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嘉峪檢測網(wǎng) 2025-04-09 08:17
近日，瑞士藥監(jiān)局發(fā)布了關(guān)于《產(chǎn)品質(zhì)量回顧的技術(shù)解釋》，該文件描述了主管當(dāng)局的檢查員在檢查藥品制造商、API 制造商或上市許可持有人時(shí)，在評(píng)估是否符合要求時(shí)可以采用的最低要求以及建立和評(píng)估 PQR 的建議。翻譯如下：
1. Purpose and scope
目的和范圍
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 分別描述和定義了執(zhí)行年度產(chǎn)品質(zhì)量回顧（PQR）的重要性和要求。PQR被認(rèn)為是確認(rèn)現(xiàn)有生產(chǎn)工藝一致性的關(guān)鍵文件。
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.
本技術(shù)文件描述了主管當(dāng)局的檢查員在檢查藥品制造商、活性藥物成分 （API） 制造商或上市許可持有人時(shí)，在評(píng)估是否符合指南時(shí)可以采用的最低要求以及建立和評(píng)估 PQR 的建議。 以確保檢查的協(xié)調(diào)進(jìn)行。
2. Basics
參考文獻(xiàn)
3. Definitions and abbreviations
定義和術(shù)語
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 必須以所有相關(guān)方（制造商、上市許可持有人、負(fù)責(zé)人和主管監(jiān)管機(jī)構(gòu)）都能理解的既定語言編寫。
4.1 Content of the PQR
PQR的內(nèi)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要求對(duì)原料藥和制劑（包括僅出口的產(chǎn)品）進(jìn)行質(zhì)量回顧，并列出了需要考慮的主題。
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題都在 PQR 中明確說明。每個(gè)主題的數(shù)據(jù)回顧的程度（例如，需要回顧的參數(shù)，例如關(guān)鍵的工藝控制）和深度應(yīng)以基于風(fēng)險(xiǎn)的方式定義，并且應(yīng)適合突出相關(guān)質(zhì)量屬性的任何趨勢，并能夠確定產(chǎn)品和/或工藝改進(jìn)的必要性。所選擇的范圍和深度的理由應(yīng)以科學(xué)為基礎(chǔ)并書面。可以在單獨(dú)的文件中描述理由。一般來說，PQR 必須涵蓋回顧周期內(nèi)生產(chǎn)的所有產(chǎn)品和產(chǎn)品的所有批次。產(chǎn)品分組是可以接受的，但分組的科學(xué)論證應(yīng)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.
為了能夠確認(rèn)現(xiàn)有生產(chǎn)工藝的一致性，所生產(chǎn)的批次數(shù)量應(yīng)盡可能多。因此，PQR 應(yīng)包括所生產(chǎn)產(chǎn)品的所有批次，而不僅僅是供應(yīng)給某一個(gè)客戶市場的批次。例如，如果某個(gè)產(chǎn)品在多個(gè)國家/地區(qū)注冊(cè)或?yàn)槎鄠€(gè)客戶生產(chǎn)（這意味著該產(chǎn)品擁有多個(gè)上市許可），但生產(chǎn)工藝、工藝控制和成品標(biāo)準(zhǔn)相同，則只需建立一個(gè)涵蓋所有批次的 PQR，并提供給所有客戶。
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.
如果產(chǎn)品在多個(gè)國家/地區(qū)注冊(cè)（多個(gè)上市許可）或?yàn)槎鄠€(gè)客戶生產(chǎn)，并且生產(chǎn)工藝基本相同，只有工藝控制和成品標(biāo)準(zhǔn)有微小差異，則只能建立一個(gè)基于最嚴(yán)格標(biāo)準(zhǔn)的 PQR，并向所有客戶提供。
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 應(yīng)包含報(bào)告期間的原始數(shù)據(jù)摘要，采用表格、圖表或任何科學(xué)合理的統(tǒng)計(jì)分析形式，以顯示趨勢并確定產(chǎn)品和工藝改進(jìn)，并在適當(dāng)時(shí)將其與先前的回顧數(shù)據(jù)進(jìn)行比較。報(bào)告期間的原始數(shù)據(jù)匯總應(yīng)包含在 PQR 的附錄中。PQR 應(yīng)包含對(duì)回顧結(jié)果的評(píng)估，以及關(guān)于是否應(yīng)根據(jù)藥品質(zhì)量體系采取糾正和預(yù)防措施或任何再驗(yàn)證的評(píng)估。它還應(yīng)考慮先前回顧的結(jié)論以及預(yù)防和/或糾正措施。
4.2 Responsibilities for the PQR
PQR 的責(zé)任
4.2.1 Responsibility for establishing the PQR
建立 PQR 的責(zé)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 的全部責(zé)任由對(duì) API 和/或成品進(jìn)行技術(shù)放行的制造商負(fù)責(zé)，或者在不同情況下，由將成品放行至市場或出口的上市許可持有人（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.
