2021年1月26日，FDA公布一封针对国内企业的警告信。值得注意的是，FDA并未对该企业进行现场检查，而是基于FD＆C法案第704(a)(4)条的规定，向该公司提出了记录和其它信息的要求，并对此进行了书面审核。

 

主要的违规项涉及产品检验、入厂物料检验和稳定性问题。FDA最后指出，该公司缺少足够的质量单位(QU)。

 

尊敬的XX先生：

 

Your facility is registered with the United States Food and Drug Administration (FDA) as a manufacturer of over-the-counter (OTC) drug products. FDA has reviewed the records you submitted in response to our March 31, 2020 request for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for your facility, XX Daily Chemical Co., Ltd., FEI XXX, at XXX Town, Ningbo.

 

你们的设施已在美国FDA注册为非处方(OTC)药品生产商。FDA根据FD＆C 法案第704(a)(4)条的规定，2020年3月31日向你们设施提出了记录和其它信息的要求，FDA审核了针对这一要求而提交的记录。你们的设施为XX日化有限公司，FEI 3XX，位于XXXXX。

 

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

 

该警告信总结了严重违反CGMP规定的情况。参见21 CFR，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)).

 

由于你用于生产、加工、包装或储存的方法、设施或控制措施不符合CGMP，因此根据FD＆C法案501(a)(2)(B)条及21 U.S.C.351(a)(2)(B) 条的规定，你们的药品被认为是掺假。

 

 

产品检验

 

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)).

 

公司没有对每批药品进行适当的实验室确认，以确定其是否符合最终产品的质量标准要求，包括放行之前的每种活性成分的鉴别和强度(21 CFR 211.165(a))。

 

Your firm listed over-the-counter (OTC) drug products, including hand sanitizer1, (b)(4), (b)(4) products, and (b)(4), with FDA. Your response to our request for records and other information under section 704(a)(4) indicates that you did not conduct adequate finished drug product testing on drug products shipped to the United States. For example, in response to our 704(a)(4) request for all finished product specifications and test methods either performed in-house or by a third party, you submitted finished product test reports for your OTC (b)(4) but did not include adequate records demonstrating that you conducted appropriate testing for identity and strength of the active ingredient, (b)(4). Your response also lacked the test methods and only listed equipment. When we requested this missing information in our follow-up communication on May 8, 2020, you restated your original response and added that you used a third party testing laboratory for assay testing, but did not include test specifications or methods for identity and strength testing used by the third-party laboratory. The documents you provided in response to our 704(a)(4) request indicate that you do not perform assay testing for identity and strength of your active ingredients. Without adequate testing, there is not scientific evidence that your drug product batches conform to appropriate specifications prior to release.

 

你们公司向FDA列出了非处方(OTC)药品，包括洗手液、XX、XX产品和XX。基于704(a)(4)条，我们提出了记录和其它信息的要求，你们对此的答复表明，你们没有对运往美国的药品进行充分的成品制剂检测。例如，针对内部或第三方执行的所有成品质量标准和检测方法，我们基于704(a)(4)条提出要求，为响应该记录要求，你们提交了OTC XX的成品检测报告，但没有包含足够的记录，表明你们对活性成分XX鉴别和强度进行了适当的检测。你们的答复也缺少检测方法，仅列出了设备。当我们在2020年5月8日的后续通信中要求提供这些缺失的信息时，你们重申了原始答复，并补充说你们使用了第三方检测实验室进行含量检测，但未包括检测质量标准、或鉴别和强度检测方法（由第三方实验室使用）。你们为响应我们的704(a)(4)要求而提供的文件表明，你们没有对活性成分的鉴别和强度进行分析检测。没有适当的检测，就没有科学证据表明你们的药品批次在放行之前，符合适当的质量标准。

 

Following our 704(a)(4) request, we note that you shipped several lots of hand sanitizer to the United States. Ensure that your response to the items below includes documentation that applies to hand sanitizer and any drug products intended for U.S. distribution.

 

根据我们的704(a)(4)要求，我们注意到你们向美国运送了几批洗手液。确保你们对以下要求的答复包括必要的文档，针对洗手液和拟在美销售的任何药品。

 

In response to this letter, provide the following for all drug products imported to the United States prior to and after our 704(a)(4) request:

 

在回信中，请针对我们提出704(a)(4)要求之前和之后进口到美国的所有药品，提供以下信息：

 

• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision.

 

•在决定批次处置之前，用于分析每批药品的化学和微生物质量标准(包括检验方法)列表。

 

• 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 that are within expiry as of the date of this letter.

 

•行动计划和时间表：对留样进行全面的化学和微生物检验，以确定分发给美国的药品批次(效期内，以本信函时间计)质量。

 

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

 

•各留样批次检验结果摘要。如果检验表明药品质量不合格，请采取迅速的纠正措施，例如通知客户和产品召回。

 

• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

 

•对实验室操作、程序、方法、设备、文档和分析人员的能力，进行全面的独立评估。在此审查的基础上，提供详细计划，以补救和评估实验室系统的有效性。

 

• Methanol test results for all batches of hand sanitizer shipped to the United States within expiry.

