12月10日，FDA发布了对Guangzhou Four E’s Scientific Co., Ltd.的警告信，警告信中披露了该公司的无菌产品，由CMO生产，FDA检查了该公司提供的来自CMO的质量标准发现，检验的是需氧菌总数，检验标准为“≤xx”。FDA表示：无菌产品必须符合USP <71>，无菌检查，应无活的微生物。

此外，还发现该CMO存在原辅料检验不充分、工艺验证不完整和成品检验不充分等GMP违规。

警告信翻译如下：

November 13, 2024

Dear Mr. Wan:

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 4, 2024 request, and subsequent correspondence, 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, Guangzhou Four E’s Scientific Co. Ltd., FEI 3009155756, at 5th Floor, Building C, No. 2 Ruitai Road, Huangpu District, Guangzhou, Guangdong 510700, China.

你们工厂在FDA注册为非处方药生产商。FDA已经审核了你们根据FD&C法案第704(a)(4)条提交的关于你们工厂的记录和其他信息的记录，该工厂位于广州黄浦区瑞泰路2号C栋5楼，FEI 3009155756，中国广东广州510700。

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations, parts 210 and 211 (21 CFR, parts 210 and 211).

本警告信总结了成品药品严重违反现行良好生产规范（CGMP）规定的情况。参见21 CFR, parts 210 and 211。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding of drugs described in your response to our 704(a)(4) request 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)).

由于你们对我们704(a)(4)要求的回复中所描述的药品生产、加工、包装或保存的方法、设施或控制不符合CGMP，根据FD&C法案第501(a)(2)(B)条(21 U.S.C. 351(a)（2)(B)），你们的药品被认定为掺假。

Following review of records and other information provided pursuant to section 704(a)(4) of the FD&C Act, significant violations were observed including, but not limited to, the following:

在对根据FD&C法案第704(a)(4)条提供的记录和其他信息进行审查后，发现重大违规行为包括但不限于以下：

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).

贵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，并符合既定的鉴定、剂量、质量和纯度标准（21 CFR 211.22）。

Your quality unit (QU) failed to have adequate oversight and procedures for your contract manufacturing organization (CMO) to ensure that they operate in compliance with CGMPs.

你们的质量部门（QU）未能对你们的合同生产组织（CMO）有足够的监督和程序来确保他们的操作符合CGMP。

Your firm utilized a CMO,(b)(4), to perform manufacturing, processing, and packaging activities on your behalf. You received drug products from this CMO and declared your firm as the manufacturer on import records.

你们公司利用CMO （xx）代表你们执行生产、加工和包装活动。你们从该CMO收到药品，并在进口记录中申报你们公司为生产商。

The records and information you provided demonstrate that your firm did not effectively exercise its CGMP responsibilities. Specifically, your firm’s QU failed to ensure that all drug products produced for your firm possessed appropriate quality attributes. For example, your quality agreement indicates that you establish your quality requirements and your CMO must satisfy the quality requirements. Your product is labeled as sterile. However, in your response dated March 18, 2024, you submitted specifications from your CMO for your(b)(4) product labeled as sterile, showing microbiological testing with specifications of “≤(b)(4)” for aerobic plate count.1 Sterile products introduced to the U.S. market must meet United States Pharmacopeia (USP) <71>, Sterility Tests, to be free from viable microorganisms.

你们提供的记录和信息证明贵公司没有有效地履行CGMP责任。具体来说，贵公司的质量部门（QU）未能确保为你们公司生产的所有药品都具有适当的质量属性。例如，你们的质量协议表明你们建立了质量要求，你们的CMO必须满足这些质量要求。你们的产品标签上声明无菌。然而，在你们2024年3月18日的回复中，你们提交了你们CMO标注无菌的xx产品的标准，显示需氧菌总数的微生物检测标准为“≤xx”。销往美国市场的无菌产品必须符合美国药典(USP) <71>，无菌检查，应无活的微生物。

Further, drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

此外，药品必须按照CGMP生产。FDA意识到许多药品制造商使用独立的承包商，如生产设施、测试实验室、包装商和贴标商。FDA将承包商视为制造商的延伸。

A 704(a)(4) records review of your CMO,(b)(4), found significant violations of CGMP including, but not limited to, inadequate testing of raw materials, incomplete process validation and inadequate testing of finished products. These CGMP violations render the products manufactured by (b)(4) adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act. FDA placed products offered for import to the United States from (b)(4) on Import Alert (b)(4), on (b)(4), and issued Warning Letter (b)(4) on (b)(4).

对你们CMO的704(A)(4)记录审核发现了重大的CGMP违规行为，包括但不限于原辅料检验不充分、工艺验证不完整和成品检验不充分。这些CGMP违规行为使得(b)(4)生产的产品在FD&C法案第501(a)(2)(b)条的意义上认定为掺假。FDA将提供从(b)(4)进口到美国的产品置于(b)(4)上的进口警报(b)(4)上，并发出警告信。

You, including your QU, are responsible for the quality of your drugs regardless of agreements in place with your contract facilities. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity. See FDA’s guidance documentContract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov>media>download.

你们，包括你们的质量部门，要对你们药品的质量负责，不管你们是否与你们的合同工厂达成了协议。你们必须确保药品是按照FD&C法案501(a)(2)(B)条款生产的，以确保安全性、鉴别、剂量、质量和纯度。见FDA指南《药品合同生产安排：质量协议》，网址：https://www.fda.gov>media>download。

See FDA’s guidance documentQuality 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.

参见FDA指南《药品CGMP法规质量体系方法》，以帮助实施质量体系和风险管理方法，以满足CGMP法规21 CFR，第210部分和211部分的要求，网址为https://www.fda.gov/media/71023/download。

In response to this letter, provide:

回复此函，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 also include, but not be limited to:

一个全面的评估和补救计划，以确保你们的QU获得有效运作的权限和资源。评估还应包括但不限于:

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

确定贵公司所使用的程序是否健全和适当。

Provisions for QU oversight throughout your operations, including an evaluation of your contract manufacturer qualification program, to evaluate adherence to appropriate practices.

在你们的整个运营过程中规定QU监督，包括对你们的合同制造商确认程序的评估，以评估对适当实践的遵守情况。

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

在作出处置决定前，对每个批次及其相关信息进行完整和最终的审查。

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

监督和批准调查并履行所有其他质检职责，以确保所有产品的鉴定、剂量、质量和纯度。

A complete evaluation of drug product specifications for the (b)(4) to determine whether the specifications are appropriate.

对药品说明书进行完整的评价，以确定说明书是否合适。