FDA警告信：印度Cipla（西普拉），高效过滤器出现大量不合格！

昨日，FDA发布了印度Cipla（西普拉）的警告信，包括以下缺陷：

• 检查员发现 设备排风管内有大量产品残留 。然后对该生产设备上采集的残留进行了分析测试，确认是不同产品。

• 然后该公司对留样样品进行检测发现被另一药品（上一批次产品）所污染。 但该公司回复含糊其辞 。此举使得FDA对其是否已全面解决严重的交叉污染问题而产生质疑。

• FDA发现， 在半年内，该公司的HEPA过滤器在短时间内出现大量异常 。超过45个过滤器出现边框泄漏和内部（过滤介质）不合格。

• 根据该公司的调查， 最可能的原因是垫圈老化，未及时更换过滤器。特别是有些过滤器是XX年前安装的，已经超出了SOP中规定的XX年更换期限。

• FDA对该公司的气流流型并不满意，FDA表示该公司 气流流型试验的烟雾并不可见，烟雾不够、受阻和摄像机角度问题，气流流型不好无法评估 。

• 未在 动态条件 下对进行气流流型试验

February 25, 2020

Warning Letter 320-20-26

Dear Mr. Vohra:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Cipla Limited, FEI 3004081307,at L138; Ll39 - 146; L147/A; L147/1 - 147/3; S103 - 105; S107 - 112; M61 - 63,Verna, Goa, from September 16 to 27, 2019.

美国 FDA 于 2019 年 9 月 16 日至 27 日检查了你们位于印度的 Cipla Limited （ FEI 3004081307 ）生产场所。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

本警告信总结了制剂生产严重违反 CGMP 的行为。参见 21CFR 第 210 与 211 部分。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

由于你们的制剂生产、加工、包装或保存的方法、场所或控制不符合 CGMP 要求，你们的药品根据 FDCA 的 501(a)(2)(B) 以及 21 U.S.C. 351(a)(2)(B) 被认为是掺假药品。

We reviewed your October 21, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司 2019 年 10 月 21 日的回复，并此告知已收到后续通信。

During our inspection, our investigators observed specific violations including, but not limited to, the following.

检查期间，我们的调查人员发现的具体问题包括但不仅限于以下：

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其他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。

2. Your firm failed to thoroughly investigate any discrepancy or failure of a batch or any of its components· to meet any ofits specifications, whether or not the batch has already been distributed (21CFR 211.192) 你公司未对已放行或未放行批次或其成分不符合其标准的情况进行彻底调查（ 21 CFR 211.192 ）。

In late 2018, your firm experienced excessive and atypical High Efficiency Particulate Air (HEPA) filters failures in a short period. More than 45 filters failed due to side leakages and media failures. The filters were often adjacent in the same room. You failed to adequately investigate these filter integrity test failures:

在 2018 下半年，你公司的 HEPA 过滤器在短时间内出现大量异常。超过 45个 过滤器出现边框泄漏和内部（过滤介质）不合格。 这些过滤器大部分在同一个房间的相近区域。你们未能对这些过滤器完整性检测不合格进行充分调查。

• DEV-1011-2018-00322, December 2018, Line (b)(4) (Unit (b)(4) ), 11 filter failures discovered during routine integrity testing of laminar air flow (LAFs) units IE/153, IE/154, IE/155 and IE/156, in Room (b)(4) (sterile (b)(4) area).

• DEV-1011-2018-00322 ， 2018 年 12 月，产线 XX ，在房间 XX （无菌 XX 区） LAF 单元 IE/153 、 IE/154 、 IE/155 和 IE/156 日常完整性测试中发现 11 个过滤器不合格

• DEV-1011-2018-00246, September 2018, Line (b)(4) (Unit (b)(4) ), filter media leakage observed in 14 filters and side leakages observed in 22 filters in sterile corridor, sterile vial filling and plugging, and (b)(4) loading & unloading room area (Room (b)(4) ).

• DEV-1011-2018-00246 ， 2018 年 9 月，产线 XX ，在无菌走廊、无菌西林瓶灌装间和加塞间，以及 XX 进料 & 卸料间（房间 XX ）发现 14 个过滤器介质泄漏， 22 个过滤器边框泄漏

• DEV-1011-2018-00261, October 2018, filter failure discovered major visible damage during routine cleaning in sterile injectable filling line (b)(4) (Unit (b)(4) ), Room (b)(4) .

• DEV-1011-2018-00261 ， 2018 年 10 月，在无菌注射剂灌装线日常清洁中发现严重可见破损，过滤器失效

According to your investigations, the most probable causes were gasket deterioration and lack of timely filter replacement. Notably, some filters were installed more than (b)(4) years ago, exceeding the already permissive limit of (b)(4) years in your procedure. Approximately 80 batches intended for the U.S. market (commercial and/or registration) were compromised.

根据你们的调查，最可能的原因是垫圈老化，未及时更换过滤器。 特别是有些过滤器是 XX 年前安装的，已经超出了你们程序规定的 XX 年限度。 约有 80 批次准备销售至美国的药品（商业化和 / 或注册批次）受到影响。

HEPA filter integrity is essential to ensure aseptic conditions. Your firm's investigation did not substantially evaluate environmental data and other manufacturing information to sufficiently determine whether the HEPA filter failures compromised the aseptic conditions of your sterile processing line and product quality.

