翻译：JULIA  来源：Julia法规翻译

警告信列举的检查缺陷摘要如下：

1、你公司未能按适当时间间隔对设备和工器具进行清洁、保存，并根据产品属性进行消毒和/或灭菌（适当时）以防止故障或污染改变药品的安全性、鉴别、剂量、质量或纯度使得超出官方或其它既定要求（21 CFR 211.67(a)）。

你们对非专用设备包括XX的清洁是不充分的。我们的检查员发现多个用于生产活性和非活性化合物的XX标示为清洁，但其中有看起来是不同药品的残留。在换产品清洁之后在XX背部发现有残留。你们设备的XX系统与药品加工的设备内部相互影响。

2、你公司未能彻底调查所有未解释的差异，或已销售或未销售批次或其组份不符合其质量标准的情形（21 CFR 211.192）。

你们对XX回收定期确认过程中的失败调查是不充分的。例如，调查DC/2018/381于20180609启动，原因是XX西林瓶注射剂所用XX定期重新确认失败。未达到所需的F0值，并且至少有XX的严重XX波动。你们得出结论说根本原因是XX不当。作为影响性评估的一部分，你们评估了使用相同XX的其它产品的确认报告，得出结论说对其它XX药品没有影响。因此你们并未扩展CAPA至其它产品。

3、你公司未能遵守恰当的书面程序，这些程序应设计用以防止理当无菌药品的微生物污染，以及包括所有无菌和灭菌工艺的验证（21 CFR 211.113(b)）。

不良无菌行为

• 操作员在无菌装配和灌装操作期间显示的不良无菌行为。例如：

• 操作员在无菌塞打开的袋子上方倾斜身体。这些袋子后来被导入胶塞槽。

• 操作员的手还越过无菌塞导槽上，在已加到导槽的灭菌后塞子上方。

• 值得注意的是，你们的程序特别禁止人员在药品或灭菌后容器和密闭器上方倾斜身体。 

4、你公司未能制订足够的系统监测无菌工艺区域的环境条件（21 CFR 211.42(c)(10)(iv)）。

你们的环境和人员监测计划有缺陷。例如，你们的程序允许人员在XX区域执行无菌干预（例如XX），在其XX上有XX菌落（CFU）而不会触发适当的调查。在我们检查期间，一位公司官员指出你们公司并未认为XX是干预行为，操作员只是遵守ISO7限度。

原文如下：

Warning Letter 320-20-05                  October 29, 2019         

Dear Mr. Patel:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Cadila Healthcare Limited, FEI 3002984011, at 419 & 420 8a Village-Moraiya, Ahmedabad, from April 22 to May 3, 2019.

美国FDA于2019年4月22日至5月3日检查了你们位于印度的Cadila Healthcare Limited，FEI 3002984011生产场所。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 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 May 24, 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5月24日对我们FDA483表的回复，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 other established requirements (21 CFR 211.67(a)) 你公司未能按适当时间间隔对设备和工器具进行清洁、保存，并根据产品属性进行消毒和/或灭菌（适当时）以防止故障或污染改变药品的安全性、鉴别、剂量、质量或纯度使得超出官方或其它既定要求（21 CFR 211.67(a)）。

Your cleaning procedure for non-dedicated equipment, including your (b)(4), is inadequate.  Our investigators observed multiple (b)(4), used in the production of potent and non-potent compounds, marked as clean and containing residues of what appeared to be different products. The residues were observed on the back of the (b)(4), after product change-over cleaning. The (b)(4) system of your equipment interacts with the interior of the equipment in which products are processed.

你们对非专用设备包括XX的清洁是不充分的。我们的检查员发现多个用于生产活性和非活性化合物的XX标示为清洁，但其中有看起来是不同药品的残留。在换产品清洁之后在XX背部发现有残留。你们设备的XX系统与药品加工的设备内部相互影响。

Significant equipment flaws and cleaning deficiencies resulted in cross-contamination between your drug products. For example, you lacked provisions for inspecting or cleaning the area behind the (b)(4).

