1.法規、指南和標準

1.1.中國GMP附錄 無菌藥品

第九條 無菌藥品生產所需的潔凈區可分為以下4個級別：A級：高風險操作區，如灌裝區、放置膠塞桶和與無菌制劑直接接觸的敞口包裝容器的區域及無菌裝配或連接操作的區域，應當用單向流操作臺（罩）維持該區的環境狀態。單向流系統在其工作區域必須均勻送風，風速為0.36-0.54m/s（指導值）。應當有數據證明單向流的狀態并經過驗證。

第三十二條：在任何運行狀態下，潔凈區通過適當的送風應當能夠確保對周圍低級別區域的正壓，維持良好的氣流方向，保證有效的凈化能力。

第三十三條：應當能夠證明所用氣流方式不會導致污染風險并有記錄（如煙霧試驗的錄像）。

1.2.歐盟GMP附錄 無菌藥品

4.15 Airflow patterns within cleanrooms and zones should be visualised to demonstrate that there is no ingress from lower grade to higher grade areas and that air does not travel from less clean areas (such as the floor) or over operators or equipment that may transfer contamination to the higher grade areas. Where unidirectional airflow is required, visualisation studies should be performed to determine compliance, (see paragraphs 4.4 & 4.19). When filled, closed products are transferred to an adjacent cleanroom of a lower grade via a small egress point, airflow visualization studies should demonstrate that air does not ingress from the lower grade cleanrooms to the grade B area. Where air movement is shown to be a contamination risk to the clean area or critical zone, corrective actions, such as design improvement, should be implemented. Airflow pattern studies should be performed both at rest and in operation (e.g. simulating operator interventions). Video recordings of the airflow patterns should be retained. The outcome of the air visualisation studies should be documented and considered when establishing the facility's environmental monitoring programme.

潔凈室及潔凈區內的氣流模式應當進行可視化呈現，以證明不存在從較低級別區域到較高級別區域的空氣流入情況，且空氣不會從較不潔凈的區域（比如地面）流動過來，也不會流經操作人員或設備（這些可能會將污染物傳播到較高級別區域）。若要求單向氣流，應當開展可視化研究以確定是否符合要求（見第 4.4 和 4.19 款）。當已灌裝、密封的產品通過一個小出口轉移至相鄰的較低級別潔凈室時，氣流可視化研究應當證明空氣不會從較低級別潔凈室流入 B 級區域。若氣流流動被證實對潔凈區或關鍵區域存在污染風險，則應當采取諸如改進設計之類的糾正措施。氣流模式研究應當在靜態及運行狀態下（例如模擬操作人員干預的情況）均開展。氣流模式的視頻記錄應當予以留存。氣流可視化研究的結果應當記錄在案，并在制定設施的環境監測方案時加以考慮。

4.20 The background environment for isolators or RABS should ensure the risk of transfer of contamination is minimized.

隔離器或RABS的背景環境應確保將污染轉移的風險降至最低。

i. Isolators:

隔離器：

c. Airflow pattern studies should be performed at the interfaces of open isolators to demonstrate the absence of air ingress.

應在開放式隔離器的接口處進行氣流流型研究，以證明沒有空氣進入。

ii. RABS:

The background environment for RABS used for aseptic processing should correspond to a minimum of grade B and airflow pattern studies should be performed to demonstrate the absence of air ingress during interventions, including door openings if applicable.

用于無菌工藝的RABS的環境應至少為B級，并且應進行氣流流型研究以證明在干預過程中沒有空氣進入，包括開門（如適用）。

7.18 Activities in clean areas that are not critical to the production processes should be kept to a minimum, especially when aseptic operations are in progress. Movement of personnel should be slow, controlled and methodical to avoid excessive shedding of particles and organisms due to over-vigorous activity. Operators performing aseptic operations should adhere to aseptic technique at all times to prevent changes in air currents that may introduce air of lower quality into the critical zone. Movement adjacent to the critical zone should be restricted and the obstruction of the path of the unidirectional (first air) airflow should be avoided. A review of airflow visualisation studies should be considered as part of the training programme.

