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近日，F(xiàn)DA發(fā)布了對(duì)Aspen Pharmacare Holdings Limited的警告信，其中提及大量的無(wú)菌生產(chǎn)操作缺陷，如下：

 

產(chǎn)品放行和穩(wěn)定性測(cè)試中未測(cè)試某雜質(zhì)，該公司表示雜質(zhì)限度是根據(jù)客戶的要求確定的，并且放行標(biāo)準(zhǔn)對(duì)此沒(méi)有任何限值。并提供了客戶的健康危害評(píng)估（HHE），該評(píng)估得出的結(jié)論：高達(dá)標(biāo)簽含量（b）（4）%的雜質(zhì)的穩(wěn)定性水平，不會(huì)對(duì)按照說(shuō)明使用產(chǎn)品的用戶造成任何安全風(fēng)險(xiǎn)。FDA不認(rèn)同該HHE 評(píng)估，并得出結(jié)論，在推薦劑量下，（b）（4）% 的雜質(zhì)水平可能會(huì)對(duì)患者安全構(gòu)成風(fēng)險(xiǎn)。

 

無(wú)菌操作不良

 

操作人員將戴手套的手直接放在未加塞的無(wú)菌瓶子上從而堵塞了第一空氣，而未將其從無(wú)菌灌裝線中清除。

 

操作人員使用戴手套的手而未使用適當(dāng)?shù)臒o(wú)菌工具來(lái)清除卡住的瓶子。

 

關(guān)鍵區(qū)域的操作人員移動(dòng)并不總是緩慢和小心翼翼的。

 

操作人員使用的護(hù)目鏡有許多開(kāi)孔，因此在生產(chǎn)線裝配和無(wú)菌生產(chǎn)過(guò)程中會(huì)暴露皮膚。

 

培養(yǎng)基灌裝批次中發(fā)現(xiàn)了污染，確定了不良無(wú)菌行為的根本原因。這些污染事件以及檢查期間觀察到的不良無(wú)菌實(shí)踐表明，無(wú)菌生產(chǎn)操作可能缺乏足夠的控制。

 

開(kāi)門干預(yù)需要打開(kāi)一個(gè)很大的門。在許多情況下，門會(huì)長(zhǎng)時(shí)間保持打開(kāi)狀態(tài)，但生產(chǎn)線仍在運(yùn)行。打開(kāi)時(shí)，門暴露在 ISO 7 區(qū)域，關(guān)閉時(shí)，存在較低質(zhì)量的空氣卷入到 ISO 5 無(wú)菌生產(chǎn)區(qū)域的重大風(fēng)險(xiǎn)。未加塞的空玻璃瓶位于離這個(gè)門非常近的地方。此外，操作人員沒(méi)有對(duì)打開(kāi)的門進(jìn)行充分的消毒。在（b）（4）上噴灑消毒劑時(shí)，操作人員沒(méi)有考慮生產(chǎn)線上未加塞的玻璃瓶，使其面臨潛在污染。

 

煙霧研究和潔凈室設(shè)計(jì)不足

 

煙霧研究缺乏對(duì)無(wú)菌生產(chǎn)線裝配、動(dòng)態(tài)操作和無(wú)菌生產(chǎn)操作期間發(fā)生的干預(yù)的模擬。

 

煙霧的產(chǎn)生不足以證明單向氣流。

 

操作人員和傳送帶上開(kāi)放的玻璃瓶之間沒(méi)有物理屏障。你們的生產(chǎn)操作人員一直在 ISO 5 無(wú)菌加工區(qū)域內(nèi)，坐在或站在輸送未加塞玻璃瓶的傳送帶旁邊。

 

對(duì)無(wú)菌生產(chǎn)線及其暴露的無(wú)菌藥品和容器/瓶塞進(jìn)行了大量的人工干擾。

 

操作人員在多次過(guò)濾器完整性測(cè)試失敗后只收集并打印了合格結(jié)果。操作人員沒(méi)有記錄或打印失敗的結(jié)果。

 

沒(méi)有對(duì)操作人員一直在里面清除掉落的瓶子的 ISO 5 區(qū)域中的空氣和表面進(jìn)行微生物監(jiān)測(cè)。

 

在線粒子探頭放置位置存在缺陷

 

缺陷翻譯如下：

 

1. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

 

