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Warning Letter 320-19-31 August 2, 2019
Mr. Wenxuan Han General Manager/Owner, NingBo Huize Commodity Co.,Ltd. 14 Lizhou Road, Yuyao, Zhejiang, 315402, China
Dear Mr. Han: The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, NingBo Huize Commodity Co., Ltd., at 14 Lizhou Road, Yuyao, Zhejiang, from March 18 to 22, 2019. 美国FDA于2019年3月18日至22日检查了你们位于中国浙江余姚市梨洲路14号的宁波市惠泽日用品有限公司生产场所。 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的行为。参见21CFR第210与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). 由于你们的制剂生产、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21 U.S.C. 351(a)(2)(B)被认为是掺假药品。 Your firm manufactures “SPF30 SUNSCREEN LOTION” 30mL and “SPF30 SUNSCREEN LOTION” 60mL that are misbranded drug products. Specifically, “SPF30 SUNSCREEN LOTION” 30mL is misbranded under sections 502(f)(1) and (f)(2) of the FD&C Act, 21 U.S.C. 352(f)(1) and (f)(2). Additionally, “SPF 30 SUNSCREEN LOTION” 60mL is misbranded under section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1). Introduction of such products into interstate commerce is prohibited under sections 301(a) of the FD&C Act, 21 U.S.C. 331(a). 你公司生产“SPF 30防晒霜” 30mL和“SPF30防晒霜”60mL为错标药品。具体来说，“SPF 30防晒霜” 30mL依据FDCA的502(f)(1) 和 (f)(2)条款， 21 U.S.C. 352(f)(1) 和 (f)(2)为错标药品，“SPF30防晒霜”60mL依据FDCA的502(f)(1) 条款， 21 U.S.C. 352(f)(1)为错标药品。根据FDCA第301(a)条款和21 U.S.C. 331(a)，该类产品禁止引入州际贸易。 We reviewed your April 10, 2019, response in detail and acknowledge subsequent correspondence. 我们已详细审核了你公司2019年4月10日的回复，并此告知已收到后续通信。 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： CGMP Violations CGMP违规 1. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22 (a)). 你公司未能设置充分的质量部门，使其具备权力和职责批准或拒收所有组份、药品容器、密闭器、中间体、包材、标签和药品（21 CFR 211.22 (a)）。 During our inspection of your facility, your quality staff provided multiple quality documents to our investigator. Based on concerns with the documents provided, our investigator questioned your Quality Manager regarding the validity of these documents. Your General Manager and Quality Manager, then stated that multiple documents provided were in fact falsified “for the purpose of this inspection.” 在我们检查你们设施期间，你们的质量人员提交了多份质量文件给我们检查员。根据所提供的文件，我们检查员询问你们质量经理关于这些文件的有效性。你们的总经理和质量经理说提供的多份文件实际上是“为了本次检查”虚造的。 Falsified documents include cleaning validation reports, batch records for multiple drug products, and annual product reviews. Furthermore, you also stated that you could not provide basic records tosupport the CGMP requirements for the manufacture of drugs, including, but notlimited to, the following: 虚造文件包括有清洁验证报告、多个药品批记录以及年度产品回顾。另外，你们还声称你们不能提供基本记录来支持药品生产的CGMP要求，包括但不仅限于： equipment qualification (21 CFR 211.63); 设备确认（21 CFR 211.63） raw material qualification and active pharmaceutical ingredient testing (21 CFR 211.84); 原料确认和API检测（21CFR211.84） finished product and raw material testing qualification (21 CFR 211.165); 成品和原料检测确认（21CFR211.165） drug product stability program (21 CFR 211.166); 药品稳定性程序（21CFR211.166） batch records (21 CFR 211.188); and 批记录（21CFR211.188） process validation (21 CFR 211.100). 工艺验证（21CFR211.100）
