某药企生产体系「全线崩溃」

沁人绿茶.

5月20日，美国FDA官网公示了一封向中国无锡某企业发出的警告信。本警告信揭示了该公司在无菌药品生产体系中的系统性缺陷，问题包括：

无菌保障体系的全面失效：从环境控制（如虫害污染、设备老化）到关键工艺验证（灭菌程序缺失、生物指示剂未评估），企业未能建立最基本的无菌保障。

质量体系形同虚设：原辅料放行依赖供应商报告而未经验证、稳定性数据不足以支持效期设定、未执行无菌检测即放行产品等行为，暴露出质量部门完全失职。

纠正措施缺乏实质改进：企业对483表格回复中承认“无力通过FDA检查”，却继续分销产品，凸显管理层对GMP合规的消极态度。

警告信内容翻译如下：

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Wuxi Medical Instrument Factory Co., Ltd., FEI 3006851654, located at No. 43 Xixin Road, Zhangjing, Xibei Town, Wuxi, from November 11 to 15, 2024.

2024年11月11日至15日，美国食品药品监督管理局（FDA）检查了药品生产设施无锡市医用仪表厂有限公司（FEI 3006851654）），其地址为中国无锡（略，见上）。

Because your drug products were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, your drug products are also adulterated within the meaning of section 501(a)(2)(A) of the FD&C Act, 21 U.S.C. 351(a)(2)(A).

由于药品的制备、包装或储存条件不卫生，可能受到污物污染或对健康造成危害，因此根据FD&C法案第 501(a)(2)(A) 条、 21 USC 351(a)(2)(A) 条的规定，这些药品也被视为掺假药品。

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

本警告信总结了成品制剂现行药品生产质量管理规范(CGMP)法规的严重违规情况。请参阅联邦法规(CFR)第21篇第210和211部分（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).

由于你们的生产、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、21 USC 351(a)(2)(B) 的规定，你们的药品被认为是掺假。

Inadequate Response | 回复不充分

We reviewed your December 5, 2024 response to our Form FDA 483 in detail. Your response is inadequate because you fail to provide adequate evidence of corrective actions taken to bring your operations into compliance with CGMP or confidence that you can manufacture sterile drugs. Your response notes that your “…company does not have the ability to pass FDA factory inspection and was not prepared to produce sterilized (b)(4) in accordance with the requirements of OCT [sic] Drug product so it does not produce sterilized (b)(4), nor carry out the testing of sterility testing.” Drug manufacturers labeling their product as sterile must recognize the serious public health implications of distributing a non-sterile product, as it poses a significant health risk to patients.

我们详细审查了你们公司2024年12月5日对FDA 483表格的回复。该回复不充分，原因在于未能提供充分证据，证明所采取的纠正措施能使生产操作符合CGMP要求，或证明你们公司具备无菌药品生产能力。

你们公司回复声明"...本公司不具备通过FDA工厂检查的能力，且未准备好按照OCT药品的要求生产无菌XX，因此公司既不生产无菌XX，也不进行无菌检测。”标识为无菌产品的药品生产企业必须认识到：流通非无菌产品对公共健康的严重威胁，因其可能对患者造成重大健康风险。

During our inspection, our investigators observed specific violations including, but not limited to, the following.

在检查过程中，我们的调查员发现的具体违规行为包括但不限于以下内容。

Insanitary Conditions | 不卫生条件

Your drug products are adulterated under section 501(a)(2)(A) of the FD&C Act because they were prepared, packed, or held under insanitary conditions whereby drugs may become contaminated with filth or rendered injurious to health. FDA investigators observed your facility to be in a state of disrepair, poorly cleaned, and maintained as evidenced by:

根据FD&C法案第501(a)(2)(A)条款，你们的药品被认定为掺假药品，因为药品的制备、包装或储存条件不卫生，可能导致药品被污物污染或对健康造成危害。FDA调查员发现，你们的设施处于失修、清洁和维护不良的状态，具体表现如下：

•        Numerous dead insects were inside the tubing used to transfer the active pharmaceutical ingredient (API), (b)(4), from storage drums to (b)(4) tanks, as well as a (b)(4) used for storing API transfer hoses and (b)(4).