貴公司未能建立實(shí)驗(yàn)室控制措施，包括科學(xué)合理且適當(dāng)?shù)囊?guī)范、標(biāo)準(zhǔn)、取樣計(jì)劃和測(cè)試程序，以確保組件、藥品容器、瓶蓋、生產(chǎn)物料、標(biāo)簽和藥品符合適當(dāng)?shù)奶匦?、?qiáng)度、質(zhì)量和純度標(biāo)準(zhǔn) （21 CFR 211.160（b））。

 

Your firm did not establish appropriate specifications or test your sterile over-the-counter (OTC)(b)(4) drug products to monitor impurities at release and throughout expiry. For example:

 

貴公司未制定適當(dāng)?shù)臉?biāo)準(zhǔn)或未能測(cè)試無(wú)菌藥品以監(jiān)測(cè)在放行時(shí)和整個(gè)有效期內(nèi)的雜質(zhì)。例如：

 

You did not perform impurity testing prior to release and     during stability for (b)(4).

 

你們?cè)诜判星昂头€(wěn)定性試驗(yàn)期間未進(jìn)行雜質(zhì)檢測(cè)。

 

You did not establish scientifically justified specifications     to monitor impurities during stability testing of drug products containing     Naphazoline Hydrochloride or Tetrahydrozoline Hydrochloride active     pharmaceutical ingredient (API).

 

在對(duì)含有鹽酸萘甲唑啉或鹽酸四氫唑啉活性藥物成分（API）的藥品進(jìn)行穩(wěn)定性檢測(cè)時(shí)，你們未制定科學(xué)合理的標(biāo)準(zhǔn)來(lái)監(jiān)測(cè)雜質(zhì)。

 

In your response, you state that the impurity limits were established based on your customer’s requirements and that no limits were included for release testing. You provide your customer’s health hazard evaluation (HHE) which concluded that the presence of Impurity(b)(4) at stability levels of up to (b)(4)% of the labeled (b)(4) content would not pose any safety risk for those that use the products according to directions. The Agency disagrees with the HHE assessment and concludes that the presence of impurity levels at (b)(4)% may pose a risk to patient safety at the recommended dosage. It is your responsibility to ensure that appropriate specifications are established to monitor impurities throughout the expiry period.

 

在回復(fù)中，你們表示雜質(zhì)限度是根據(jù)客戶的要求確定的，并且放行標(biāo)準(zhǔn)對(duì)此沒(méi)有任何限值。你們提供了客戶的健康危害評(píng)估（HHE），該評(píng)估得出的結(jié)論：高達(dá)標(biāo)簽含量（b）（4）%的雜質(zhì)（b）（4）的穩(wěn)定性水平，不會(huì)對(duì)按照說(shuō)明使用產(chǎn)品的用戶造成任何安全風(fēng)險(xiǎn)。FDA不認(rèn)同該HHE 評(píng)估，并得出結(jié)論，在推薦劑量下，（b）（4）% 的雜質(zhì)水平可能會(huì)對(duì)患者安全構(gòu)成風(fēng)險(xiǎn)。你們有責(zé)任確保建立適當(dāng)?shù)臉?biāo)準(zhǔn)，以在整個(gè)有效期內(nèi)監(jiān)測(cè)雜質(zhì)。

 

Your response is inadequate. You lack adequate scientific rationale for the current impurity specifications of your drug products. A similar deficiency for the lack of impurity specifications for release and stability testing for(b)(4) API containing products was also identified during the 2016 inspection. However, this deficiency has not been fully addressed to date. Additionally, your risk assessment does not include an evaluation of reserve samples of potentially impacted product batches distributed to the United States.

 

你們的回復(fù)是不充分的。你們目前的藥品雜質(zhì)標(biāo)準(zhǔn)缺乏足夠的科學(xué)依據(jù)。在 2016 年的檢查中，還發(fā)現(xiàn)了類似的缺陷，即缺乏用于 （b）（4） API 產(chǎn)品放行和穩(wěn)定性測(cè)試的雜質(zhì)標(biāo)準(zhǔn)。然而，這一缺陷迄今尚未得到完全解決。此外，你們的風(fēng)險(xiǎn)評(píng)估不包括對(duì)已分銷的潛在受影響產(chǎn)品批次的留樣樣品的評(píng)估。

 

Drug product batches must be tested for identity, strength, quality, and purity prior to release. Insufficient release and stability testing to appropriately detect impurities in your drug products could potentially impact product quality and patient safety.