潔凈區中對生產過程不重要的活動應保持在最低限度，特別是在進行無菌操作時。人員移動應緩慢、受控并有條不紊，以避免由于過度活動導致的微粒和微生物的過量脫落。執行無菌操作的操作人員應始終遵循無菌技術，以防止氣流的變化可能將較低質量的空氣引入關鍵區域。應限制關鍵區附近的移動，應避免單向流（初始氣流）通路的阻塞。應考慮將氣流可視化研究的回顧作為培訓計劃的一部分。

8.126 Points to consider for the design of loading (and unloading, where the lyophilised material is still unsealed and exposed), include but are not limited to:

裝載（如果凍干后物料仍未密封并暴露，還包括卸載）的設計要點，包括但不限于：

iii. Airflow patterns should not be adversely affected by transport devices and venting of the loading zone.

轉移裝置和裝載區的通風不應對氣流模式造成不良影響。

9.22 Where aseptic operations are performed, microbial monitoring should be frequent using a combination of methods such as settle plates, volumetric air sampling, glove, gown and surface sampling (e.g. swabs and contact plates). The method of sampling used should be justified within the CCS and should be demonstrated not to have a detrimental impact on grade A and B airflow patterns. Cleanroom and equipment surfaces should be monitored at the end of an operation.

當進行無菌操作時，應采用多種方法經常進行微生物監測，例如沉降碟、定量空氣釆樣、手套、潔凈服和表面采樣（例如棉簽擦拭和接觸碟）。所使用的采樣方法的合理性應在CCS中進行論證，并證明不會對A級和B級的氣流模式造成不利影響。在操作結束后應對潔凈室和設備表面進行監測。

1.3.無菌工藝模擬試驗指南（無菌制劑）

6.1.4 無菌生產區域的氣流及環境達到了設計要求，并能穩定運行。但不得采用對環境或者器具進行過度滅菌或消毒的方式提高無菌保證水平。

1.4.無菌工藝模擬試驗指南（無菌原料藥）

6.1.4 無菌生產區域的氣流及環境達到了設計要求，并能穩定運行。依據規定的消毒方法和頻次進行環境消毒，應避免消毒劑的過度使用。

1.5.FDA ：無菌加工生產的無菌藥品 GMP 指南

Proper design and control prevents turbulence and stagnant air in the critical area . Once relevant parameters are established, it is crucial that airflow patterns be evaluated for turbulence or eddy currents that can act as a channel or reservoir for air contaminants （e.g., from an adjoining lower classified area）. In situ air pattern analysis should be conducted at the critical area to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. The studies should be well documented with written conclusions, and include evaluation of the impact of aseptic manipulations （e.g., interventions） and equipment design. Videotape or other recording mechanisms have been found to be useful aides in assessing airflow initially as well as facilitating evaluation of subsequent equipment configuration changes. It is important to note that even successfully qualified systems can be compromised by poor operational, maintenance, or personnel practices.

合理的設計與管控可防止關鍵區域出現湍流和空氣滯留現象。一旦確定了相關參數，對氣流形態進行評估就至關重要，要查看是否存在可能成為空氣污染物（例如來自相鄰較低潔凈級別區域的污染物）傳播通道或聚集之處的湍流或渦流。應當在關鍵區域進行現場氣流形態分析，以證實在動態條件下氣流是單向的，并且能對產品上方進行吹掃并使其遠離產品。這些研究應當做好詳細記錄并附上書面結論，還要包含對無菌操作（例如人工干預情況）以及設備設計所產生影響的評估。實踐發現，錄像或其他記錄手段有助于初步評估氣流情況，也便于對后續設備配置變更進行評價。需要著重指出的是，即便那些已成功通過驗證的系統，也可能會因操作、維護不善或人員操作不當等情況而受到影響。