 

•有效期内运往美国的所有批次的洗手液的甲醇检测结果。

 

 

入厂物料检验

 

2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product (21 CFR 211.84(d)(1)).

 

你们公司未进行至少一项检验，来确认药品中每种成分的鉴别。

 

Based on the records and information you provided, you have not demonstrated that you are testing incoming raw materials used to manufacture your drug products to determine their identity.

 

根据你们提供的记录和信息，你们无法说明：对于用于生产药品的入厂物料进行了检测，以确定其鉴别。

 

For example, when we requested whether you perform raw material identity testing, you replied that the testing is done by your supplier. When we requested which identity test is performed in our follow-up communication on May 8, 2020, you provided the supplier certificate of analysis (COA) for the (b)(4), which does not include a specification or results for identity testing, and you did not provide documentation showing that you have qualified the supplier or that you have verified the information on the supplier’s COA. You also did not provide identity testing information related to other products shipped from your facility.

 

例如，当我们询问你们是否执行物料鉴别检测时，你们答复说检测是由供应商完成的。在2020年5月8日的后续通信中，我们要求说明执行哪种鉴别检测，此时你们提供了XX的供应商分析证书(COA)，其中不包括鉴别检测的质量标准或结果；你们也没有提供证明，说明你们已经确认了供应商资质、或已确认供应商COA上的信息。就其它从你们的工厂发货的产品，你们也没有提供相关的鉴别检测信息。

 

In response to this letter, provide the following for all components used in drug products imported to the United States prior to and after our 704(a)(4) request:

 

在回信中，请针对向美国进口药品中使用的所有成分（无论在我们提出的704(a)(4)要求之前、还是之后），提供以下信息：

 

• 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.

 

•对物料系统进行全面、独立的审查，以确定所有组分、容器和密封件供应商是否有资质，且为物料指定适当有效期或再验日。对于入厂物料的控制措施，审查还应确定是否足以防止使用不合适的组分、容器和密封件。

 

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.

 

•每批入厂组分(生产目的)，用于检验和放行的化学和微生物质量标准。

 

• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. We note that identity testing is required for every lot of components regardless of supplier test result validation.

 

•说明如何检验每个批次，确定是否符合有关鉴别、强度、质量和纯度质量标准。如果你们打算接受供应商COA的任何结果，而不是检验每个组分批次的强度、质量和纯度，请指定如何进行初始验证和定期再验证，从而稳健地确定供应商结果的可靠性。需要注意的是，无论供应商检验结果如何验证，每个组分都需要进行鉴别检测。

 

• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.

 

•结果摘要：对所有组分进行检验，以评估每个组分生产商的COA可靠性。包括描述此COA验证程序的SOP。

 

• A summary of your program for qualifying and overseeing contract laboratory facilities that test the active ingredients used in the drug products you manufacture.

 

•计划摘要：对检验药品的合同设施进行资质确认和监督。

 

 

稳定性稳定

 

3. 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 stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

 

3.你们公司未能建立并遵循适当的书面检验程序，以评估药品的稳定性特征；未能使用稳定性检验结果，来确定适当的储存条件和有效期(21 CFR 211.166(a))。

 

You did not provide adequate stability data to demonstrate that the chemical properties of your drug products remain acceptable throughout the labeled expiry period. For example, your stability data for (b)(4) does not include testing for the active ingredient. Therefore, the data does not demonstrate that the drug’s active ingredient is stable throughout its shelf life. Additionally, the data provided does not include microbiological stability data.

 

你们没有提供足够的稳定性数据，来证明你们药品在标记的有效期内，仍保持可接受的化学性质。例如，你们的XX稳定性数据不包括活性成分检测。因此，数据不能证明该药物的活性成分在整个有效期内都是稳定的。此外，提供的数据不包括微生物稳定性数据。

 

In response to this letter, provide the following for all drug products imported to the United States prior to and after our 704(a)(4) request:

 

在回信中，请针对进口到美国的所有药品（无论在我们提出的704(a)(4)要求之前、还是之后），提供以下信息：

 

• A comprehensive, independent assessment and corrective and preventive action plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:

 

全面、独立的评估和CAPA计划，以确保你们的稳定性计划是充分的。你们的补救计划应包括但不限于：

 

o Stability indicating methods

 

稳定性指示方法

 

o Stability studies for each drug product in its marketed container-closure system before distribution is permitted

 

在分销之前，对市售容器密闭系统中的每种药物进行稳定性研究

 

o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid

 

正在进行的计划，每年将每种产品的代表性批次添加到其中，以确定有效期声明是否仍然有效

 

o Detailed definition of the specific attributes to be tested at each station (timepoint)

 

每个点(时间点)要检验的特定属性的详细定义

 

o All stability data from your ongoing stability program for all products manufactured from January 1, 2016 to present

 

就 2016 年 1 月 1 日至今生产的所有产品，持续稳定性计划的所有稳定性数据

 

• All procedures that describe these and other elements of your remediated stability program

 

针对稳定性补救计划的这些以及其它元素，其所有相关的描述性程序。

 

 

缺少充分的质量单元

 

4. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit (21 CFR 211.22(d)).

