印度Anicare Pharmaceutical

地球球长

转自：Julia法规翻译Warning Letter:320-19-13

February 28, 2019

Mr. Hitesh Mehta

Director, Anicare Pharmaceutical Pvt.Ltd.

Plot No. A 143/5&6, TTC IndustrialArea, Khairne Village, Thane-Belapur Road, Navi Mumbai, 400710

INDIA

Dear Mr. Mehta:

The U.S. Food and Drug Administration(FDA) inspected your drug manufacturing facility, Anicare Pharmaceutical Pvt.Ltd., at Plot No. A 143/5&6, TTC Industrial Area, Khairne Village,Thane-Belapur Rd., Navi Mumbai, from July 30 to August 3, 2018.

美国FDA于2018年7月30日至8月3日检查了你们位于印度新孟买的Anicare Pharmaceutical Pvt.Ltd.生产场所。

This warning letter summarizessignificant 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, orcontrols for manufacturing, processing, packing, or holding do not conform toCGMP, your drug products are adulterated within the meaning of section501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21U.S.C. 351(a)(2)(B).

由于你们的生产、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第501(a)(2)(B)款21 U.S.C. 351(a)(2)(B)被认为是假药。

As formulated and labeled, LuckySuperSoft Hydrocortisone Anti-Itch Cream and U Hydrocortisone 1% Anti-Itch Creamare unapproved new drugs in violation of section 505(a) of the FD&C Act,21U.S.C. 355(a). Introduction of such products into interstate commerce isprohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).

依据其配方和标示，幸运超柔氢化可的松止痒膏和U氢化可的松1%止痒膏为未经批准的新药，违反了FDCA第505(a)款21 U.S.C.355(a)。FDCA第301(d)款21 U.S.C. 331(d)禁止将此类产品引入州际贸易。

Anicare Pharmaceuticals Pvt Ltd. alsomanufactures the over-the-counter (OTC) drug products Budpak 1% HydrocortisoneAnti-Itch Cream, Budpak Antifungal 1% Clotrimazole Cream, Budpak AntifungalMiconazole Nitrate Cream, Budpak Feminine Anti-Itch Cream, Budpak First AidCream, Budpak Hemorrhoid Anesthetic Ointment, Budpak Medicated Anti-Itch,Budpak Muscle Rub Pain Relieving Gel, Budpak Triple Antibiotic First AidAntibiotic Ointment, Lucky SuperSoft Itch Stopping Cream, Lucky SuperSoftAntifungal Athlete’s Foot Cream, Lucky SuperSoft First Aid Triple Antibiotic,Lucky SuperSoft Muscle& Joint Pain Relieving Cream, U Anti-Itch Cream, UFirst Aid Cream, U Hemorrhoid Anesthetic Ointment, and U Muscle Rub PainReliever Gel that are misbranded under sections 502(c) and (x) of the FD&CAct, 21 U.S.C. 352(c) and (x). Introduction of such products into interstatecommerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C.331(a).

Anicare药业亦生产OTC药品Budpak1%氢化可的松止痒膏、Budpak抗真菌1%克霉唑膏、Budpak抗真菌硝酸咪康唑膏、Budpak女用止痒膏、Budpak急救膏、Budpak痔疮麻醉软膏、Budpak医用止痒剂、Budpak肌肉解痛凝胶、Budpak三倍抗生急救抗生软膏、幸运超柔止痒膏、幸运超柔抗真菌脚气膏、幸运超柔急救三倍抗生剂、幸运超柔肌肉&关节镇痛膏、U止痒膏、U急救膏、U痔疮麻醉软膏以及U肌肉镇痛凝胶，这些药品依照FDCA第502(c)和(x)款21 U.S.C.352(c)和(x)均为错标药品。FDCA第301(a)款21U.S.C. 331(a)禁止将此类产品引入州际贸易。

We reviewed your August 17, 2018,response in detail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司2018年8月17日的回复，并此告知已收到后续通信。

During our inspection, our investigatorobserved 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.   Yourfirm failed to establish and follow an adequate written testing programdesigned to assess the stability characteristics of drug products and to useresults of stability testing to determine appropriate storage conditions andexpiration dates (21 CFR 211.166(a)).

你公司未建立和遵守足够的书面检验程序，用以评估药品的稳定性特性并使用稳定性测试结果来确定适当的存贮条件和有效期（21 CFR 211.166(a)）。

Your stability program is inadequatebecause you failed to test your drug products, such as (b)(4), formicrobial attributes (e.g., total count and absence of objectionablemicroorganisms). Additionally, you did not use stability indicating assaymethods to determine active ingredient levels.

