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嘉峪檢測網 2025-03-19 19:58
近日，FDA發布了對Aspen Pharmacare Holdings Limited的警告信，其中提及大量的無菌生產操作缺陷，如下：
產品放行和穩定性測試中未測試某雜質，該公司表示雜質限度是根據客戶的要求確定的，并且放行標準對此沒有任何限值。并提供了客戶的健康危害評估（HHE），該評估得出的結論：高達標簽含量（b）（4）%的雜質的穩定性水平，不會對按照說明使用產品的用戶造成任何安全風險。FDA不認同該HHE 評估，并得出結論，在推薦劑量下，（b）（4）% 的雜質水平可能會對患者安全構成風險。
無菌操作不良
操作人員將戴手套的手直接放在未加塞的無菌瓶子上從而堵塞了第一空氣，而未將其從無菌灌裝線中清除。
操作人員使用戴手套的手而未使用適當的無菌工具來清除卡住的瓶子。
關鍵區域的操作人員移動并不總是緩慢和小心翼翼的。
操作人員使用的護目鏡有許多開孔，因此在生產線裝配和無菌生產過程中會暴露皮膚。
培養基灌裝批次中發現了污染，確定了不良無菌行為的根本原因。這些污染事件以及檢查期間觀察到的不良無菌實踐表明，無菌生產操作可能缺乏足夠的控制。
開門干預需要打開一個很大的門。在許多情況下，門會長時間保持打開狀態，但生產線仍在運行。打開時，門暴露在 ISO 7 區域，關閉時，存在較低質量的空氣卷入到 ISO 5 無菌生產區域的重大風險。未加塞的空玻璃瓶位于離這個門非常近的地方。此外，操作人員沒有對打開的門進行充分的消毒。在（b）（4）上噴灑消毒劑時，操作人員沒有考慮生產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計不足
煙霧研究缺乏對無菌生產線裝配、動態操作和無菌生產操作期間發生的干預的模擬。
煙霧的產生不足以證明單向氣流。
操作人員和傳送帶上開放的玻璃瓶之間沒有物理屏障。你們的生產操作人員一直在 ISO 5 無菌加工區域內，坐在或站在輸送未加塞玻璃瓶的傳送帶旁邊。
對無菌生產線及其暴露的無菌藥品和容器/瓶塞進行了大量的人工干擾。
操作人員在多次過濾器完整性測試失敗后只收集并打印了合格結果。操作人員沒有記錄或打印失敗的結果。
沒有對操作人員一直在里面清除掉落的瓶子的 ISO 5 區域中的空氣和表面進行微生物監測。
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)).
貴公司未能建立實驗室控制措施，包括科學合理且適當的規范、標準、取樣計劃和測試程序，以確保組件、藥品容器、瓶蓋、生產物料、標簽和藥品符合適當的特性、強度、質量和純度標準 （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:
貴公司未制定適當的標準或未能測試無菌藥品以監測在放行時和整個有效期內的雜質。例如：
You did not perform impurity testing prior to release and during stability for (b)(4).
你們在放行前和穩定性試驗期間未進行雜質檢測。
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）的藥品進行穩定性檢測時，你們未制定科學合理的標準來監測雜質。
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.
在回復中，你們表示雜質限度是根據客戶的要求確定的，并且放行標準對此沒有任何限值。你們提供了客戶的健康危害評估（HHE），該評估得出的結論：高達標簽含量（b）（4）%的雜質（b）（4）的穩定性水平，不會對按照說明使用產品的用戶造成任何安全風險。FDA不認同該HHE 評估，并得出結論，在推薦劑量下，（b）（4）% 的雜質水平可能會對患者安全構成風險。你們有責任確保建立適當的標準，以在整個有效期內監測雜質。
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.
你們的回復是不充分的。你們目前的藥品雜質標準缺乏足夠的科學依據。在 2016 年的檢查中，還發現了類似的缺陷，即缺乏用于 （b）（4） API 產品放行和穩定性測試的雜質標準。然而，這一缺陷迄今尚未得到完全解決。此外，你們的風險評估不包括對已分銷的潛在受影響產品批次的留樣樣品的評估。
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行鑒定、劑量、質量和純度測試。如果放行和穩定性檢測不足，無法正確檢測藥品中的雜質，可能會影響產品質量和患者安全。
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的書面程序，以防止聲稱無菌的藥品受到微生物污染，包括驗證所有無菌和滅菌工藝（21 CFR 211.113（b））。
Poor Aseptic Practices
無菌操作不良
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，我們觀察到無菌藥品生產過程中 ISO 5 區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菌瓶子上從而堵塞了第一空氣，而未將其從無菌灌裝線中清除。
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的無菌工具來清除卡住的瓶子。
Operator movements in the critical areas were not always slow and deliberate.
關鍵區域的操作人員移動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.
