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嘉峪檢測網(wǎng) 2025-03-13 08:20
近日，F(xiàn)DA發(fā)布了對Shree Jaya Laboratories PVT. LTD.的警告信，其中提及專用設備的清潔、可見異物投訴調(diào)查及數(shù)據(jù)完整性相關的問題：
FDA在“已清潔”的專用設備上發(fā)現(xiàn)了過量的殘留，該公司表示該設備是專用的，并且所生產(chǎn)的產(chǎn)品與在設備表面發(fā)現(xiàn)的殘留是相同的化合物，因此，預計不會發(fā)生交叉污染。
FDA并不接受此觀點，并表示盡管該公司表明可能預計不會交叉污染，但產(chǎn)品在未清潔的設備上累積可能會形成產(chǎn)品殘留和未知雜質(zhì)。
可見異物的投訴，該公司將根本原因歸因于XX設備的袋的清潔/使用不當。提出了更頻繁地更換袋的 CAPA，但在檢查期間發(fā)現(xiàn)某設備年久失修，內(nèi)襯磨損和腐蝕。設備的某個單元位于室外，暴露在外部環(huán)境中，還觀察到含有嚴重銹跡和一只死蟲。該公司管理層承認設備狀況和環(huán)境條件未被評估為潛在的污染源。
FDA在該公司的廢棄物堆放場發(fā)現(xiàn)了幾份原始的批生產(chǎn)記錄，該公司解釋說：一些批生產(chǎn)記錄頁面因化學品泄漏而損壞，并且這些頁面已由 QA 部門更換。損壞的頁面沒有退回給QA，而是被送到了廢品堆放場。
檢查人員要求查看與損毀文件相關的批記錄時，該公司管理層提供了此記錄的另一個版本的批記錄。該公司沒有解釋為什么會有兩套原始批生產(chǎn)記錄。
批生產(chǎn)記錄沒有同步完成。FDA發(fā)現(xiàn)：在生產(chǎn)作過程中，批記錄實際存放在QA部門。
操作人員所執(zhí)行的生產(chǎn)作不是自己記錄的，而是隨后由同時監(jiān)督5 個生產(chǎn)車間的生產(chǎn)主管來完成，該公司解釋說生產(chǎn)主管填寫批生產(chǎn)記錄是因為操作人員不精通英語。
FDA質(zhì)疑一個生產(chǎn)主管同時監(jiān)督5個生產(chǎn)車間，該公司則解釋：幾名生產(chǎn)人員因病無法上班，這就是為什么一名生產(chǎn)主管必須監(jiān)督和記錄多個區(qū)域操作的原因。
缺陷翻譯如下：
1. 未清潔設備 用于防止污染或攜帶會改變的材料 中間體的質(zhì)量超出官方或其他既定 規(guī)格。
未能清潔設備和器具以防止導致中間體的質(zhì)量變化而超出官方或其他既定標準的污染或物料殘留。
您未能制定適當?shù)某绦?制造設備和設施的清潔和維護。我們 檢查發(fā)現(xiàn)制造設備標記為“已清潔”，并發(fā)現(xiàn) 以下缺陷。例如：
貴公司未能制定適當?shù)某绦騺砬鍧嵑途S護生產(chǎn)設備和設施。我們的檢查發(fā)現(xiàn)生產(chǎn)設備被標記為“已清潔”，并發(fā)現(xiàn)了以下缺陷。例如：
（二）（4） #B-（b）（4）-404 在生產(chǎn)區(qū)塊 - （b）（4） 中記錄了設備使用情況 2024 年 9 月 5 日記錄為“已根據(jù) SOP 清潔”;然而，過多的 （b）（4） 顏色 當天晚些時候在 （b）（4） 內(nèi)觀察到殘留物。 此 （b）（4） 用于制造 （b）（4）。
2024 年 9 月 5 日，XX生產(chǎn)區(qū)中的 #B-XX-404在設備使用日志中被記錄為“已根據(jù) SOP 清潔”;然而，當天晚些時候在XX部件內(nèi)觀察到過量的XX有色殘留物。此部件用于制造xx產(chǎn)品。
（二）（4） #BI/（b）（4） 房間 #（b）（4） 用于制造 （b）（4） 中間體， 在 8 月 30 日的設備使用日志中記錄為“已按照 SOP 清潔”， 2024;然而，在內(nèi)部和外部都觀察到 （b）（4） 設備的產(chǎn)品卸貨區(qū)。
