的方式定义，并且应适合突出相关质量属性的任何趋势，并能够确定产品和/或工艺改进的必要性。所选择的范围和深度的理由应以科学为基础并书面。可以在单独的文件中描述理由。一般来说，PQR 必须涵盖回顾周期内生产的所有产品和产品的所有批次。产品分组是可以接受的，但分组的科学论证应是 PQR 的一部分。

 

To be able to verify the consistency of the existing production process, the number of batches produced should be as large as possible. Therefore, the PQR should include all the batches of a product produced and not only the batches supplied to one customer. For example, if a cer-tain product is registered in several countries or produced for multiple customers (this means the products has multiple marketing authorisations), but the production process, the in-process controls and finished product specifications are the same, only one PQR covering all batches should be established and made accessible to all customers.

 

为了能够确认现有生产工艺的一致性，所生产的批次数量应尽可能多。因此，PQR 应包括所生产产品的所有批次，而不仅仅是供应给某一个客户市场的批次。例如，如果某个产品在多个国家/地区注册或为多个客户生产（这意味着该产品拥有多个上市许可），但生产工艺、工艺控制和成品标准相同，则只需建立一个涵盖所有批次的 PQR，并提供给所有客户。

 

If a product is registered in several countries (multiple marketing authorisations) or produced for multiple customers, and the production process is essentially the same, with only minor varia-tions in process controls and finished product specifications, only one PQR based on the most stringent criteria may be established and made accessible to all customers.

 

如果产品在多个国家/地区注册（多个上市许可）或为多个客户生产，并且生产工艺基本相同，只有工艺控制和成品标准有微小差异，则只能建立一个基于最严格标准的 PQR，并向所有客户提供。

 

The PQR should contain summaries of the raw data for the reporting period, in form of tables, graphs or any scientifically sound statistical analysis to show trends and identify product and process improvements, comparing them with data of the previous reviews where appropriate. The summarized raw data of the reporting period should be included in the appendix of the PQR. The PQR should contain an evaluation of the results of the review and an assessment as to whether corrective and preventive action or any revalidation should be undertaken, under the Pharmaceutical Quality System. It should also consider conclusions and preventive and/or cor-rective actions from previous reviews.

 

PQR 应包含报告期间的原始数据摘要，采用表格、图表或任何科学合理的统计分析形式，以显示趋势并确定产品和工艺改进，并在适当时将其与先前的回顾数据进行比较。报告期间的原始数据汇总应包含在 PQR 的附录中。PQR 应包含对回顾结果的评估，以及关于是否应根据药品质量体系采取纠正和预防措施或任何再验证的评估。它还应考虑先前回顾的结论以及预防和/或纠正措施。

 

4.2 Responsibilities for the PQR

 

PQR 的责任

 

4.2.1 Responsibility for establishing the PQR

 

建立 PQR 的责任

 

The overall responsibility for establishing the PQR lies with the manufacturer technically releas-ing the API and/or the finished product, or where different, with the Marketing Authorisation holder (MAH) releasing the finished product for the Swiss market or for export.

 

建立 PQR 的全部责任由对 API 和/或成品进行技术放行的制造商负责，或者在不同情况下，由将成品放行至市场或出口的上市许可持有人（MAH）。

 

Where several companies are involved in the manufacture, analysis and release of the finished product, it is expected that all activities are summarized in one overall PQR. If the overall PQRrefers to PQRs, which are covering parts of the manufacturing activities, the conclusions from these partial PQRs should be included in the overall PQR and the covered partial PQRs should be listed in the PQR and be accessible to the manufacturer.

 

如果多家公司参与成品的制造、分析和放行，则要求所有活动都汇总在一个总 PQR 中。如果总PQR涵盖部分制造活动的 PQR，则这些部分 PQR 的结论应包含在总 PQR 中，并且涵盖的部分 PQR 应列在 总PQR 中，并向制造商提供。

 

The manufacturers involved are expected to have SOPs for the preparation of the respective PQRs. These procedures should ensure that the content of the PQR is appropriate and that the necessary conclusions are drawn out of the reviewed data, documented in the PQR and neces-sary corrective and preventive actions are documented under their Pharmaceutical Quality Sys-tem. Procedures for the application of trend analysis should be defined.