1.6.ISO 14644-4:2022 潔凈室及相關受控環境：設計、建造、啟動

單向氣流通過供應清潔空氣來排出污染空氣。氣流最常見的是垂直(向下)或水平，但也可以是對角線或向上。重要的設計特點是在工藝核心處保持氣流的均勻性。

1.7.GB：GB 50457-2019 醫藥工業潔凈廠房設計規范

氣流流型的設計應符合下列要求：

高級別區域A級通過單向流來實現，B級的潔凈級別可采用非單向流的紊流空氣形式。在這種混合流的潔凈室內，氣流的形態應從該空間潔凈度高的一端流向潔凈度低的一端，以避免污染風險。

2.檢查缺陷

氣流流型測試目前是被 NMPA、WHO 和 EU等各級監管機構提出缺陷項較多的一個項目，GMP現場檢查中氣流流型常見的問題有以下幾方面：

2.1.測試項目不充分或測試項目缺失

Our inspection found that you lacked smoke studies to evaluate whether unidirectional airflow exists on your (b)(4) ointment aseptic processing line.我們的檢查人員發現你們的煙霧研究不足以評估 b4 軟膏無菌生產線上是否存在單向流。

Your response states that you completed dynamic airflow studies, and you provided three brief smoke study videos. While you state that these studies were conducted under “dynamic” conditions, we note that they still lack an evaluation of operational conditions and aseptic interventions (e.g., reloading tubes and caps; filling the (b)(4)). In addition, the view of the aseptic processing zone was obstructed, and the smoke manifold was not stationary for sufficient time.

你們的回答表明你們完成了動態氣流研究，并提供了三個簡短的煙霧研究視頻。雖然貴公司說這些研究是在“動態”條件下進行的，但我們注意到，它們仍然缺乏對操作條件和無菌干預措施的評估（例如，重新安裝膠管和軋蓋；灌裝(b) (4)）。此外，無菌處理區的視野被遮擋，煙霧在足夠長的時間內是不穩定的。

You did not perform smoke studies under “at rest” and “dynamic” conditions to evaluate air flow characteristics of your open Restricted Access Barrier System (RABS). You subsequently released the sterile (b)(4) products manufactured on this aseptic processing line without studies to demonstrate unidirectionalairflow over the exposed sterile product during processing.

貴公司沒有在“靜態和“動態”條件下進行煙霧研究，以評估貴公司的 ORABS 的氣流特性。隨后，貴公司放行了在無菌生產線上生產的無菌(b)(4)產品，而沒有對在生產過程中對暴露的無菌產品進行單向氣流的研究。

You produced and distributed drug product purporting to be sterile without first conducting adequate process simulations. Specifically, your airflow simulations (smoke studies) for filling line(b)(4) did not adequately demonstrate unidirectional airflow during (b)(4) interventions within the (b)(4)-RABS ISO 5 area. For example, airflow was observed flowing outward and upward during (b)(4) interventions. However, the simulation did not adequately depict airflow (the smoke was not visible) to determine whether HEPA filtered air was reaching the critical (b)(4).

你在沒有首先進行充分的工藝模擬的情況下生產和銷售聲稱無菌的藥品。具體來說，您對灌裝線(b)(4)的氣流模擬(煙霧試驗)沒有充分證明在(b)(4)-RABS ISO 5區域內(b)(4)干預期間的單向氣流。例如，在(b)(4)干預期間，觀察到氣流向外和向上流動。然而，模擬沒有充分描繪氣流(煙霧不可見)，以確定HEPA過濾的空氣是否達到關鍵(b)(4)。

2.2.設計缺陷導致氣流不合格

During the airflow analysis (smoke study) of aseptic connections on your (b)(4) equipment inside the laminar air flow (LAF) ISO-5 area, our investigator identified air flow disturbances and turbulence. Under dynamic conditions, air did not sufficiently sweep across and away from sterile con- nections, so the sterility of any product processed under these conditions could be compromised.

