药智网获悉湖北兵兵药业（集团）有限公司在10月3日收到了FDA的警告信，信中指出该公司2018年由于搬厂导致在原厂址生产的一些批次药品的CGMP书面资料和样品丢失，并且在收到对这些批次药品的投诉后用不同批次的样品进行检测等问题。11月5日，FDA官网挂出了警告信全文。

       湖北兵兵药业（集团）有限公司原名武汉兵兵药业有限公司（BINGBING PHARMA），成立于2006年，是一家专业从事以水凝胶为主体的研发、生产和销售的现代化新型制药企业。公司于2011年8月4日获取了吲哚美辛巴布膏生产批件，该产品为国内首家也是国内独家获批的巴布剂品种。

       11月5日，FDA官网挂出的警告信具体内容如下：

Dear Mr. Yu:

尊敬的余先生：

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Bingbing Pharmaceutical (Hubei) Co. Ltd., FEI 3014538973, at No. 698 Bingbing Road, Economic Development Zone, Shiyan, Hubei, from May 7 to 10, 2019.

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

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美国食品药品监督管理局（FDA）于2019年5月7日至10日检查了湖北兵兵药业（集团）有限公司。 本警告函汇总了成品药CGMP法规的重大违规。详见美国联邦法规第21卷，第210和211章。

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).

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因为你们的方法、设施、生产工艺、包装或者储存的方式不符合CGMP法规，你们的药品根据《联邦食品、药品和化妆品法》（FD&C）第501(a)(2)(B)章节，《美国法典》第21卷第351(a)(2)(B)节被认定为违规。

We reviewed your May 31, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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我们详细审查了你们于2019年5月31日对FDA 483表格的回复，并确认收到你们之后的回复。

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

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在检查期间，我们的检查员发现的具体违规包括但不限于如下。

1. Your firm failed to maintain written production, control, or distribution records specifically associated with a batch of a drug product for at least one year after the expiration date of the batch (21 CFR 211.180(a)).

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你们公司未能在一批药品有效期后至少一年内保持与该批药品相关的书面的生产、控制或分销记录（《美国联邦法规》第21卷第211.180（a）条）。

You manufactured drugs at your Wuhan facility at Building (b)(4), No. 5, Kangda Street, Longyang Avenue, Hanyang District, Wuhan, and then transferred drug production to your Hubei facility and closed the Wuhan facility. Your firm failed to maintain manufacturing records, raw material and finished product testing records, retain samples, stability samples, and other CGMP records for your over-the-counter (OTC) (b)(4) drug products manufactured at your Wuhan facility. During the inspection at the Hubei facility, you stated that you lost CGMP manufacturing documentation and drug product samples during the transfer of your manufacturing facility from Wuhan to Hubei in May 2018.

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你们在武汉市汉阳区龙阳大道康达街5号楼的武汉工厂生产药品，然后将药品生产转移到湖北工厂并关闭了武汉工厂。但是未能为武汉工厂生产的非处方药（OTC）保留生产记录、原材料和成品测试记录、样品、稳定性样品和其他CGMP记录。在湖北工厂检查期间，你方声明，你方在2018年5月从武汉转移到湖北期间丢失了CGMP生产文件和药品样本。

In your response, you stated that you initiated an investigation to assess the scope of impacted product, will attempt to collect samples from the market to evaluate and take “all mandatory and necessary measures,” and will conduct a quality system evaluation using a third-party consultant. Your response is inadequate because you failed to appropriately address the impact of missing records and samples on drug products already on the market. Maintaining all manufacturing and testing records, as well as representative product samples, is critical to establish that your products meet their required quality attributes.

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在你们的回复中声明，你们发起了一项调查，以评估受影响产品的范围，将尝试从市场收集样品进行评估并采取“所有强制性和必要的措施”，并将使用第三方顾问进行质量体系评估。你们的回复是不充分的，因为没有适当地解决丢失记录和样品对已经上市的药品的影响。维护所有的生产和测试记录，以及有代表性的产品样品，对于确定产品符合所要求的质量属性是至关重要的。

In response to this letter, provide:

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针对本函，请提供：

· A complete, independent assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

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对整个生产和实验室操作过程中使用的文件系统进行完整、独立的评估，以确定记录规范的不足之处。包括详细的纠正措施和预防措施（CAPA）计划，全面纠正公司的文记录规范，以确保公司在整个经营过程中保留可归属的、清晰的、完整的、原始的、准确的、同期的记录。

· A detailed risk assessment of drug products on the market without any manufacturing documentation and without retains or stability samples to support investigations and expiration dating. Specify actions, with timelines, that you will take in response to the risk assessment, such as customer notifications and initiating recalls.

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对市场上没有生产文件和没有保留样品的药品进行详细的风险评估，以支持调查和有效期的确定。详细说明针对风险评估将要采取的行动，例如客户通知和发起召回。

2. 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))

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你们未能对每批药品进行适当的实验室测定，以确定其是否符合药品的最终规格（包括每种活性成分的特性和强度）。

Your firm released OTC drug products to the United States market without testing the identity and strength of each active ingredient. For example, your firm failed to test for the active ingredients, (b)(4), in your (b)(4)products. Testing is essential to ensuring that the drug products you manufacture meet established specifications for the required chemical attributes.

