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来自Julia翻译 Warning Letter 320-18-57 June 8, 2018 Mr. Pierre-Louis Delapalme, Co-President Biologique Recherche (B.R.) SAS 28 rue de la Procession, Suresnes,92150 France Dear Mr. Delapalme: The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Biologique Recherche (B.R.) SAS at 28 rue de la Procession, Suresnes, from September 18 to 22, 2017. 美国FDA于2017年9月18-22日检查了你们位于法国苏雷斯尼的Biologique Recherche (B.R.) SAS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要求，以及制剂生产严重违反CGMP法规21CFR第210和211部分的行为。 Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, your drug product is 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). 由于你们的药品生产、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21U.S.C. 351(a)(2)(B)被认为是掺假药品。 We reviewed your October 13, 2017, response in detail. Your response did not provide adequate corrective actions for any of the observations made during the inspection. 我们已详细审核了你公司2017年10月13日的回复。你们的回复并未针对检查期间所发现的缺陷提供充分的纠正措施。 During our inspection, our investigator 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 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)).你公司未能在放行前为每批制剂进行适当的化验室检测以确定是否满足其最终质量标准，包括每种活性物质的鉴别和剂量（21 CFR 211.165(a)）。 Your firm released your over-the-counter (OTC) drug product,(b)(4), without adequate testing for the identity and strength of the active ingredients, (b)(4) and (b)(4). Without this testing you cannot determine if your drug products conform to specifications. 你公司放行了你们的OTC药品XX，但并未充分检测其中活性成分XX和XX的鉴别和剂量。没有这些检测，你们无法确定你们的药品是否符合质量标准。 Your response stated that you will test future batches for active ingredients. Your response is inadequate. You have not provided sufficient information regarding testing of future batches, including whether you will use a third party. You also failed to conduct a retrospective assessment of your OTC drug products that lack identity, strength, and other appropriate quality attribute tests for batches that may currently be in U.S.distribution. 你们的回复说你们将来会检测批次中的活性成分。你们的回复是不充分的。你们针对未来批次的检测并未提供足够的信息，包括你们是否会使用第三方。你们亦未对你们当前销往美国的OTC药品批次缺少鉴别、剂量和其它适当质量属性检测的情况进行回顾性评估。 In response to this letter, provide: 在回复此函时，请提交： all chemical and microbial test methods and specifications used to analyze each of your OTC drug products prior to a batch disposition decision;
所有在批处置决策前用以分析每批OTC药品的化学和微生物方法和质量标准； remediated microbiological testing methods (i.e., total counts and objectionable microbes) that conform to USP <61> and <62>. These methods should be capable of identifying all microorganisms in product bioburden to determine whether any are objectionable in view of the product’s intended use. 经过弥补的符合USP<61>和<62>的微生物检测方法（即，总计数和致病菌）。这些方法应能够鉴别出产品生物负载里的所有微生物以从药品即定用途的角度确定是否是致病菌； a summary of test results obtained from testing retain samples of all OTC drug products within expiry that have been distributed in the United States. These test results should include identity and strength of active ingredients, and all other appropriate quality attributes. 一份所有销售至美国且在效期内的OTC药品留样检测结果汇总。这些检测结果应包括活性成分的鉴别和剂量以及其它所有适当的质量属性。
2. Your firm failed to conductat least one test to verify the identity of each component of a drug product.Your firm also failed to establish the reliability of component supplier analyses on which you rely in lieu of certain tests through appropriate validation of the supplier’s test results at appropriate intervals (21 CFR211.84(d)(1) and (2)).你公司未能对药品的每种组份至少检测一项鉴别。你公司亦未能通过在适当时间间隔适当验证供应商结果建立组份供应商分析的可靠性，却依赖其替代自己的某些检测（21 CFR 211.84(d)(1) and (2)）。 Your firm failed to test incoming raw materials, including (b)(4), for their identity, purity, strength, and other appropriate quality attributes.Instead, your firm relied on certificates of analysis (COA) from unqualified suppliers. (b)(4) contains the active ingredient (b)(4) which you use in your OTC drug products. 你公司未能检测进厂物料，包括XX，的鉴别、纯度、剂量和其它适当的质量属性。相反，你公司依赖于未经确认供应商的COA。XX中含有你用于你们OTC药品中的活性成分XX。 