在 ISO-5 區域內(b)(4)設備無菌連接的氣流分析（煙霧研究）中，我們的研究人員發現了氣流擾動和湍流。在動態條件下，空氣不能充分地從無菌區掃過和離開，因此在這些條件下生產的任何產品的無菌性都可能受到影響。

Furthermore, in our review of the smoke study, we identified multiple aseptic technique breaches during aseptic connection of the (b)(4) equipment. Your equipment design and aseptic processing operator competencies appear to contribute to the lack of unidirectionality. Aseptic processing equipment should provide for appropriate ergonomics that enable operators to reproducibly conduct aseptic manipulations. In addition, it is critical that your aseptic processing operators have the knowledge and skills to practice strict aseptic techniques. Even operations that have been successfully qualified can be compromised by poor operational, maintenance, or personnel practices.

此外，在我們對煙霧研究的審核中，我們發現了(b)(4)設備在無菌連接期間多次出現無菌操作不符合無菌規范。貴公司的設備設計和無菌操作人員的能力似乎是導致氣流缺乏單向性的原因。無菌工藝設備應符合人體工程學，使操作人員能夠重現無菌操作。此外，具備無菌知識和技能的工藝操作人員執行嚴格的無菌技術至關重要。即使是已經成功通過資格確認的操作，也可能會受到操作、維護或人員實踐不佳的影響。

During the inspection, our investigator reviewed and noted turbulent airflow in the September 2015 smoke studies (airflow visualization studies) conducted on your aseptic processing line in room (b)(4) where you manufacture (b)(4) and (b)(4) for the U.S. market. This turbulent airflow poses a significant contamination hazard to your product.

檢查員在審查你們 2015 年 9 月在用于無菌灌裝線生產(b)(4)和(b)(4)的(b)(4)房間中做的煙霧研究（氣流流型試驗）時發現存在亂流。這種亂流會對你們的產品造成重大污染危害。

In your response, you submitted additional smoke studies conducted in December 2016. Like yourSeptember 2015 studies, the December 2016 smoke studies show turbulent airflow in multiple locations on the aseptic filling line. (FDA, 2017ah)

在你們的回復中，你們提交了 2016 年 12 月所做的其他氣流流型研究。同你們 2015 年 9 月的試驗一樣，2016 年 12 月的煙霧流型研究也顯示，在無菌灌裝線的多個位置存在亂流。

You have not established that unidirectional airflow exists at the station where the cap is applied to the container. Additionally，your dynamic smoke study videos show turbulent airflow when operators manually (b)(4) the sterile container-closure components into (b)(4) bowls, which are located outside of the filling and sealing enclosure. Operators reach over the (b)(4) bowls while loading sterile container-closure components to overcome a limitation in your current equipment and process design. The ergonomics of these manual manipulations pose a significant hazard in your aseptic processing operation.

你們沒有為軋蓋操作工位提供單向流。此外，你們的動態煙霧流型研究視頻顯示，當操作員將無菌密封件手工加料至料斗時出現亂流，這些亂流位于灌裝和密封區域外部。操作員將無菌密封件加入料斗時需把手伸過(b)(4)料斗，以克服現有設備和工藝設計的缺陷。這些手工操作的人體工程學問題會給無菌操作造成重大風險。

2.3.測試方法存在問題

The most recent smoke study conducted by your firm to validate the xxx installed in Building xxx room xxx which is used to fill xxx finished drug product vials following xxx was not conducted in a manner that accurately simulated actual processing conditions. Multiple video recordings made during the smoke study conducted on this xxx in September 2021 show the operator responsible for holding and positioning the smoke wand during intervention simulations standing inside of the xxx. These video recordings also show a second operator using the xxx to perform interventions, such as the changing of environmental monitoring settle plates, while the body of the operator holding the smoke wand was standing within approximately 50 cm or less of the location the intervening operator is working. Per your records, xxx lots of xxx finished drug product, totalling approximately xxx vials, have been filled in this xxx and released for commercial distribution in the US. since this smoke study was conducted.