In your response, you provided some CGMP documents in writing. However, considering you falsified documents in the past, FDA is concerned regarding their validity. 在你们的回复中，你们提供了一些书面CGMP文件。但是考虑到你们曾经虚造文件，FDA对这些文件的有效性甚为担心。 Your response is inadequate because you failed to fully review the scope of your deficiencies, and provide evidence that you have comprehensively remediated your systems, and to implement procedures and programs that ensure ongoing control over your drug manufacturing operation. 你们的回复是不充分的，因为你们未能全面审核你们缺陷的范围，并提供证据证明你们已全面补救你们的系统，执行程序，确保持续控制你们的药品生产操作。 In your response to this letter, provide: 在回复此函时请提交： A comprehensive assessment and remediation plan to ensure your quality unit (QU) is given the authority and resources to effectively function. The assessment should also include, but not be limited to: 一份全面评估和补救计划，确保你们质量部门（QU）获得了权力和资源有效运行。这些评估亦应包括但不仅限于：
a determination of whether procedures used by your firm are robust and appropriate; 确定你公司所用程序是否稳健和适当 provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices; QU监管你们整个操作以评估是否遵守适当规范的要求 a complete and final review of each batch and its related information before the QU disposition decision; and QU处置决策之前对每批及其相关信息进行完整最终审核 oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products. 监管和批准调查和履行所有其它QU职责，以确保所有产品的鉴别、剂量、质量和纯度
A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures. Include a detailed corrective action and preventive action (CAPA) plan to remediate this system. Your CAPA plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, quality unit oversight, and written procedures. It should also address how you will ensure all phases of investigations were appropriately conducted and the CAPA is effective. 一份对你们偏差、差异、投诉、OOS结果和失败调查的全面系统的独立全面评估。包括一份详细的CAPA计划用于补救此系统。你们的CAPA计划应包括但不仅限于调查能力、范围确定、根本原因评估、质量部门监管和书面程序的重大改进。亦应说明你们要如何确保所有调查阶段均已适当执行，且CAPA是有效的。
A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures. 一份对你们物料体系的独立全面审核，以确定是否所有组份、容器和密闭器供应商均已确认，且物料均已给定适当的有效期或复验期。审核亦应确定进厂物料控制是否足以防止使用不适当的组份、容器和密闭器。
A complete, independent assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation. 一份对你们整个生产和实验室操作所用文件系统的全面独立评估，确定文件规范是否不充分。包括一份详细的CAPA计划，全面补救你公司的文件规范，以确保你们整个操作保持有可追溯、清晰、完整、原始、准确和同步记录。
A full summary of data integrity assessments performed by your third-party consultant. Include a copy of your protocols, which should include a detailed description of all aspects of your operation that were subject to independent evaluation, and the depth and extent of the assessments. See the Data Integrity Remediation heading below for the full remediation request. 一份由你们第三方顾问所执行的数据完整性评估全面总结。包括一份你们方案副本，其中应包括你们经过独立评估的操作所有方面的详细描述，以及评估的深度和程度。参见以下数据完整性补救标题下内容的全面补救要求。
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 forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA. 根据我们在你们公司发现的违规情况，我们强烈建议你们聘请一位具备21CFR211.34所要求资质的顾问协助你公司符合CGMP要求。我们亦建议有资质的顾问对你公司整个运营进行CGMP合规全面审计，在你公司寻求FDA合规之前由该顾问评估你们CAPA的完成情况和有效性。 Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance. 你们使用顾问并不能解除你们公司符合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。 The consultant should provide certification tha tyour remediated quality systems are satisfactory, and that all documents submitted to the FDA are valid. 顾问应提交证明说明你们经过补救后的质量体系是令人满意的，所有提交给FDA的文件均是有效的。 Quality Systems 质量体系 Your firm’s quality systems are inadequate. 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 and211 at https://www.fda.gov/media/71023/download. 你公司的质量体系是不充分的。参见FDA指南文件“药品CGMP法规质量体系”。 Data Integrity Remediation 数据完整性补救 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/119267/download. 你们的质量体系不能充分确保数据的准确性和完整性，无法支持你们生产的药品的安全性、有效性和质量。