清潔驗證一直是制藥企業最頭疼的事，總有企業在這件事上“馬失前蹄”。Biocon Limited（百康）作為印度最大的生物制藥公司在FDA檢查中依然沒能幸免，在FDA發布的483報告中列舉了清潔驗證、OOS、設備確認和數據完整性相關典型缺陷，下面我們重點看一下涉及清潔驗證缺陷項：

 

1.Cleaning Validation Protocols designed to assess potential product-to-product carryover in non-dedicated, are not adequately performed. Specifically,  設計用于評估非專用設備中產品間殘留的清潔驗證方案未得到充分執行。具體來說：

 

Per SOPNo. QA/SOP/016, “Cleaning Validation”, the “total carryover should be calculated based on swab result”. Cleaning Validation Protocols are product specific and define the process, procedures, materials and documentation requirements. During execution of the cleaning validations, the performed cleaningactions are documented on the respective “Equipment Cleaning Checklist”, while details of samples are documented on the “Technical Information Sheet for Equipment Cleaning Sample”. However, neither the “Equipment Cleaning Checklist” or “Technical Information Sheet for Equipment Cleaning Sample”, document the diluent used in the swab sample collection preparation, volume of diluent, or total area swabbed, as required by the respective protocol and SOP No.QA/SOP/016.

 

根據SOP QA/SOP/016“清潔驗證”，“總殘留應根據擦拭取樣結果進行計算”。清潔驗證方案是按產品制訂的，規定了工藝、程序、物料和文件記錄要求。在執行清潔驗證過程中，所執行的清潔動作記錄在對應的“設備清潔檢查清單中”，而樣品的詳細信息則記錄在“設備清潔樣品技術信息表”中。而兩者均未按對應方案和SOPQA/SOP/016記錄擦拭樣品采集準備過程中所用的稀釋劑、稀釋劑體積和總擦拭面積。

 

2.Equipment used in production operations arenot adequately qualified. Specifically, 生產操作用設備未經充分確認。具體來說：

 

Transportation of Microbiological samples for Identification, per SOP No. CQCM/SOP/038, “Receipt and Transport of Microbiology Samples”, Version 02, Effective Date: May 25th, 2018, does not require documentation of the temperature conditions during transport of microbiological (b)(4) Environmental Monitoring, Cleaning Validation) samples to (b)(4), for species identification. However, the procedure specifies storage of microbiological samples at 2-8°C is required, if not analyzed “immediately”.

 

SOP CQCM/SOP/038“微生物樣品的接收與運輸”版本號02生效日期20180525中未要求記錄微生物鑒別（環境監測、清潔驗證樣品）樣品運輸過程中的溫度條件。但是程序要求微生物樣品如果不能“立即”分析則存貯在2-8°C。

 

無獨有偶FDA在檢查印度的Cipla Limited（FEI 3004081307）公司時針對嚴重違反CGMP的行為發出警告信，其中不乏清潔驗證的缺陷，詳情如下：

 

1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or established requirements (21 CFR 211.67(a)). 你公司未能以適當時間間隔對設備和工器具進行清潔、維護，以及根據藥品特性進行適當消毒和/或滅菌，以防止可能改變藥品的安全性、鑒別、含量、質量或純度使得超出正式或既定要求的故障或污染（21 CFR 211.67(a)）。

 

Your cleaning procedure for non-dedicated equipment, including your (b)(4) and tablet (b)(4)equipment ((b)(4)), is inadequate. Our investigators observed multiple (b)(4) and (b)(4) containing residues of what appeared to be different products inside the exhaust ducts. Analytical testing conducted by your firm onthe residues collected from this manufacturing equipment confirmed the presence of multiple active ingredients.