如果多家公司參與成品的制造、分析和放行，則要求所有活動(dòng)都匯總在一個(gè)總 PQR 中。如果總PQR涵蓋部分制造活動(dòng)的 PQR，則這些部分 PQR 的結(jié)論應(yīng)包含在總 PQR 中，并且涵蓋的部分 PQR 應(yīng)列在 總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.
制造商應(yīng)制定 SOP 來準(zhǔn)備相應(yīng)的 PQR。這些程序應(yīng)確保 PQR 的內(nèi)容是適當(dāng)?shù)模幕仡櫟臄?shù)據(jù)中得出必要的結(jié)論，記錄在 PQR 中，并在藥品質(zhì)量體系下記錄必要的糾正和預(yù)防措施。還應(yīng)明確用于趨勢分析的程序。
4.2.2 Responsibility for evaluating the PQR
評(píng)估 PQR 的責(zé)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.
制造商和上市許可持有人（如果不同）都應(yīng)評(píng)估 PQR 的結(jié)果。制造商應(yīng)在整體 PQR 中評(píng)估是否應(yīng)采取糾正和預(yù)防措施或任何再確認(rèn)或再驗(yàn)證。評(píng)估應(yīng)涉及高級(jí)管理層（例如生產(chǎn)負(fù)責(zé)人、質(zhì)量控制/質(zhì)量部門負(fù)責(zé)人）和制造商或 MAH 的負(fù)責(zé)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:
上市許可持有人應(yīng)確認(rèn)產(chǎn)品是否始終符合上市許可中規(guī)定的要求。如果制造商不是上市許可持有人，則上市許可持有人應(yīng)制定一份標(biāo)準(zhǔn)操作程序（SOP），其中應(yīng)包含對(duì)制造商的PQR的評(píng)估流程，以及對(duì)在藥品質(zhì)量體系（PQS）下記錄的產(chǎn)品特定方面進(jìn)行質(zhì)量回顧的流程。審查至少應(yīng)涵蓋以下方面：
a) a verification, that the reviews as defined in the Guide to GMP have been conducted
確認(rèn)已進(jìn)行 GMP 指南中所規(guī)定的回顧
b)an evaluation of the conclusions drawn in the PQR, including a review of the trend analysis
對(duì) PQR 中得出的結(jié)論的評(píng)估，包括對(duì)趨勢分析的審查
c)a verification that the product is in compliance with the marketing authorization
確認(rèn)產(chǎn)品符合上市許可
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
審查PQS 中記錄的特定國家方面：拒絕或投放市場的批次數(shù)量、召回、退貨、投訴、質(zhì)量缺陷、偏差、變更控制、委外協(xié)議審查和上市許可變更
e)an evaluation if corrective or preventive actions are necessary
評(píng)估是否需要采取糾正或預(yù)防措施
f)review and follow up of previously defined actions
回顧和跟進(jìn)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
一般的合理性檢查，例如，PQR 是否實(shí)際涵蓋了投放市場的批次，以及持續(xù)穩(wěn)定性程序是否涵蓋了必要的批次
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.
應(yīng)記錄PQR 的評(píng)估結(jié)果和對(duì)國家特定方面的審查。應(yīng)在 MAH 審查和制造商的 PQR 之間建立明確的聯(lián)系，例如在回顧周期內(nèi)投放市場的成品批次清單。如果在回顧周期內(nèi)收到/放行市場批次，且制造商在上一周期的 PQR 中已討論過，則應(yīng)在 MAH 審查報(bào)告中提及相應(yīng)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.