2024 年 8 月 30 日，用于制造某中間體的XX房間的XX設備，在使用日志中被記錄為“已根據(jù)SOP 清潔”;然而，在設備的產(chǎn)品卸料區(qū)域的內(nèi)部和外部觀察到XX殘留。
此外，用于 生產(chǎn)中使用的關鍵起始材料和中間體 的 API 未保持良好的修復狀態(tài)。例如，天花板 上述 （b）（4） 位于生產(chǎn)區(qū)塊 （b）（4） 之外 觀察到有嚴重的污漬，有裂縫和掉落的石膏。這些 （b）（4） 是 用于制造 （b）（4）。
此外，用于制造關鍵原料和用于生產(chǎn) API 中間體的廠房沒有保持良好的維護狀態(tài)。例如，位于生產(chǎn)大樓-（b）（4） 外的XX上方的天花板被觀察到嚴重染色，并有裂縫和掉落的石膏。此設備用于制造XX產(chǎn)品。
在您的回復中，您指出 （b）（4） 加工區(qū)域使用的設備是專用的，并且 設備表面的 （b）（4） 對應于 相同的化合物，因此，預計不會有交叉污染。您承認 在確保遵守清潔規(guī)定方面監(jiān)督不足 程序和對清潔間隔的監(jiān)控不足。此外，您 指出日常衛(wèi)生程序沒有得到充分執(zhí)行以防止 物質(zhì)積累，但它們將得到加強。您還指出 立即采取的糾正措施是修復和恢復外面的天花板 生產(chǎn)區(qū)塊-（b）（4）。
在你們的回復中，你們聲明（b）（4）加工區(qū)域中使用的設備是專用的，并且所生產(chǎn)的產(chǎn)品與在設備表面發(fā)現(xiàn)的殘留是相同的化合物，因此，預計不會發(fā)生交叉污染。你們承認在確保遵守清潔程序方面監(jiān)督不足，并且對清潔間隔的監(jiān)控不足。此外，你們表示日常清潔衛(wèi)生程序沒有得到充分執(zhí)行以防止物料累積，但這些程序?qū)⒌玫郊訌?。你們還指出，立即采取的糾正措施是修復和恢復XX生產(chǎn)區(qū)之外的天花板。
Your response is inadequate. Although you indicate cross-contamination may not be expected, product carryover and unknown impurities may form as a result of product build up on unclean equipment. You also do not acknowledge why personnel signed off on equipment usage logs as equipment being clean when it was not clean. In addition, no evidence of the ceiling repair was provided.
你們的回復是不充分的。盡管你們表明可能預計不會交叉污染，但產(chǎn)品在未清潔的設備上累積可能會形成產(chǎn)品殘留和未知雜質(zhì)。你們也未說明為什么工作人員在設備使用日志上簽字說設備已清潔。此外，沒有提供天花板維修的證據(jù)。
In response to this letter, provide the following:
回復此函，請?zhí)峁?/span>
A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.
對你們的清潔效果進行全面、獨立的回顧性評估，以評估交叉污染危害的范圍。包括殘留的鑒定、可能清潔不當?shù)钠渌a(chǎn)設備，以及評估是否可能已放行存在交叉污染的產(chǎn)品。評估應確定清潔程序和實踐的任何不當之處，并涵蓋用于生產(chǎn)多產(chǎn)品的每個生產(chǎn)設備。
A corrective action and preventive action (CAPA) plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.