 

你們的非專用設備包括你們的XX和壓片機設備XX的清潔程序不充分。我們檢查員發現排風管內有多個XX和XX殘留，看起來是不同產品。你公司對該生產設備上采集的殘留進行了分析測試，確認是多種活性成分。

 

After our inspection, your firm also tested reserve samples of selected batches to assess the potential for cross contamination.Your testing confirmed the presence of active ingredients from a previous product in batches of the next product, including but not limited to:

 

在我們檢查之后，你公司亦檢測了所選批次的留樣，對潛在交叉污染進行評估。你們檢測確認了下一產品的批次中存在前一產品的活性成分殘留，包括但不僅限于：

 

•      Residues of (b)(4) active ingredient in (b)(4) tablets

 

•      在XX片劑中有XX活性成分殘留

 

•      Residues of (b)(4) active ingredient in (b)(4)((b)(4)) tablets

 

•      在XX片劑中有XX活性成分殘留

 

Your response stated that 261 out of 268 batches tested did not show traces of previous product manufactured. You also indicated your belief that the layer of (b)(4) drug product residue seen in the exhaust duct did not pose a risk of contamination to your drug products.

 

你們的回復聲稱所測268批中有261批未發現前一生產產品的痕跡。你們還說你們相信在排風管中看到的XX藥品殘留層對你們的藥品沒有污染風險。

 

Your response is inadequate. Retain samples from several batches were found to be contaminated with another drug. However, your response continues to be equivocal about the source of the contamination. This lack of a clear root cause casts doubt on whether you have fully resolved aserious cross-contamination problem.

 

你們的回復是不充分的。有幾批留樣已發現被另一藥品所污染。但你們的回復仍對污染來源含糊其辭。如此缺乏根本原因說明使得我們嚴重懷疑你們是否已全面解決嚴重的交叉污染問題。

 

In addition, reserve sample testing alone is insufficient to determine the scope of the cross-contamination issue and mitigate risks associated with it. Your response also failed to address that, in about 10 percent of the batches tested, your firm detected unknown peaks eluting at the retention time of a previous product. Your firm indicated that the carryover was not confirmed because the peak did not match the (photo-diode array) peak spectra of the standard solution from the previous product. However, your firm did not provide an adequate investigation that addressed the identity of each unknown peak and its source. Your response also acknowledged challenges with the analytical methodology due to interference of product matrix and poor peak response, but it lacked supporting documentation demonstrating that these challenges were adequately resolved.

 

另外，僅對留樣進行檢測并不足以確定交叉污染問題的范圍并降低其所帶來的風險。你們的回復亦未說明在所檢測的批次中有約10%在前一產品的保留時間檢出未知峰的問題。你公司說無法對殘留進行確認，因為該峰并不匹配前一產品標準溶液中的峰（二極管陣列PDA）。但你們公司并未提交充分調查，說明每個未知峰鑒定及其來源。你們的回復亦承認由于產品基質干擾和峰響應不良，因此分析方法頗受挑戰，但并沒有支持性文件證明已充分解決了這些挑戰。

 

There is no assurance that the scope of your evaluation was comprehensive. Your rationale for testing reserve samples consisted solely in selecting products with the largest amount of potential carryover, as represented by the longest campaign prior to a product changeover. Your selection also did not seem to include a toxicological hazard assessment to identify active ingredients that may represent a higher risk to patients due to low permitted exposure levels. ·

 

你們無法確保評估的全面性。你們對留樣檢測合理性僅是在選擇有殘留數量可能最大的產品，選擇的是更換產品之前生產周期最長的批次。你們的選擇貌似亦未包括毒性危害評估，識別出因允許暴露水平較低而可能對患者有更高風險的活性成分。

 

In response to this letter, provide the following:

 

在回復本函時請提交：

 

•      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 expanded assessment to determine whether cross-contaminated product batches 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.

 

•      一份對你們清潔效果的全面獨立回顧性評估，評價交叉污染的范圍。包括殘留的成分，其它可能不當清潔的生產設備，并將評估擴展至確定是否有受到交叉污染的藥品被放行銷售。該評估應找出清潔程序和做法的所有不足處，并包括生產多個產品的每臺生產設備。

 

•      A corrective action and preventive action (CAP A) plan, based on the retrospective assessment, 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.