HEPA 过滤器完整性是确保无菌条件的基本要求。你公司的调查并未深入评估环境数据和其它生产信息，以充分确定 HEPA 过滤器失效对你们无菌工艺产线的无菌条件和产品质量的影响。

We acknowledge your commitment to conduct an independent retrospective review of the deviations related to the HEP A filter integrity failures. However, your response is insufficient. Your response lacked sufficient data to support that there was no impact on marketed batches. For example:

我们知晓你们承诺会对 HEPA 过滤器完整性失败有效的偏差进行独立的回顾性审核。但是你们的回复是不充分的，回复中缺少足够的数据来支持已上市批次不受影响。例如：

• Your response' documented missing and/or unclear information in your assessments for products potentially impacted by the filter failures. Unclear elements include but are not limited to correlations of viable excursions with breached filters; inconsistencies in the exposure time of settle plates; and lack of assurance that the cleaning and (b)(4) activities were performed as per the procedures. It is not clear if these and other weaknesses in the investigation have been addressed and CAPA identified.

• 你们的回复记录缺失和 / 或未写明你们对可能受过滤器失效影响的产品的评估信息。不明要素包括但不仅限于：过滤器受损与微生物超标的关联性，沉降碟暴露时长的不一致情况，以及未按程序执行清洁和 XX 活动。不清楚调查中的薄弱点是否已解决，并已制订 CAPA 。

• Your response acknowledged a trend increase in environmental monitoring excursions from May 2018 to August 2018 in Room (b)(4) , but you lacked sufficient evidence to indicate that these excursions were unrelated to the HEPA filter failures. Your response acknowledged that the environmental trend warranted a review of the existing controls.

• 你们的回复承认 2018 年 5 月至 2018 年 8 月 XX 房间内环境监测超标有增长趋势，但你们并没有足够的证据证明这些超标与 HEPA 过滤器失效没有关系。你们的回复承认根据环境趋势分析需要对现有控制进行审核。

• We acknowledge that you rejected certain batches during this period due to microbiological environmental excursions in critical (ISO 5) areas. Your response indicated that approximately 18 batches processed in Unit (b)(4) were rejected from April 2018 to September 2018. Your response failed to include information about what type of failure occurred, the root causes, the impact on other products manufactured under the same conditions, and all CAPA implemented regardless of whether the specific rejected batches were intended for the U.S. market.

• 我们知晓你们在此期间因关键（ ISO 5 ）区域微生物环境超标而拒收了一些批次。你们的回复说自 2018 年 4 月至 2018 年 9 月在 XX 单元生产的产品约有 18 批被拒收。你们的回复未包括所发生失败类型的信息、根本原因、对相同条件下所生产其它产品的影响，以及无论所拒批次是否准备销售至美国市场，对其所执行的所有 CAPA 。

There is no assurance that all batches produced under inadequate conditions have been thoroughly evaluated, and that your firm has identified all contamination hazards associated with your sterile process.

你们未能确保在不充分条件下生产的所有批次均进行彻底评估，未能确保你公司识别出你们无菌工艺所有污染危害。

In response to this letter, provide the following:

在回复本函时请提交以下内容：

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) 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 assurance unit oversight, and written procedures. Address how your firm will ensure that all phases of investigations are conducted appropriately.

• 一份对你们偏差、差异、投诉、 OOS 结果和失败调查的全面系统的全面独立评估。提交一份详细的行动计划以补救该系统。你们的行动计划应包括但不仅限于对调查能力、范围界定、根本原因评估、 CAPA 有效性、质量部门监管和书面程序的重大改进。说明你们公司要如何确保恰当地执行了所有调查阶段。

• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether staff possesses proper investigation competencies, effectively conducts root cause analysis, and assures CAPA effectiveness. Also determine whether your quality system ensures you regularly review investigation trends, implement improvements to the CAPA program when needed, ensure appropriate quality unit decision rights, and receive full executive management that promotes timely lifecycle manufacturing improvements.

• 一份对你们 CAPA 程序的独立评估和补救计划。提交一份评估员工是否拥有适当调查能力、有效执行根本原因分析，以及确保 CAPA 有效性的报告。亦要评估你们质量体系是否能确保你们对调查趋势的定期审核，必要时对 CAPA 程序进行改进，确保适当的质量部门决策权，并得到全面的高级管理层促进及时生命周期生产改进。

• For all batches produced from February to December 2018 intended for the U.S. market, submit full environmental data for all ISO 5 air and contact surfaces (including operator gloves) in rooms (b)(4) and (b)(4) . Submit individual results, action/alert limits for each of theselocations, batch manufactured that day, microbial identification, and whetherthe batch was supplied to the U.S. Include potential correlations between the HEPA filter failures and these micro excursions.

• 对于 2018 年 2-12 月生产的准备销售至美国市场的所有批次，提交房间 XX 和 XX 内所有 ISO 5 级空气和接触表面（包括操作员手套）的全面环境数据。提交每个位置的单个结果、行动 / 警戒限、该天生产的批次、微生物鉴别，以及该批次是否销售至美国。包括 HEPA 过滤器失效与这些微生物超标之间的潜在关联。

• Your action plan to address any potential product quality or safety risks for any drug products in U.S. distribution.

• 你们解决销售至美国的所有药品的所有潜在产品质量或安全风险的行动计划

• A detailed root cause analysis that explains why numerous and clustered HEPA filter failures occurred in such a very short period.

• 一份详细的根本原因分析，解释为何在如此短的时间内有大量聚集性 HEPA 过滤器失效

3. 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)). 你公司未遵守适当的书面程序，设计用于防止既定无菌的药品微生物污染，并包括所有无菌和灭菌工艺的验证（ 21 CFR 211.113(b) ）。

You failed to perform adequate smoke studies to evaluate whether unidirectional flow exists in your aseptic operations. For example:

你们未执行足够的发烟试验，评估你们的无菌操作是否存在单向流。例如：

•