你们的稳定性试验程序是不充分的，因为你们未能检验你们的药品，如XX的微生物属性（例如，细菌总数和致病菌）。另外，你们未使用稳定性指示性含量方法来确定活性成分水平。

In your response, you indicated thatyour revised procedure for stability studies includes testing samples formicrobial growth. Your response is inadequate because it does not include yourrevised stability program protocol and microbial testing results from stabilitystudies. Your response also lacks a plan to perform microbiological examinationtesting of retain samples for all batches that remain within expiry.

在你们的回复中，你们说你们修订后的稳定性研究程序包括了微生物生长的检验样品。你们的回复是不充分的，因为其中未包括你们修订后的稳定性方案和稳定性研究中的微生物检验结果。你们的回复亦没有对所有仍在效期内的批次的留样实施微生物检测的计划。

In response to this letter, provide:

在回复此函时请提交

·     A comprehensive, independentassessment and corrective action and preventative action (CAPA) plan to ensurethe adequacy of your stability program. Your CAPA plan should include, but notbe limited to:

·     一份全面独立的评估和CAPA计划，确保你们稳定性计划的充分性。你们的CAPA应包括但不仅限于：

○    A remedied standard operatingprocedure (SOP) describing your stability program

○    一份描述你们稳定性计划的修订好的SOP

○    Stability indicating methods

○     稳定性指示性方法

○    Stability studies for each drugproduct in its container-closure system before distribution is permitted

○     每种药品在其允许销售前使用其容器密闭系统进行的稳定性研究

○    An ongoing program in whichrepresentative batches of each product are added each year to the program todetermine if the shelf-life claim remains valid

○     一份每年向计划中加入每种药品具有代表性批次以确定货架期申明是否保持有效的持续计划

○    Specific attributes to be testedat each station

○     每个时间点要检验的具体指标

·     A retrospective risk assessment ofthe stability of drug products on the U.S. market within expiry. Include yourCAPA plan, including testing your retain samples for both chemical andmicrobiological attributes, to ensure that these drug products will maintaintheir purported quality attributes throughout their expiry.

·     一份对销售至美国仍有效期内的药品的回顾性稳定性风险评估，包括你们的CAPA计划，包括你们留样的化学和微生物指标检验，以确保这些药品在有效期内保持其既定质量属性。

2.   Yourfirm's quality control unit did not review and approve written procedures forproduction and process control, including any changes to them, designed toensure that the drug products you manufacture have the identity, strength, quality,and/or purity they purport or are represented to possess (21 CFR211.100(a)).

你们公司的质量部门未审核和批准书面生产和工艺控制程序，包括所有对其进行的变更，以确保你们生产的药品具备其理应具备的鉴别、剂量、质量和/或纯度（21CFR 211.100(a)）

A.) You failed to adequately validateyour drug product manufacturing processes. For example, you lacked thefollowing validation studies:

你们未能充分验证你们药品生工艺，例如你们缺少以下验证研究：

·     An adequate demonstration ofhomogeneity throughout a batch (e.g. lack of (b)(4) tank samples atspecific locations)

·     充分证明批内均匀性（例如，缺少指定位置的XX罐样品）

·     Adequate validation of your (b)(4)filling operations

·     对你们的XX灌装操作进行充分验证

The purpose of process validation is toestablish scientific evidence that a process is capable of consistentlydelivering quality product. Sampling and testing of in-process materials anddrug products requires control procedures to monitor output and validateperformance of manufacturing processes that may cause variability in drugproduct characteristics. Samples must be representative of the batch, provideappropriate statistical confidence, and meet predetermined specifications. SeeFDA’s guidance document Process Validation: General Principles and Practicesfor approaches that FDA considers appropriate elements of processvalidation at http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf.

工艺验证的目的是建立科学证据来证明工艺能够持续生产出具备指定质量产品的能力。中间体和成品的取样和检验需要控制程序来监测可能导致药品特性波动的生产工艺的输出和验证表现。样品必须代表该批次，提供适当的统计学置信度，符合预定的标准。参见FDA工艺验证指南。

In your response, you indicated youdeveloped a new procedure for homogeneity and uniformity testing. Your responsewas inadequate because it did not include a comprehensive review of yourprocess validation studies for all of your drug products.

在你们的回复中，你们说你们制订了新的均一性检测程序。你们的回复是不充分的，因为其中未包括对你们所有产品工艺验证研究的全面回顾。

In response to this letter, provide:

在回复此函时请提交

·     A comprehensive review of yourmanufacturing processes to determine your current state of control and toidentify any deficiencies in your validation studies. Include your CAPA plan orplans.

