FDA警告信：北京蓝戈医药用品有限公司

恨我不成钢

昨夜，FDA发布了对蓝戈医药用品(北京)有限公司的警告信，根据该警告信，蓝戈医药用品(北京)有限公司涉及缺陷如下：

• 产品由第三方外包商进行最终灭菌，但未对外包灭菌工艺进行验证；
• 外包灭菌工艺没有完整的记录：未能提供充分的记录证实外包商对产品进行了最终灭菌。也未能提供证据证实质量部门在放行前审核了灭菌记录。
• 检查期间发现许多不受控的非正式生产和实验室记录。包括带有不完整字段和删除线的重复记录；
• 缺陷回复称将对管理层进行培训，而不是包括所有员工；
• 未对生产工艺进行验证，未进行持续工艺确认；
  
  

该警告信摘译如下：

Longood Medicine (Beijing) Co., Ltd.

蓝戈医药用品(北京)有限公司

No. 13, Yunteng Road, Miyun Economic Development Area

北京市密云县经济技术开发区云腾路13号

Beijing 101500

China              

1.    Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products, including drug products manufactured, processed, packed or held under contract by another company. Your firm failed to establish a quality unit with the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)).

贵公司未能建立充分的质量控制部门，使其具有职责和权力批准或拒绝所有原辅料、药品容器、密封部件、中间产品、包装材料、标签和药品，包括委托其他公司生产、加工、包装或保存的药品。贵公司未能建立一个质量部门，使其具有权力审核生产记录以确保没有错误发生，或者确认发生错误时，得到充分的调查。

Contractor Oversight

合同商监管

You failed to ensure that your third-party contractor uses a validated terminal sterilization process, consistent with the requirements of 21 CFR 211.113(b), to sterilize your drug product, Chlora-Cleanze Proprep applicators, purported as sterile and labeled for “use prior to surgery.”   

你们未能确保第三方合同商使用一个经验证有效符合21 CFR 211.113(b)要求的最终灭菌工艺来灭菌你们标签为“手术前使用”的无菌药品Chlora-Cleanze Proprep。

You released Chlora-Cleanze Proprep applicators without assurance of their sterility. For example, you were unable to provide adequate records demonstrating that your contractor terminally sterilized Chlora-Cleanze Proprep applicators lot 20170601, distributed to the United States. You also failed to provide evidence that your quality unit reviewed all appropriate records prior to releasing the lot.  

你们放行了Chlora-Cleanze Proprep applicators而未能保证其无菌性。例如，你们未能提供充分的记录证实你们的外包商对批号为20170601的Chlora-Cleanze Proprep applicators 进行了最终灭菌。你们也未能提供证据证实你们的质量部门在放行前审核了所有适当的记录。

In your response, you acknowledged that your terminal sterilization contractor provided incomplete records for Chlora-Cleanze Proprep applicators (lot 20170601). Your response is inadequate. You failed to describe how your firm determined the lot was acceptable for release without complete documentation from your contractor. In addition, you failed to provide evidence from your contractor demonstrating this lot was terminally sterilized.   

在你们的回复中，你们确认了你们的最终灭菌外包商对Chlora-Cleanze Proprep applicators (批号20170601)提供了不完整的记录。你们的回复是不充分的，你们未能描述你们在没有外包商提供的完整记录的情况下如何确定该批次可接受放行。另外，你们未能提供你们外包商证明该批次得到最终灭菌的证据。

Your response also provided terminal sterilization validation documentation for a different (b)(4) product ((b)(4)) to support the sterilization of Chlora-Cleanze Proprep applicators. Your response is inadequate in that it lacks sufficient validation data to support sterilization efficacy. You did not provide scientific rationale demonstrating validation studies for the (b)(4) sterilization process are representative of the sterilization process for Chlora-Cleanze Proprep applicators. (b)(4) drug product has a different formulation, including a different active ingredient. You failed to address whether you will validate the terminal sterilization process for the Chlora-Cleanze Proprep applicators.