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你们公司向美国市场投放的非处方药产品，没有测试每种活性成分的特性和强度例如，没有检测产品中的活性成分。测试对于确保您生产的药品符合所需化学特性的规范至关重要。

We acknowledge your commitment to discontinue the manufacture and distribution of (b)(4) products until analytical methods for (b)(4) active ingredients have been established and validated or verified. However, your response is inadequate. You failed to provide details for establishing that your OTC drug products in distribution meet their specifications.

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我们收到了你方承诺在活性成分分析方法建立、验证或验证之前停止生产和销售产品。然而，你们的回复是不充分的，你们没有提供详细资料证明你的非处方药产品符合规格。

In response to this letter, provide a list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision. The list should include:

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针对本函，你们需要提供一份化学和微生物规格清单，包括测试方法，用来分析每一批药品，然后再做一个批量处置的决定。清单应该包括：

An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States within expiry as of the date of this letter.

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一份行动计划和时间表，用于对保留样品进行全面的化学和微生物测试，以确定自本函日期起有效期内在美国销售的所有批次药品的质量。

A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

…翻译…

从测试中获得的所有结果的汇总，保留每个批次的样品。如果检测发现药品质量不合格，应迅速采取措施，如通知顾客和产品召回。

3. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

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你们公司的质量控制部门未能履行其职责，以确保所生产的药品符合CGMP的要求，符合规定的特性、强度、质量和纯度规范。

During the inspection, our investigator observed that your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC (b)(4). For example, your QU failed to ensure:

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在检查过程中，我们的调查员发现你们公司的质量部门没有对公司的OTC的生产提供足够的监督。例如，他们未能确保：

Full testing of drug products and review of their results are performed prior to batch release.

Contract laboratory used for identity testing is qualified following your written procedures.

Cleaning validation of shared (b)(4) tanks include justifications for the worst-case sampling locations following your cleaning validation procedure.

Written procedures for sampling and testing of the (b)(4) system are followed.

Procedures to review electronic data generated from GC, HPLC, IR, and TOC systems are written and followed.

Controlled records, including logs, are maintained to track receipt of all components used to manufacture drug products.

Every OOS result is appropriately investigated and each investigation is extended to all affected batches, as applicable.

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在批量销售之前，对药品进行全面测试并审查结果。 

用于鉴定测试的合作实验室符合你们的书面程序。 

共享罐的清洁检测包括根据清洁检测程序对最坏情况下的采样位置进行检测。 

遵循系统取样和测试的书面程序。 

编写并遵循审查气相色谱、高效液相色谱、红外光谱和运输系统生成的电子数据的程序。 

保存受控记录包括日志，以用于跟踪生产药品的所有成分的接收情况。 

对每一个超标测试结果进行适当的调查，并在适用的情况下将每一调查扩展到所有受影响的批次。

In your response, you admitted that due to cash flow problems you “were unable to ensure all products were completely tested and ensure conformance with all pre-determined specification prior to be shipped out”. You also submitted numerous CAPA to address each example of your quality unit failures cited above.

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在你们的回复中，你们承认由于资金问题，你们“无法确保所有产品在出厂前都经过了完整的测试，并确保符合所有预先确定的规格”还提交了许多CAPA，以解决上面提到的每个质量问题。

Because you failed to include supporting documentation, your response is inadequate and cannot be fully evaluated. You also failed to conduct a comprehensive review of your quality unit to identify deficiencies. You did not provide evidence that you have implemented procedures that ensure adequate control over your drug manufacturing processes. In addition, you failed to include a plan to address the quality of your drugs that were manufactured without appropriate quality oversight.

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因为你们没有包含辅助文件，所以你们的回复不充分，无法进行全面评估。也没有对质量部门进行全面的审查，以找出不足之处。没有提供证据证明已经实施了确保对药品生产过程进行充分控制的程序。此外，也没有一个计划，以解决你的药品是在没有适当的质量监督下生产的。

In response to this letter, provide:

…翻译…

针对本函，请提供：

· A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should include, but not be limited to:

…翻译…

全面的评估和补救计划，以确保你们的质量部门获得有效运作的权力和资源评估，应包括但不限于：

A determination of whether procedures used by your firm are robust and appropriate.

Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.

A complete and final review of each batch and its related information before the QU disposition decision.

Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and assure a continuing state of control.

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确定贵公司所采用的程序是否有效合适。

在整个运营过程中，为质量部门提供监督，以评估对规定的遵守情况。

在质量部门处置决定之前，对每批产品及其相关信息进行完整和最终审查。

监督和批准调查并履行所有其他质量管理职责，以确保所有产品的特性、强度、质量和纯度。

还应说明最高管理层如何支持质量保证和可靠的操作，包括但不限于及时提供信息，以主动解决新出现的生产/质量问题，并确保持续可控制状态。

· A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, 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 oversight, and written procedures. Describe how your firm will ensure all phases of investigations are appropriately conducted.