 

•      根據回顧性評估制訂的CAPA計劃，其中包括對你們清潔工藝和做法的適當補救措施，以及完成的時間表。提交一份對你們產品清潔生命周期管理中清潔工藝薄弱點的詳細總結，闡述對你們清潔程序的改進，包括提高清潔有效性、改進對所有產品和設備清潔執行適當性的核查，以及所有其它必須改進措施。

 

· In addition to this holistic remediation, provide specific CAPA activities that are being undertaken to effectively remediate the conditions that caused the specific cross-contamination incidents discussed above. Provide an independent review by your consultant that determines the effectiveness of your CAPA, including but not limited to:

 

· 除了這份全面補救措施外，還要提交一份正在有效補救導致上面所討論的特定交叉污染的情形的特定CAPA行動。提交一份你們顧問的獨立審核，確定你們CAPA的有效性，包括但不僅限于：

 

•      a list of all enhancements to cleaning and maintenance procedures including specific frequencies and locations to be cleaned in all relevant equipment (e.g., (b)(4), (b)(4), ductwork)

 

•      一份清潔和維護程序的所有改進措施清單，包括具體頻次和所有相關設備要清潔的位置（例如XX、風管）

 

•      identify any other sources of cross contamination other than (b)(4) equipment, (b)(4) and ductwork

 

•      找出XX設備、XX和風管以外的所有其它交叉污染來源

 

•      determine the adequacy of your analytical methodology to identify residual carryover

 

•      確定你們鑒定殘留物的分析方法的充分性

 

•      your investigations into the unknown (unidentified) peaks detected in your reserve samples

 

•      你們對留樣檢測中發現的未知（未鑒定）峰的調查

 

•      supporting evidence to demonstrate that the challenges identified during your study, such as interference of product matrix and co-eluting peaks, were adequately resolved

 

•      證明你們研究中所發現的挑戰，如產品基質干擾，和重疊峰已得到充分解決的支持性證據

 

•      adequacy of scope of the investigation and its related CAPA

 

•      調查及其相關CAPA范圍的充分性

 

· We also understand that you are performing a study to determine cleanliness of ducts and assessing them (b)(4). Explain your interim plan for preventing any cross-contamination from the ducts before the given (b)(4) cleaning interval elapses.

 

· 我們亦了解你們正在進行研究，以確定風管的清潔度，評估XX。解釋你們在指定的XX清潔時間間隔之前，防止風管交叉污染的臨時計劃

 

•      The latest update on your improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

 

•      對你們清潔驗證程序改進的最新情況，特別注意結合你們藥品生產操作中識別為最差情形的條件。其中包括但不僅限于對所有最差情形的識別和評估：

 

· drugs with higher toxicities

 

· 毒性高的藥品

 

· drugs with higher drug potencies

 

· 藥物效價高的藥品

 

· drugs of lower solubility in their cleaning solvents

 

· 在其清潔溶劑中溶解度較低的藥品

 

· drug~ with characteristics that make them difficult to clean

 

· 具有難以清潔特性的藥品

 

· swabbing locations for areas that are most difficult to clean

 

· 最難清潔部位的擦拭取樣點

 

· maximum hold times before cleaning

 

· 清潔前的最長放置時長

 

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

 

另外要說明引入新生產設備或新產品之前在你們變更管理系統中必須采取的措施

 

•      A full description of the correction factor for recovery that your firm applied in the reserve sample study. Include examples of the calculations and their applications for all seven batches in which you confirmed carryover. Describe whether any lot that appeared to have cross-contamination was discounted from your risk assessment due to the application of your correction factor.

 

•      完整說明你公司在留樣研究中所用的回收校正因子。包括計算例子及其在所有7個你們確認有殘留批次中的應用情況。說明在你們風險評估中是否有因為你們使用了校正因子而低估了交叉污染的批次。

 

•      For the seven products that were found contaminated with traces of other actives, provide details of at least the 30 prior batches manufactured in all non-dedicated equipment. Include the name of the product, stage of processing, all equipment identifications, and dates of manufacture. Also highlight any correlation between these preceding batches, residues present in the ductwork, and finished product batches found to be contaminated.

 

•      對于發現有其它活性成分痕跡的7個批次，提交所有非專用設備中生產的之前至少30個批準的詳細信息，包括產品名稱、工藝步驟、所有識別編號和生產日期。亦要突出顯示這些之前批次之間的相互關系、網管中的殘留以及發現被污染的成品批次。