用于将原料药（API）(b)(4)从储罐转移至(b)(4)罐的管道内部、用于贮存API转移软管的(b)(4)装置及(b)(4)内，发现大量死亡昆虫。

•        Multiple pieces of unknown debris in an (b)(4) solution that was being (b)(4) to a filling machine and transferred (b)(4) that were packaged and labelled as sterile.

在通过(b)(4)输送至灌装机的(b)(4)溶液中，发现多块不明异物，这些溶液经灌装后作为无菌产品包装并贴标。

•        Multiple pieces of tubing used to transfer (b)(4) solution from holding containers to filling machines were cracked, leaking, discolored, or contained unidentified residues.

用于将(b)(4)溶液从储存容器转移至灌装机的多根管道存在开裂、泄漏、变色或含有不明残留物。

•        Bulk (b)(4) of (b)(4) used to make (b)(4) had hair, unknown particulates, or insects on them.

用于制备(b)(4)的(b)(4)半成品中发现毛发、不明颗粒物或昆虫。

•        The ceiling areas above uncovered filling and packaging machines used to manufacture (b)(4) labelled as sterile were visibly dirty and damaged.

在用于生产标识为无菌的(b)(4)产品的敞开式灌装和包装设备上方天花板区域，存在明显污垢和破损。

CGMP Violations CGMP | 违规项无菌工艺

• Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all sterilization processes (21 CFR 211.113(b)).
  

你们未能建立并遵循适当的书面程序，包括验证所有无菌和灭菌工艺的程序，以防止声称无菌的药品受到微生物污染（21 CFR 211.113(b)）。

In addition to the insanitary conditions described above, FDA investigators observed during the inspection that since the previous inspection, your firm discontinued sterilization via (b)(4) without implementing a new sterilization procedure. Furthermore, your firm lacked a procedure for conducting environmental monitoring during manufacturing operations and failed to ensure operators adhered to proper gowning requirements, thereby compromising the sterility assurance of (b)(4) labeled as sterile.

除上述不卫生条件外，调查员发现你们公司自上次检查后已停止使用(b)(4)灭菌工艺，但未实施新的灭菌程序。此外，你们公司缺乏生产操作过程中的环境监测程序，且未确保操作人员遵守更衣规范，导致标识为无菌的(b)(4)产品无菌保证水平受损。

See FDA’s guidance document, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice, to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing, at https://www.fda.gov/downloads/Drugs/Guidances/ucm070342.pdf.

请参阅 FDA 的指南《通过无菌工艺生产的无菌药品 - 现行药品生产质量管理规范》，以帮助你们在使用无菌工艺生产无菌药品时满足 CGMP 要求，网址（略，见上）。

In response to this letter, provide:

在回复本函时，请提供：

•        Comprehensive, independent risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, that includes, but is not limited to:

•        针对无菌工艺、设备及设施污染风险的全面独立风险评估，包括但不限于：

o        All human interactions within the ISO 5 area

ISO 5级区域内所有人员干预

o        Equipment placement and ergonomics

设备布局与人机工程学

o        Air quality in the ISO 5 area and surrounding room

ISO 5级区域及周边房间空气质量

o        Facility layout

设施布局

o        Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)

人员与物料流向（涵盖所有执行和支持无菌操作相关区域）

•        A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made in the design and control of the aseptic processing operation.

一份详细的整改计划，并附上时间表，以解决污染危害风险评估的发现。描述你们设施对无菌工艺操作设计和控制的具体切实改进。

•        Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to ensure routine and effective supervisory oversight for all production batches. Also describe the frequency of quality unit oversight (e.g., audit) during aseptic processing and its support-operations.

确保生产过程中采用适当无菌操作和洁净室行为的计划。包括更好地确保对所有生产批次进行常规和有效监督的步骤。此外，描述无菌工艺操作和其它操作期间质量部门监督（例如审计）的频率。

•        A thorough retrospective review and risk assessment that evaluates how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.