·     一份对你们生产工艺的全面审核，确定你们当前的受控状态，识别你们验证研究中的所有缺陷。包括你们的CAPA计划

·     A data-driven and scientificallysound validation program that identifies and controls all sources ofvariability such that your production and packaging processes will consistentlymeet appropriate manufacturing standards and parameters. This includes, but isnot limited to, evaluating suitability of equipment for its intended use,ensuring quality of input materials, and determining the capability andreliability of each manufacturing process step and control.

·     一份基于数据的科学合理的验证程序，识别并控制所有波动的来源，使得你们的生产和包装工艺能够始终符合适当的生产标准和参数。其中包括但不仅限于评估设备是否适合其既定用途，确保输入原料的质量，以及确定每个生产工艺步骤和控制的能力和可靠性。

·     A retrospective risk assessment ofdrug products on the U.S. market within expiry affected by inadequate processvalidation studies.

·     一份对受到工艺验证研究不充分影响的在美国市场仍在效期内的药品的回顾性风险评估

B.) You lacked adequate design andcontrol over your (b)(4) system. Our investigator observed that your (b)(4)system was not in constant circulation. Raw data related to chemicaltesting of the (b)(4) was unavailable during the inspection.Additionally, the sampling plan for your (b)(4) system was inadequate.It is essential that (b)(4) used in the manufacturing and equipmentcleaning meet chemical standards for (b)(4), USP, and appropriatemicrobial standards for your topical products.

你们的XX系统缺少足够的设计和控制。我们的调查人员发现你们的XX系统未保持循环。与XX化学检验相关的原始数据在检查时未能呈交。另外，你们XX系统的取样计划是不充分的。在生产和设备清洁过程中使用的XX需要进行清洁，符合XX化学标准、USP和你们局部用药适当的微生物标准。

In your response, you indicated thatyour SOP was revised to include sampling frequency. Your response is inadequatebecause it did not provide your revised procedure or evidence to support thesampling points of use, frequency, and results.

在你们的回复中，你们说你们的SOP已进行了修订，在其中包括有取样频次。你们的回复是不，因为其中未提供你们修订后的程序或证据来支持取样点的使用、频次和结果。

In response to this letter, provide:

在回复此函时请提交

·     A comprehensive, independentassessment of your (b)(4) system design, control, and maintenance.

·     一份对你们XX系统设施、控制和维护的独立全面评估

·     A comprehensive CAPA plan forremediating design, control, and maintenance of the (b)(4) system.

·     一份补救XX系统的设计、控制和维护的全面CAPA计划

·     Appropriate microbial action andalert limits to ensure this system produces (b)(4) suitable for theintended uses of each of your products.

·     适当的微生物行动限和警戒限，以确保该系统生产出XX合适于用于你们每个产品

·     Your (b)(4) systemvalidation report. Include the summary of improvements made to system design andthose made for ongoing control and maintenance.

·     你们的XX系统验证报告。包括对系统设计以及持续控制和维护所做的改进综述。

·     A detailed risk assessmentaddressing the potential effects of the (b)(4) system deficiencies onthe quality of all drug product batches in U.S. distribution within expiry. Ifdeficiencies are found, specify actions that you will take, such as customernotifications and product recalls.

·     一份详细的风险评估，说明XX系统缺陷对所有销至美国仍在效期内药品质量的潜在影响。如果发现缺陷，指明你们将采取的措施如通知客户和召回产品。

3.   Yourfirm failed to establish and follow adequate written procedures for cleaningand maintenance of equipment (21 CFR 211.67(b)).

你公司未建立和遵守足够的书面设备清洁和维护程序（21 CFR 211.67(b)）。

Your cleaning validation program formanufacturing equipment is inadequate.

你们的生产设备清洁验证程序是不充分的。

For example, your report APPL/CVPD/010,dated January 29, 2014, documented the cleaning validation of (b)(4) from(b)(4) tank APPL/PROD/02. The report concluded that (b)(4) washingswith water achieved a (b)(4) sample acceptance criteria of less than (b)(4)ppm for the (b)(4) tank. However, your report documented values thatindicated presence of chemicals greater than your acceptance criteria of (b)(4)ppm.