严重的设备瑕疵和清洁缺陷导致你们药品之间的交叉污染。例如，你们缺少XX后面区域的检查或清洁规定。

After our inspection, your firm observed residues in additional non-dedicated equipment and confirmed the recovery of multiple active ingredients through swab samples and visible (b)(4) residues collected from product-contact surfaces. For example:

在我们检查之后，你们公司在其它非专用设备中也发现了残留，并确认从与产品接触的表面擦拭取样发现多个活性成分和可见XX残留。例如：

• Equipment ID #CH/PM/013 – (b)(4) active ingredients were identified in swab and (b)(4) residues out of (b)(4) products processed in the equipment.

• 生产XX个药品的设备ID #CH/PM/013 –擦拭取样中检出XX活性成分和XX残留

• Equipment ID #CH/PP/028 – (b)(4) active ingredients were identified in swab and (b)(4) residues out of (b)(4)  products processed in the equipment.

• 生产XX个药品的设备ID #CH/PP/028–擦拭取样中检出XX活性成分和XX残留

• Equipment ID #CH/TS/013 - (b)(4) active ingredients were identified in swab and (b)(4) residues out of (b)(4) products processed in the equipment.

• 生产XX个药品的设备ID #CH/TS/013 –擦拭取样中检出XX活性成分和XX残留

• Equipment ID #CH/MC/TAB/1999/19 - (b)(4) active ingredients were identified in swab and (b)(4) residues out of (b)(4) products processed in the equipment.

• 生产XX个药品的设备ID #CH/MC/TAB/1999/19 –擦拭取样中检出XX活性成分和XX残留

• Equipment ID #CH/MC/TAB/2004/176 - (b)(4) active ingredients were identified in swab and (b)(4) residues out of (b)(4) products processed in the equipment.

• 生产XX个药品的设备ID #CH/MC/TAB/2004/176 –擦拭取样中检出XX活性成分和XX残留

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 manufactured in numerous samples tested, including but not limited to:

在我们检查后，你公司亦检测了所选批次的留样，以评估交叉污染的可能性。你们的测试确认了在许多受检样品中检出所生产的活性成分，包括但不仅限于：

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

• XX片剂中XX活性成分的残留

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

• XX片剂中XX活性成分的残留

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

• XX片剂中XX活性成分的残留

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

• XX片剂中XX活性成分的残留

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

• XX片剂中XX活性成分的残留

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

• XX片剂中XX活性成分的残留

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

• XX片剂中XX活性成分的残留

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

• XX片剂中XX活性成分的残留

• Residues of (b)(4) active ingredientsin (b)(4) tablets

• XX片剂中XX活性成分的残留

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

• XX片剂中XX活性成分的残留

As a result of these inspectional findings your firm initiated a recall of numerous batches manufactured in your (b)(4) #CH/TS/013 (dedicated to potent compounds). 

基于检查发现情况，你公司对你们XX #CH/TS/013（专用于活性化合物）大量批次的启动了召回。

In your response, you committed to corrective and preventive actions (CAPA) for non-dedicated equipment, including revisions to cleaning procedures, mechanical changes to equipment to prevent (b)(4), cleaning validation for all processing equipment, and further testing to analyze reserve samples of batches manufactured using (b)(4) to quantify the potential carryover of previous products.

在你们的回复中，你们承诺了对非专用设备的CAPA，包括修订清洁程序、对设备进行机械性修改、对所有工艺设备进行清洁验证，以及进行进一步检测从而分析使用XX所生产批次的留样以确定前一药品的残留数量。

Your firm’s review concluded that the significant cross-contamination identified by your firm does not represent a risk to patients.

你公司的审核结论说你们发现严重的交叉污染，但对患者没有风险。

Your response is insufficient. Your response stated that any potential residue that enters the (b)(4) and contaminates the next drug product can produce a nearly uniform distribution in the (b)(4) and that (b)(4) steps minimize localization of carryover residue. Your rationale is not scientifically sound in that cross-contamination cannot be assumed to be uniformly distributed.

