[GMP] FDA对英国CP(印度Wockhardt)发布警告信: 无菌环境与药品的污染

Your Preferred Partner to Compliance

November 16, 2016

Dr. Habil Khorakiwala

Founder, Chairman & Group CEO

Wockhardt Limited

Wockhardt Towers

Bandra Kurla Complex, Bandra (East)

Mumbai, Maharashtra 400 051, India

Dear Dr. Khorakiwala:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, CP Pharmaceuticals, Ash Road North, Wrexham Industrial Estate, Wrexham, United Kingdom, from October 5 to 9 and October 12 to 13, 2015.

FDA在2015年10月5-9和12-13日检查了你们在英国雷克瑟姆的生产场所。

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

本警告信总结了你们制剂生产CGMP严重违规情况。

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).

由于你们生产、加工、包装和保存的方法、设施和控制不符合CGMP要求，你们的药品根据FDCA的定义被认为是掺假药品。 

We reviewed your firm’s November 3, 2015, response in detail and acknowledge receipt of your subsequent responses.

我们详细审核了你们于2015年11月3日及随后发来的回复。

Our investigator observed specific violations during the inspection, including, but not limited to, the following.

在我们检查期间，我们的调查人员发现的违规情况包括但不仅限于以下：

1. 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))

你们公司未能遵守适当的书面程序，该程序是设计来防止无菌药品受到微生物污染的，其中包括所有无菌和灭菌工艺的验证。(21 CFR 211.113(b))

Our investigator observed poor practices during aseptic set-up and filling, including but not limited to the following examples.

我们的调查人员发现无菌安装和灌装过程中不良做法，包括但不仅限于以下例子：

• Multiple operators who had touched surfaces and items in the ISO-7 clean area failed to disinfect their hands before performing activities within the ISO-5 area.   For instance, we observed operators touching the external control panel and push carts. Without disinfecting their gloved hands, these operators then opened the Restricted Access Barrier System (RABS) and performed activities in the ISO-5 area.

  多个操作人员在接触了ISO-7洁净区的表面和物品后，手没有消毒即在ISO-5洁净区内进行活动。例如，我们发现操作人员接触外控制面板，推了小车，然后没有对戴着手套的手进行消毒，同样这些操作人员就打开RABS，在ISO-5洁净区进行活动。

• We observed operators moving briskly and causing excessive movement of the (b)(4) located immediately adjacent to the RABS. This excessive movement occurred while the RABS (b)(4) were open.

  我们发现操作人员快速移动，引起紧邻RABS的XX过量移动。此过量移动是在RABS打开的时候发生的。

• You do not routinely disinfect the cart used for holding (b)(4) items prior to use. This cart is stored in the Grade B area for an extended period, and is cleaned and disinfected only (b)(4).

  你们日常并没有对用于保存XX物件的小车在使用之前进行消毒。此小车存贮在B级区超过了时长，但只是在XX时候进行了清洁和消毒。

• We observed (b)(4) bags with sterile supplies coming in contact with the (b)(4) in the ISO-7 area when being transported to the RABS. These bags were not disinfected prior to entry into the RABS. 

  我们发现XX无菌袋子在传递到RABS的时候与ISO-7区的XX有接触。这些袋子在进入RABS之前没有消毒。

These deviations were neither documented in your batch production record, nor captured by the quality unit during their observation of videos of the operation as per your SOP #QAP-199-0-1704. This procedure requires quality unit personnel to review the acceptability of general techniques and behaviors of cleanroom personnel within classified areas (ISO 5 and ISO 7).   

这些偏差在你们的批生产记录中没有记录，质量部门在按照你们的SOP #QAP-199-0-1704其对录像的观看中也没有发现。该SOP要求质量部门人员审核通用技术和洁净间人员在洁净区（ISO 5和ISO 7）里行为的可接受性。

The ISO 5 is a critical area 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.

ISO 5是一个关键区域，因为无菌产品暴露在其中，因而不可避免会受到污染。你们的无菌灌装工艺的设计和所执行的操作应防止对你们的无菌产品的污染危害。

Your firm’s response is inadequate. Although your response includes a revised procedure (QAP-199-0-1704) on quality oversight of operations, you did not retrospectively evaluate video footage to identify poor aseptic practices and identify any batches produced under these conditions. In response to this letter, provide a third party’s independent assessment of aseptic processing practices and affected batches.   

你们公司的回复是不充分的。虽然你们的回复包括了修改质量部门监管操作的程序(QAP-199-0-1704)，但你们没有回顾评估视频录像以找出不良的无菌做法，找出所在有这种条件下生产的批次。在对此函的回复中，请提供第三方对无菌处理做法和受影响批次的独立评估。

2. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas. (21 CFR 211.42(c)(10))

你们公司未能在特别指定的具有足够空间，有分隔或所需同类的其它控制系统中实施操作，以防止无菌处理区域的污染和混料。(21 CFR 211.42(c)(10))

a. Environmental Monitoring 环境监测

Your environmental monitoring program did not sufficiently cover personnel in your ISO-5 area during set-up, filling, and other activities in your aseptic processing rooms. For example, our review of the Class 100 entry/exit log and other production records for 9/16-17/15 showed that (b)(4) operators participated on the filling line. However, most of these operators were not monitored.   

