FDA警告信：西班牙Natura Bisse International S.A.（节译）

Via UPS                                                                                 Warning Letter  320-17-11

Return Receipt Requested

December 15, 2016

  

Ms. Veronica Fisas Verges, CEO

Natura Bisse International S.A.

Parque Tecnologico del Valles

C/Artesans 12

Cerdanyola del Valles

08290 Barcelona

Spain

Dear Ms. Fisas Verges:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Natura Bisse International S.A. at Parque Tecnologico del Valles, C/Artesans 12, Cerdanyola del Valles, Barcelona, from January 25 to 29, 2016.

美国FDA于2016年1月25日29日检查了你们位于西班牙巴塞罗那的工厂。

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产品严重违背CGMP的情况。参见21CFR第210和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).

由于你们生产、加工、包装和存贮药品的方法、设施和控制不符合CGMP，根据FDAC501(a)(2)(B)和21 U.S.C. 351(a)(2)(B) ，你们的药品被认为是掺假药。

We reviewed your February 19, 2016, response in detail and acknowledge your subsequent correspondence.

我们详细审核了你们公司于2016年2月19日及之后发送的回复。

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

我们的调查人员发现的具体违规情况包括但不仅限于以下：

1.    Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).

你们公司对各批药品在放行前没有适当的化验室检测确定药品产质量令人满意地符合最终药品质量标准，包括每种活性成分的鉴别和剂量。(21 CFR 211.165(a))

Our investigator observed that you did not test your over-the-counter (OTC) (b)(4) drug products for identity and strength prior to release.

我们的调查人员发现你们没有在放行前检测你们的OTC药品XX的鉴别和剂量。

In a previous inspection conducted from February 11 to February 15, 2013, FDA identified a similar deficiency. You proposed specific remediation for the failure to conduct testing for identity and strength in your March 7, 2013, response. Nonetheless, during our January 2016 inspection, FDA observed that you still failed to conduct testing for identity and strength before releasing your drugs.  These repeated failures demonstrate that your facility’s oversight and control over the manufacture of drugs is inadequate.

在之前的2013年2月11-15日期间进行的现场检查中，FDA发现了类似的缺陷。你们在2013年3月7日的回复中说会对没有实施鉴别和剂量检测采取某些补救措施。但是，在2016年1月的检查中，FDA发现你们仍然没有在药品放行之前进行鉴别和剂量检测。这些重复的缺陷证明你们工厂对药品生产的监管和控制是不充分的。

In response to this letter, provide your corrective actions to ensure that you conduct testing for identity and strength of each active ingredient for all products intended for the U.S. market. Provide your:

在回复此函时，请提交你们的纠正措施以确保你们会对要发往美国市场的所有药品中每种活性成分进行鉴别和剂量检测。请提交以下资料：

• Release testing program, including a written standard operating procedure (SOP) detailing the test methods you will use to test each product and the acceptance criteria for each test.
• 放行检测计划，包括一份书面标准操作规程（SOP），其中详细说明你们将用于检测每种药品的方法以及每种检测的可接受标准。
• Retroactive assessment of batches produced for the U.S. market within expiry. Include a list of all batches, the date each was released, and the date on which you or your contract laboratory conducted retroactive analysis. Provide the type of testing conducted for each batch, and the results of the tests. Indicate the actions you will take if you find that any of the batches you released were out of specification (OOS) for strength, identity, or any other attribute.
• 追溯评估为美国市场生产的仍在有效期内的批次。其中要包括一份所有批次的清单，每批放行的日期，你们合同化验室追溯检测的日期。提交对每个批号所进行的检测项目，以及各检测的结果。说明如果发现你们已放行的批次如果剂量、鉴别和其它属性超出标准（OOS），你们将要采取的措施。
• Copies of quality agreement(s) covering the release testing performed by your contract laboratory
• 覆盖你们合同化验室所实施的放行检测的质量协议副本。
  

2.    Your firm failed to ensure that its drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).

你们公司未能确保公司的药品有效期有适当的稳定性检测的支持(21 CFR 211.137(a))。

Our investigator observed that you failed to implement a stability testing program for any of your products. You had no test data to support the expiration dates of your drugs. Your failure to implement a stability program and generate data in support of your expiration dates limited your ability to detect and react to quality problems with your products.

我们的调查人员发现你们对你们所有药品均未能实施稳定性检测计划。你们没有检测数据来支持你们药品的有效期。你们未能实施稳定性计划，生成数据支持你们的有效期，这限制了你们发现产品质量问题并采取措施的能力。

For example, our investigator documented that you conducted a recall of multiple lots of (b)(4) in 2015. You recalled lots (b)(4), (b)(4), and (b)(4) in response to consumer complaints about product separation. Separation of creams such as your(b)(4) products is an indicator that the products are not stable over their labeled shelf lives.Because you did not adequately study the drug as part of a stability program, you were not made aware of the product separation issue until the product was already in the hands of consumers.