你们的回复是不充分的。你们的回复声称所有进入XX的潜在残留和污染下一药品可能在XX得到近乎均匀的分布，并且XX步骤会降低携入残留的集中。你们的理由不够科学合理，因为不能假定交叉污染会均匀分布。

In addition, your response described failure modesthat may have contributed to the accumulation of residues in the (b)(4). But you failed to explain when the cross-contamination involving numerous products started and why it had not been detected. Your response also stated that testing for cross-contamination in the products provides good assurance that any carryover is detected. However, reserve sample testing alone is insufficient to mitigate associated risks.  The extent of the cross-contamination found suggests a lack of assurance that products meet appropriate standards for identity, quality, purity and safety.

另外，你们的回复阐述了可能对XX中残留累积起作用的失效模式。但你们并未解释自何时起交叉污染涉及到大量药品，以及为何一直未发现。你们的回复亦声称对药品中交叉污染的检测提供了良好的保证证明检出所有残留。但是仅仅检测留样是不足以缓解相关风险的。所发现的交叉污染的程度说明不能保证药品符合适当的鉴别、质量、纯度和安全性标准。

In response to this letter provide the following:

在回复本函时请提交以下：

• Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment.  This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to     appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review. 

• 你们对设施和设备实施常规化警觉操作管理监管的CAPA计划。该计划应确保（除其它外）快速发现设备/设施性能问题、有效进行修理、遵守适当的预防性维护计划、及时对设备/厂房基础设施进行技术升级，以及改进持续管理审评体系。

• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards and recalls initiated to determine if     additional batches were affected. This should include, but not be limited to:

• 一份对你们清洁效果的独立全面回顾评估，以评估交叉污染危害和所启动召回的范围，确定是否还有其它批次受到影响。其中应包括但不仅限于：

  • Identification of any inadequacies of cleaning procedures and practices for each piece of manufacturing equipment used to manufacture more than one product.

  • 找出多产品生产所用每台生产设备的清洁程序和做法的所有不足；

  • Any updates to your investigation regarding the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether additional cross-contaminated products may have been released for distribution.

  • 对你们残留鉴定方面，其它可能被不当清洁的生产设备，以及评估是否还有其它被交叉污染的药品放行销售调查的任何更新。

• A CAPA 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. 

• 一份基于回顾性评估的CAPA计划，其中包括对你们清洁工艺和做法的适当补救措施，以及完成时间表。提交一份对你们设备清洁生命管理工艺中弱点的详细总结。说明你们清洁程序的改进，包括对清洁有效性的改进、改进后的所有药品和设备清洁执行情况持续确认，以及所有其它所需补救措施。

• Appropriate 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的适当改进，特别要强调在你们药品生产操作中结合判定为最差情形的条件。其中应包括但不仅限于所有最差情形的识别与评估：

  • drugs with higher toxicities

  • 较高毒性的药品

  • drugs with higher drug potencies

  • 较高药品效价的药品

  • drugs of lower solubility in their cleaning solvents

  • 在其清洁溶剂中溶解度较低的药品

  • drugs with characteristics that make them difficult to clean

  • 难以清洁的药品

  • swabbing locations for areas that are most difficult to clean

  • 最难清洁区域的擦拭取样位置

  • maximum hold times before cleaning

  • 清洁前最长放置时长

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，说明你们引入新的生产设备或新产品之前变更管理系统中要采取的步骤。

• A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment. Also, include a copy of your cleaning validation report once completed.

• 一份更新后的SOP的总结，确保具备产品、工艺和设备清洁程序确认和验证程序。另外要包括一份你们清洁验证报告的副本（完成后立即提交）。

2.    Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).你公司未能彻底调查所有未解释的差异，或已销售或未销售批次或其组份不符合其质量标准的情形（21 CFR 211.192）。

Your investigations into failures during periodic qualification of the (b)(4) cycles are inadequate. For example, investigation DC/2018/381 was initiated on June 9, 2018 for a failure during periodic requalification of the (b)(4) used for (b)(4) Injection (b)(4)ml in (b)(4) ml vial. The required F0 was not achieved and there was significant (b)(4) variation for at least (b)(4). You concluded that the root cause was improper (b)(4). As part of the impact assessment, you evaluated the qualification reports for other products that utilize the same (b)(4)and concluded that there was no impact on other (b)(4) products. Therefore, you did not extend the CAPA to other products.