 

制造商应制定 SOP 来准备相应的 PQR。这些程序应确保 PQR 的内容是适当的，并从回顾的数据中得出必要的结论，记录在 PQR 中，并在药品质量体系下记录必要的纠正和预防措施。还应明确用于趋势分析的程序。

 

4.2.2 Responsibility for evaluating the PQR

 

评估 PQR 的责任

 

Both, the manufacturer, and where different, the Marketing Authorisation holder, should evalu-ate the results of the PQR. The manufacturer should make an assessment in the overall PQR of whether corrective and preventative action or any requalification or revalidation should be un-dertaken. The evaluation should involve the senior management (e. g. head of manufacturing, head of quality control or quality unit) and the responsible person of the manufacturer or MAH.

 

制造商和上市许可持有人（如果不同）都应评估 PQR 的结果。制造商应在整体 PQR 中评估是否应采取纠正和预防措施或任何再确认或再验证。评估应涉及高级管理层（例如生产负责人、质量控制/质量部门负责人）和制造商或 MAH 的负责人。

 

The marketing authorisation holder should verify whether the product consistently fulfils the re-quirements as specified in the marketing authorisation. Where the manufacturer is not the mar-keting authorisation holder, the marketing authorisation holder should have a process described in an SOP for the evaluation of the FP PQR of the manufacturer and for performing a quality re-view of product specific aspects documented under the local Pharmaceutical Quality System (PQS). The review should at least include the following aspects:

 

上市许可持有人应确认产品是否始终符合上市许可中规定的要求。如果制造商不是上市许可持有人，则上市许可持有人应制定一份标准操作程序（SOP），其中应包含对制造商的PQR的评估流程，以及对在药品质量体系（PQS）下记录的产品特定方面进行质量回顾的流程。审查至少应涵盖以下方面： 

 

a) a verification, that the reviews as defined in the Guide to GMP have been conducted

 

确认已进行 GMP 指南中所规定的回顾

 

b)an evaluation of the conclusions drawn in the PQR, including a review of the trend analysis

 

对 PQR 中得出的结论的评估，包括对趋势分析的审查

 

c)a verification that the product is in compliance with the marketing authorization

 

确认产品符合上市许可

 

d) review of country-specific aspects documented under his PQS: number of batches rejected or released for the market, recalls, returns, complaints, quality defects, deviations, change controls, review of contractual agreements and marketing authorisation variations

 

审查PQS 中记录的特定国家方面：拒绝或投放市场的批次数量、召回、退货、投诉、质量缺陷、偏差、变更控制、委外协议审查和上市许可变更

 

e)an evaluation if corrective or preventive actions are necessary

 

评估是否需要采取纠正或预防措施

 

f)review and follow up of previously defined actions

 

回顾和跟进先前所制定的措施

 

g)a general plausibility check, e. g. if batches released to the market are actually covered by the PQR and if the on-going stability program is covering the necessary batches

 

一般的合理性检查，例如，PQR 是否实际涵盖了投放市场的批次，以及持续稳定性程序是否涵盖了必要的批次

 

The results of the evaluation of the FP PQR and the review of country specific aspects should be documented. A clear link between MAH review and manufacturer’s PQR should be estab-lished, for instance with a list of finished product batches dispositioned for the Swiss market dur-ing the review period. If batches have been received/released for the market during the review period which have been discussed in the manufacturer’s PQR of a previous period, reference to the corresponding document(s) should be made in the MAH review report.

 

应记录PQR 的评估结果和对国家特定方面的审查。应在 MAH 审查和制造商的 PQR 之间建立明确的联系，例如在回顾周期内投放市场的成品批次清单。如果在回顾周期内收到/放行市场批次，且制造商在上一周期的 PQR 中已讨论过，则应在 MAH 审查报告中提及相应的文件。

 

The evaluation of the FP PQR of the MAH and the review of country specific aspects (i.e. re-packaging and quality defects) must also include batches of medicinal products that have been temporarily been authorised for use and limited placing on the market by Swissmedic according to Article 9 letter b TPA to bridge a period when an identical medicinal product authorized in Switzerland is not available.

 

对 MAH 的 PQR 的评估和对国家/地区特定方面（即重新包装和质量缺陷）的审查还必须包括 Swissmedic 根据TPA 第 9 条第b 款临时授权使用和有限投放市场的药品批次，以弥补在瑞士无法获得授权的相同医药商品的时期。

 

4.2.3 Responsibility for reviewing the PQR process

 

审核 PQR 流程的责任

 

The manufacturer or MAH should review the management of the PQRs, their timely preparation and approval, the implementation of defined actions and the effectiveness as part of the local Management Review process and verify these in self-inspections.