糾正措施和預防措施 （CAPA） 計劃，基于對清潔程序的回顧性評估，包括對清潔工藝和實踐的適當補救措施，以及完成時間表。提供設備清潔生命周期管理流程中漏洞的詳細摘要。描述清潔程序的改進，包括提高清潔效果;改進對所有產(chǎn)品和設備正確清潔執(zhí)行的持續(xù)確認;以及所有其他需要的補救措施。
2. Failure of your quality unit to ensure that quality-related complaints are investigated and resolved.
你們的質(zhì)量部門未能確保質(zhì)量相關的投訴得到調(diào)查和解決。
You failed to adequately investigate a complaint of(b)(4) particles in the intermediate, (b)(4), Stage-(b)(4), batch (b)(4). The root cause was attributed to improper cleaning/usage of the (b)(4) bag. A CAPA to change the (b)(4) bag more frequently (i.e., after (b)(4) batches instead of (b)(4) batches) was proposed.
你們未能充分調(diào)查中間體、（b）（4）、階段性XX、批次（b）（4）中（b）（4）可見異物的投訴。根本原因歸因于 （b）（4）袋的清潔/使用不當。提出了更頻繁地更換（b）（4）袋的 CAPA（即，在（b）（4）批次而不是（b）（4）批次之后）。
The complaint investigation was deficient because it did not extend to other batches, as required by your procedure, and it failed to identify other potential causes of the(b)(4) particles. Despite CAPA implementation of more frequent (b)(4) bag changes, the (b)(4) in Production Block – (b)(4) was observed during the inspection to be in disrepair, with the interior lining worn and corroded. The (b)(4) is located outdoors, exposed to the outside environment, and was also observed to contain heavy rust and a dead insect. Your management acknowledged the condition of the equipment and environmental conditions were not evaluated as potential source(s) of the contamination.
此投訴調(diào)查存在缺陷，因為它沒有按照你們的程序要求擴展到其他批次，并且未能確定 （b）（4） 顆粒的其他潛在原因。盡管 CAPA 實施了更頻繁的（b）（4）換袋，但在檢查期間觀察到生產(chǎn)區(qū) –（b）（4）的（b）（4）年久失修，內(nèi)襯磨損和腐蝕。（b）（4）位于室外，暴露在外部環(huán)境中，還觀察到含有嚴重銹跡和一只死蟲。你們的管理層承認設備狀況和環(huán)境條件未被評估為潛在的污染源。
In your response, you acknowledge your procedure for handling complaint investigations, but did not account for environmental conditions, which likely contributed to the complaint. You provided an addendum investigation report extending the investigation to other batches and including environmental conditions. You also state that the(b)(4) equipment will be upgraded and enclosed to create a controlled environment.
在回復中，你們確認了處理投訴調(diào)查的程序沒有考慮可能導致投訴的環(huán)境條件。你們提供了一份調(diào)查報告附件，將調(diào)查范圍擴大到其他批次，并包括環(huán)境條件。還聲明（b）（4）設備將被升級和保護起來，以創(chuàng)建一個受控環(huán)境。
Your response is inadequate. You do not commit to conduct a retrospective review of all complaints to ensure they were adequately investigated, extended to other batches, and considered environmental conditions, if necessary.
你們的回復是不充分的。你們未承諾對所有投訴進行回顧性審核，以確保這些投訴得到充分調(diào)查，擴展到其他批次，并在必要時考慮環(huán)境條件。
In response to this letter, provide a comprehensive assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
回復此函，請對你們的整體系統(tǒng)進行全面評估，以調(diào)查偏差、差異、投訴、OOS結(jié)果和失敗。提供詳細的行動計劃來修復此系統(tǒng)。你們的行動計劃應包括但不限于調(diào)查能力、范圍確定、根本原因評估、CAPA 有效性、質(zhì)量單位監(jiān)督和書面程序方面的重大改進。說明你們公司將如何確保調(diào)查的所有階段都得到適當進行。
3. Failure of your quality unit to exercise its responsibility to ensure the intermediates manufactured at your facility are in compliance with CGMP.
你們的質(zhì)量部門未能履行其責任以確保貴工廠生產(chǎn)的中間體符合 CGMP。
Several original batch production records were found torn in your scrapyard. The investigator asked to review the batch records associated with the torn documents. Your management then provided a second set of these batch records in question. During the inspection, no explanation was provided regarding how there could be two sets of original batch production records or who authorized the disposition of these documents.
