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1.法規(guī)、指南和標(biāo)準(zhǔn)

 

1.1.中國(guó)GMP附錄 無(wú)菌藥品

 

第九條 無(wú)菌藥品生產(chǎn)所需的潔凈區(qū)可分為以下4個(gè)級(jí)別：A級(jí)：高風(fēng)險(xiǎn)操作區(qū)，如灌裝區(qū)、放置膠塞桶和與無(wú)菌制劑直接接觸的敞口包裝容器的區(qū)域及無(wú)菌裝配或連接操作的區(qū)域，應(yīng)當(dāng)用單向流操作臺(tái)（罩）維持該區(qū)的環(huán)境狀態(tài)。單向流系統(tǒng)在其工作區(qū)域必須均勻送風(fēng)，風(fēng)速為0.36-0.54m/s（指導(dǎo)值）。應(yīng)當(dāng)有數(shù)據(jù)證明單向流的狀態(tài)并經(jīng)過驗(yàn)證。

 

第三十二條：在任何運(yùn)行狀態(tài)下，潔凈區(qū)通過適當(dāng)?shù)乃惋L(fēng)應(yīng)當(dāng)能夠確保對(duì)周圍低級(jí)別區(qū)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(yīng)當(dāng)能夠證明所用氣流方式不會(huì)導(dǎo)致污染風(fēng)險(xiǎn)并有記錄（如煙霧試驗(yàn)的錄像）。

 

1.2.歐盟GMP附錄 無(wú)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(qū)內(nèi)的氣流模式應(yīng)當(dāng)進(jìn)行可視化呈現(xiàn)，以證明不存在從較低級(jí)別區(qū)域到較高級(jí)別區(qū)域的空氣流入情況，且空氣不會(huì)從較不潔凈的區(qū)域（比如地面）流動(dòng)過來(lái)，也不會(huì)流經(jīng)操作人員或設(shè)備（這些可能會(huì)將污染物傳播到較高級(jí)別區(qū)域）。若要求單向氣流，應(yīng)當(dāng)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(dāng)已灌裝、密封的產(chǎn)品通過一個(gè)小出口轉(zhuǎn)移至相鄰的較低級(jí)別潔凈室時(shí)，氣流可視化研究應(yīng)當(dāng)證明空氣不會(huì)從較低級(jí)別潔凈室流入 B 級(jí)區(qū)域。若氣流流動(dòng)被證實(shí)對(duì)潔凈區(qū)或關(guān)鍵區(qū)域存在污染風(fēng)險(xiǎn)，則應(yīng)當(dāng)采取諸如改進(jìn)設(shè)計(jì)之類的糾正措施。氣流模式研究應(yīng)當(dāng)在靜態(tài)及運(yùn)行狀態(tài)下（例如模擬操作人員干預(yù)的情況）均開展。氣流模式的視頻記錄應(yīng)當(dāng)予以留存。氣流可視化研究的結(jié)果應(yīng)當(dāng)記錄在案，并在制定設(shè)施的環(huán)境監(jiān)測(cè)方案時(shí)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(huán)境應(yīng)確保將污染轉(zhuǎn)移的風(fēng)險(xiǎn)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(yīng)在開放式隔離器的接口處進(jìn)行氣流流型研究，以證明沒有空氣進(jìn)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(wú)菌工藝的RABS的環(huán)境應(yīng)至少為B級(jí)，并且應(yīng)進(jìn)行氣流流型研究以證明在干預(yù)過程中沒有空氣進(jìn)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(qū)中對(duì)生產(chǎn)過程不重要的活動(dòng)應(yīng)保持在最低限度，特別是在進(jìn)行無(wú)菌操作時(shí)。人員移動(dòng)應(yīng)緩慢、受控并有條不紊，以避免由于過度活動(dòng)導(dǎo)致的微粒和微生物的過量脫落。執(zhí)行無(wú)菌操作的操作人員應(yīng)始終遵循無(wú)菌技術(shù)，以防止氣流的變化可能將較低質(zhì)量的空氣引入關(guān)鍵區(qū)域。應(yīng)限制關(guān)鍵區(qū)附近的移動(dòng)，應(yīng)避免單向流（初始?xì)饬鳎┩返淖枞?。?yīng)考慮將氣流可視化研究的回顧作為培訓(xùn)計(jì)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(shè)計(jì)要點(diǎn)，包括但不限于：

