近日，瑞士藥監(jiān)局發(fā)布了EU GMP附錄1《無菌藥品生產(chǎn)》（同時也是PIC/S和WHO?GMP附錄1）的解讀文件，該文件側重于新版EU、PIC/S和WHO GMP附錄1的一些最重要的變化，也涵蓋了長期以來反復引起問題的方面。反映了檢查員對這些主題的一般意見，并在無菌藥品制造商檢查期間提供支持。

文件包含內容如下：

1 Purpose and scope

目的和范圍

2 Basics

基本情況

3 Definitions and abbreviations

定義和縮寫

4 Interpretation: Questions and Answers

解讀：問答

4.1 Scope (Annex 1, Chapter 1)

范圍（附錄1，第1章）

4.2 Premises (Annex 1, Chapter 4)

廠房（附錄1，第4章）

4.3 Utilities (Annex 1, Chapter 6)

公用系統(tǒng)（附錄1，第6章）

4.4 Personnel/Training (Annex 1, Chapter 7)

人員/培訓（附錄1，第7章）

4.5 Production and Specific Technologies (Annex 1, Chapter 8)

生產(chǎn)和特定技術（附錄1，第8章）

4.6 Environmental & Process monitoring (Annex 1, Chapter 9)

環(huán)境和過程監(jiān)測（附錄1，第9章）

4.7 Quality Control (QC) (Annex 1, Chapter 10)

質量控制（QC）（附錄1，第10章）

5 Changes to the previous version

對先前版本的變更

在廠房設施方面

，關于是否必須嚴格遵循潔凈梯度，是否允許從一般區(qū)（CNC區(qū)域）直接進入C級，文件給出了意見：

Is it always required to strictly adhere to the area cleanliness cascade (i.e., respecting the sequential order of cleanroom classes) for material transfer through airlocks or pass-through hatches or is it possible to skip a grade (e.g., moving from CNC directly to class C) under certain circumstances?

是否總是要求嚴格遵守區(qū)域潔凈度梯度（即，按照潔凈室級別的順序）通過氣閘或傳遞艙進行物料傳遞，或者在某些情況下是否可以跳過一個級別（例如，從CNC直接進入到C級）？

Compliance with the cleanroom sequence for the transfer of materials via airlocks or pass-through hatches is expected to be fulfilled for zones A and B (exceptions from this rule are possible for sterility test rooms). For cleanroom areas with lower classification, it is principally feasible for materials to be transferred from one low zone (CNC) through an airlock or pass-through hatch directly into an area with two grades higher classification (grade C area), provided that suitable technical and/or procedural measures are established ensuring fulfilment of the cleanroom specifications in the respective areas. The adequacy of the established systems/procedures needs to be demonstrated by appropriate qualification activities and the results of regular environmental monitoring. The defined measures and the risk analyses on which they are based must be part of the CCS.

對于A級和B級，通過氣閘或傳遞艙傳遞物料要求符合潔凈室梯度（無菌檢查室可能例外）。對于級別較低的潔凈室區(qū)域，物料通過氣閘或傳遞艙直接轉移到高兩個級別的區(qū)域（C級區(qū)域）基本上是可行的，前提是建立了適當?shù)募夹g和/或程序措施，確保滿足相應區(qū)域的潔凈室規(guī)。需要通過適當?shù)拇_認活動和定期環(huán)境監(jiān)測的結果來證明已建立的系統(tǒng)/程序的充分性。所定義的措施及其所依據(jù)的風險分析必須是CCS的一部分。

文件提及對于

不能滿足新版附錄1所有要求的舊屏障技術（RABS或隔離器）系統(tǒng)

，公司必須對當前的屏障技術進行深入的內部評估，并評估安裝、潔凈室背景和所有相關系統(tǒng)/程序是否符合新版附錄1 的要求，或者是否需要采取技術措施。如有必要，必須啟動一個項目，例如升級背景潔凈室并安裝額外的氣閘。

從?2023?年8月?25?日起

，所有不符合新版附錄 1 的屏障技術設備均被視為有缺陷，并將在檢查期間發(fā)現(xiàn)偏差（缺陷）時發(fā)布偏差（缺陷）。根據(jù)CAPA計劃和確定的臨時風險降低措施，可以接受大約一年的額外實施時間表。

What are the expectations for older barrier technology systems that do not meet all the requirements according to the new Annex 1? By when do they have to be replaced or upgraded?

對于不能滿足新版附錄1所有要求的舊屏障技術系統(tǒng)，有何期望？什么時候必須更換或升級它們？

The company has to perform an in-depth internal evaluation of the current barrier technology and assess whether the installation, its cleanroom background and all related systems/procedures meet the requirements of the new Annex 1 or whether technical measures are required. If necessary, a project has to be initiated for example to upgrade the cleanroom used as background and install additional airlocks. From August 25th 2023, all barrier technology equipment not com plying with the revised Annex 1 are considered deficient and deviations will be issued upon findings during inspections. Depending on the CAPA plan and interim risk reducing measures defined, an additional implementation timeline of approx. one year may be acceptable.

公司必須對當前的屏障技術進行深入的內部評估，并評估安裝、潔凈室背景和所有相關系統(tǒng)/程序是否符合新版附錄1?的要求，或者是否需要采取技術措施。如有必要，必須啟動一個項目，例如升級背景潔凈室并安裝額外的氣閘。從?2023?年?8?月?25?日起，所有不符合新版附錄?1?的屏障技術設備均被視為有缺陷，并將在檢查期間發(fā)現(xiàn)偏差（缺陷）時發(fā)布偏差（缺陷）。根據(jù)CAPA計劃和確定的臨時風險降低措施，可以接受大約一年的額外實施時間表。

關于

風速標準和測量位置

，文件給出如下意見：

Is it acceptable that for barrier technology systems with unidirectional air flow other air speed and speed measurement positions are defined than those mentioned in Annex 1?