在你們的廢棄物堆放場發(fā)現(xiàn)了幾份原始的批生產(chǎn)記錄。檢查人員要求查看與撕毀文件相關的批記錄。然后，你們的管理層提供了此記錄的另一個版本的批記錄。在檢查期間，沒有解釋為什么會有兩套原始批生產(chǎn)記錄或誰授權處理這些記錄的。
In addition, batch production records are not completed contemporaneously. Batch records were observed to be stored in the Quality Assurance (QA) department while manufacturing operations were ongoing. Production tasks performed by operators were recorded later by the production supervisor, who was overseeing five production rooms at the same time.
此外，批生產(chǎn)記錄沒有同步完成。觀察到在生產(chǎn)操作進行期間，批記錄存放在質(zhì)量保證（QA）部門。操作人員所執(zhí)行的生產(chǎn)任務隨后由同時監(jiān)督 5 個生產(chǎn)車間的生產(chǎn)主管記錄下來。
In your response, you state that some of the batch production record pages were damaged by chemical spillages and the pages were replaced by the QA department. The damaged pages were not returned to QA and were sent to the scrapyard. You explain that your production supervisor fills out the batch production records because your operators lack proficiency in English. You also state that several production staff members were unable to attend work due to illness, which is why one production supervisor had to oversee and record operations in multiple areas.
在你們的回復中，你們指出一些批生產(chǎn)記錄頁面因化學品溢出而損壞，并且這些頁面已由 QA 部門更換。損壞的頁面沒有退回給QA，而是被送到了廢品堆放場。你們解釋說，你們的生產(chǎn)主管填寫批生產(chǎn)記錄是因為你們的操作人員不精通英語。你們還指出，幾名生產(chǎn)人員因病無法上班，這就是為什么一名生產(chǎn)主管必須監(jiān)督和記錄多個區(qū)域操作的原因。
Your response is inadequate. You failed to provide supporting evidence of any incident or deviation regarding chemical spills on CGMP documents. You also do not address your practice of tearing CGMP documents and its potential impact, including ensuring accurate results were reported when the batch production records were recreated. In addition, there is no assurance that CGMP activities are adequately performed and documented, given that the records are not in a language understood by your employees executing such activities.
你們的回復是不充分的。你們未能提供與 CGMP 文件上化學品泄漏有關的任何事件或偏差的支持證據(jù)。你們也沒有解決撕毀CGMP 文件記錄的做法及其潛在影響，包括確保在重新創(chuàng)建批生產(chǎn)記錄時報告準確的結(jié)果。此外，如果記錄不是以執(zhí)行此類活動的員工所理解的語言編寫的，則無法保證CGMP 活動得到充分執(zhí)行和記錄。
Complete and accurate batch production and control records must be contemporaneously documented to ensure that manufacturing processes are consistently followed and reproducible. Additionally, incomplete manufacturing records deprive you of the ability to adequately investigate deviations.
必須同時記錄完整和準確的批生產(chǎn)和控制記錄，以確保生產(chǎn)過程得到一致遵循和可重復性。此外，不完整的生產(chǎn)記錄會剝奪你們充分調(diào)查偏差的能力。
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance documentData Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.
您的質(zhì)量體系無法充分確保數(shù)據(jù)的準確性和完整性，以支持所生產(chǎn)的藥物的安全性、有效性和質(zhì)量。了解有關建立和遵循 CGMP 合規(guī)數(shù)據(jù)可靠性實踐的指南，請參閱 FDA 指南《藥物 CGMP 數(shù)據(jù)完整性和合規(guī)性》：https://www.fda.gov/media/119267/download。
In response to this letter provide a current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.
回復此函，請?zhí)峁┧^察到的缺陷對藥物質(zhì)量的潛在影響的當前風險評估。你們的評估應包括分析因數(shù)據(jù)完整性失效而影響的藥物放行對患者造成的風險，以及分析對持續(xù)運營帶來的風險。
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