 

公司未建立适用于质量控制部门的适当书面责任和程序，并没有遵循此类书面程序(21 CFR 211.22(d))。

 

The records and information you submitted demonstrate that you lack an adequate quality unit (QU). For example, your firm failed to provide adequate written procedures for QU responsibilities such as batch record review, supplier qualification, equipment qualification and calibration, process validation, cleaning validation, and annual product review.

 

你们提交的记录和信息表明：你们缺少充分的质量单元(QU)。例如，你们公司未能为QU的职责提供足够的书面程序，例如批记录审核、供应商资质确认、设备确认和校准、工艺验证、清洁验证以及年度产品回顾。

 

In response to this letter, provide:

 

针对此信，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 also include, but not be limited to:

 

•提供全面的评估和补救计划，以确保你们的QU拥有有效行使职责的授权和资源。评估还应包括但不限于：

 

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

 

确定你们公司使用的程序是否健全和适当。

 

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

 

整个运营过程中，对QU监督规定的评估，已确定对良好实践的遵守情况。

 

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

 

在QU决定处置之前，对每批产品及其相关信息进行完整和最终审查。

 

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

 

进行监督和批准，调查并履行所有其它QU职责，以确保所有产品的鉴别、强度、质量和纯度。

 

 

质量体系

 

Quality Systems

 

Based on FDA’s review of records and information provided in response to our request, your firm’s quality systems are inadequate. Please see FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for helpful information regarding implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at

 

根据FDA对应我们要求提供的记录和信息的审查，你们公司的质量体系不完善。请参阅FDA指南《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，满足CGMP法规21 CFR第210和211部分的要求。

 

CGMP顾问推荐

 

CGMP Consultant Recommended

 

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 evaluate the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA. 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.

 

根据我们发现的违规行为的性质，我们强烈建议聘请符合21 CFR 211.34规定的合格顾问，来协助你们公司满足CGMP要求。我们还建议，有资质的顾问对你们的整个 CGMP 合规运营进行全面审计，并在你们寻求解决你们公司与 FDA 的合规状态之前，评估你们的CAPA的完成情况和有效性。你们聘用顾问并不能免除公司遵守CGMP的义务。你们公司的执行管理层仍然负责解决所有缺陷和系统性缺陷，以确保持续符合CGMP。

 

结论

 

Conclusion

 

The violations cited in this letter are not intended to be an all-inclusive list of violations associated with your drug products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

 

本信函中引用的违规行为并非旨在列出与你们的产品相关的所有违规行为。你们有责任调查和确定这些违规的原因，并防止其再次发生或发生其它违规情况。

 

Note that FDA placed all drugs and drug products manufactured by your firm on Import Alert 66-40 on September 23, 2020, as the methods used in and controls used for the manufacture, processing, packing, or holding of these products do not appear to conform to current good manufacturing practice within the meaning of section 501(a)(2)(B) of the FD&C Act. Drugs and drug products that appear to be adulterated or misbranded may be detained or refused admission without physical examination pursuant to section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).

 

请注意，FDA于2020年9月23日将你们公司生产的所有药品置于进口警报66-40上，因为生产、加工、包装或保存这些产品所用的方法和控制措施不符合cGMP，即FD＆C法案501(a)(2)(B)条所要求的的。根据FD＆C法案801(a)(3)条和21 USC 381(a)(3)条，对于掺假或标识错误的药品，可在未经物料检查的情况下，被扣留或拒绝入境。

 

All drugs and drug products manufactured by your firm may remain listed on this import alert until there is evidence establishing that the conditions that gave rise to the appearance of this violation have been resolved, and the Agency has confidence that future entries will be in compliance with the FD&C Act. This may include an inspection prior to the Agency considering the appearance of adulteration to be addressed.

 

你们公司生产的所有药品仍会保留在此进口警报中，直到有证据表明导致这种违法行为出现的条件得到了解决，并且FDA相信以后的入境产品将符合FD＆C法案。这可以包括现场检查，已确定解决了掺假问题。

 

Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.

 

及时纠正任何违规行为。对于新药申请或补充申请，FDA不会批准将你们公司列为药品生产商，直到违法行为得到纠正，并且我们确认你们遵守CGMP。我们可能会重新检查，以确认针对任何违规行为，你们已采取了纠正措施。

 

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any deviations and violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot do so within 15 working days, state your reasons for delay and your schedule for completion.

 

这封信告知我们的发现，并为你们提供解决上述缺陷的机会。收到这封信后，请在15个工作日内以书面形式答复FDA办公室。说明你们所做的事情，以纠正你们的违规行为，并防止其再次发生。在回信中，你们可以提供其它信息供我们考虑，以便我们继续评估你们的活动和实践时。如果你们无法在15个工作日内这样做，请说明延误原因和完成时间表。