操作人員使用的護目鏡有許多開孔，因此在生產線裝配和無菌生產過程中會暴露皮膚。
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，貴公司在兩個培養基灌裝批次中發現了污染，一個在“（b）（4）”無菌灌裝線上，另一個在“（b）（4）”無菌灌裝線上。你們確定了不良無菌行為的根本原因。這些污染事件以及我們在檢查期間觀察到的不良無菌實踐表明，你們的無菌生產操作可能缺乏足夠的控制。貴公司沒有對操作人員的無菌行為進行足夠全面的評估，以作為這種反復出現的趨勢分析的一部分。
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，開門干預需要打開一個很大的門。在許多情況下，門會長時間保持打開狀態，但生產線仍在運行。打開時，門暴露在 ISO 7 區域，關閉時，存在較低質量的空氣卷入到 ISO 5 無菌生產區域的重大風險。未加塞的空玻璃瓶位于離這個門非常近的地方。此外，操作人員沒有對打開的門進行充分的消毒。在（b）（4）上噴灑消毒劑時，操作人員沒有考慮生產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計不足
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菌灌裝線上用于無菌灌裝的 ISO 5 區域中的單向氣流。例如：
Your smoke studies lacked simulation of aseptic line set-up, dynamic operations, and interventions that occur during aseptic manufacturing operations.
煙霧研究缺乏對無菌生產線裝配、動態操作和無菌生產操作期間發生的干預的模擬。
Generation of smoke was not sufficient to demonstrate unidirectional air flow.
煙霧的產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，你們的潔凈室和無菌加工生產線的設計有多個方面存在污染風險：
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放的玻璃瓶之間沒有物理屏障。你們的生產操作人員一直在 ISO 5 無菌加工區域內，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.
對無菌生產線及其暴露的無菌藥品和容器/瓶塞進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 （b）（4） 或 （b）（4） 進行灌裝期間執行了多次人工干預。這些干預措施可能會給你們的無菌工藝帶來固有的風險。
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 區域至關重要，因為無菌產品暴露在其中，因此容易受到污染。你們的無菌灌裝工藝應經過精心設計，并應以防止對無菌產品造成污染風險的方式操作。灌裝線的缺陷設計和無菌操作不良加劇了污染物流入關鍵的灌裝區域。
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.
在你們的回復中，你們表示暫時停止了“（b）（4）”無菌灌裝線的生產。你們承認你們的無菌灌裝線的設計并非最佳，并表示將對你們的 “（b）（4）” 和 “（b）（4）” 無菌灌裝線的設計和補救計劃進行獨立審查。你們還承諾在靜態和動態條件下進行新的煙霧研究，并評估相關風險。你們表示已聘請第三方顧問協助改進無菌實踐。
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.
你們的回復是不充分的，因為它沒有充分解決對操作人員無菌行為缺乏監督的問題。此外，你們沒有充分調查不良的無菌實踐，以確定對無菌藥品生產和無菌加工區域的影響。你們也沒有明確說明將如何改進煙霧研究，包括將包括哪些干預，以及將如何解決潛在的缺陷。有關無菌加工的其他指南，請參閱 FDA 指南文件《無菌加工生產的無菌藥品 -現行藥品生產質量管理規范》：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)).
貴公司未能對計算機或相關系統進行適當的控制，以確保只有經授權人員才能更改主生產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:
你們的生產和質量部門在批放行之前未審查電子原始數據和審計追蹤以確保數據完整性。你們的操作人員在多次過濾器完整性測試失敗后只收集并打印了合格結果。你們的操作人員沒有記錄或打印失敗的結果。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（b）（4）批次進行了4次使用后除菌過濾器完整性測試。這四次測試包含 3 次不合格結果和最終合格結果。你們的操作人員只報告了合格的結果。
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，兩名操作人員進行了9 次過濾器完整性測試。這 9 個測試包括 5 個失敗的結果、3 個中止的測試以及最終的合格結果。你們的操作人員只報告了合格的結果。
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.
在你們的回復中，你們承認存在缺陷并承諾對生產設備進行全面的審計追蹤審查。你們還表明正在完成對異常過濾器完整性測試的調查。
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.
你們的回復是不充分的，因為沒有提供調查結果的詳細信息或解釋是否已實施有效的糾正措施和預防措施（CAPA）。此外，你們沒有提供回顧性審查的范圍和時間段，以確保所有可能受影響的批次都被評估。
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的系統來監測無菌加工區域的環境條件 （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:
你們沒有建立適當的系統來監測“（b）（4）”無菌灌裝線的環境條件。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.
你們沒有對操作人員一直在里面清除掉落的瓶子的 ISO 5 區域中的空氣和表面進行微生物監測。
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:
你們沒有將非活性顆粒子監測（NVPM） 探頭放置在產品和主要組件暴露的代表性 ISO 5 區域。我們的檢查人員注意到以下內容：
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將移動 NVPM 設備放置在與你們的程序中指定的位置不同的位置，以監控 ISO 5 區域。因此，NVPM 數據可能無法準確代表生產中的關鍵區域。
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).
在你們的回復中，你們承諾升級“（b）（4）”無菌灌裝線，并對NVPM 進行質量風險評估。
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.
你們的回復是不充分的。雖然你們承諾對 NVPM 進行質量風險評估以識別、評估和緩解所有差距，但尚未提供有關風險評估狀態的任何更新。應設計警惕且反應迅速的環境監測計劃，以提供有關無菌加工環境控制狀態的有意義信息。包括高度手動密集型無菌活動的操作需要更廣泛的環境和人員監測計劃，包括但不限于，更加強調及時采樣，以適當監測批次生產條件。
來源：Internet