你们对XX回收定期确认过程中的失败调查是不充分的。例如，调查DC/2018/381于20180609启动，原因是XX西林瓶注射剂所用XX定期重新确认失败。未达到所需的F0值，并且至少有XX的严重XX波动。你们得出结论说根本原因是XX不当。作为影响性评估的一部分，你们评估了使用相同XX的其它产品的确认报告，得出结论说对其它XX药品没有影响。因此你们并未扩展CAPA至其它产品。

However, in March 2019, you initiated investigation DC/2019/190 and DC/2019/195 because of another failure during the periodic requalification of the same (b)(4) used for the (b)(4) of (b)(4) Injection (b)(4) ml in (b)(4) ml vial. Again, several sensors did not achieve the required F0, and one did not reach the (b)(4) temperature. In addition, at the end of the incubation, the biological indicators at multiple locations in the (b)(4) showed microbiological growth. This resulted in the recall of (b)(4) batch of (b)(4) Injection, USP, (b)(4)mg per (b)(4) ml ((b)(4) mg perml), due to lack of (b)(4) assurance.  

但是，2019年3月，你们启动了调查DC/2019/190 和DC/2019/195，原因是XX西林瓶注射剂所用相同XX定期重新确认失败。仍然是未达到所需的F0值，，并且有一个未到达XX温度。另外，在培养结束时，XX中多个位置的生物指示剂显示有微生物生长。该偏差导致召回XX批次XX注射剂，理由是缺少XX保证。

In this instance you also concluded that the root cause was improper (b)(4). There was no assurance that your assessment of other (b)(4) products using this (b)(4) was thorough and that adequate CAPA were identified and implemented. In addition, your investigation did not sufficiently address why your originally validated cycle parameters were not met and why the process fell out of a state of control. 

在此事件中，你们也是得出结论说根本原因是XX不当。无法确保你们对使用该XX的其它XX产品的评估足够彻底，并且识别和执行了充分的CAPA。另外，你们的调查未充分说明为何不符合你们原来的验证周期参数，以及为何工艺不在受控状态。

Your response adds that there has been some drift in the calibration of the built-in (b)(4) that control the (b)(4) cycle since 2017.  However, your response lacks an assessment of the adequacy of the (b)(4) calibration standards, as you acknowledge in the response that the variation observed is within your established acceptance criteria. Also, calibration of (b)(4) was verified as part of your original investigation.

你们的回复补充说自2017年以来用于控制XX循环的内置XX校正有一些漂移。但是你们的回复缺少对XX校正标准充分性的评估，因为你们在回复中承认所观察到的波动在你们制订的可接受标准内。另外，XX的校正作为你们原始调查的一部分是经过了核查的。

According to your firm’s investigation report there have been seven deviations during the periodic requalification of this (b)(4) in the past two years. Recurrent failures suggest that you have not adequately identified the root cause and lack (b)(4) assurance.

根据你们公司的调查报告，过去2年里该XX在定期重新确认中有7个偏差。重复发生的失败说明你们并未充分识别根本原因，且缺少XX保证。

In response to this letter provide the following:

在回复本函时请提交以下：

• A comprehensive retrospective, independent review of all batches (b)(4) with this (b)(4) that were distributed in the U.S. market and remain within expiry. This review should include, but not be limited, to:

• 一份对销售至美国仍在效期内使用本XX的所有批次的独立全面回顾审核。该审核应包括但不仅限于：

  • Review of your (b)(4) parameters, including time and (b)(4) settings to ensure a (b)(4) assurance level of (b)(4) or more. 

  • 对你们XX参数的审核，包括时间和XX设置以确保XX或更多XX保证水平

  • Evaluations of F-value and Z-value data and any related assumptions; (b)(4); D-value determinations and population enumerations for each biological indicator lot; and commercial batch data to determine whether (b)(4) cycles used for your products were complete/adequate.