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

轉(zhuǎn)移裝置和裝載區(qū)的通風(fēng)不應(yīng)對(duì)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(dāng)進(jìn)行無(wú)菌操作時(shí)，應(yīng)采用多種方法經(jīng)常進(jìn)行微生物監(jiān)測(cè)，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(yīng)在CCS中進(jìn)行論證，并證明不會(huì)對(duì)A級(jí)和B級(jí)的氣流模式造成不利影響。在操作結(jié)束后應(yīng)對(duì)潔凈室和設(shè)備表面進(jìn)行監(jiān)測(cè)。

 

1.3.無(wú)菌工藝模擬試驗(yàn)指南（無(wú)菌制劑）

6.1.4 無(wú)菌生產(chǎn)區(qū)域的氣流及環(huán)境達(dá)到了設(shè)計(jì)要求，并能穩(wěn)定運(yùn)行。但不得采用對(duì)環(huán)境或者器具進(jìn)行過度滅菌或消毒的方式提高無(wú)菌保證水平。

 

1.4.無(wú)菌工藝模擬試驗(yàn)指南（無(wú)菌原料藥）

6.1.4 無(wú)菌生產(chǎn)區(qū)域的氣流及環(huán)境達(dá)到了設(shè)計(jì)要求，并能穩(wěn)定運(yùn)行。依據(jù)規(guī)定的消毒方法和頻次進(jìn)行環(huán)境消毒，應(yīng)避免消毒劑的過度使用。

 

1.5.FDA ：無(wú)菌加工生產(chǎn)的無(wú)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(shè)計(jì)與管控可防止關(guān)鍵區(qū)域出現(xiàn)湍流和空氣滯留現(xiàn)象。一旦確定了相關(guān)參數(shù)，對(duì)氣流形態(tài)進(jìn)行評(píng)估就至關(guān)重要，要查看是否存在可能成為空氣污染物（例如來(lái)自相鄰較低潔凈級(jí)別區(qū)域的污染物）傳播通道或聚集之處的湍流或渦流。應(yīng)當(dāng)在關(guān)鍵區(qū)域進(jìn)行現(xiàn)場(chǎng)氣流形態(tài)分析，以證實(shí)在動(dòng)態(tài)條件下氣流是單向的，并且能對(duì)產(chǎn)品上方進(jìn)行吹掃并使其遠(yuǎn)離產(chǎn)品。這些研究應(yīng)當(dāng)做好詳細(xì)記錄并附上書面結(jié)論，還要包含對(duì)無(wú)菌操作（例如人工干預(yù)情況）以及設(shè)備設(shè)計(jì)所產(chǎn)生影響的評(píng)估。實(shí)踐發(fā)現(xiàn)，錄像或其他記錄手段有助于初步評(píng)估氣流情況，也便于對(duì)后續(xù)設(shè)備配置變更進(jìn)行評(píng)價(jià)。需要著重指出的是，即便那些已成功通過驗(yàn)證的系統(tǒng)，也可能會(huì)因操作、維護(hù)不善或人員操作不當(dāng)?shù)惹闆r而受到影響。

 

1.6.ISO 14644-4:2022 潔凈室及相關(guān)受控環(huán)境：設(shè)計(jì)、建造、啟動(dòng)

單向氣流通過供應(yīng)清潔空氣來(lái)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(duì)角線或向上。重要的設(shè)計(jì)特點(diǎn)是在工藝核心處保持氣流的均勻性。

 

1.7.GB：GB 50457-2019 醫(yī)藥工業(yè)潔凈廠房設(shè)計(jì)規(guī)范

氣流流型的設(shè)計(jì)應(yīng)符合下列要求：

高級(jí)別區(qū)域A級(jí)通過單向流來(lái)實(shí)現(xiàn)，B級(jí)的潔凈級(jí)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(nèi)，氣流的形態(tài)應(yīng)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(fēng)險(xiǎn)。

 

2.檢查缺陷

 

氣流流型測(cè)試目前是被 NMPA、WHO 和 EU等各級(jí)監(jiān)管機(jī)構(gòu)提出缺陷項(xiàng)較多的一個(gè)項(xiàng)目，GMP現(xiàn)場(chǎng)檢查中氣流流型常見的問題有以下幾方面：

