2022年8月定稿的EU GMP附錄1對全球無菌行業影響持續發酵。雖然中國藥政部門對中國2010版GMP的附錄1-無菌藥品修訂的工作還沒有公開消息，但是毫無疑問，這部重要的國際法規對于中國無菌行業的影響還是在不斷擴大。
EU GMP附錄1對影響無菌藥品質量屬性的關鍵要素如何監控、監控頻率有哪些新的變化，也是行業關注的要點之一。筆者今天匯總分析EU GMP附錄1關于這方面的信息，希望可以為行業從業者提供借鑒。
第一部分：按照批次監管的關鍵要素
(資料圖)
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.
一批產品涉及的所有不符合情況，例如無菌測試失敗、環境監控結果偏離或者活動偏差，都應該在這批產品放行之前被充分調查。調查工作應該確定對工藝和產品質量潛在的影響，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試應該在每批次生產的開始和結束時，或者在每個生產周期的開始和結束時，以最小的頻率來進行。根據驗證的生產周期長度，額外的手套完整性測試可能是必要的。
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.
對于采用手工無菌工藝生產單個無菌產品或者很小批量的情況，手套完整性核實的頻率可能基于其他標準，例如每個生產階段的開始和結束時。
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.
在工藝用水系統被允許再次使用之前，化學測試結果應該被批準；應該核實微生物/內毒素測試結果應該確認在限度內，并且在使用相關批次工藝用水生產的產品在放行之前，應該對工藝用水進行批準。
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.
如果過濾器以批次頻率來使用（例如，用于過濾覆蓋無菌灌裝產品的氣體），或者作為儲存產品的罐體呼吸器，則過濾器的完整性測試和測試結果應該作為產品批次放行的審核任務的一部分來被審核。
8.16。。。
Any non-qualified interventions should be thoroughly assessed by the quality department and considered during batch disposition.
在批次產品處理過程中，無菌操作中所有未確認的干預行為都應該被質量部門徹底評估。
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.
無菌生產中的干預和停頓應記錄在批次記錄中。每個生產線停頓或干預都應充分記錄在批次記錄中，并附上相關的時間、事件的持續時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.
在使用自動化檢查方法的情況下，應驗證該工藝以檢測已知缺陷（可能影響產品質量或安全性），并且證明自動化工藝等于或優于手動檢查方法。在啟動之前，應使用具有代表性的缺陷樣品來挑戰設備的性能，并在整個批次中定期進行。
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.
在使用新批號的生物指示劑時，指示微生物的數量、純度和身份需要按照批次來核實。
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.
每次滅菌運行都應提供滅菌記錄。每個滅菌周期都應具有唯一的標識編號。作為批次放行程序的一部分，應審核和批準滅菌記錄的符合性。
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.
液體除菌級過濾器應在處理單批次產品后丟棄，并且同一過濾器不應連續使用超過一個工作日，除非此類使用情況已經過驗證。
8.101 Critical process parameters for FFS should be determined during equipment qualification and should include, but are not limited to:
在設備確認工作中，應該確認FFS工藝的關鍵工藝參數。包括但是不限于：
v. Batch-specific testing of package seal strength and uniformity.
對每個批次測試藥品包裝密封的強度和一致性。
8.115 Critical process parameters for BFS should be determined during equipment qualification and should include, but are not limited to:
在設備確認工作中，應該確認BFS工藝的關鍵工藝參數。包括但是不限于：
vi. Batch-specific testing of package wall-thickness at critical points of the container.
在容器的關鍵點的容器壁厚的每批次測試結果。
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.
每次使用系統之前，應該對維護凍干機完整性的過濾器進行滅菌；過濾器完整性測試結果是批次放行審核內容的一部分。
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.
來自這些系統的信息（指的是前面提到的EM信息）應用于常規批次放行，以及在工藝審核或調查期間進行定期評估。這適用于終端滅菌工藝和無菌工藝，但是，根據產品和過程類型，影響的嚴重程度可能會有所不同。
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級和B級地區檢測到的微生物應進行菌種鑒別，鑒別到種的水平，并應評估此類微生物對產品質量（涉及的每一批）和總體控制狀態的潛在影響。
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.
對于無菌灌裝產品和終端滅菌產品，應對每批產品進行生物負荷測定，并將結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.
對于獲準進行參數放行的產品，應在啟動滅菌周期之前為灌裝的產品制定配套的滅菌前生物負荷量監測程序，并應對每批產品進行生物負荷量測定。
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.
對于無菌灌裝的產品，取樣樣品應包括在批次開始和結束時灌裝的容器。應根據風險考慮其他樣品，例如在關鍵干預后采集的樣品。
10.10 Environmental monitoring data and trend data generated for classified areas should be reviewed as part of product batch certification/release.
為QC分級潔凈區生成的環境監測數據和趨勢數據應作為產品批次放行的一部分內容進行審查。
第二部分：按照月度監管的關鍵要素
4.32。。。
The maximum time interval for requalification of grade A & B areas, is 6 months.
對于A/B級潔凈區，再確認最大周期是6個月。
The maximum time interval for requalification of grade C & D areas, is 12 months.
對于C/D級潔凈區，再確認最大周期是12個月。
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（定期重新驗證）應每年重復兩次（大約每6個月一次），用于每個無菌工藝，每個灌裝線和每個班次。
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.
在發生手動無菌操作（例如無菌配制或灌裝）的情況下，應首先驗證每種類型的容器、容器系統和設備組合，每個操作員至少連續參與3次成功的APS，并且每個操作員大約每6個月使用一個APS進行重新驗證。
總結
通過上面的匯總和分析，無菌制藥同仁應該可以看出，這一版EU GMP附錄1對于無菌制藥行業的要求提高很多。對于那些意圖進軍歐美市場的無菌企業，應該及時調整管理規程和提升PQS，為迎接即將到來的嚴苛檢查做好準備。
說明：本文不構成任何投資建議和價值判斷。
作者簡介：zhulikou431，高級工程師、PDA會員、ISPE會員、ECA會員、PQRI會員、資深無菌GMP專家，在無菌工藝開發和驗證、藥品研發和注冊、CTD文件撰寫和審核、法規審計、國際認證、國際注冊、質量體系建設與維護領域，以及無菌檢驗、環境監控等領域皆具有較深造詣。近幾年開始著力關注制藥宏觀領域趨勢分析和制藥企業并購項目的風險管理工作。
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