  • 对F值和Z值数据和任何相关假设的评估；XX；每批生物指示剂的D值和含菌量的计算；以及商业化批次数据以确定你们药品所用XX周期是否完整/充分。

• A comprehensive and independent assessment of your system for investigating deviations, and failures. Your CAPA plan should include, but not be limited to, improvements in investigations, root cause analysis, written procedures, staff competencies (e.g., evaluating potential root causes), and quality unit oversight. Also, include your process for evaluating CAPA plan effectiveness.

• 一份对你们调查偏差以及失败的系统的独立全面评估。你们的CAPA计划应包括但不仅限于对调查、根本原因分析、书面程序、员工能力（例如评估潜在根本原因）以及质量部门监管的改进。还需包括你们评估CAPA计划有效性的流程。

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 CFR211.113(b)). 你公司未能遵守恰当的书面程序，这些程序应设计用以防止理当无菌药品的微生物污染，以及包括所有无菌和灭菌工艺的验证（21 CFR 211.113(b)）。

Poor Aseptic Behavior 不良无菌行为

Operators displayed poor aseptic practices during aseptic set-up and filling operations. For example:

操作员在无菌装配和灌装操作期间显示的不良无菌行为。例如：

• Operators leaned over the open bag of sterilized stoppers. These bags are subsequently introduced into the stopper chute. Also, the operator’s hands passed over the sterile stopper  chute and over sterilized stoppers already added into the chute. Notably, your procedures specifically prohibit personnel leaning over the product or sterilized containers and closures.

• 操作员在无菌塞打开的袋子上方倾斜身体。这些袋子后来被导入胶塞槽。操作员的手还越过无菌塞导槽上，在已加到导槽的灭菌后塞子上方。值得注意的是，你们的程序特别禁止人员在药品或灭菌后容器和密闭器上方倾斜身体。

• Operators used (b)(4) Restricted Access Barrier Systems ((b)(4)RABS) (b)(4) to pick up sterile forceps and remove fallen vials. During that intervention, the (b)(4) extend over open vials without clearing them. According to your procedures, (b)(4)RABS (b)(4)are sterilized only (b)(4). Your firm’s staff confirmed that these (b)(4) cannot be considered sterile during this extended use period.

• 操作员使用了XX RABS 捡起无菌钳子，清除倒掉的西林瓶。在此干扰过程中，XX伸到开口的西林瓶上方却没有清除它们。根据你们的程序，XX RABS XX仅XX灭菌的。你公司的员工确认在此延长使用期间这些XX不能认为是无菌。

Inadequate Cleanroom Designand Smoke Study Deficiencies

清洁间设计不足和发烟试验缺陷

Your stopper chute leans (b)(4) of the filling line during stopper loading operations thereby creating turbulence as the air flows (b)(4)filters (b)(4) the chute.

你们的塞子导槽在加塞操作期间倾向灌装线的XX，因此在空气流动XX时导致扰动。

In addition to this inadequate design, your smoke studies performed for your (b)(4) areas also lacked simulation of multiple critical interventions that occur during aseptic manufacturing operations.

除开此设计不足外，你们XX区域所实施的发烟试验亦缺乏对无菌生产操作期间发生的多个关键干预的模拟。

Thorough smoke studies are essential to evaluate the effects of such interventions on unidirectional airflow and to ensure design modifications are made wherever necessary.

彻底的发烟试验对于单向流中此类干预影响的评估，以及确保必要时对设计进行修正是必须的。

The (b)(4) 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 promoted influx of contamination into the critical filling areas.

XX区域是关键的，因为无菌药品暴露在其中，因此易受污染。你们的无菌灌装工艺的设计以及操作应防止对你们无菌药品的污染危害。灌装线设计和无菌操作执行瑕疵使得关键灌装区域易受污染。

Your firm’s response is inadequate. You did not provide a thorough evaluation of all batches produced under inadequate conditions.