 

2.1.測(cè)試項(xiàng)目不充分或測(cè)試項(xiàng)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(fā)現(xiàn)你們的煙霧研究不足以評(píng)估 b4 軟膏無(wú)菌生產(chǎn)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(dòng)態(tài)氣流研究，并提供了三個(gè)簡(jiǎn)短的煙霧研究視頻。雖然貴公司說這些研究是在“動(dòng)態(tài)”條件下進(jìn)行的，但我們注意到，它們?nèi)匀蝗狈?duì)操作條件和無(wú)菌干預(yù)措施的評(píng)估（例如，重新安裝膠管和軋蓋；灌裝(b) (4)）。此外，無(wú)菌處理區(qū)的視野被遮擋，煙霧在足夠長(zhǎng)的時(shí)間內(nèi)是不穩(wěn)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(tài)和“動(dòng)態(tài)”條件下進(jìn)行煙霧研究，以評(píng)估貴公司的 ORABS 的氣流特性。隨后，貴公司放行了在無(wú)菌生產(chǎn)線上生產(chǎn)的無(wú)菌(b)(4)產(chǎn)品，而沒有對(duì)在生產(chǎn)過程中對(duì)暴露的無(wú)菌產(chǎn)品進(jìn)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(jìn)行充分的工藝模擬的情況下生產(chǎn)和銷售聲稱無(wú)菌的藥品。具體來(lái)說，您對(duì)灌裝線(b)(4)的氣流模擬(煙霧試驗(yàn))沒有充分證明在(b)(4)-RABS ISO 5區(qū)域內(nèi)(b)(4)干預(yù)期間的單向氣流。例如，在(b)(4)干預(yù)期間，觀察到氣流向外和向上流動(dòng)。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(dá)到關(guān)鍵(b)(4)。

 

2.2.設(shè)計(jì)缺陷導(dǎo)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(qū)域內(nèi)(b)(4)設(shè)備無(wú)菌連接的氣流分析（煙霧研究）中，我們的研究人員發(fā)現(xiàn)了氣流擾動(dòng)和湍流。在動(dòng)態(tài)條件下，空氣不能充分地從無(wú)菌區(qū)掃過和離開，因此在這些條件下生產(chǎn)的任何產(chǎn)品的無(wú)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(duì)煙霧研究的審核中，我們發(fā)現(xiàn)了(b)(4)設(shè)備在無(wú)菌連接期間多次出現(xiàn)無(wú)菌操作不符合無(wú)菌規(guī)范。貴公司的設(shè)備設(shè)計(jì)和無(wú)菌操作人員的能力似乎是導(dǎo)致氣流缺乏單向性的原因。無(wú)菌工藝設(shè)備應(yīng)符合人體工程學(xué)，使操作人員能夠重現(xiàn)無(wú)菌操作。此外，具備無(wú)菌知識(shí)和技能的工藝操作人員執(zhí)行嚴(yán)格的無(wú)菌技術(shù)至關(guān)重要。即使是已經(jīng)成功通過資格確認(rèn)的操作，也可能會(huì)受到操作、維護(hù)或人員實(shí)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(wú)菌灌裝線生產(chǎn)(b)(4)和(b)(4)的(b)(4)房間中做的煙霧研究（氣流流型試驗(yàn)）時(shí)發(fā)現(xiàn)存在亂流。這種亂流會(huì)對(duì)你們的產(chǎn)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(fù)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(yàn)一樣，2016 年 12 月的煙霧流型研究也顯示，在無(wú)菌灌裝線的多個(gè)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(dòng)態(tài)煙霧流型研究視頻顯示，當(dāng)操作員將無(wú)菌密封件手工加料至料斗時(shí)出現(xiàn)亂流，這些亂流位于灌裝和密封區(qū)域外部。操作員將無(wú)菌密封件加入料斗時(shí)需把手伸過(b)(4)料斗，以克服現(xiàn)有設(shè)備和工藝設(shè)計(jì)的缺陷。這些手工操作的人體工程學(xué)問題會(huì)給無(wú)菌操作造成重大風(fēng)險(xiǎn)。

 