貴公司最近進行的煙霧研究用以驗證安裝在xxx大樓xxx室的xxx(用于在xxx之后灌裝xxx成品藥瓶)，并不是以準確模擬實際生產條件的方式進行的。在2021年09月對該xxx進行的煙霧研究過程中制作的多個視頻記錄顯示，進行干預模擬的過程中，負責握住和定位煙霧棒的操作員站在xxx內部。這些視頻記錄還顯示，第二名操作員使用xxx進行干預，例如更換環境監測沉降皿，而手持煙棒的操作員的身體站在距離干預操作員工作位置大約50 cm或更近的地方。根據您的記錄，自從這項煙霧研究開展以來，xxx批次的xxx成品藥品，總計約xxx瓶，已在此xxx灌裝并在美國進行商業銷售。

2.4.無菌操作有問題

For example, during the aseptic filling of vials, an operator used restricted access barrier system (RABS) (b)(4) to remove a jammed stopper by reaching over exposed sterile stoppers in the stopper bowl. The RABS (b)(4) disrupted the unidirectional airflow over the stopper bowl, creating a risk for microbial contamination. After the operator removed the jammed stopper, the filling line was restarted, but the affected stoppers were not cleared.

例如，在西林瓶無菌灌裝過程中，操作員使用限制進入屏障系統(RABS) (b)(4)通過在膠塞震蕩鍋中的暴露的無菌膠塞上面移除一個堵塞。RABS (b)(4)破壞了在膠塞震蕩鍋上方的單向氣流，造成了微生物污染的風險。在操作員移除堵塞后，灌裝線重新啟動，但受影響的塞子沒有清除。

2.5.測試未達到標準/法規要求

During the airflow analysis (smoke study) of aseptic connections on your (b)(4) equipment inside the laminar air flow (LAF) ISO-5 area, our investigator identified air flow disturbances and turbulence. Under dynamic conditions, air did not sufficiently sweep across and away from sterile con- nections, so the sterility of any product processed under these conditions could be compromised.

在 ISO-5 區域內(b)(4)設備無菌連接的氣流分析（煙霧研究）中，我們的研究人員發現了氣流擾動和湍流。在動態條件下，空氣不能充分地從無菌區掃過和離開，因此在這些條件下生產的任何產品的無菌性都可能受到影響。

Air flow visualization studies for the (b)(4) line used to aseptically fill (b)(4) for the US market did not meet the acceptance criteria of airflow that is unidirectional and free from turbulence or follow the established execution instructions in the study protocol.

用于美國市場的 (b)(4) 無菌灌裝線 (b)(4) 的氣流可視化試驗不符合單向且無湍流的氣流的驗收標準，或不符合試驗方案中已建立的執行說明。

a. In the area where empty(b)(4) are opened and exposed to the environment there is a gap between the overhead HEPA filters of approximately (b)(4) Raw video footage obtained during the smoke studies of this area show air turbulence and upward flowing air, The raw video footage showing this deficient air flow pattern was not included in the final edited versions of the videos discussed in the validation report

在空的 (b)(4) 打開并暴露于環境的區域，高處的HEPA過濾器之間存在大約 (b)(4) 的間隙，該區域煙霧試驗期間獲得的原始視頻顯示空氣湍流和向上流動的空氣，顯示該缺陷氣流的視頻在并沒有包含在驗證報告中最終編輯的視頻版本中。

b. The videos show upward flowing smokealong the RABS barrier near (b)(4) inside the filling and stoppering RABS. This area is below an approximately (b)(4) gap between the edge of the HEPA filter and the RABS barrier. The validation report did not identify any deficiencies in this area. A similar gap between the RABS barrier and the HEPA filters exists on all (b)(4) sides of the RABS filling barrier. The air flow visualization studies have not thoroughly evaluated this gap.