你们的回复还提供了另一个不同产品的最终灭菌验证文件来支持Chlora-Cleanze Proprep applicators的灭菌。你们的回复是不充分的，因为缺乏充分的验证数据来支持灭菌有效性。你们没有提供科学依据证实XX产品灭菌工艺的验证试验可以代表Chlora-Cleanze Proprep applicators的灭菌工艺。

In your response to this letter, provide:

回复此函，请提供：

•Your qualification procedures for assessing the suitability and competence of potential contractors before outsourcing, and for ongoing monitoring and review of the performance of the contract facility to identifying and implement any needed improvements;

•您在外包之前评估潜在承包商的适用性和能力，以及持续监督和审查合同工厂的表现以确定和实施任何必要的改进的确认程序;

•A detailed plan for ensuring that the process your contractor uses to terminally sterilize all products, including Chlora-Cleanze Proprep applicators, is adequately validated;

•确保你们的外包商用于对包括Chlora-Cleanze Proprep在内的所有产品进行最终灭菌的工艺得到充分验证的详细计划;

•Complete sterilization records from your contractor for Chlora-Cleanze Proprep applicators, lot 20170601. If you do not have sufficient evidence that the lot in question or any lot intended for the U.S. market was adequately sterilized, indicate the corrective actions you will take, such as customer notifications and product recalls.

•外包商对Chlora-Cleanze Proprep（批号：20170601）的完整灭菌记录。如果你们没有足够的证据证明该批次或任何用于美国市场的批次已经得到充分灭菌，请说明将要采取的纠正措施，例如客户通知和产品召回。

•A corrective action and preventive action (CAPA) plan to fully remediate your review and release procedures for finished drug products. Your procedures should require that third-party contractors provide sufficient production and control records to demonstrate compliance with established, approved written procedures and specifications before a lot is released or distributed by your quality unit.  

•纠正和预防措施（CAPA）计划以彻底整改你们对成品药品的审核和放行程序。你们的程序应要求第三方外包商提供足够的生产和控制记录，以证明在你们的质量部门放行或销售之前遵守既定的，经批准的书面程序和规范。

Uncontrolled Documents

不受控的文件

Our investigators found numerous uncontrolled and unofficial production and laboratory records associated with Chlora-Cleanze Proprep applicators (lot 20170601) during the inspection. These include duplicate records which contain incomplete fields and strike-throughs.

我们的检查员在检查期间发现许多关于Chlora-Cleanze Proprep applicators（批号20170601）的不受控的非正式生产和实验室记录。包括带有不完整字段和删除线的重复记录。

In your response, you state that you will examine your document control procedures and provide training to management. Your response is inadequate. Training should include all employees involved in the manufacturing process. Additionally, you failed to indicate whether the uncontrolled and unofficial production and laboratory records for lot 20170601 were reviewed prior to release of the lot. Further, you did not perform a full retrospective review to determine the extent of the production and laboratory record deficiencies, and commit to a CAPA plan to comprehensively identify and address root causes.

在你们的回复中，你们说将检查你们的文件控制程序并对管理层进行培训。你们的回复是不充分的。培训应包括参与生产过程的所有员工。此外，你们未能指出批次20170601的不受控的非正式生产和实验室记录是否在批次放行之前进行了审核。此外，你们没有进行全面的回顾性审查，以确定生产和实验室记录缺陷的程度，并承诺CAPA计划全面识别和解决根本原因。

In your response to this letter, provide:

回复此函，请提供：

•A comprehensive, independent assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are deficient. Include a detailed CAPA plan that systemically remediates deficient documentation practices, and ensures you retain complete and accurate records.

