歐盟GMP附錄1對(duì)關(guān)鍵要素監(jiān)控頻率分析

       2022年8月定稿的EU GMP附錄1對(duì)全球無(wú)菌行業(yè)影響持續(xù)發(fā)酵。雖然中國(guó)藥政部門(mén)對(duì)中國(guó)2010版GMP的附錄1-無(wú)菌藥品修訂的工作還沒(méi)有公開(kāi)消息，但是毫無(wú)疑問(wèn)，這部重要的國(guó)際法規(guī)對(duì)于中國(guó)無(wú)菌行業(yè)的影響還是在不斷擴(kuò)大。

       EU GMP附錄1對(duì)影響無(wú)菌藥品質(zhì)量屬性的關(guān)鍵要素如何監(jiān)控、監(jiān)控頻率有哪些新的變化，也是行業(yè)關(guān)注的要點(diǎn)之一。筆者今天匯總分析EU GMP附錄1關(guān)于這方面的信息，希望可以為行業(yè)從業(yè)者提供借鑒。

       第一部分：按照批次監(jiān)管的關(guān)鍵要素

       3.2 All non-conformities, such as sterility test failures, environmental monitoring excursions or deviations from established procedures should be adequately investigated before certification/release of the batch. The investigation should determine the potential impact upon process and product quality and whether any other processes or batches are potentially impacted.

       一批產(chǎn)品涉及的所有不符合情況，例如無(wú)菌測(cè)試失敗、環(huán)境監(jiān)控結(jié)果偏離或者活動(dòng)偏差，都應(yīng)該在這批產(chǎn)品放行之前被充分調(diào)查。調(diào)查工作應(yīng)該確定對(duì)工藝和產(chǎn)品質(zhì)量潛在的影響，以及是否任何其他工藝或者批次被潛在影響。

       4.21。。。

       i. Isolators: 對(duì)于隔離器而言

       Generally glove integrity testing should be performed at a minimum frequency of the beginning and end of each batch or campaign. Additional glove integrity testing may be necessary depending on the validated campaign length.

       通常，隔離器上面的手套的完整性測(cè)試應(yīng)該在每批次生產(chǎn)的開(kāi)始和結(jié)束時(shí)，或者在每個(gè)生產(chǎn)周期的開(kāi)始和結(jié)束時(shí)，以最小的頻率來(lái)進(jìn)行。根據(jù)驗(yàn)證的生產(chǎn)周期長(zhǎng)度，額外的手套完整性測(cè)試可能是必要的。

       For manual aseptic processing activities where single unit or small batch sizes are produced, the frequency of integrity verification may be based on other criteria, such as the beginning and end of each manufacturing session.

       對(duì)于采用手工無(wú)菌工藝生產(chǎn)單個(gè)無(wú)菌產(chǎn)品或者很小批量的情況，手套完整性核實(shí)的頻率可能基于其他標(biāo)準(zhǔn)，例如每個(gè)生產(chǎn)階段的開(kāi)始和結(jié)束時(shí)。

       6.12。。。

       Chemical testing results should be approved before the water system is returned to use and microbiological/endotoxin results verified to be within specification and approved before batches manufactured using water from the system are considered for certification/release.

       在工藝用水系統(tǒng)被允許再次使用之前，化學(xué)測(cè)試結(jié)果應(yīng)該被批準(zhǔn)；應(yīng)該核實(shí)微生物/內(nèi)毒素測(cè)試結(jié)果應(yīng)該確認(rèn)在限度內(nèi)，并且在使用相關(guān)批次工藝用水生產(chǎn)的產(chǎn)品在放行之前，應(yīng)該對(duì)工藝用水進(jìn)行批準(zhǔn)。

       6.19。。。

       Where the filter is used on a batch basis (e.g. for filtration of gas used for overlay of aseptically filled products) or as product vessel vent filter, then the filter should be integrity tested and the results reviewed as part of the batch certification/release process.

       如果過(guò)濾器以批次頻率來(lái)使用（例如，用于過(guò)濾覆蓋無(wú)菌灌裝產(chǎn)品的氣體），或者作為儲(chǔ)存產(chǎn)品的罐體呼吸器，則過(guò)濾器的完整性測(cè)試和測(cè)試結(jié)果應(yīng)該作為產(chǎn)品批次放行的審核任務(wù)的一部分來(lái)被審核。

       8.16。。。

       Any non-qualified interventions should be thoroughly assessed by the quality department and considered during batch disposition.

       在批次產(chǎn)品處理過(guò)程中，無(wú)菌操作中所有未確認(rèn)的干預(yù)行為都應(yīng)該被質(zhì)量部門(mén)徹底評(píng)估。

       8.17 Interventions and stoppages should be recorded in the batch record. Each line stoppage or intervention should be sufficiently documented in batch records with the associated time, duration of the event, and operators involved.

