清洁验证一直是制药企业最头疼的事，总有企业在这件事上“马失前蹄”。Biocon Limited（百康）作为印度最大的生物制药公司在FDA检查中依然没能幸免，在FDA发布的483报告中列举了清洁验证、OOS、设备确认和数据完整性相关典型缺陷，下面我们重点看一下涉及清洁验证缺陷项：

 

1.Cleaning Validation Protocols designed to assess potential product-to-product carryover in non-dedicated, are not adequately performed. Specifically,  设计用于评估非专用设备中产品间残留的清洁验证方案未得到充分执行。具体来说：

 

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.

 

根据SOP QA/SOP/016“清洁验证”，“总残留应根据擦拭取样结果进行计算”。清洁验证方案是按产品制订的，规定了工艺、程序、物料和文件记录要求。在执行清洁验证过程中，所执行的清洁动作记录在对应的“设备清洁检查清单中”，而样品的详细信息则记录在“设备清洁样品技术信息表”中。而两者均未按对应方案和SOPQA/SOP/016记录擦拭样品采集准备过程中所用的稀释剂、稀释剂体积和总擦拭面积。

 

2.Equipment used in production operations arenot adequately qualified. Specifically, 生产操作用设备未经充分确认。具体来说：

 

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“微生物样品的接收与运输”版本号02生效日期20180525中未要求记录微生物鉴别（环境监测、清洁验证样品）样品运输过程中的温度条件。但是程序要求微生物样品如果不能“立即”分析则存贮在2-8°C。

 

无独有偶FDA在检查印度的Cipla Limited（FEI 3004081307）公司时针对严重违反CGMP的行为发出警告信，其中不乏清洁验证的缺陷，详情如下：

 

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)). 你公司未能以适当时间间隔对设备和工器具进行清洁、维护，以及根据药品特性进行适当消毒和/或灭菌，以防止可能改变药品的安全性、鉴别、含量、质量或纯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.

 

你们的非专用设备包括你们的XX和压片机设备XX的清洁程序不充分。我们检查员发现排风管内有多个XX和XX残留，看起来是不同产品。你公司对该生产设备上采集的残留进行了分析测试，确认是多种活性成分。

 

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:

 

在我们检查之后，你公司亦检测了所选批次的留样，对潜在交叉污染进行评估。你们检测确认了下一产品的批次中存在前一产品的活性成分残留，包括但不仅限于：

 

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

 

•      在XX片剂中有XX活性成分残留

 

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

 

•      在XX片剂中有XX活性成分残留

 

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.

 

你们的回复声称所测268批中有261批未发现前一生产产品的痕迹。你们还说你们相信在排风管中看到的XX药品残留层对你们的药品没有污染风险。

 

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.

 

你们的回复是不充分的。有几批留样已发现被另一药品所污染。但你们的回复仍对污染来源含糊其辞。如此缺乏根本原因说明使得我们严重怀疑你们是否已全面解决严重的交叉污染问题。

 

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，仅对留样进行检测并不足以确定交叉污染问题的范围并降低其所带来的风险。你们的回复亦未说明在所检测的批次中有约10%在前一产品的保留时间检出未知峰的问题。你公司说无法对残留进行确认，因为该峰并不匹配前一产品标准溶液中的峰（二极管阵列PDA）。但你们公司并未提交充分调查，说明每个未知峰鉴定及其来源。你们的回复亦承认由于产品基质干扰和峰响应不良，因此分析方法颇受挑战，但并没有支持性文件证明已充分解决了这些挑战。

 

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. ·

 

你们无法确保评估的全面性。你们对留样检测合理性仅是在选择有残留数量可能最大的产品，选择的是更换产品之前生产周期最长的批次。你们的选择貌似亦未包括毒性危害评估，识别出因允许暴露水平较低而可能对患者有更高风险的活性成分。

 

In response to this letter, provide the following:

 

在回复本函时请提交：

 

•      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.

 

•      一份对你们清洁效果的全面独立回顾性评估，评价交叉污染的范围。包括残留的成分，其它可能不当清洁的生产设备，并将评估扩展至确定是否有受到交叉污染的药品被放行销售。该评估应找出清洁程序和做法的所有不足处，并包括生产多个产品的每台生产设备。

 

•      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.

 

•      根据回顾性评估制订的CAPA计划，其中包括对你们清洁工艺和做法的适当补救措施，以及完成的时间表。提交一份对你们产品清洁生命周期管理中清洁工艺薄弱点的详细总结，阐述对你们清洁程序的改进，包括提高清洁有效性、改进对所有产品和设备清洁执行适当性的核查，以及所有其它必须改进措施。

 

· 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:

 

· 除了这份全面补救措施外，还要提交一份正在有效补救导致上面所讨论的特定交叉污染的情形的特定CAPA行动。提交一份你们顾问的独立审核，确定你们CAPA的有效性，包括但不仅限于：

 

•      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)

 

•      一份清洁和维护程序的所有改进措施清单，包括具体频次和所有相关设备要清洁的位置（例如XX、风管）

 

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

 

•      找出XX设备、XX和风管以外的所有其它交叉污染来源

 

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

 

•      确定你们鉴定残留物的分析方法的充分性

 

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

 

•      你们对留样检测中发现的未知（未鉴定）峰的调查

 

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

 

•      证明你们研究中所发现的挑战，如产品基质干扰，和重叠峰已得到充分解决的支持性证据

 

•      adequacy of scope of the investigation and its related CAPA

 

•      调查及其相关CAPA范围的充分性

 

· 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.

 

· 我们亦了解你们正在进行研究，以确定风管的清洁度，评估XX。解释你们在指定的XX清洁时间间隔之前，防止风管交叉污染的临时计划

 

•      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:

 

•      对你们清洁验证程序改进的最新情况，特别注意结合你们药品生产操作中识别为最差情形的条件。其中包括但不仅限于对所有最差情形的识别和评估：

 

· drugs with higher toxicities

 

· 毒性高的药品

 

· drugs with higher drug potencies

 

· 药物效价高的药品

 

· drugs of lower solubility in their cleaning solvents

 

· 在其清洁溶剂中溶解度较低的药品

 

· drug~ with characteristics that make them difficult to clean

 

· 具有难以清洁特性的药品

 

· swabbing locations for areas that are most difficult to clean

 

· 最难清洁部位的擦拭取样点

 

· maximum hold times before cleaning

 

· 清洁前的最长放置时长

 

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

 

另外要说明引入新生产设备或新产品之前在你们变更管理系统中必须采取的措施

 

•      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.

 

•      完整说明你公司在留样研究中所用的回收校正因子。包括计算例子及其在所有7个你们确认有残留批次中的应用情况。说明在你们风险评估中是否有因为你们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.

 

•      对于发现有其它活性成分痕迹的7个批次，提交所有非专用设备中生产的之前至少30个批准的详细信息，包括产品名称、工艺步骤、所有识别编号和生产日期。亦要突出显示这些之前批次之间的相互关系、网管中的残留以及发现被污染的成品批次。