全面的风险评估，针对不良无菌技术和洁净室行为（例如检查期间观察到的）可能如何影响药品的质量和无菌性。

•        A robust sterilization method and rigorous validation protocol that assures a sterility assurance level of 10^-6 or more is achieved (e.g., provide F-value and Z-value data for any heat sterilization method), and uses an appropriate resistant biological indicator that represents the worst-case resistance of microbes that could be found in your environment and product. Include D-value determinations for each biological indicator lot to demonstrate its resistance to the specific sterilization method proposed for use by your firm.

确保达到10^-6或更高无菌保证水平的稳健灭菌方法与验证方案（如提供热灭菌方法的F值与Z值数据），并使用代表环境与产品中微生物最差耐受情况的生物指示剂。请提供每个生物指示剂批次的D值测定结果，以证明其对你们公司拟使用的特定灭菌方法的耐药性。

无菌检测

• Your firm failed to conduct appropriate laboratory testing to determine whether each batch of drug product purporting to be sterile and pyrogen-free conforms to such requirements (21 CFR 211.167(a)).
  

未能对声称无菌且无热原的药品批次进行适当的实验室检测，以确认符合标准（21 CFR 211.167(a)）

You manufactured and distributed an (b)(4) product labeled as "sterile." However, you failed to perform sterility testing. It is essential that you conduct sterility testing on these and other purportedly sterile drugs prior to batch disposition decisions.

你们公司生产并流通标签为"无菌"的(b)(4)产品，但未实施无菌检测。必须在批次放行前，对此类声称无菌的药品进行无菌检测。

In response to this letter, provide a list of chemical and microbial test methods and specifications used to analyze each batch of your drug product before making a batch disposition decision, and the associated written procedures.

在回复本函时，请提供：批次放行决策前用于分析各药品批次的化学与微生物检测方法、质量标准及相关书面程序

物料检验

• Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).
  

你们公司未能对各成分样品进行鉴别检测，且未能按照所有相关的纯度、含量和质量书面质量标准进行符合性检测。你们公司亦未能按适当的时间间隔，验证并确定成分供应商检测分析的可靠性（21 CFR 211.84(d)(1) 和 211.84(d)(2)）。

Your firm relied solely on certificates of analysis (COAs) for incoming lots of (b)(4), instead of conducting identity testing and verification for purity, strength, and quality or qualifying your component supplier. Additionally, your firm failed to test the (b)(4) system for (b)(4) and microbial limits, despite its use in drug production. Without adequate testing, there is no assurance that these critical components meet required specifications before use in manufacturing. The failure to perform appropriate identity and testing raises concerns about product quality and associated potential risks to patients.

你们公司仅依赖(b)(4)的进场物料分析报告（COA），未实施鉴别检测及纯度、含量与质量确认，亦未对组分供应商进行资质确认。此外，尽管(b)(4)系统用于药品生产，但未对其(b)(4)与微生物限度进行检测。如果没有充分的检测，就无法保证这些关键成分在投入生产前符合规定的质量标准。未能进行适当的鉴别和检测，这引发了对产品质量及其对患者的潜在风险的担忧。

In response to this letter, provide:

在回复本函时，请提供：

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

针对每批用于生产目的的进场物料 ，用于检验和放行的化学和微生物质控标准。

•        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 robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.

说明如何检验每个批次，确定是否符合有关鉴别、含量、质量和纯度质量标准。如果你们打算接受供应商COA的结果，而不是检验每个物料批次的含量、质量和纯度，请说明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。此外，还应承诺：对于每个进场物料批次，至少进行一个专属鉴别检验。

•        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.

一份从所有物料检验获得的结果汇总，以评估每个物料生产商的 COA 的可靠性。请附上描述此 COA 验证计划的程序。

稳定性研究

• 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)).
  

你们未能建立并执行一套充分的书面检验程序，该程序旨在评估药品的稳定性特征（21 CFR 211.166(a)）。

Your firm assigned a (b)(4) expiration date to your sterile (b)(4) despite having only (b)(4) of stability data. Additionally, your firm's procedure did not address ongoing stability testing to monitor your drug’s integrity throughout its shelf life. Without sufficient data, there is no assurance that your drug product maintains its identity, strength, quality, and purity for the full labeled expiration period.