對于具有單向流的屏障技術系統(tǒng)，定義了其他風速和風速測量位置，而不采用附錄1中提到的要求，是否可以接受？

?The most important requirement for barrier technology systems stated in paragraph 4.30 is that the air velocity in unidirectional airflow systems must be defined in such a way that unidirectional and uniform airflow conditions prevail at the working positions where high-risk operations take place, suitable to protect the product and open components (e.g., containers) from contamination. The air speed range of 0.36 - 0.54 m/s is, as stated in the above paragraph itself, merely a guideline value that has been encountered in the pharmaceutical industry for decades. Annex 1, however, clearly allows for the establishment of alternative air speed ranges or measurements at different heights in the system than the working position, provided this is “scientifically justified in the CCS”. It is important that the suitability of the defined airflow conditions is proven by airflow visualisation studies (part of the system qualification) covering the entire sys tem and that these are correlated with the respective defined air speed range at specified height/position. The air speed must be measured continuously during operations and kept within this defined range.

第4.30款所述的屏障技術系統(tǒng)的最重要要求是，單向流系統(tǒng)中的風速必須以這樣一種方式，即在發(fā)生高風險操作的工作位置上普遍存在單向和均勻的氣流條件，適合保護產(chǎn)品和打開的部件（例如容器）免受污染。0.36 - 0.54 m/s?的風速范圍，如上段所述，只是制藥行業(yè)幾十年來遇到的一個指導值。然而，附錄1明確允許在系統(tǒng)中與工作位置不同的高度建立替代風速范圍或測量值，前提是這“在?CCS?中具有科學合理性”。重要的是，通過涵蓋整個系統(tǒng)的氣流可視化研究（系統(tǒng)確認的一部分）來證明所定義的氣流條件的適用性，并且這些研究與指定高度/位置下各自定義的風速范圍相關聯(lián)。在運行過程中必須連續(xù)測量風速，并保持在此定義的范圍內。

關于

工藝氣體的監(jiān)測位置

，文件指出，對工藝氣體的監(jiān)測應盡可能靠近

除菌過濾器前端（上游）

進行(除菌前的污染程度應得到控制，以保證氣體除菌過程的效率)。

Where should process gas be monitored?

工藝氣體應該在哪里監(jiān)測？

The monitoring of process gas should be performed as close as possible before the sterilization filter (the level of contamination before sterilization should be under control to ensure the efficiency of the gas sterilization process).

對工藝氣體的監(jiān)測應盡可能靠近除菌過濾器前端進行(除菌前的污染程度應得到控制，以保證氣體除菌過程的效率)。

關于滅菌柜首次驗證和周期性再驗證的裝載模式

：

Sterilisation: what are the required loading patterns for initial and periodic autoclave (re-) validations?

滅菌：滅菌柜首次和定期（再）驗證所需的裝載模式是什么？

Initially each loading pattern must be validated. Re-validation of each loading pattern must be done annually. If a suitable worst-case load (the same material, same loading pattern, same cycle) for re-validation (backed up with data) can be identified, not every load of this material needs to be re-vali dated. A theoretical reference load is not acceptable, as 8.36 states that “each type of load” needs to be validated.

首次驗證必須驗證每個裝載模式。必須每年對每種裝載模式進行再驗證。如果可以確定合適的

最差情況裝載

（相同的材料、相同的裝載模式、相同的程序）進行再驗證（有數(shù)據(jù)備份），則并非該材料的每個裝載都需要再驗證。理論上的參考裝載是不可接受的，因為?8.36款規(guī)定“每種類型的裝載”都需要驗證。

關于新版附錄1中提出的

除菌級過濾器使用前/滅菌后完整性測試（“PUPSIT”）是否強制

要求，文件表示期望使用PUPSIT來確認除菌過濾器組件的完整性。然而，第8.87款允許

在風險分析支持并包含在CCS中的合理情況下有一定的靈活性

。

Is a pre-use / post-sterilisation integrity testing (“PUPSIT”) of sterilising grade filters used in aseptically processes mandatory?

在無菌工藝中使用的除菌級過濾器進行使用前/滅菌后的完整性測試（“PUPSIT”）是否強制要求？

The expectation is that PUPSIT be applied to verify the integrity of the sterilized filter assembly. However, paragraph 8.87 allows some flexibility in justified cases supported by risk analysis and covered in the CCS.

期望使用PUPSIT來確認除菌過濾器組件的完整性。然而，第8.87款允許

在風險分析支持并包含在CCS中的合理情況下有一定的靈活性

。

金現(xiàn)代是國內領先的數(shù)字化解決方案供應商。在生物醫(yī)藥領域，我們以幫助生物醫(yī)藥企業(yè)完成數(shù)字化轉型為愿景，以GMP規(guī)范為指引，打造了覆蓋研發(fā)、質量、生產(chǎn)、倉儲全鏈路的數(shù)字化解決方案，幫助企業(yè)全面落地GMP規(guī)范。

宜明（蘇州）細胞生物是我們服務的一家坐落在蘇州生物醫(yī)藥園區(qū)的企業(yè)。我們幫助宜明完成了數(shù)字化轉型，實現(xiàn)了GMP標準下的全鏈條數(shù)字化管理，將線下業(yè)務轉到線上，進行跨部門集中統(tǒng)一管理。有效保障了企業(yè)的合規(guī)性，并利用AI信息識別、物聯(lián)網(wǎng)等技術，提升了生產(chǎn)、實驗室等部門的工作效率。