對(duì) MAH 的 PQR 的評(píng)估和對(duì)國家/地區(qū)特定方面（即重新包裝和質(zhì)量缺陷）的審查還必須包括 Swissmedic 根據(jù)TPA 第 9 條第b 款臨時(shí)授權(quán)使用和有限投放市場的藥品批次，以彌補(bǔ)在瑞士無法獲得授權(quán)的相同醫(yī)藥商品的時(shí)期。
4.2.3 Responsibility for reviewing the PQR process
審核 PQR 流程的責(zé)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 應(yīng)審查PQR 的管理、及時(shí)準(zhǔn)備和批準(zhǔn)、明確CAPA的實(shí)施和有效性作為管理評(píng)審流程一部分，并在自檢中確認(rèn)這些內(nèi)容。
4.2.4 Technical Agreements
技術(shù)協(xié)議
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.
參與 API 和成品制造和放行的各方之間應(yīng)建立技術(shù)協(xié)議，定義誰將全面負(fù)責(zé)建立 PQR，以及為 PQR 提供數(shù)據(jù)的方式、范圍和責(zé)任。此類協(xié)議必須符合GMP 指南第 I 部分的第 7 章或GMP 指南 第 II 部分的第 16 章的規(guī)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，則 MAH 與負(fù)責(zé)提供總 PQR 的制造商之間應(yīng)簽訂技術(shù)協(xié)議，由負(fù)責(zé)人簽署，明確他們?cè)谶M(jìn)行產(chǎn)品質(zhì)量回顧時(shí)各自的責(zé)任。
4.3 Review period of the PQR
PQR的回顧周期
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應(yīng)至少每年建立一次。年期間可以獨(dú)立于日歷年的設(shè)置，即不一定從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.
審查時(shí)間框架可以根據(jù)制造和活動(dòng)分配進(jìn)行適當(dāng)調(diào)整，并有充分的理由。應(yīng)在 SOP 中建立時(shí)間框架標(biāo)準(zhǔn)。如果當(dāng)年沒有生產(chǎn)批次或生產(chǎn)批次很少，則回顧期可能超過 1 年。為此類情況選擇的回顧期應(yīng)至少包括 5 個(gè)批次。對(duì)于在回顧期間生產(chǎn)的批次很少的產(chǎn)品，可以考慮與其他產(chǎn)品進(jìn)行合理的分組。趨勢分析可以包括從上一周期收集的結(jié)果，以確保其穩(wěn)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).
在任何情況下，即使沒有生產(chǎn)，或只生產(chǎn)了很少的批次，也應(yīng)最遲在 3 年內(nèi)進(jìn)行 PQR，并應(yīng)涵蓋相關(guān)的要求（例如，審查上市許可變更、穩(wěn)定性試驗(yàn)計(jì)劃的結(jié)果、與質(zhì)量相關(guān)的退貨、投訴和召回、糾正措施的充分性、 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.
同樣，如果在質(zhì)量和監(jiān)管審查（例如管理評(píng)審）期間注意到特殊情況，例如關(guān)于穩(wěn)定性結(jié)果、退貨、召回、投訴和/或偏差的負(fù)面趨勢（包括由確認(rèn)和驗(yàn)證活動(dòng)引起的偏差）或監(jiān)管問題，即使沒有生產(chǎn)或很少生產(chǎn)批次，也應(yīng)建立 PQR。應(yīng)包括對(duì)上一次PQR 所制定的行動(dòng)進(jìn)行回顧。
4.4 Timelines for establishing and evaluating the PQR
建立和評(píng)估 PQR 的時(shí)間表
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.
制造商應(yīng)及時(shí)進(jìn)行PQR。「及時(shí)」是指在回顧周期結(jié)束后的6 個(gè)月內(nèi)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 對(duì)PQR 的評(píng)價(jià)和評(píng)估應(yīng)最遲在回顧周期結(jié)束后12 個(gè)月內(nèi)并在新的回顧周期開始前完成（兩者取其最嚴(yán)）。
來源：Internet