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对整个系统进行全面、独立的评估，以调查偏差、差异、投诉、测试超标结果和故障。提供修复此系统的详细操作计划。行动计划应包括但不限于在调查能力、范围确定、根本原因评估、CAPA有效性、质量保证监督和书面程序方面的重大改进，请描述将如何确保调查的所有阶段都得到有效适当的执行。

See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.

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参见FDA的指导文件《药品CGMP法规的质量体系方法》，以帮助实施质量体系和风险管理方法，以满足 美国联邦法规第21卷第210和211部分的CGMP要求。

4. Your firm failed to maintain an adequate written record of each complaint (21 CFR 211.198(b)).

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你们公司没有对每一项投诉保留充分的书面记录。

You firm failed to maintain a complete and accurate record of your complaint investigations. You opened investigations B-18002 and B-19001 in response to complaints of poor (b)(4) for batches manufactured in Wuhan. In these investigations you stated that you evaluated reserve samples and found no deficiencies. However, you had previously stated that all reserve samples were lost for batches manufactured at your Wuhan site and therefore reserve samples were not available for evaluation.

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你们公司未能保留针对武汉生产的批次的不良投诉的调查的完整和准确记录，你们展开的调查B-18002和B-19001，在这些调查中，表示你们评估了保留样品，没有发现任何缺陷。但是，你们之前已经声明，武汉工厂生产的批次的所有保留样品都丢失，因此无法对保留样品进行评估。

In your response, you stated that testing was performed on reserve samples manufactured in your Hubei facility. Your response is inadequate because testing a batch that is different from the complaint batch does not provide you with batch specific information needed to identify potential quality defects in the complaint batch.

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在你们的回复中，声明测试是在湖北工厂生产的保留样品上进行的。你们的回复不充分，因为测试与投诉批次是不同的批次，并不能提供识别投诉批次中潜在质量缺陷和所需的批次特定信息。

In response to this letter, provide:

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针对本函，请提供：

· The status of lots identified in investigations B-18002 and B19001.

· Your plan for evaluating complaints for batches manufactured in your Wuhan facility.

· The process you will follow if a complaint cannot be appropriately investigated. Indicate the corrective actions you will take including notifying customers and initiating recalls.

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调查B-18002和B19001中所说的批次状态。 

你们对武汉工厂生产批次的投诉进行调查评估的计划。 

如果投诉无法得到适当调查，你们应遵循流程指出将采取的纠正措施，包括通知客户和发起召回。

Data Integrity Remediation

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数据完整性修复

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119570/download.

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你们的质量体系不能充分确保数据的准确性和完整性，以支持生产的药物的安全性、有效性和质量。关于建立和遵循符合CGMP的数据完整性实践的指导，请参见FDA的指导文件里数据完整性和CGMP药物的一致性。

We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following:

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我们强烈建议您聘请一名合格的顾问协助你们进行补救。针对本函，请提供以下内容：

A comprehensive investigation into the extent of the inaccuracies in data records and reporting, including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

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对数据记录和报告不准确度的全面调查，包括对在美国销售的药物的数据审查结果。包括对数据完整性失效的范围和根本原因的详细描述。 

当前观察到的问题对药物质量的潜在影响的风险评估。评估应包括分析由于数据完整性失效而影响药物对患者造成的风险，以及分析正在进行的操作所带来的风险。 

公司的管理策略，包括全球补救措施和预防措施计划的细节。详细的补救措施计划应说明你们打算如何确保生成的所有数据的可靠性和完整性，包括微生物和分析数据、生产记录以及提交给FDA的所有数据。

Conclusion

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结论

The violations cited in this letter are not intended to be an all-inclusive statement 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.

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这封信中所列举的违规行为并不是对你们公司存在的违规行为的全面陈述。你们负责调查和确定这些违规行为的原因，并防止其再次发生或发生其他违规行为。

FDA placed your firm on Import Alert 66-40 on August 22, 2019.

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FDA在2019年8月22日将贵公司放在重要警报66-40。

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.

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在你们完全纠正所有违规行为，并且我们确认符合CGMP规定之前，FDA可能会拒绝批准任何新的药物申请或将贵公司列为药物制造商的补充产商。

Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at Bingbing Pharmaceutical (Hubei) Co., Ltd, at No. 698 Bingbing Road, Economic Development Zone, Shiyan, Hubei, 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).

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如果不纠正这些违规行为，食品和药物管理局可能会按照《食品和药品法》的规定，拒绝将兵兵药业（湖北）有限公司生产的物品进口美国。本授权下的物品可能会被拒绝入境，因为其制造过程中使用的方法和控制措施不符合《美国法典》的CGMP规定。

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.

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收到此信后，请在15个工作日内以书面形式回复。请说明自我方检验以来，你们为纠正偏差并防止其再次发生所做的工作。如果您无法在15个工作日内完成纠正措施，请说明延迟的原因和完成计划。

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

Carlos M. González   

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 3014538973.

Sincerely,

/S/

Francis Godwin

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research