 

制造商或 MAH 应审查PQR 的管理、及时准备和批准、明确CAPA的实施和有效性作为管理评审流程一部分，并在自检中确认这些内容。

 

4.2.4 Technical Agreements

 

技术协议

 

Technical agreements should be established between all parties involved in the manufacture and release of the API and finished product, defining who will take the overall responsibility for establishing the PQR and the way, the extent and the responsibility for providing data for the PQR. Such agreements must comply with chapter 7 of the Guide to GMP part I or chapter 16 of the Guide to GMP part II.

 

参与 API 和成品制造和放行的各方之间应建立技术协议，定义谁将全面负责建立 PQR，以及为 PQR 提供数据的方式、范围和责任。此类协议必须符合GMP 指南第 I 部分的第 7 章或GMP 指南 第 II 部分的第 16 章的规定。

 

Where the MAH is not the manufacturer, there should be a technical agreement in place be-tween the MAH and the manufacturer responsible for providing the overall FP PQR, signed by the responsible persons, that defines their respective responsibilities in producing the product quality review.

 

如果 MAH 不是制造商，则 MAH 与负责提供总 PQR 的制造商之间应签订技术协议，由负责人签署，明确他们在进行产品质量回顾时各自的责任。

 

4.3 Review period of the PQR

 

PQR的回顾周期

 

The PQR should be established at least annually. The yearly periods may be set independently from the calendar year, i.e. not necessarily from January to December.

 

PQR应至少每年建立一次。年期间可以独立于日历年的设置，即不一定从1 月到12 月。

 

Review timeframes can be appropriately adjusted based upon manufacturing and campaign du-ration with adequate justification. The timeframe criteria should be established in a SOP. Where no or very few batches were produced during the year, the review period might be longer than 1 year. The chosen review period for such cases should include at least 5 batches. For those products with very few batches produced during a review period, a reasonable grouping with other products might be considered. The trend analysis can include results gathered from the previous period to ensure its robustness.

 

审查时间框架可以根据制造和活动分配进行适当调整，并有充分的理由。应在 SOP 中建立时间框架标准。如果当年没有生产批次或生产批次很少，则回顾期可能超过 1 年。为此类情况选择的回顾期应至少包括 5 个批次。对于在回顾期间生产的批次很少的产品，可以考虑与其他产品进行合理的分组。趋势分析可以包括从上一周期收集的结果，以确保其稳健性。

 

In any case, the PQR should be performed at latest after 3 years even if no production has taken place, or only very few batches have been produced, and should cover the relevant as-pects (e. g. review of marketing authorisation variations, results of the stability monitoring pro-gramme, quality-related returns, complaints and recalls, adequacy of corrective actions, con-tractual arrangements).

 

在任何情况下，即使没有生产，或只生产了很少的批次，也应最迟在 3 年内进行 PQR，并应涵盖相关的要求（例如，审查上市许可变更、稳定性试验计划的结果、与质量相关的退货、投诉和召回、纠正措施的充分性、 委外安排）。

 

Likewise, if during the quality and regulatory review (e. g. the Management Review) a special situation has been noticed e. g. regarding stability results, returns, recalls, negative trends with respect to complaints and/or deviations (including those arising from qualification and validation activities) or regulatory issues, a PQR should be established even if no or very few batches have been produced. A review of the defined actions of the last PQR should be included.

 

同样，如果在质量和监管审查（例如管理评审）期间注意到特殊情况，例如关于稳定性结果、退货、召回、投诉和/或偏差的负面趋势（包括由确认和验证活动引起的偏差）或监管问题，即使没有生产或很少生产批次，也应建立 PQR。应包括对上一次PQR 所制定的行动进行回顾。

 

4.4 Timelines for establishing and evaluating the PQR

 

建立和评估 PQR 的时间表

 

The PQR should be established in a timely manner by the manufacturer. “Timely” is considered as within 6 months after the end of the review period.

 

制造商应及时进行PQR。「及时」是指在回顾周期结束后的6 个月内完成。

 

The evaluation and assessment of the FP PQR by the MAH should be completed at the latest 12 months after the end of the reviewed period and before the start of the new review period (whatever occurs before).

 

MAH 对PQR 的评价和评估应最迟在回顾周期结束后12 个月内并在新的回顾周期开始前完成（两者取其最严）。

来源：Internet

关键词： 药品