例如，你们报告APPL/CVPD/010，日期20140129，记录了XX罐APPL/PROD/02的清洁验证。报告结论说XX用水清洗，结果符合样品可接受标准NMT XX ppm。但是，你们的报告记录的值显示化学残留大于你们的可接受标准XX ppm。

Additionally, on February 2, 2018, afterproduction of (b)(4), your water sample collected from the (b)(4) tankfailed your chemical determination cleaning acceptance criteria. During theinspection, you indicated this failure was not investigated. Because this tankwas used to manufacture different drug products, there was a risk ofcross-contamination.

另外，在20180202，XX生产之后，你们从XX罐采集的水样化学检验不符合清洁可接受标准。在检查期间，你们说此次不合格未进行调查。因为该罐是用于生产不同的样品，因此有交叉污染的风险。

In your response, you indicated that anew system and process for cleaning the vessels will be validated. Yourresponse is inadequate because it did not include an assessment of otherequipment cleaning validations and lacked a timeframe for completion.

在你们的回复中，你们说会验证一个新的贮罐清洁系统和工艺。你们的回复是不充分的，因为其中未包括对其它设备清洁验证的评估，缺少完成时间表。

In response to this letter, provide:

在回复此函时请提交

·     A comprehensive plan to evaluatecleaning procedures, practices, and validation study results for each piece ofmanufacturing equipment used to manufacture more than one product

·     一份全面计划用于评估清洁程序、颗粒物，以及生产多个产品所用每台生产设备的验证研究结果

·     Scientific rationale for yourcleaning validation strategy to ensure your cleaning procedures are effective

·     清洁验证策略的科学合理性，确保你们的清洁程序有效

·     A summary of updates to yourcleaning validation protocol incorporating conditions identified as worst case.This should include, but not be limited to:

·     一份对你们清洁验证方案更新综述，包括识别为最差情形有条件。其中应包括但不仅限于：

○    Evaluating drugs of the highesttoxicity

○     评估最高毒性药品

○    Assessing drugs of the lowestsolubility in their cleaning solvents

○     评估在其清洁溶剂中溶解度最低的药品

○    Evaluating drugs withcharacteristics that make them difficult to clean

○     评估具有难清洁特性的药品

○    Swabbing equipment locations thatare most difficult to clean

○     最难清洁的设备位置擦拭

·     A summary of updated SOPs thatensure an appropriate program is in place for verification and validation ofcleaning procedures for new products, processes, and equipment

·     一份更新SOP综述，确保新产品、工艺和设备具备适当的清洁程序确认和验证程序

·     A retrospective risk assessment ofdrug products in the U.S. market within expiry affected by your inadequatecleaning program

·     一份受清洁程序不充分影响的美国市场仍在效期内的回顾风险评估

Quality Unit Authority  质量部门权力

Significant findings in this letterindicate that your quality unit is not fully exercising its authority and/orresponsibilities. Your firm must provide the quality unit with the appropriateauthority and sufficient resources to carry out its responsibilities andconsistently ensure drug quality.

在本函中的严重缺陷显示你们质量部门未能全面履行其权力和/或职责。你们公司必须为质量部门提供适当的权力和足够的资源让其履行其职责，持续确保药品质量。

CGMP Consultant Recommended  CGMP顾问建议

Based upon the nature of the violationswe identified at your firm, we strongly recommend engaging a consultantqualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMPrequirements. Your use of a consultant does not relieve your firm’s obligationto comply with CGMP. Your firm’s executive management remains responsible forresolving all deficiencies and systemic flaws to ensure ongoing CGMPcompliance.

根据我们在你们公司所发现的违规情况的性质，你们强烈建议你们聘用一位具备21.CFR211.34资质的顾问，协助你们公司符合CGMP要求。你们使用顾问的行为并不会解除你们公司符合CGMP的义务。你们公司的执行管理层负有解决所有缺陷和系统瑕疵，确保持续符合CGMP要求的责任。

Unapproved New Drug Charges  未批新药指控

（以下为销售未获得FDA批准的药品的内容，略去2118字）

Conclusion  结论

Violations cited in this letter are notintended as an all-inclusive list. You are responsible for investigating theseviolations, for determining the causes, for preventing their recurrence, andfor preventing 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 islikely to lead to a disruption in the supply of drugs produced at yourfacility, 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 mosteffective way to bring your operations into compliance with the law. Contactingthe Drug Shortages Staff also allows you to meet any obligations you may haveto report discontinuances or interruptions in your drug manufacture under 21U.S.C.356C(b) and allows FDA to consider, as soon as possible, what actions, ifany, may be needed to avoid shortages and protect the health of patients whodepend 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 violationscompletely and we confirm your compliance with CGMP, FDA may withhold approvalof any new applications or supplements listing your firm as a drugmanufacturer.