2.3.測(cè)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(jìn)行的煙霧研究用以驗(yàn)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(zhǔn)確模擬實(shí)際生產(chǎn)條件的方式進(jìn)行的。在2021年09月對(duì)該xxx進(jìn)行的煙霧研究過程中制作的多個(gè)視頻記錄顯示，進(jìn)行干預(yù)模擬的過程中，負(fù)責(zé)握住和定位煙霧棒的操作員站在xxx內(nèi)部。這些視頻記錄還顯示，第二名操作員使用xxx進(jìn)行干預(yù)，例如更換環(huán)境監(jiān)測(cè)沉降皿，而手持煙棒的操作員的身體站在距離干預(yù)操作員工作位置大約50 cm或更近的地方。根據(jù)您的記錄，自從這項(xiàng)煙霧研究開展以來(lái)，xxx批次的xxx成品藥品，總計(jì)約xxx瓶，已在此xxx灌裝并在美國(guó)進(jìn)行商業(yè)銷售。

2.4.無(wú)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(wú)菌灌裝過程中，操作員使用限制進(jìn)入屏障系統(tǒng)(RABS) (b)(4)通過在膠塞震蕩鍋中的暴露的無(wú)菌膠塞上面移除一個(gè)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(fēng)險(xiǎn)。在操作員移除堵塞后，灌裝線重新啟動(dòng)，但受影響的塞子沒有清除。

 

2.5.測(cè)試未達(dá)到標(biāo)準(zhǔn)/法規(guī)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(qū)域內(nèi)(b)(4)設(shè)備無(wú)菌連接的氣流分析（煙霧研究）中，我們的研究人員發(fā)現(xiàn)了氣流擾動(dòng)和湍流。在動(dòng)態(tài)條件下，空氣不能充分地從無(wú)菌區(qū)掃過和離開，因此在這些條件下生產(chǎn)的任何產(chǎn)品的無(wú)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(guó)市場(chǎng)的 (b)(4) 無(wú)菌灌裝線 (b)(4) 的氣流可視化試驗(yàn)不符合單向且無(wú)湍流的氣流的驗(yàn)收標(biāo)準(zhǔn)，或不符合試驗(yàn)方案中已建立的執(zhí)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(huán)境的區(qū)域，高處的HEPA過濾器之間存在大約 (b)(4) 的間隙，該區(qū)域煙霧試驗(yàn)期間獲得的原始視頻顯示空氣湍流和向上流動(dòng)的空氣，顯示該缺陷氣流的視頻在并沒有包含在驗(yàn)證報(bào)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(nèi)部 (b)(4) 附近，煙霧是沿著RABS屏障向上流動(dòng)的。該區(qū)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(yàn)證報(bào)告沒有發(fā)現(xiàn)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(cè)面 (b)(4) 上。氣流可視化試驗(yàn)尚未徹底評(píng)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(jí)A分類區(qū)域在機(jī)器的組裝和干預(yù)期間使用 (b)(4) ，驗(yàn)證報(bào)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(yàn)沒有徹底評(píng)估這種支撐對(duì)該區(qū)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(lái)引入煙霧，并且應(yīng)該移動(dòng)噴嘴以覆蓋過濾器的整個(gè)區(qū)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(cè)試結(jié)果未能指導(dǎo)環(huán)境監(jiān)測(cè)

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(wú)菌加工區(qū)域環(huán)境狀況監(jiān)測(cè)系統(tǒng)。

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(duì)于無(wú)菌灌裝室環(huán)境監(jiān)測(cè)采樣點(diǎn)缺乏科學(xué)依據(jù)（此處信息暫缺）。在對(duì)危險(xiǎn)點(diǎn)進(jìn)行評(píng)估時(shí)，并未將煙霧研究結(jié)果、操作人員數(shù)量及位置以及歷史微生物數(shù)據(jù)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(fā)現(xiàn)沉降平板在關(guān)鍵區(qū)域的放置并不恰當(dāng)。貴公司的煙霧研究顯示，在設(shè)備安裝及灌裝過程中，氣流會(huì)朝著隔離操作器（RABS）的前部（當(dāng)此處信息暫缺打開時(shí)）或后部流動(dòng)。然而，近期卻取消了兩個(gè)相關(guān)采樣點(diǎn)。結(jié)果就是，這些風(fēng)險(xiǎn)增加的點(diǎn)位未得到監(jiān)測(cè)。