       無(wú)菌生產(chǎn)中的干預(yù)和停頓應(yīng)記錄在批次記錄中。每個(gè)生產(chǎn)線(xiàn)停頓或干預(yù)都應(yīng)充分記錄在批次記錄中，并附上相關(guān)的時(shí)間、事件的持續(xù)時(shí)間和所涉及的操作員工信息。

       8.32 Where automated methods of inspection are used, the process should be validated to detect known defects (which may impact product quality or safety) and be equal to, or better than, manual inspection methods. The performance of the equipment should be challenged using representative defects prior to start up and at regular intervals throughout the batch.

       在使用自動(dòng)化檢查方法的情況下，應(yīng)驗(yàn)證該工藝以檢測(cè)已知缺陷（可能影響產(chǎn)品質(zhì)量或安全性），并且證明自動(dòng)化工藝等于或優(yōu)于手動(dòng)檢查方法。在啟動(dòng)之前，應(yīng)使用具有代表性的缺陷樣品來(lái)挑戰(zhàn)設(shè)備的性能，并在整個(gè)批次中定期進(jìn)行。

       8.43。。。

       Prior to use of a new batch/lot of BIs, the population, purity and identity of the indicator organism of the batch/lot should be verified.

       在使用新批號(hào)的生物指示劑時(shí)，指示微生物的數(shù)量、純度和身份需要按照批次來(lái)核實(shí)。

       8.45 Sterilisation records should be available for each sterilisation run. Each cycle should have a unique identifier. Their conformity should be reviewed and approved as part of the batch certification/release procedure.

       每次滅菌運(yùn)行都應(yīng)提供滅菌記錄。每個(gè)滅菌周期都應(yīng)具有唯一的標(biāo)識(shí)編號(hào)。作為批次放行程序的一部分，應(yīng)審核和批準(zhǔn)滅菌記錄的符合性。

       8.94 Liquid sterilising grade filters should be discarded after the processing of a single batch and the same filter should not be used continuously for more than one working day unless such use has been validated.

       液體除菌級(jí)過(guò)濾器應(yīng)在處理單批次產(chǎn)品后丟棄，并且同一過(guò)濾器不應(yīng)連續(xù)使用超過(guò)一個(gè)工作日，除非此類(lèi)使用情況已經(jīng)過(guò)驗(yàn)證。

       8.101 Critical process parameters for FFS should be determined during equipment qualification and should include, but are not limited to:

       在設(shè)備確認(rèn)工作中，應(yīng)該確認(rèn)FFS工藝的關(guān)鍵工藝參數(shù)。包括但是不限于：

       v. Batch-specific testing of package seal strength and uniformity.

       對(duì)每個(gè)批次測(cè)試藥品包裝密封的強(qiáng)度和一致性。

       8.115 Critical process parameters for BFS should be determined during equipment qualification and should include, but are not limited to:

       在設(shè)備確認(rèn)工作中，應(yīng)該確認(rèn)BFS工藝的關(guān)鍵工藝參數(shù)。包括但是不限于：

       vi. Batch-specific testing of package wall-thickness at critical points of the container.

       在容器的關(guān)鍵點(diǎn)的容器壁厚的每批次測(cè)試結(jié)果。

       8.124。。。

       The filter used to maintain lyophilizer integrity should be sterilised before each use of the system and its integrity testing results should be part of the batch certification/release.

       每次使用系統(tǒng)之前，應(yīng)該對(duì)維護(hù)凍干機(jī)完整性的過(guò)濾器進(jìn)行滅菌；過(guò)濾器完整性測(cè)試結(jié)果是批次放行審核內(nèi)容的一部分。

       9.3 The information from these systems should be used for routine batch certification/release and for periodic assessment during process review or investigation. This applies for both terminal sterilisation and aseptic processes, however, the criticality of the impact may differ depending upon the product and process type.

       來(lái)自這些系統(tǒng)的信息（指的是前面提到的EM信息）應(yīng)用于常規(guī)批次放行，以及在工藝審核或調(diào)查期間進(jìn)行定期評(píng)估。這適用于終端滅菌工藝和無(wú)菌工藝，但是，根據(jù)產(chǎn)品和過(guò)程類(lèi)型，影響的嚴(yán)重程度可能會(huì)有所不同。

       9.31 Microorganisms detected in the grade A and grade B areas should be identified to species level and the potential impact of such microorganisms on product quality (for each batch implicated) and overall state of control should be evaluated.

       在A級(jí)和B級(jí)地區(qū)檢測(cè)到的微生物應(yīng)進(jìn)行菌種鑒別，鑒別到種的水平，并應(yīng)評(píng)估此類(lèi)微生物對(duì)產(chǎn)品質(zhì)量（涉及的每一批）和總體控制狀態(tài)的潛在影響。

       10.3 The bioburden assay should be performed on each batch for both aseptically filled product and terminally sterilised products and the results considered as part of the final batch review.

