远程检查，国内企业又收到FDA警告信

3月16日，FDA公布一封针对国内企业（佛山拜澳生物科技有限公司）的警告信。这是FDA公布的第二封基于远程检查的警告信。

FDA警告信：对国内某企业的远程审计

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、清洁验证和稳定性问题。FDA最后强烈建议该公司聘请有资质的顾问，来协助解决GMP问题。

Warning Letter 320-21-34

March 10, 2021

Dear Mr. Huang:

警告信320-21-34

2021年3月10日

黄先生：

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 April 3, 2020 request, and subsequent requests, 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, Foshan Biours Biosciences Co., Ltd., FEI 3011474550, at 13 East Xile Road, Tower B F1 Complex Bldg., Rooms 201, 202, 203 (2nd Floor) & 302 (3rd Floor), Foshan, Guangdong.

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4月3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。你们的设施为佛山拜澳生物科技有限公司，FEI 3011474550，位于广东省佛山市西乐大道东13号F1综合楼B座二楼201、202、203号、B座三楼302号。

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)).

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

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 manufactures an over-the-counter (OTC) drug product, (b)(4) Patch containing (b)(4). Your response to our request for records and other information under section 704(a)(4) indicates that you distributed this drug product into the United States without adequate finished drug product testing.

你们公司生产一种非处方(OTC)药品，是包含XX的贴剂XX。基于704(a)(4)条，我们提出了记录和其它信息的要求，你们对此的回复表明，你们没有对分销美国的药品进行充分的成品制剂检测。

For example, in response to our request to provide release specifications of U.S. products and the test method used to evaluate them, you submitted a certificate of analysis for your OTC (b)(4) Patch that shows you did not conduct adequate testing for identity and strength of the active ingredient, (b)(4), as is required prior to release per 211.165(a). No other information provided was responsive to our request for information about release testing. Your response indicates that you do not perform assay testing for identity and strength of your active ingredient.

例如，我们要求提供美国产品的放行质量标准和用于评估它们的检验方法，作为回应，你们提交了OTC贴剂XX的分析证书，表明你们未进行充分的检验，包括活性成分XX的鉴别和强度，这是基于211.165(a)的放行前检验要求。提供的其它信息均未能响应我们对放行检验信息的要求。你们的回复表明你们未对活性成分的鉴别和强度进行检验。

Without adequate testing, you do not have scientific evidence that your drug product batches conform to appropriate specifications prior to release.

没有适当的检验，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。

In response to this letter, provide the following for all drug products imported to the United States:

针对此信，请对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.

在做出批处置决定之前，用于分析每批药品的化学和微生物质量标准(包括检测方法)列表。

o 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测，对于分发给美国的所有效期内(本函发出之日计)药品批次，确定其质量。

o 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.

所有批次的留样检验摘要。如果此类检测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.

对你们的实验室操作、程序、方法、设备，文档和分析人员的能力进行全面、独立的评估。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。

清洁验证缺陷

2. Your firm failed to establish and follow written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

2.你们公司未建立并遵循适当的书面程序，来清洁和维护设备(21 CFR 211.67(b))。

Based on the information you provided in response to our request for cleaning procedures for cleaning equipment for U.S. product lines, you have not conducted cleaning validation studies. For example, in response to our records request you indicated that there was no validated cleaning procedure for the equipment used in the manufacture and packaging of your OTC (b)(4) Patch. Additionally, you stated that the equipment used in the manufacture and packaging of your OTC (b)(4) Patch is not dedicated to that drug product.

我们要求提供美国产品线清洁设备的清洁程序，基于你们为响应这一要求而提供的信息，你们尚未进行清洁验证研究。例如，根据我们的记录要求，你们指出在OTC贴剂XX的生产和包装中所用的设备没有已验证的清洁程序。此外，你们指出，在OTC贴剂XX的生产和包装中使用的设备并非专用于该药品。

Without cleaning validation studies you cannot demonstrate that your cleaning procedures for non-dedicated production equipment are adequate to prevent cross-contamination.

没有清洁验证研究，你们将无法证明你们非专用生产设备的清洁程序足以防止交叉污染。

In response to this letter, provide the following for all drug products imported to the United States:

针对此信，请对进口到美国的所有药品提供以下信息：

• Steps your firm has taken to develop an adequate cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

你们为开发清洁验证程序已经采取的步骤，特别着重于纳入在药品生产工艺中确定为最差情况的条件。最差情况的识别和评估，应包括但不限于：

o drugs with higher toxicities

o具有较高毒性的

o drugs with higher drug potencies

o产品具有较高活性的

o drugs of lower solubility in their cleaning solvents

o产品在清洁溶剂中溶解度较低的产品

o drugs with characteristics that make them difficult to clean

o具有使其难以清洁的特性的产品

o swabbing locations for areas that are most difficult to clean

o 清洁最困难区域的擦拭位置

o maximum hold times before cleaning

o清洁前的最长放置时间

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

另外，描述在引入新的生产设备或新产品之前，变更管理系统必须采取的步骤。

• A summary of updated SOPs that ensure an appropriate program is in place to verify and validate cleaning procedures for products, processes, and equipment.

更新的SOP的摘要，以确保制定适当的程序，来验证和确认产品、工艺和设备的清洁程序。

稳定性数据缺陷

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)).

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))。

In response to our request for a list all batches in stability and a list of all stability studies, 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 OTC (b)(4) Patch 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.

我们要求提供稳定性研究中的批次清单、以及所有稳定性研究的清单，作为响应，你们没有提供充分的稳定性数据，来证明你们药品的化学特性在整个标识效期内仍然可以接受。例如，你们的OTC贴剂XX的稳定性数据不包括活性成分检验。因此，数据不能证明该药物的活性成分在整个效期内都是稳定的。

In response to this letter, provide the following for all drug products imported to the United States:

针对此信，请对进口到美国的所有药品提供以下信息：

• A comprehensive, independent assessment and CAPA 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

• 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。

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.

根据我们在你们公司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。我们还建议合格的顾问对你们整个操作过程进行全面审计，以确保其符合CGMP要求，并建议在你们寻求公司与FDA的合规性解决方案之前，顾问对你们CAPA的完成情况和有效性进行评估。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 the drug product manufactured by your firm on Import Alert 66-40 on October 22, 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 practices 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10月22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、包装或仓储这些产品所用的方法和控制措施不符合cGMP，cGMP在FD＆C法案第501(a)(2)(B)条(即21 U.S.C. 381(a)(3)条)中规定。视为掺假或标识错误的药品，可在未经物理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 a violation have been resolved, and the Agency has confidence that future entries will be in compliance with the 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都可能会保留在此进口警报中，直到有证据表明导致违法行为的条件得到解决，并且FDA相信将来将符合该法案的要求。这包括FDA考虑对你们工厂进行检查(基于掺假问题)。

Until all violations are addressed completely and we confirm your compliance with CGMP, they may be cause for FDA to withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.

在所有违规行为得到彻底解决且我们确认你们遵守CGMP之前，FDA不会批准将你们公司列为药品生产商的任何新药申请或补充申请。

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 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.

这封信通知你们我们的发现，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回复FDA办公室。说明你们为解决任何违规行为、并防止其再次发生所采取的措施。在回信中，当我们继续评估你们活动和做法时，你们可以提供其它信息供我们考虑。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。

Ref.: Warning Letter. Foshan Biours Biosciences Co., Ltd. MARCS-CMS 611319 — March 10, 2021. FDA.