•对生产和实验室操作中使用的文件系统进行全面，独立的评估，以确定文件操作的缺陷。 包括详细的CAPA计划，系统地整改文档操作的不足，并确保保留完整和准确的记录。

•A comprehensive CAPA for your training program to ensure all staff at your facility are fully trained in CGMP. Provide a fully remediated training program for your entire operation. Place special emphasis on assuring that all staff involved in any CGMP function are trained and competent in acceptable recordkeeping practices, such as retaining all records, completing records contemporaneously, documenting any error in records, and ensuring that all procedures are approved by quality unit.     

•对你们的培训程序提供全面的CAPA，以确保贵单位的所有员工都经过CGMP的全面培训。提供一份完全整改的培训程序。特别强调确保任何具备CGMP职能的所有人员都得到可接受的记录保存规范的培训并可以胜任，例如保留所有记录，记录同步完成，在记录中的记录任何错误，并确保所有程序都得到质量部门的批准。

2.    Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

贵公司未能建立充分的生产和过程控制的书面规程，以确保所生产的药品具备所声称的鉴定、剂量、质量和纯度。

Your firm does not have an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality for your Chlora-Cleanze Proprep applicators. You told our investigator that you had validated your process for manufacturing another drug product, and that the process was similar to your Chlora-Cleanze Proprep manufacturing process. You did not provide validation of the Chlora-Cleanze Proprep manufacturing process.

贵公司没有一个充分的持续监测过程控制的计划以确保稳定的生产操作和一致的Chlora-Cleanze Proprep药品的质量。你们告诉我们的检查员你们验证了另一个药品的生产工艺，该工艺与Chlora-Cleanze Proprep的生产工艺相似。你们没有提供Chlora-Cleanze Proprep的生产工艺的验证。

Your response states that you conduct in-process testing of batches (b)(4) to filling operations. You also state that you will conduct stability testing on Chlora-Cleanze Proprep applicators. Your response is inadequate. In the absence of process validation, testing alone is insufficient to determine whether your processes are of sound design and operating in a state of control throughout a product’s lifecycle.

你们的回复说你们在批生产过程中对分装操作进行了过程中测试。你们还说你们将会对Chlora-Cleanze Proprep applicators进行稳定性测试。你们的回复是不充分的。缺乏工艺验证，仅仅进行测试不足以确定你们的工艺是否设计合理，并且在整个产品生命周期中都处于控制状态。

In response to this letter, detail your validation plan for ensuring a state of control throughout the product lifecycle. Include a timeline for performing appropriate process performance qualification (PPQ) for your Chlora-Cleanze Proprep applicator manufacturing process, and describe your program for vigilantly monitoring batch-to-batch variation to ensure an ongoing state of control for all of your products. Also include your PPQ protocol.

回复此函，详述你们用以确保在整个产品生命周期内保持受控状态的验证计划。包括对Chlora-Cleanze Proprep applicator生产工艺执行适当工艺性能确认的时间计划，并描述你们用以监测批间变异确保产品持续受控状态的程序。同时给出你们的PPQ方案。

When significant variability is observed in one or more stages of pharmaceutical production, it is essential that executive management support and implement effective actions to address the source(s) of the variation and provide for a continued state of control. See FDA’s guidance document, Process Validation: General Principles and Practices, for approaches that FDA considers appropriate elements of process validation, at https://www.fda.gov/downloads/dr ... nces/ucm070336.pdf.

当在药物生产的一个或多个阶段中观察到显着的变化时，管理层必须支持并实施有效的行动以解决变异的来源并提供持续受控的状态。 有关FDA认为适当的工艺验证要素的方法，请参阅FDA的指导文件，工艺验证：一般原则和规范，网址为https://www.fda.gov/downloads/dr ... nces/ucm070336.pdf.

快活王

不知道具体的情况，但是看警告信的问题还是比较大的，估计回复483的时候也不用心，数据完整性的问题整改竟然这么简单，连公司层面的诚信教育都没说，数据的回顾也不说。另外，483出来之后，不应该第一时间对第三方进行审计来证明灭菌的合理性么？这些工作都不做，只是简单的回复表面的问题，警告信会随之而来的。
个人建议，仅供参考。