       對(duì)于無(wú)菌灌裝產(chǎn)品和終端滅菌產(chǎn)品，應(yīng)對(duì)每批產(chǎn)品進(jìn)行生物負(fù)荷測(cè)定，并將結(jié)果視為最終批次審核的一部分。

       10.4 For products authorised for parametric release, a supporting pre-sterilisation bioburden monitoring programme for the filled product prior to initiating the sterilisation cycle should be developed and the bioburden assay should be performed for each batch.

       對(duì)于獲準(zhǔn)進(jìn)行參數(shù)放行的產(chǎn)品，應(yīng)在啟動(dòng)滅菌周期之前為灌裝的產(chǎn)品制定配套的滅菌前生物負(fù)荷量監(jiān)測(cè)程序，并應(yīng)對(duì)每批產(chǎn)品進(jìn)行生物負(fù)荷量測(cè)定。

       10.6。。。

       i. For products which have been filled aseptically, samples should include containers filled at the beginning and end of the batch. Additional samples, e.g. taken after critical interventions should be considered based on risk.

       對(duì)于無(wú)菌灌裝的產(chǎn)品，取樣樣品應(yīng)包括在批次開(kāi)始和結(jié)束時(shí)灌裝的容器。應(yīng)根據(jù)風(fēng)險(xiǎn)考慮其他樣品，例如在關(guān)鍵干預(yù)后采集的樣品。

       10.10 Environmental monitoring data and trend data generated for classified areas should be reviewed as part of product batch certification/release.

       為QC分級(jí)潔凈區(qū)生成的環(huán)境監(jiān)測(cè)數(shù)據(jù)和趨勢(shì)數(shù)據(jù)應(yīng)作為產(chǎn)品批次放行的一部分內(nèi)容進(jìn)行審查。

       第二部分：按照月度監(jiān)管的關(guān)鍵要素

       4.32。。。

       The maximum time interval for requalification of grade A & B areas, is 6 months.

       對(duì)于A/B級(jí)潔凈區(qū)，再確認(rèn)最大周期是6個(gè)月。

       The maximum time interval for requalification of grade C & D areas, is 12 months.

       對(duì)于C/D級(jí)潔凈區(qū)，再確認(rèn)最大周期是12個(gè)月。

       9.38。。。

       Normally, APS (periodic revalidation) should be repeated twice a year (approximately every six months) for each aseptic process, each filling line and each shift.

       通常，APS（定期重新驗(yàn)證）應(yīng)每年重復(fù)兩次（大約每6個(gè)月一次），用于每個(gè)無(wú)菌工藝，每個(gè)灌裝線(xiàn)和每個(gè)班次。

       9.39 Where manual operation (e.g. aseptic compounding or filling) occurs, each type of container, container closure and equipment train should be initially validated with each operator participating in at least 3 consecutive successful APS and revalidated with one APS approximately every 6 months for each operator.

       在發(fā)生手動(dòng)無(wú)菌操作（例如無(wú)菌配制或灌裝）的情況下，應(yīng)首先驗(yàn)證每種類(lèi)型的容器、容器系統(tǒng)和設(shè)備組合，每個(gè)操作員至少連續(xù)參與3次成功的APS，并且每個(gè)操作員大約每6個(gè)月使用一個(gè)APS進(jìn)行重新驗(yàn)證。

       總結(jié)

       通過(guò)上面的匯總和分析，無(wú)菌制藥同仁應(yīng)該可以看出，這一版EU GMP附錄1對(duì)于無(wú)菌制藥行業(yè)的要求提高很多。對(duì)于那些意圖進(jìn)軍歐美市場(chǎng)的無(wú)菌企業(yè)，應(yīng)該及時(shí)調(diào)整管理規(guī)程和提升PQS，為迎接即將到來(lái)的嚴(yán)苛檢查做好準(zhǔn)備。

       說(shuō)明：本文不構(gòu)成任何投資建議和價(jià)值判斷。

       作者簡(jiǎn)介：zhulikou431，高級(jí)工程師、PDA會(huì)員、ISPE會(huì)員、ECA會(huì)員、PQRI會(huì)員、資深無(wú)菌GMP專(zhuān)家，在無(wú)菌工藝開(kāi)發(fā)和驗(yàn)證、藥品研發(fā)和注冊(cè)、CTD文件撰寫(xiě)和審核、法規(guī)審計(jì)、國(guó)際認(rèn)證、國(guó)際注冊(cè)、質(zhì)量體系建設(shè)與維護(hù)領(lǐng)域，以及無(wú)菌檢驗(yàn)、環(huán)境監(jiān)控等領(lǐng)域皆具有較深造詣。近幾年開(kāi)始著力關(guān)注制藥宏觀領(lǐng)域趨勢(shì)分析和制藥企業(yè)并購(gòu)項(xiàng)目的風(fēng)險(xiǎn)管理工作。