 

藥品批次在放行前必須進(jìn)行鑒定、劑量、質(zhì)量和純度測(cè)試。如果放行和穩(wěn)定性檢測(cè)不足，無(wú)法正確檢測(cè)藥品中的雜質(zhì)，可能會(huì)影響產(chǎn)品質(zhì)量和患者安全。

 

2. Your firm failed to follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

 

貴公司未能遵循適當(dāng)?shù)臅?shū)面程序，以防止聲稱無(wú)菌的藥品受到微生物污染，包括驗(yàn)證所有無(wú)菌和滅菌工藝（21 CFR 211.113（b））。

 

Poor Aseptic Practices

 

無(wú)菌操作不良

 

During the inspection of your facility, we observed poor practices and behaviors in ISO 5 areas during the manufacturing of sterile(b)(4) drug products. These poor practices included, but were not limited to:

 

在檢查期間，我們觀察到無(wú)菌藥品生產(chǎn)過(guò)程中 ISO 5 區(qū)域中的不良操作和行為。這些不良操作包括但不限于：

 

Operators blocked first air by placing their gloved hands     directly over open sterilized bottles without clearing them from the     aseptic filling line.

 

操作人員將戴手套的手直接放在未加塞的無(wú)菌瓶子上從而堵塞了第一空氣，而未將其從無(wú)菌灌裝線中清除。

 

Operators used their gloved hands instead of using appropriate     sterile tools to remove jammed bottles.

 

操作人員使用戴手套的手而不是使用適當(dāng)?shù)臒o(wú)菌工具來(lái)清除卡住的瓶子。

 

Operator movements in the critical areas were not always slow     and deliberate.

 

關(guān)鍵區(qū)域的操作人員移動(dòng)并不總是緩慢和小心翼翼的。

 

Operators used goggles that had numerous open holes and     therefore had exposed skin during line set-up and aseptic processing.

 

操作人員使用的護(hù)目鏡有許多開(kāi)孔，因此在生產(chǎn)線裝配和無(wú)菌生產(chǎn)過(guò)程中會(huì)暴露皮膚。

 

In 2022, your firm identified contamination in two media fill batches one on the “(b)(4)” aseptic filling line and another on the “(b)(4)” aseptic filling line. You identified the root cause as poor aseptic behavior. These contamination events along with the poor aseptic practices observed during our inspection indicate your aseptic manufacturing operations may lack adequate control. Your firm did not perform a sufficiently comprehensive evaluation of aseptic behavior of operators as part of this recurrent trend.

 

2022 年，貴公司在兩個(gè)培養(yǎng)基灌裝批次中發(fā)現(xiàn)了污染，一個(gè)在“（b）（4）”無(wú)菌灌裝線上，另一個(gè)在“（b）（4）”無(wú)菌灌裝線上。你們確定了不良無(wú)菌行為的根本原因。這些污染事件以及我們?cè)跈z查期間觀察到的不良無(wú)菌實(shí)踐表明，你們的無(wú)菌生產(chǎn)操作可能缺乏足夠的控制。貴公司沒(méi)有對(duì)操作人員的無(wú)菌行為進(jìn)行足夠全面的評(píng)估，以作為這種反復(fù)出現(xiàn)的趨勢(shì)分析的一部分。

 

We also note that open door interventions required a large door to be opened. On numerous occasions, the door remained opened for extended periods of time while the line was still in-operation. When opened, the door was exposed to the ISO 7 area, and when being closed, there was a significant risk of the lower quality room air sweeping into the ISO 5 aseptic processing area. Empty sterile containers were located extremely close to the door. In addition, operators did not adequately disinfect the open door. While spraying disinfectant on the(b)(4), operators failed to consider open sterilized bottles on the line, exposing them to potential contamination.

 

我們還注意到，開(kāi)門干預(yù)需要打開(kāi)一個(gè)很大的門。在許多情況下，門會(huì)長(zhǎng)時(shí)間保持打開(kāi)狀態(tài)，但生產(chǎn)線仍在運(yùn)行。打開(kāi)時(shí)，門暴露在 ISO 7 區(qū)域，關(guān)閉時(shí)，存在較低質(zhì)量的空氣卷入到 ISO 5 無(wú)菌生產(chǎn)區(qū)域的重大風(fēng)險(xiǎn)。未加塞的空玻璃瓶位于離這個(gè)門非常近的地方。此外，操作人員沒(méi)有對(duì)打開(kāi)的門進(jìn)行充分的消毒。在（b）（4）上噴灑消毒劑時(shí)，操作人員沒(méi)有考慮生產(chǎn)線上未加塞的玻璃瓶，使其面臨潛在污染。