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 mayalso result in FDA refusing admission of articles manufactured at AnicarePharmaceutical Pvt. Ltd., at Plot No. A 143/5&6, TTC Industrial Area,Khairne Village, Thane-Belapur Rd., Navi Mumbai into the United States undersection 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the sameauthority, articles may be subject to refusal of admission, in that the methodsand controls used in their manufacture do not appear to conform to CGMP withinthe 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, respondto this office in writing within 15 working days. Specify what you have donesince our inspection to correct your violations and to prevent theirrecurrence. 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。

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严重违反CGMP的行为......

罗伊鲱

FDA's regulations regarding cleaning validation are now relatively old. A GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES dates back to the early 90s. In this context, Warning Letters show the "current thinking" of the FDA.

FDA关于清洁验证的规定现在相对陈旧。清洁过程的检查验证指南可以追溯到90年代早期。在这种背景下，警告信显示了FDA的“当前想法”。

An example of this is a current Warning Letter from Anicare. What has been criticised?

这方面的一个例子是当前来自Anicare的警告信。被批评的是什么？

With reference to 21 CFR 211.67 (b), the FDA criticised that the cleaning validation report confirmed that the acceptance criteria for the residues had been met, although there were values that exceeded the limit. In addition, an exceeded limit was found in the routine production, which has not been investigated. The limit excess was identified by the FDA as critical with regard to cross-contamination for the corresponding tank.
参考21 CFR 211.67 (b)，FDA批评，清洁验证报告证实，残留物已经达到可接受标准，尽管有些值超过了限度。另外，在常规生产中发现超标，未进行调查。FDA确定了该限量超标，考虑到对应反应罐的交叉污染，这是关键的。

Anicare replied that they would validate a new cleaning procedure.

Anicare答复说，他们将验证新的清洁程序。

This simple answer was not enough for the FDA. The FDA expects a broader consideration, also with regard to other cleaning validation processes and a timetable for the completion of cleaning validation runs. It is explicitly required to provide:

这个简单答复对FDA来说是不够的。FDA期望更广泛的考虑，也包括其他清洁验证过程和完成清洁验证运行的时间表。它明确要求提供：

• A plan showing how the cleaning processes, practices and validation study   results are evaluated for each piece of multipurpose manufacturing equipment.
  一份显示如何对每一个多用途制造设备的清洁程序、实践和验证研究结果进行评估的计划。
• A scientific rationale for the cleaning validation strategy that shows that the cleaning processes are effective.
  表明清洁程序有效的清洁验证策略的科学原理。
• A summary about updating the cleaning validation protocol with - at least   - the worst case scenarios:
  关于更新清洁验证方案的总结，至少在最差情况下:
  - Evaluation of the medicinal products with   the highest toxicity
    毒性最高的药品评价
  - Evaluation of medicinal products with regard to the lowest solubility in their cleaning agents
     药品在其清洁剂中的最低溶解度评估
  - Evaluation of the   characteristics of the medicinal products that are difficult to clean
     难清洗药品的特性评估
  -  Swab sampling points of the locations that are most difficult to clean.
     在最难清洁的地方擦拭取样
  
  
  

The FDA also requires an overview of the updated SOPs to ensure that an appropriate programme is in place to verify and validate cleaning processes for new products, processes and equipment.

FDA还要求对更新后的标准操作规程进行概述，以确保有适当的程序对新产品、工艺和设备的清洁过程进行确认和验证。

Retrospectively, the company should provide the FDA with a risk assessment of the medicinal products affected by the inadequate cleaning programme and still on the US market within the expiration date.

该公司应该向FDA提供一份药品的回顾性风险评估，受不充分的清洁程序影响的药品，在保质期内仍在美国市场销售。

Regardless of the deficits in cleaning validation, insufficient process validation with regard to homogeneity within a batch was also criticised. As a corrective measure, the FDA requires a data-based, scientifically founded validation programme that identifies the sources of variability and also demonstrates their control. This applies to both manufacturing and packaging processes. This includes demonstrating the suitability of equipment, the consistent quality of raw materials and the determination of capabilities and reliability of each manufacturing step.

尽管清洁验证存在缺陷，但也有人批评在批次内一致性方面的工艺验证不足。作为一项纠正措施，FDA需要一个基于数据、有科学依据的验证程序，该程序能够识别变异性的来源，并证明其控制。这适用于制造和包装过程。这包括证明设备的适宜性、原材料的一致质量以及每个制造步骤的能力和可靠性的确定。

https://www.gmp-compliance.org/gmp-news/what-does-the-fda-expect-from-cleaning-validation-today

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