你们公司仅依据(b)(4)稳定性数据，即对无菌(b)(4)设定(b)(4)有效期此外，你们公司的程序并未涉及持续稳定性测试，以监控你们药品在整个有效期内的完整性。由于缺乏足够的数据，无法保证你们的药品在整个标示的有效期内保持其鉴别、含量、质量和纯度。

In response to this letter, provide:

在回复本函时，请提供：

•        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。你们的整改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

在流通之前，对市售容器密闭系统中的每种药品进行稳定性研究

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

持续进行的计划，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.

针对稳定性整改计划的这些以及其它元素，其所有相关的描述性程序。

Drug Recall | 药品召回

On January 21, 2025, the FDA held a teleconference with you recommending you consider removing any batches of sterile (b)(4) currently in distribution from the U.S. market.

2025年1月21日，FDA于召开电话会议建，议你们公司考虑从美国市场撤回所有已流通的无菌(b)(4)批次。

On February 11, 2025, you issued a voluntary recall of sterile (b)(4) due to a lack of sterility assurance and CGMP violations observed during an inspection.

2025年2月11日，你们公司因缺乏无菌保证及CGMP违规发起自愿召回。

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 and 211 at https://www.fda.gov/media/71023/download.

你们的质量体系不完善。请参阅FDA的指南《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，满足CGMP法规21CFR第210和211部分的要求，网址为(略，见上)。

CGMP Consultant Recommended | 建议聘用CGMP顾问

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPAs before you pursue resolution of your firm’s compliance status with FDA.

鉴于我们发现的违规情况的性质，若你们公司拟恢复对美药品生产，你们应聘请符合21 CFR 211.34规定的有资质顾问，对运营进行评估，并协助你们达到CGMP要求。有资质的顾问还应对你们的整个运营进行全面的六大系统审核，以确保 CGMP 合规性，并评估你们纠正和预防措施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免除你们遵守 CGMP 的义务。你们的高级管理层仍负责解决所有缺陷和系统性问题，以确保持续遵守 CGMP。

Conclusion | 结论

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

本函中提到的并非是你们设施中存在的违规情况的完整清单。你们有责任调查和确定所有违规情况的原因，并防止其再次发生或发生其它违规行为。

FDA placed products offered for import into the United States from your firm on Import Alert 66-40 on January 21, 2025.

FDA已于2025年1月21日将你们公司进口产品列入66-40进口警示。

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.

及时纠正所有违规情况。FDA 可能会暂停批准将你们列为新药申请或补充申请的药品生产商，直到所有违规情况得到彻底解决、且我们确认你们公司符合 CGMP 要求。我们可能会再次检查，以确认你们是否已针对所有违规情况采取了纠正措施。

Failure to address any violations may also result in the FDA continuing to refuse admission of articles manufactured at Wuxi Medical Instrument Factory Co., Ltd., Wuxi, China, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused 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).

根据FD＆C法案21801(a)(3)条、USC381(a)(3)条，不纠正这些违规行为也可能导致FDA拒绝你们设施生产的产品，无法进入美国。根据该授权，视为掺假或标识错误的产品可能会被扣留或拒绝入境，因为其生产使用的方法与控制不符合CGMP，CGMP是在FD＆C法案(501)(a)(2)(B)条、21USC351(a)(2)(B)条中被要求的。

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 complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

本信函通知你们我们的发现，并为你们提供解决上述缺陷的机会。收到本信函后，请在15个工作日内以书面形式回复本办公室。说明你们为解决所有偏差并防止其再次发生所做的工作。在回复本信函时，你们可以提供更多信息供我们考虑，因为我们将继续评估你们的活动和实践。如果你们无法在15个工作日内完成纠正措施，请说明延误原因和完成时间表。

classicboy

啥玩意儿，美国FDA自己报告都写不清楚，人家明明是器械产品，FDA自己报告写成药品。