1) 质量部门（QU）未能对合同制造商（CMO）提供足够的监督和程序，以确保其符合 CGMP。

2) 该公司利用一家CMO进行制造、加工和包装活动，但在进口记录上申报该公司为制造商。

3) 质量部门未能确保为公司生产的所有药品均具备适当的质量属性。例如，产品标签上写着无菌，然而，在提交产品的标准上显示微生物检测的菌落计数标准为“≤(b)(4)”。

4) 原材料检测不充分、工艺验证不完整和成品检测不充分。

警告信中提出，FDA 将承包商视为制造商的延伸。无论与合同工厂达成何种协议，公司均应对药品质量负责，需要确保药品按照《FD&C法案》的要求生产，并符合相应的标准。

注：从该警告信可以看出，该公司对CMO活动的监督不够充分，并缺少适当的程序确保产品按CGMP要求生产。这里提醒MAH，应重视对CMO等承包商的监管，确保生产出质量可靠的药品，MAH对最终的药品质量负责。

另外，本警告信也是未进行现场检查，仅通过审查提交的文件即发布了警告信，同类的情形还有其他警告信，在这里也再次提醒重视提交资料的合规性。

【基础信息】

Posted Date：2024.12.10

Letter lssue Date：2024.11.13

FEI：xxxxx

Firm name：xxx

Type establishment inspected：Drug Manufacturing Facility

Investigator：N/A

你们的工厂已在美国食品药品监督管理局 (FDA) 注册为非处方 (OTC) 药品制造商。FDA 已审查了你们提交的记录以及随后的回复，这些记录和回复是我们依据《联邦食品、药品和化妆品法案》 (FD&C 法案) 第 704(a)(4) 节的规定于2024年3月4日的针对你们工厂（XXX）所索要的。

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)).

由于你们在对我们 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《联邦食品药品和化妆品法案》（FD&C 法案）第 501(a)(2)(B) 节（21 U.S.C.351(a)(2)(B)）的规定，你们的药品被视为掺假。

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:

根据《联邦食品、药品和化妆品法案》第 704(a)(4) 节，审查你们提供的记录和其他信息后，发现了严重违规行为，包括但不限于以下情况：

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).

你们公司的质量控制部门未能履行其职责，确保生产的药品符合 CGMP，并满足既定的鉴别、规格、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）未能对你们的合同制造商（CMO）提供足够的监督和程序，以确保其符合 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.

你们公司利用一家CMO(b)(4)代表贵公司进行生产、加工和包装活动。你们公司从该CMO处收到药品，并在进口记录上申报你们公司为制造商。

The records and information you provided demonstrate that your firm did not effectively exercise its CGMP responsibilities. Specifically,your firm's QUfailed to ensure that alldrug 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表明你们公司未能有效履行其 CGMP 职责。具体而言，你们公司的质量部门未能确保为你们公司生产的所有药品均具备适当的质量属性。例如，你们的质量协议表明你们建立了质量要求，并且你的 CMO 必须满足该质量要求。你们的产品标签上标记为无菌，然而，在 2024 年 3 月 18 日的回复中，你们提交了 CMO 对标记为无菌的(b)(4)产品的质量标准，显示微生物检测的菌落计数标准为“≤(b)(4)”。进入美国市场的无菌产品必须符合美国药典(USP)<71>无菌检测标准，不含活体微生物。

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 进行生产。FDA 了解到，许多药品制造商使用独立承包商，例如生产工厂、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。

A704(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 tothe United States from(b)(4)on Import Alert(b)(4),on (b)(4),and issued Warning Letter(b)(4)on(b)(4).

通过对你们CMO，(b)(4)的704(a)(4)记录的审查，发现了严重CGMP违规行为，包括但不限于原材料检测不充分、工艺验证不完整和成品检测不充分。这些CGMP违规行为导致(b)(4)生产的产品依据FD&C法案第501(a)(2)(b)条被视为掺假。FDA于(b)(4)将拟从(b)(4)进口到美国的产品列入进口警报(b)(4)，并在(b)(4)发出了警告信(b)(4)。

You,including your QU,are responsible for the quality of your drugs regardless ofagreements in place with your contract facities.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.

无论与合同工厂达成何种协议，你们公司（包括你们的 QU）均应对药品质量负责。你们需要确保药品按照《FD&C法案》第 501(a)(2)(B) 节的要求生产，以确保安全、可识别、规格、质量和纯度。

• 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:

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

• Adetermination of whether procedures used by your firm are robust and appropriate.

  确定你们公司所采用的程序是否健全且适当。

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

  QU 全面监督你们运营过程的规定，包括对你们合同制造商资格认定程序的评估，以评估是否遵守适当的规范。

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

  QU在作出处置决定前，对每个批次及其相关信息进行了完整和最终的审查。

• 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 QU 职责，以确保所有产品的鉴别、规格、质量和纯度。

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

  对(b)(4)药品的质量标准进行全面评估，以确定其质量标准是否合适。

本信中列举的违规行为并非你们工厂存在的所有违规行为的详尽清单。你有责任调查和确定所有违规行为的原因，并防止其再次发生或发生其他违规行为。

FDA placed products offered for import into the United States from your firm on Import Alert 66-40 on October 17,2024.

FDA 于 2024 年 10 月 17 日将贵公司拟进口到美国的产品列入进口警报 66-40 中。

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

及时纠正所有违规行为。FDA 可能会暂停批准将你们公司列为药品制造商的新申请或补充申请，直到所有违规行为得到彻底解决并且我们确认贵公司符合 CGMP。我们可能会检查以确认你们公司是否已完成所有违规行为的纠正措施。