視頻顯示，在灌裝和加塞RABS內部 (b)(4) 附近，煙霧是沿著RABS屏障向上流動的。該區域在HEPA過濾器的邊緣與RABS屏障之間的間隙大約 (b)(4) 下方。驗證報告沒有發現這方面的任何缺陷。RABS屏障和HEPA過濾器之間的類似間隙存在于RABS灌裝屏障的所有側面 (b)(4) 上。氣流可視化試驗尚未徹底評估這一縫隙。

c. The videos show upward flowing and turbulent air flow near a gap between the HEPA filter edge and the barrier(b)(4) outside of the filling barrier, near (b)(4) There is an approximately (b)(4) gap between the edge of the HEPA filter and the RABS barrier, This Grade A classified area is used during (b)(4) assembly of the machine, and interventions, The raw video footage showing this deficient air flow pattern was not included in the final versions of the videos discussed in the validation report.

視頻顯示了HEPA過濾器邊緣和灌裝屏障外部的屏障 (b)(4) 之間的間隙附近的向上的氣流和湍流，在 (b)(4) 附近。在HEPA過濾器的邊緣和RABS屏障之間存在大約 (b)(4) 的間隙，該等級A分類區域在機器的組裝和干預期間使用 (b)(4) ，驗證報告中討論的視頻的最終版本中不包括顯示該缺陷氣流模式的原始視頻片段。

d. The(b)(4) barrier used to open and load empty (b)(4) has a support for the (b)(4) positioned about (b)(4) below the HEPA filter, The smoke studies did not thoroughly evaluate the impact of this support on the air flow in this area.

d. 用于打開和裝載空的(b)(4)的(b)(4) 屏障具有用于 (b)(4) 的支撐件，其位于HEPA過濾器下方大約 (b)(4)，煙霧試驗沒有徹底評估這種支撐對該區域氣流的影響。

e. Protocol(b)(4) OA/AFVP/017 for the (b)(4) line states the smoke needs to be introduced by placing the nozzle with the smoke upwards and the nozzle should be moved to cover the entire area of the filter. Raw video files show the smoke nozzle pointed in downward direction and in fixed locations. The final edited videos did not show the smoke from where it was introduced near the filter to the working location.

e.(b)(4)線的方案(b)(4)OA/AFVP/017 指出，需要通過將帶有煙霧的噴嘴向上放置來引入煙霧，并且應該移動噴嘴以覆蓋過濾器的整個區域。原始視頻文件顯示煙霧噴嘴指向向下的方向和固定的位置。最終編輯的視頻沒有顯示煙霧從過濾器附近的哪里引入到工作位置的地方。

2.6.氣流流行測試結果未能指導環境監測

Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

貴公司未能建立一套完備的無菌加工區域環境狀況監測系統。

You do not have a scientific rationale for the environmental monitoring sampling locations in aseptic filling Suites (b)(4). You did not include factors such as smoke study findings, number and location of operators, and historical microbial data in your assessment of hazardous points.

貴公司對于無菌灌裝室環境監測采樣點缺乏科學依據（此處信息暫缺）。在對危險點進行評估時，并未將煙霧研究結果、操作人員數量及位置以及歷史微生物數據等因素納入考量范圍。

For example, we found that settling plates are not appropriately placed in critical areas. Your smoke study showed that during set-up and filling, air flows toward the front (when (b)(4) open) or back of the RABS. However, two relevant sampling points were recently eliminated. As a result, these points of increased risk are not monitored.

例如，我們發現沉降平板在關鍵區域的放置并不恰當。貴公司的煙霧研究顯示，在設備安裝及灌裝過程中，氣流會朝著隔離操作器（RABS）的前部（當此處信息暫缺打開時）或后部流動。然而，近期卻取消了兩個相關采樣點。結果就是，這些風險增加的點位未得到監測。