参见FDA指南文件“数据完整性和药品GMP合格”指导建立和遵守CGMP合格数据完整性规范。 We strongly recommend that you retain a qualified consultant to assist in your remediation. 我们强烈建议你们聘请具备资质的顾问协助你们进行补救。 In response to this letter,provide the following: 在回复此函时请提交以下资料： A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:一份对数据记录和报告不准确性程度的全面调查。你们的调查应包括 A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude. 详细的调查方案和方法学，所有实验室、生产操作和评估所覆盖的系统的总结，如有除外部分请论证 Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party. 对现有和已离职员工进行面谈，找出数据不准确的程度、范围和根本原因。我们建议这些面谈由有资质的第三方进行。 An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses. 你们工厂数据完整性缺陷的程度的评估。识别出省略、修改、删除、记录销毁、不同步记录填写和其它缺陷。说明你们已发现的数据完整性问题所涉及的工厂操作。 A comprehensive retrospective evaluation of the nature of the testing and manufacturing data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses. 一份对检测和生产数据完整性缺陷情况的全面回顾性评估。我们建议由具备在已发现可能有问题的领域的专业能力的有资质的第三方对所有数据完整性问题进行评估。
B. 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. 你们药品质量中所发现的不合格情况的潜在影响的当前风险评估。你们的评估应包括由于受到数据完整性问题影响的药品放行导致的患者风险的分析，以及持续运营所具有的风险。 C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include: 你们公司的管理策略，包括你们全球CAPA计划详细情况。你们的策略应包括：
A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA. 详细的CA计划，描述你们准备如何确保你们生成的所有数据的可靠性和完整性，包括分析数据、生产记录和所有提交给FDA的数据。 A comprehensive description of the root causes of your data integrity lapses including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm. 一份对你们数据完整性问题根本原因的全面描述，包括当前行动计划的范围和深度与调查和风险评估发现相称的证据。说明负责数据完整性的人员是否还有能力影响你公司与CGMP有关或药品申报数据。 Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring. 临时措施，描述你们已采取或将采取用来保护患者和确保你们药品质量的措施，如通知你们的客户、召回产品、执行额外检测、增加批次至稳定性计划以确保稳定性、药品申报措施和加强投诉监测。 Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data. 长期措施，其中描述所有对用以确保你们公司数据完整性的程序、流程、方法、控制、系统、管理监管和人力资源（例如培训、员工提高）的弥补和提升。 A status report for any of the above activities already underway or completed. 对上述活动已开展或已经完成的状态报告。
Misbranded Drugs Violations 错标药品违规 “SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL “SPF 30防晒霜” 30mL和“SPF30防晒霜”60mL “SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL, are “drugs” as defined by section 201(g)(1)(B) of the FD&C Act, 21U.S.C. 321(g)(1)(B), because they are intended for the diagnosis, cure, mitigation, treatment, or prevention of disease and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body. Specifically, “SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL are intended for use as sunscreens. “SPF 30防晒霜” 30mL和“SPF30防晒霜”60mL依FDCA第201(g)(1)(B)条款21U.S.C. 321(g)(1)(B)定义为“药品”，因为其目的是诊断、治愈、缓解、治疗或防止疾病和/或依据FD&CAct第201(g)(1)(C)条款， 21U.S.C. 321(g)(1)(C)为“药品”，因为其目的是影响人体结构或功能。具体来说“SPF 30防晒霜” 30mL和“SPF30防晒霜”60mL用于防晒。 Examples of claims observed on the product labels for “SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL that establish the intended uses, as defined in 21 CFR 201.128, of the products include, but may not be limited to, the following: 在“SPF 30防晒霜” 30mL和“SPF30防晒霜”60mL标签上发现的声明例子说明了产品的预期用途，依21CFR201.128，包括但不仅限于以下： “SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30SUNSCREEN LOTION” 60mL product labels: “SPF 30防晒霜” 30mL和“SPF30防晒霜”60mL产品标示为： “SPF 30 Sunscreen” “SPF 30防晒霜” The labeling for such drugs,like all OTC drugs, must comply with all of the requirements of section 502 of the FD&C Act and all pertinent regulations found in Title 21 of the Code of Federal Regulations (21 CFR). However, your products do not meet these requirements for the reasons described below. 