Your response states, “Raw materials in stock will be sampled for analysis and will be sent for characterization before October 27.”Your response is inadequate. You have not provided sufficient information regarding testing of these raw materials, including whether you will use a third party for testing. 你们回复说“会对在库原料取样分析，并在10月27日前送去进行特性鉴定”。你们的回复是不充分的，你们并未提交充分的原料检测信息，包括你们是否会使用第三方进行检测。 In response to this letter, provide: 在回复此函时，请提交： quality control release specifications for all incoming components, and the tests you perform for each lot; 所有进厂组份的质量控制放行标准，以及你们为每个批次执行的检测； a summary of test results obtained from full testing of all your incoming components to validate the COA from each raw material manufacturer; 所有你们进厂组份进行全检所得检测结果的汇总，以验证每个原料生产商的COA； a summary of your procedures for qualifying and overseeing the adequacy of contract facilities that test the OTC drug products you manufacture; 你们确认和监管检测你们所生产的OTC药品的合同场所充分性的程序汇总； a comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified, assigned appropriate expiration or retest dates, and incoming material lot controls are adequate to prevent use of unsuitable containers, closures, and components. 一份对你们原料系统的全面独立审核，以确定是否来自每个供应商的所有容器、密闭器和成分均经过充分确认、定有适当的效期或复验期，并且进厂物料批次控制足以防止容器、密闭器和组份的不恰当使用。
3. Your firm failed toestablish written responsibilities and procedures applicable to the quality control unit (21 CFR 211.22(d)).你公司未能建立适用质量部门的书面职责和程序（21 CFR 211.22(d)）。 Your firm failed to establish written procedures for numerous functions of the quality unit. For example, there were no procedures for the following manufacturing operations: 你公司未能建立许多质量部门的职能。例如，以下生产操作均无程序： investigating deviations; 偏差调查 conducting annual product quality reviews; 年度产品质量审核 investigating out-of-specification results; OOS结果调查 handling product returns; 产品退回处理 reprocessing and reworking; 返工和再加工 reconciling labels; 标签数量衡算 creating batch records and issuing master batch records; and 创建批记录和签发主批记录，以及 approving batch records and releasing batches. 批准批记录和放行批次
Your response stated, “A procedure describing there sponsibilities of the quality service will be drafted by the end of November.” Your response is inadequate. You failed to describe how this procedure will ensure that your firm will establish and maintain a robust quality system. 你们的回复称“会在11月底起始一份描述质量服务职责的程序”。你们的回复是不充分的。你们未能描述这些程序将如何确保你们公司会建立和维护一套稳健的质量体系。 In response to this letter, provide a comprehensive assessment and a corrective action and preventive action (CAPA) plan to ensure that you establish an effective quality unit with appropriate authority, responsibilities and resources. Your response should also include a detailed procedure describing your remediated quality unit’s responsibilities. 在回复此函时，请提交一份全面的评估和一份CAPA计划确保你们会建立一个有效的质量部门，具备适当的权力和职责以及资源。你们的回复还应包括一份详细的程序描述你们弥补后的质量部门职责。 4. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21CFR 211.166(a)).你公司未能建立和遵守足够的书面检测程序，设计用以评估药品的稳定性特性，并使用此稳定性检测结果来确定适当的存贮条件和有效期（21 CFR 211.166(a)）。 You did not have adequate stability data to demonstrate that the chemical and microbiological properties of your drug products remain acceptable throughout their labeled expiry period. For example, your firm performed an accelerated stability study on (b)(4) lot ((b)(4)) but did not test for assay or impurities during this study. 你们没有足够的稳定性数据证明你们药品的化学和微生物属性在其标示的有效期内会保持可接受。例如，你公司对XX批次XX进行了加速稳定性研究，但在些研究中并未检测含量和杂质。 Your response stated you would undertake “to restart stability tests.” Your response is inadequate. You have not provided details regarding your stability testing program, including which tests you willperform, whether you will use a third party for testing, and where products will be stored during testing. 你们的回复说你们会“重新开始稳定性测试”。你们的回复是不充分的。你们未提交你们稳定性测试计划的详情，包括你们会执行哪些测试项目，是否会使用第三方进行检测，以及在检测期会将产品放在何处。 In response to this letter, provide your standard operating procedure (SOP) describing your firm’s ongoing stability program. Also, provide stability data demonstrating that each OTC drug product distributed by your firm to the United States meets all specifications throughout its expiry. 在回复此函时，请提供你们描述你公司持续稳定性计划的SOP。还有，请提供稳定性数据证明你们公司销往美国的每种OTC药品在其有效期内符合所有质量标准。 5. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21CFR 211.100(a)).