 

Inadequate Smoke Studies and Cleanroom Design

 

煙霧研究和潔凈室設(shè)計(jì)不足

 

Your smoke studies did not adequately demonstrate unidirectional air flow in the ISO 5 classified areas used for the aseptic filling of ophthalmic drug products on the “(b)(4)” and “(b)(4)” aseptic filling lines. For example:

 

你們的煙霧研究未充分證明無(wú)菌灌裝線上用于無(wú)菌灌裝的 ISO 5 區(qū)域中的單向氣流。例如：

 

Your smoke studies lacked simulation of aseptic line set-up,     dynamic operations, and interventions that occur during aseptic     manufacturing operations.

 

煙霧研究缺乏對(duì)無(wú)菌生產(chǎn)線裝配、動(dòng)態(tài)操作和無(wú)菌生產(chǎn)操作期間發(fā)生的干預(yù)的模擬。

 

Generation of smoke was not sufficient to demonstrate     unidirectional air flow.

 

煙霧的產(chǎn)生不足以證明單向氣流。

 

We also note that there were multiple aspects of your cleanroom and aseptic processing line design which represented fundamental contamination risks:

 

我們還注意到，你們的潔凈室和無(wú)菌加工生產(chǎn)線的設(shè)計(jì)有多個(gè)方面存在污染風(fēng)險(xiǎn)：

 

There was no physical barrier between the operator and the     open (b)(4)-sterilized bottles on the conveyor. Your     production operator remained inside the ISO 5 aseptic processing area,     sitting or standing next to the conveyor line where open, exposed bottles     pass.

 

操作人員和傳送帶上開(kāi)放的玻璃瓶之間沒(méi)有物理屏障。你們的生產(chǎn)操作人員一直在 ISO 5 無(wú)菌加工區(qū)域內(nèi)，坐在或站在輸送未加塞玻璃瓶的傳送帶旁邊。

 

There were extensive manual interactions with the aseptic     processing line and its exposed sterile drug product and     containers/closures.

 

對(duì)無(wú)菌生產(chǎn)線及其暴露的無(wú)菌藥品和容器/瓶塞進(jìn)行了大量的人工干擾。

 

Operators performed multiple manual interventions during     filling by (b)(4) or (b)(4) due to (b)(4) not     being installed on these (b)(4). These interventions may pose     inherent risks to your aseptic processes.

 

由于未將（b）（4） 安裝在（b）（4） 上，因此操作人員在通過(guò) （b）（4） 或 （b）（4） 進(jìn)行灌裝期間執(zhí)行了多次人工干預(yù)。這些干預(yù)措施可能會(huì)給你們的無(wú)菌工藝帶來(lái)固有的風(fēng)險(xiǎn)。

 

The ISO 5 area is critical because sterile product is exposed and therefore vulnerable to contamination. Your aseptic filling process should be designed, and operations executed, to prevent contamination hazards to your sterile product. The flawed design of the filling line and execution of the aseptic operations promote influx of contamination into the critical filling areas.

 

ISO 5 區(qū)域至關(guān)重要，因?yàn)闊o(wú)菌產(chǎn)品暴露在其中，因此容易受到污染。你們的無(wú)菌灌裝工藝應(yīng)經(jīng)過(guò)精心設(shè)計(jì)，并應(yīng)以防止對(duì)無(wú)菌產(chǎn)品造成污染風(fēng)險(xiǎn)的方式操作。灌裝線的缺陷設(shè)計(jì)和無(wú)菌操作不良加劇了污染物流入關(guān)鍵的灌裝區(qū)域。

 

In your response, you indicate that you temporarily suspended manufacturing on the “(b)(4)” aseptic filling line. You acknowledge that the design of your aseptic filling lines is not optimal and indicate that an independent review of your design and remediation plans for both “(b)(4)” and “(b)(4)” aseptic filling lines will be performed. You also commit to perform new smoke studies under static and dynamic conditions and evaluate associated risks. You indicate that you have engaged a third-party consultant to assist in improving aseptic practices.