你公司的回复是不充分的。你们并未提交对在不充分条件下所生产的所有批次的彻底评估。

In response to this letter, provide the following:

在回复本函时请提交以下：

• A risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:

• 一份对你们无菌工艺、设备和设施方面所有污染危害的风险评估，包括一份独立评估，其中包括但不仅限于：

  • All human interactions within the (b)(4) area

  • XX区域内所有人为扰动

  • Equipment placement and ergonomics

  • 设备放置和人体工程学

  • Air quality in the (b)(4) area and surrounding room

  • XX区域和周边房间的空气质量

  • Facility layout

  • 设施平面布局

  • Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)

  • 人流和物流（实施和支持无菌操作所用的所有房间）

• A comprehensive, independent retrospective review of all batches that remain within expiry in the U.S. market, which incorporates the knowledge of hazards gained from your risk assessment.  Include any additional actions you intend to initiate because of the retrospective review.

• 一份对在美国市场上仍在效期内的所有批次的独立全面回顾性审核，其中要结合从你们风险评估中所获得的危害性知识。包括所有你们因回顾性审核而准备启动的其它措施。

4.    Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)). 你公司未能制订足够的系统监测无菌工艺区域的环境条件（21 CFR 211.42(c)(10)(iv)）。

Your environmental and personnel monitoring programis deficient. For example, your procedures allowed personnel performing aseptic interventions (e.g., (b)(4)) in the (b)(4) area to have (b)(4) colony-forming units (CFU) on their (b)(4) without triggering an appropriate investigation.  During our inspection, a firm official indicated that your firm does not consider the (b)(4) to be an (b)(4) intervention and operators are only held to ISO 7 limits.

你们的环境和人员监测计划有缺陷。例如，你们的程序允许人员在XX区域执行无菌干预（例如XX），在其XX上有XX菌落（CFU）而不会触发适当的调查。在我们检查期间，一位公司官员指出你们公司并未认为XX是干预行为，操作员只是遵守ISO7限度。

The (b)(4) step in your operation is acritical aseptic intervention, and it is manually intensive. Our inspection noted significant aseptic technique breaches during performance of this intervention.

你们操作中的XX步骤为关键的无菌干预，人为动作密集。我们检查注意到在此干预实施期间有严重的无菌技术问题。

Your firm’s response is inadequate. We acknowledge your commitment to conduct a protocol-based assessment to evaluate the adequacy of limits of viable monitoring based on the classification of the area and the criticality of the operation. However, your response did not include a retrospective review of your personnel monitoring data to identify the instances in which operators held to ISO 7 limits conducted activities in the (b)(4) area, and if the (b)(4) limits were exceeded. Growth observed on (b)(4) samples taken from personnel performing any activities within the (b)(4) area should, at a minimum, lead to trending and assessment, and could trigger further actions and investigation.

你公司的回复是不充分的。我们知晓你们承诺会根据一份方案基于区域级别和操作关键程度对微生物监测限度充分性进行评估。但是你们的回复并未包括对你们人员监测数据的回顾性审核，以发现操作员遵守ISO7限度时所在XX区域执行的活动情况，以及是否超出了XX限度。从XX区域内执行任何活动的人员所采集的XX样品中观察到的微生物生长情况至少应进行趋势分析和评估，可能触发进一步措施和调查。

In response to this letter, provide the following for products that remain within expiry in the U.S. market:

在回复本函时，请提交仍在美国市场上且在效期内的药品的以下信息：

• A risk assessment of personnel and environmental monitoring data since April 2017, including but not limited to identification of adverse trends or acute findings, and any potential impact on marketed products. Place special emphasis on data from your aseptic processing rooms, as well as any adverse trends that indicate any loss of environmental control in your facility’s overall suite of cleanrooms.

• 对自2017年4月以来人员和环境监测数据的风险评估，包括但不仅限于识别不良趋势或严重问题，以及对已销售药品的任何潜在影响。特别要注意你们无菌工艺房间的数据，以及显示出你们设施整体洁净间环境失控的任何不良趋势

• A detailed update to the CAPAs implemented and their current status in light of your decision to permanently close down the injectable manufacturing lines that serve the U.S. market.