此类药品的标签象所有OTC药品一样，必须符合FDCA第502条款的所有要求以及21CFR中所有相关法规要求。但是你们的产品并不符合这些要求，原因如下。 “SPF 30 SUNSCREEN LOTION” 30mL is misbranded under<span section 502(f)(1) of the FD&C Act, 21 U.S.C.352(f)(1), because the product label does not include any directions for use required under 21 CFR 201.327(e). “SPF 30 SUNSCREEN LOTION” 30mL is further misbranded under section 502(f)(2) of the FD&C Act, 21 U.S.C. 352(f)(2), because the product label does not include all of the required warnings described under 21 CFR 201.327(d). For example, the warnings section for SPF 30 SUNSCREEN LOTION” 30mL does not include “Do not use [bullet] on damaged or broken skin,” “When using this product [bullet] keep out of eyes. Rinse with water to remove,” and “Stop use and ask a doctor if [bullet] rash occurs” as required under 21 CFR 201.327(d)(1). “SPF 30防晒霜” 30mL依据FD&CA的502(f)(1)条款， 21 U.S.C. 352(f)(1)为错标产品，因为产品标签未包括21CFR201.327(e)所要求的使用说明。“SPF 30防晒霜” 30mL依据FD&CA第502(f)(2)条款， 21U.S.C. 352(f)(2)亦为错标产品，因为该药品标签并没有21 CFR 201.327(d)所述要求的警示信息。例如“SPF 30防晒霜” 30mL的警示部分未包括21 CFR 201.327(d)(1)所要求的“不得用于破损皮肤”，“使用时应避开眼睛，如入眼以水淋洗”以及“如有皮疹应停止使用咨询医生”。 Furthermore, “SPF 30 SUNSCREEN LOTION” 60mL is misbranded under section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1), because the product label does not include all of the applicable directions for use as required under 21 CFR 201.327(e). For example, the directions for use sectionfor “SPF 30 SUNSCREEN LOTION” 60mL does not include “[bullet] apply liberally 15 minutes before sun exposure” as required by 21 CFR 201.327(e)(1)(ii) or “[bullet] reapply at least every 2 hours [bullet] use a water resistant sunscreen if swimming or sweating” as required by 21 CFR 201.327 (e)(4). 另外，“SPF30防晒霜”60mL依据FD&CA的502(f)(1)条款， 21 U.S.C. 352(f)(1)为错标产品，因为产品标签未包括21CFR201.327(e)所要求的使用说明。例如“SPF 30防晒霜” 60mL标示未包括21 CFR 201.327(e) (1)(ii)所要求的“最好于暴露于太阳下之前15分钟使用”，或按21 CFR 201.327 (e)(4)要求标明“如游泳或出汗，使用拒水防晒霜，至少每2小时再次使用”。 The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). Therefore, the marketing of “SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL violate this provision of the FD&C Act. 将错标药品引入州际贸易或运输为FDCA第301(a)条款21 U.S.C. 331(a)所禁止。因此销售“SPF 30防晒霜” 30mL和“SPF30防晒霜”60mL违反了FDCA的此条款。 Recall of Drug Products 药品召回 We acknowledge that, based on the FDA inspectional findings, you agreed to recall drug products distributed to the U.S. marketwithin expiry. 我们知晓你们根据FDA检查发现已同意召回销往美国市场的所有在效期内药品。 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，防止你们设施内其它偏差的发生。 FDA placed your firm on Import Alert 66-40 on June13, 2019. FDA已于2019年6月13日将你公司置于进口禁令66-40中。 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 NingBo Huize Commodity Co., Ltd., 14 Lizhou Road, Yuyao, Zhejiang 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). 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 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. 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。 Chhaya Shetty Interdisciplinary Scientist 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 3012941723. Sincerely, /S/ Francis Godwin Director Office of Manufacturing Quality Office of Compliance Center for Drug Evaluation and Research
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发表于 2019-8-24 21:17:52
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