 

在你們的回復(fù)中，你們表示暫時(shí)停止了“（b）（4）”無(wú)菌灌裝線的生產(chǎn)。你們承認(rèn)你們的無(wú)菌灌裝線的設(shè)計(jì)并非最佳，并表示將對(duì)你們的 “（b）（4）” 和 “（b）（4）” 無(wú)菌灌裝線的設(shè)計(jì)和補(bǔ)救計(jì)劃進(jìn)行獨(dú)立審查。你們還承諾在靜態(tài)和動(dòng)態(tài)條件下進(jìn)行新的煙霧研究，并評(píng)估相關(guān)風(fēng)險(xiǎn)。你們表示已聘請(qǐng)第三方顧問(wèn)協(xié)助改進(jìn)無(wú)菌實(shí)踐。

 

Your response is inadequate because it does not sufficiently address the lack of oversight of aseptic behavior of operators. Further, you do not adequately investigate poor aseptic practices to determine the impact on sterile drug products manufactured and aseptic processing areas. You also do not clearly specify how you will improve your smoke studies, including what interventions will be included, and how you will address potential deficiencies.For additional guidance on aseptic processing see FDA’s guidance document,Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.

 

你們的回復(fù)是不充分的，因?yàn)樗鼪](méi)有充分解決對(duì)操作人員無(wú)菌行為缺乏監(jiān)督的問(wèn)題。此外，你們沒(méi)有充分調(diào)查不良的無(wú)菌實(shí)踐，以確定對(duì)無(wú)菌藥品生產(chǎn)和無(wú)菌加工區(qū)域的影響。你們也沒(méi)有明確說(shuō)明將如何改進(jìn)煙霧研究，包括將包括哪些干預(yù)，以及將如何解決潛在的缺陷。有關(guān)無(wú)菌加工的其他指南，請(qǐng)參閱 FDA 指南文件《無(wú)菌加工生產(chǎn)的無(wú)菌藥品 -現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范》：https://www.fda.gov/media/71026/download。

 

3. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

 

貴公司未能對(duì)計(jì)算機(jī)或相關(guān)系統(tǒng)進(jìn)行適當(dāng)?shù)目刂疲源_保只有經(jīng)授權(quán)人員才能更改主生產(chǎn)和控制記錄或其他記錄 （21 CFR 211.68（b））。

 

Your Production and QU did not review electronic raw data and audit trails to ensure data integrity prior to batch release. Your operators obtained and printed a passing result after multiple production filter integrity tests failed. Your operators did not record or print the failing results. For example:

 

你們的生產(chǎn)和質(zhì)量部門在批放行之前未審查電子原始數(shù)據(jù)和審計(jì)追蹤以確保數(shù)據(jù)完整性。你們的操作人員在多次過(guò)濾器完整性測(cè)試失敗后只收集并打印了合格結(jié)果。你們的操作人員沒(méi)有記錄或打印失敗的結(jié)果。例如：

 

On August 8, 2024, two operators performed four post-use     sterilizing filter integrity tests for (b)(4) batch (b)(4).     The four tests included three failing results and the final passing     result. Your operators only reported the passing result.

 

2024 年 8 月 8 日，兩名操作人員對(duì)（b）（4）批次進(jìn)行了4次使用后除菌過(guò)濾器完整性測(cè)試。這四次測(cè)試包含 3 次不合格結(jié)果和最終合格結(jié)果。你們的操作人員只報(bào)告了合格的結(jié)果。

 

On July 25, 2024, two operators performed nine filter integrity     tests associated with (b)(4), bulk batch (b)(4).     The nine tests included five failing results, three aborted tests, and the     final passing result. Your operators only reported the passing result.

 

2024 年 7 月 25 日，兩名操作人員進(jìn)行了9 次過(guò)濾器完整性測(cè)試。這 9 個(gè)測(cè)試包括 5 個(gè)失敗的結(jié)果、3 個(gè)中止的測(cè)試以及最終的合格結(jié)果。你們的操作人員只報(bào)告了合格的結(jié)果。

 

In your response, you acknowledge the deficiency and commit to perform a full audit trail review of your production equipment. You also indicate that you are completing the investigations into anomalous filter integrity tests.

 

在你們的回復(fù)中，你們承認(rèn)存在缺陷并承諾對(duì)生產(chǎn)設(shè)備進(jìn)行全面的審計(jì)追蹤審查。你們還表明正在完成對(duì)異常過(guò)濾器完整性測(cè)試的調(diào)查。

 

Your response is inadequate as you do not provide details of the investigation outcome or explain whether effective corrective actions and preventive actions (CAPAs) have been implemented. Further, you do not provide the scope and time period of the retrospective review to ensure all batches potentially affected are part of the assessment.