• 根据你们永久关闭美国市场注射车间线的决定，一份对已实施的CAPA的详细更新，及其当前状态

• Describe how your firm will ensure continued accountability and responsibility for all products remaining in distribution from this facility (e.g. complaint evaluation, stability testing, handling of reserve samples, post-marketing reporting activities, OOS investigations and document retention).  State who will be performing these duties and procedures that will be followed for all marketed products.

• 说明你们公司将如何确保对该设施所生产的所有在市药品的持续义务和责任（例如，投诉评估、稳定性测试、留样处理、上市后报告活动、OOS调查和文件保存）。说明谁将履行这些义务，以及所有在市药品将要遵守的程序。

Cessation of Sterile Drug Manufacturing for U.S. Marketed Products停止在美国上市的无菌药品生产

In your October 2, 2019 communication, you informed the FDA that you would permanently cease production of injectable drug products for the United States. It is important to note that full remediation of the related CGMP violations cited will be necessary if you decide to resume the manufacturing of injectable drug products at this site, or if any successor firm assumes responsibility over the site’s operation in the future. In your response include your action plan for transferring any of your injectable drug products to other facilities. Notify this office in writing if you decide to revisit your decision and resume manufacturing injectable drugs for the U.S. in the future.  

在你们2019年10月2日的沟通中，你们通知FDA你们将永久停止生产美国市场的注射药品。需要注意的是，如果你们决定恢复该场所注射药品的生产，如果任何后续公司在将来恢复对该场所的运营责任，则需要全面纠正所引用的相关CGMP违规情况。在你们的回复中请包括你们转移任何注射药品至其它设施的行动计划。如果你们决定重新审核你们的决策，在将来恢复美国注射药品的生产，请书面通知本办公室。

Additional Guidance on Aseptic Processing 其它无菌工艺指南

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practiceto help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.

参见FDA指南文件“无菌工艺生产的无菌药品CGMP”。

Repeat Violations at Facility 场所重复违规

In previous warning letters (WL 320-11-015 and 320-16-05), FDA cited similar CGMP violations. You proposed specific remediation for these violations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

在之前的警告信（WL 320-11-015 and 320-16-05）中，FDA引用了相似的CGMP违规。你们在回复中对这些违规行为提出了具体的补救措施。重复失败证明执行管理层对药品生产的监管和控制是不充分的。

Conclusion 结论

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

此函中所引用的违规并不是全部。你们有责任对这些偏差进行调查，确定原因，防止其再次发生，防止你们设施内其它偏差的发生。

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuancesor interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

如果你们在考虑要采取的措施可能会导致你们工厂所生产的药品供应中断，FDA要求你立即联系CDER药品短缺负责人员，这样FDA可以与你们一起采用最为高效的方式引导你们的操作符合法规要求。联系药品短缺负责人员还能让你满足依据21 U.S.C. 356C(b)你可能必须报告你们药品中止或中断的义务，让FDA尽快考虑是否需要采取何种措施来避免短缺，保护依赖于你们药品的患者健康。

Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.

在贵公司未能完成所有偏差纠正并且由我们确认你们符合CGMP之前，FDA可能会搁置所有将你公司列为药品生产的新申报和增补申报的批准。

Failure to correct these violations may also result in the FDA refusing admission of articles manufactured at Cadila Healthcare Limited, 3002984011, at 419 & 420 8a Village-Moraiya, Ahmedabad, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C.351(a)(2)(B).

未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21 U.S.C. 381(a)(3)拒绝接受在上述地址生产的产品进入美国。

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

在收到此函后，请在15个工作日内回复至本办公室。在回复中说明自从检查后，你们做了哪些工作来纠正你们的偏差，防止其再次发生。如果不能在15个工作日内完成纠正措施，说明延迟的原因以及完成计划。

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

 Rebecca Parrilla, M.S.

Compliance Officer

 U.S. Food and Drug Administration

White Oak Building 51, Room 4235

10903 NewHampshire Avenue

           Silver Spring, MD20993           

Please identify your response with FEI 3002984011.

Sincerely,

/S/

FrancisGodwin                                                                       

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research