你们的环境监测计划不够充分，没有覆盖你们ISO 5级区域里在安装和灌装及其它无菌处理间活动期间的人员。例如，我们审核你们15年9月16-17日的100级进出日志和其它生产记录，记录显示某操作人员参与了灌装线活动，但是，这些操作人员大多数都没有进行监测。

In your response, you committed to perform a risk assessment (RAS-088-3950) of the failure to sufficiently monitor all personnel conducting aseptic activities in the ISO-5 area. Your response failed to describe any details of how this assessment will be conducted.

在你们的回复中，你们承诺要对ISO 5区域内所有实施无菌活动的人员没有进行充分监测的情况实施风险评估(RAS-088-3950)。你们的回复未能描述要如何实施该评估的详细情况。

In response to this letter, provide a copy of your current risk assessment. Inform this office of all actions to be taken as a result of your risk assessment. 

在回复此函时，请提供你们目前风险评估的副本。通知本办公室你们风险评估后认为所需要采取的所有措施。

Also, explain whether production staff performing aseptic setup activities are part of your routine monitoring program.

还有，要解释是否实施无菌安装活动的生产人员是你们日常监测计划的一部分。

Our previous warning letter (no. 320-11-002, dated October 29, 2010) also cited inadequate personnel monitoring. Your repeated failure to create a robust monitoring program indicates insufficient oversight of your aseptic production operation.

我们之前的警告信（2010年10月29日，编号320-11-002）也引用了人员监测不充分的条款。你们一直未能建立健全的监测计划显示出你们对无菌和平操作的监管不充分。

b. Disinfection Qualification 消毒确认

We observed that your firm did not adequately disinfect your RABS. For example, surfaces (b)(4) the RABS (b)(4) were not routinely disinfected, and your firm incompletely disinfected the bottom of the RABS (b)(4).

我们发现你们公司没有对你们的RABS进行充分地消毒。例如，RABS某表面日常不进行消毒，你们公司对RABS的底部消毒也不完全。

In addition, you have not sufficiently established the efficacy of disinfectants you use in aseptic processing cleanrooms. Your disinfectant study only challenged (b)(4) and (b)(4) manufacturing surfaces. You did not provide an adequate scientific rationale for not challenging other representativesurfaces, such as glass windows, (b)(4), (b)(4), (b)(4), (b)(4), or other interior RABS surfaces.  

另外，你们没有充分建立起你们在无菌工艺洁净间所用的消毒剂的有效性。你们的消毒剂研究只是挑战了XX和XX生产表面。你们没有提供足够的科学合理性来支持不去挑战其它具有代表性的表面，例如，玻璃窗，XXX和其它RABS内表面。

In response to this letter, provide data to support the efficacy of your disinfection procedures on additional representative surfaces.

在回复此函时，请提供数据支持你们对其它具有代表性表面的消毒程序的有效性。

Aseptic processing guidance 无菌工艺指南 

See FDA’s guidance document, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice, to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing. It is available online at

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070342.pdf.  

参见FDA指南文件《无菌工艺生产的无菌药品---CGMP》帮助你们在使用无菌工艺生产无菌药品时符合CGMP要求。上述网址可以下载。

Aseptic processing consultant recommended 无菌工艺顾问建议 

Based upon the nature of the violations we identified at your firm and because you failed to correct repeat violations, we strongly recommend engaging a consultant qualified as set forth in 21 CFR section 211.34, to assist your firm in meeting CGMP requirements for aseptic processing. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.

根据我们发现的你们违规情况，由于你们未能纠正重复违规行为，我们强烈建议你们聘请有资质的顾问，帮助你们公司符合无菌工艺的CGMP要求。

In response to this letter, provide the following:

• A comprehensive evaluation of the design, control, maintenance, and oversight of your aseptic processing lines, including but not limited to:  

• A thorough assessment of the adequacy of personnel behaviors and activities for all aseptic processing lines, including during both setup and processing.  

• A full review of the sufficiency of your RABS disinfection practices and procedures. This should include an evaluation of the adequacy of sporicidal disinfection of the interior prior to each RABS use. Also provide an evaluation of the adequacy of disinfection practices for operators’ gloved hands and RABS surfaces during setup and batch operations.  

• An overall evaluation of CGMP compliance, including identification of additional contamination hazards in the operation, as well as any deficiencies in manufacturing design, systems, procedures, controls, maintenance, supervision, and training effectiveness. 
  

• A risk assessment of the potential effects of the observed deficiencies on the quality of your drug products. Describe how these deficiencies may have impacted the quality of drug products released for distribution.
  

• An overall management strategy that describes how your executive management will oversee improvements in operations and ensure on

  going oversight to provide for sustainable quality assurance. 

Conclusion

Violations cited in this letter are not intended as an all-inclusive list. You are responsible for determining the causes of these violations, for preventing reoccurrences, and for preventing other violations.

 

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 [e-mail], 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 discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) and 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.

 

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

 

Failure to correct these violations may also result in FDA refusing admission of articles manufactured at CP Pharmaceuticals, Ash Road North, Wrexham Industrial Estate, Wrexham, United Kingdom, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles 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).

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.

 

Send your electronic reply to [e-mail] or mail your reply to:

 

Rafael Arroyo, Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

 

Please identify your response with FEI 3003369660.

  

Sincerely,

Francis Godwin

Acting Director

Office of Manufacturing Quality

Center for Drug Evaluation and Research

来源：JuliaBlog，感谢朱玉姣老师。