例如，我们的调查人员记录了你们在2015年对某产品的多个批准进行了召回。你们由于消费者投诉产品离解而召回了批次XX、YY和ZZ。膏剂，例如你们产品XX离解是产品在其标示的生命周期内不稳定的指征。因为你们没有对药品进行充分的研究作为稳定性计划的一部分，你们在药品到达消费者手中之前都不了解药品会离解的问题。

In a previous inspection, conducted from February 11–15, 2013, FDA cited a similar deficiency. You proposed specific remediation for your lack of a stability program in your March 7, 2013, response. Nonetheless, you had not implemented this corrective action at the time of our most recent inspection. These repeated failures demonstrate that your facility’s oversight and control over the manufacture of drugs is inadequate.

在之前2013年2月11-15日的检查中，FDA签发了类似的缺陷。你们在2013年3月7日提交的回复中给出了一份补救稳定性计划缺失的补救措施。但是，你们在我们最近的检查时仍未实施这些纠正措施。这些重复的缺陷证明你们工厂对药品生产的监管和控制是不充分的。

According to your response dated February 19, 2016, you will have an outside laboratory perform “assay for (b)(4) and microbiological analysis” on your products. Your response is inadequate because you have not provided enough information regarding the tests you or the outside laboratory will perform to ensure that the stability program will demonstrate that your products conform to their quality attributes over their labeled shelf lives.

根据你们在2016年2月19日的回复，你们会要求外包化验室对你们产品进行“XX含量和微生物分析”。你们的回复是不充分的，因为你们并没有提交充分的信息，说明你或外包化验室会实施的检测，以确保稳定性计划能够证明你们的产品在其标示的货架期符合其质量属性。

In response to this letter, provide:

在回复此函时，请提交：

• Your stability testing program, including stability-indicating methods and acceptance criteria for each test to support the labeled storage conditions and expiry dates for your products. Indicate which methods, if any, you will perform at your own facility, and which will be performed at your contract laboratory.
• 你们的稳定性检测计划，包括每项检测的稳定性指示性方法和可接受标准以支持你们药品标示的存贮条件和有效期。说明哪个方法将在你们自己的工厂实施，哪个会在合同化验室实施。
• Retroactive assessment of the stability of batches produced for the U.S. market within expiry. Include a list of all batches, the date each was released, and the date on which you or your contract laboratory conducted retroactive analysis. Provide the type of testing conducted for each batch, and the results of the tests. Indicate the actions you will take if you find that any of the batches you released were OOS for strength, identity, or any other attribute.
• 追溯评估为美国市场生产的所有仍在有效期内的批次的稳定性，其中要包括一份所有批次的清单，各批放行的日期，你们或你们合同化验室实施追溯分析的日期。提交对每个批次要进行的检测的项目，各项检测的结果。说明如果发现你们所放行的批次的剂量、鉴别和其它属性是OOS，你们将采取的措施。
• Copies of quality agreement(s) covering the stability testing performed by your contract laboratory
• 覆盖你们合同化验室所实施的放行检测的质量协议副本。
  

3.    Your firm failed to follow required laboratory control mechanisms, including any changes made to them, which were drafted by the appropriate organizational unit and reviewed and approved by the quality control unit (21 CFR 211.160(a)).

你们公司未能遵守所要求的化验室控制机制，其中包括对这些机制的变更。这些要求是由适当的部门编写，由质量控制部门审核和批准的(21 CFR 211.160(a))。

Your laboratory lacks appropriate controls over laboratory log sheets recording microbiology, physico-chemical and organoleptic test results.

你们化验室对化验室记录微生物、理化和感官测试结果的登记记录纸缺乏适当的控制。

In your February 19, 2016, response, you stated that you amended your SOP PR-33 Documentation Management to require that log sheets and logbooks are to be controlled, reviewed, and approved by appropriate quality unit personnel.

在你们2016年2月19日的回复中，你们声明你们会修订你们的SOP PR-33《文件管理》，要求记录纸和日志由适当的质量部门人员进行控制、审核和批准。

Your response is inadequate because it did not include a copy of the SOP or sufficient details regarding your proposed changes.  

你们的回复是不充分的，因为其中没有包括一份SOP的副本，或者是关于你们拟定变更的足够详细的情况。

In response to this letter, include your revised SOP PR-33. Also provide your investigation into how the uncontrolled documents may have affected the quality of your products, and your proposed corrective actions.

在回复此函时，请包括你们修订后的SOP PR-33。还要提交你们对失控文件对你们产品可能产生的影响的调查，以及你们拟定的纠正措施。

Conclusion

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

FDA placed your firm on Import Alert 66-40 on October 28, 2016.         

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 manufacturer.

Failure to correct these violations may also result in FDA continuing to refuse admission of articles manufactured at Natura Bisse International S.A. at Parque Tecnologico del Valles, Artesans, 12 Cerdanyola, 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 CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

           

Carlos M. Gonzalez, PhD

Consumer Safety 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 3008301076.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research