你公司未能建立足够的书面生产和工艺控制程序，用以确保你们生产的药品具备其理当具备的鉴别、剂量、质量和纯度（21 CFR 211.100(a)）。 You have not validated the processes you use to manufacture your drug products. For example, you did not conduct process performance qualification studies, and you lack an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document, Process Validation: General Principles and Practices, for general principles and elements of process validation athttp://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf. 你们未验证你们用以生产你们药品的工艺。例如，你们未进行工艺性能确认研究，你们缺少为确保稳定的生产操作和持续的药品质量而持续监测工艺控制的计划。参见FDA工艺验证指南。 In your response, you provided a timetable for the (b)(4) system qualification, and cleaning and manufacturing validation processes. Your response is inadequate. You did not provide sufficient details describing your qualification and validation program. 在你们的回复中，你们提供了一份XX系统确认和清洁和生产验证工艺的时间表。你们的回复是不充分的。你们并未提供充分的详情描述你们的确认和验证程序。 In response to this letter, provide the protocols for your validation and qualification activities. Also, describe how you will monitor sources of variability in your operation throughout the drug lifecycle to minimize batch variation and assure consistent product quality. 在回复此函时，请提交一份你们验证和确认活动的方案。还有，请描述你们将如何在药品生命周期中监测你们生产操作中波动的来源以减少批差异并确保持续的产品质量。 Your response also failed to evaluate the impact of manufacturing your products using unvalidated processes and procedures. 你们的回复亦未评估使用未经验证的工艺和程序生产你们产品的影响。 In your response to this letter, conduct an assessment into distributed batches of your OTC drug products. Provide your plans for addressing product quality and patient safety risks for any OTC drugs still indistribution, including customer notifications or market withdrawals. 在回复此函时，请对你们已销售的OTC药品批次进行评估。请提交你们的仍在销售中所有OTC药品的产品质量和患者安全风险处理计划，包括客户通知和市场撤回。 Quality Unit Authority 质量部门权力 Significant findings in this letter indicate that your quality unit is not able to fully exercise its authority and responsibilities.Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality. 在本函中的重大缺陷显示你们的质量部门无力全面属性其职权。你公司必须为质量部门提供适当的权力和足够的资源以执行其职责并持续确保药品质量。 CGMP consultant recommended CGMP顾问建议 Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant, qualified as set forthin 21 CFR 211.34, to assist your firm in meeting CGMP requirements. We also recommend that the qualified third party perform a comprehensive audit of your entire operation for CGMP compliance, including the quality assurance system,materials system, facility and equipment system, laboratory system, production system, and packaging and labeling system. Your CAPA should then be evaluated by the third party to help ensure systemic remediation before you pursue resolution of your firm’s compliance status. 依据我们在你们工厂发现的违规情况，我们强烈建议你们使用一位有资质的顾问来协助你们公司符合CGMP要求。我们还建议具备资质的第三方对你们的所有操作进行一次全面的CGMP合规审计，包括质量保证体系、物料体系、设施和设备体系、实验室体系、生产体系和包装及标签体系。然后，你们的CAPA应由第三方进行评估以帮助确保进行系统地补救来解决你们的公司合规状态问题。 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. 你们使用顾问并不解除你们公司符合CGMP的义务。你们公司的高级管理层仍负有义务全面解决所有缺陷，确保持续CGMP符合性。 Conclusion 结论 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. 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，防止其它偏差的发生。 FDA placed your firm on Import Alert 66-40 on January 17,2018. FDA已于2018年1月17日将你公司列入进口禁令第66-40项下。 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. 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 FDA continuing to refuse admission of articles manufactured at Biologique Recherche (BR SAS) at 28 rue de la Procession, Suresnes, 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, respond to this office inwriting within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannotcomplete corrective actions within 15 working days, state your reasons for delay and your schedule for completion. 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。 Bryce Hammer 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 1000373305. Sincerely, /S/ Francis Godwin Acting Director Office of Manufacturing Quality Office of Compliance Center for Drug Evaluation and Research
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发表于 2018-6-25 21:32:48
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