 

你們的回復(fù)是不充分的，因?yàn)闆](méi)有提供調(diào)查結(jié)果的詳細(xì)信息或解釋是否已實(shí)施有效的糾正措施和預(yù)防措施（CAPA）。此外，你們沒(méi)有提供回顧性審查的范圍和時(shí)間段，以確保所有可能受影響的批次都被評(píng)估。

 

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

 

貴公司未能建立適當(dāng)?shù)南到y(tǒng)來(lái)監(jiān)測(cè)無(wú)菌加工區(qū)域的環(huán)境條件 （21 CFR 211.42（c）（10）（iv））。

 

You did not establish an adequate system for monitoring environmental conditions on the “(b)(4)’ aseptic filling line. For example:

 

你們沒(méi)有建立適當(dāng)?shù)南到y(tǒng)來(lái)監(jiān)測(cè)“（b）（4）”無(wú)菌灌裝線的環(huán)境條件。例如：

 

You did not conduct viable monitoring of the air and surfaces     in ISO 5 areas where an operator was continuously present removing fallen     bottles.

 

你們沒(méi)有對(duì)操作人員一直在里面清除掉落的瓶子的 ISO 5 區(qū)域中的空氣和表面進(jìn)行微生物監(jiān)測(cè)。

 

You did not place the non-viable particle monitoring (NVPM)     probes in representative ISO 5 areas where the product and primary     components were exposed. Our investigators noted the following:

 

你們沒(méi)有將非活性顆粒子監(jiān)測(cè)（NVPM） 探頭放置在產(chǎn)品和主要組件暴露的代表性 ISO 5 區(qū)域。我們的檢查人員注意到以下內(nèi)容：

 

The NVPM probe closest to the (b)(4) was located     approximately (b)(4) above the level of the (b)(4).

 

最靠近 （b）（4） 的 NVPM 探頭位于     （b）（4） 水平上方約 （b）（4） 的位置。  

 

The NVPM probe nearest to the sterile cap (b)(4) was     located approximately (b)(4) above the level of the (b)(4).

 

最靠近無(wú)菌鋁蓋（b）（4）的 NVPM 探頭位于（b）（4）水平上方約 （b）（4） 處。

 

Your operators routinely placed mobile NVPM devices in     locations different from those specified in your procedures to monitor the     ISO 5 areas. As such, NVPM data may not accurately represent the critical     areas in operation.

 

你們的操作人員通常會(huì)將移動(dòng) NVPM 設(shè)備放置在與你們的程序中指定的位置不同的位置，以監(jiān)控 ISO 5 區(qū)域。因此，NVPM 數(shù)據(jù)可能無(wú)法準(zhǔn)確代表生產(chǎn)中的關(guān)鍵區(qū)域。

 

In your response, you commit to upgrade your “(b)(4)” aseptic filling line and perform a Quality Risk Assessment for NVPM in Suite(b)(4).

 

在你們的回復(fù)中，你們承諾升級(jí)“（b）（4）”無(wú)菌灌裝線，并對(duì)NVPM 進(jìn)行質(zhì)量風(fēng)險(xiǎn)評(píng)估。

 

Your response is inadequate. While you commit to conducting a Quality Risk Assessment for NVPM to identify, assess, and mitigate all gaps, you have not provided any updates on the status of risk assessment. Vigilant and responsive environmental monitoring programs should be designed to provide meaningful information on the state of control of your aseptic processing environment. Operations that include highly manually intensive aseptic activities warrant a more extensive environmental and personnel monitoring program, including but not limited to, heightened emphasis on well-timed sampling to appropriately monitor batch manufacturing conditions.

 

你們的回復(fù)是不充分的。雖然你們承諾對(duì) NVPM 進(jìn)行質(zhì)量風(fēng)險(xiǎn)評(píng)估以識(shí)別、評(píng)估和緩解所有差距，但尚未提供有關(guān)風(fēng)險(xiǎn)評(píng)估狀態(tài)的任何更新。應(yīng)設(shè)計(jì)警惕且反應(yīng)迅速的環(huán)境監(jiān)測(cè)計(jì)劃，以提供有關(guān)無(wú)菌加工環(huán)境控制狀態(tài)的有意義信息。包括高度手動(dòng)密集型無(wú)菌活動(dòng)的操作需要更廣泛的環(huán)境和人員監(jiān)測(cè)計(jì)劃，包括但不限于，更加強(qiáng)調(diào)及時(shí)采樣，以適當(dāng)監(jiān)測(cè)批次生產(chǎn)條件。