首页 > 资讯 > 课前热身：第一封 CAR-T 临床研究的“基本”警告信

出自识林

2024-09-19

8月27日，FDA公布了CARsgen的警告信，基于2023年11月28日至2023年12月6日对该公司位于美国Durham设施的检查中发现的GMP违规行为。

FDA最近不断加强对Car-T产品的监管，继2023年12月5日，FDA公布给诺华的关于Kymriah生产CGMP问题的无标题信之后，对CARsgen的这封警告信是识林警告信数据库记录的第一封发给CAR-T企业的警告信。

同时，该设施生产的细胞用于一项II期临床试验，这也是识林警告信数据库记录的第一封发给非商业化生产设施的警告信，是理解FDA的监管边界和临床研究的GMP要做到什么程度的重要参考案例。因此，IPEM邀请盛德律所的FDA业务合伙人Chris Fanelli律师，在9月23日的课程深入讨论这封警告信的监管、技术和法律考量。

尽管这封警告信的意义如此特殊，但信中描述的缺陷都较为基本。五条缺陷分别是

1. 厂房清洁和卫生不足 21 CFR 211.56(a) ，在警告信数据库出现15次，排名第33；（但检查中发现的问题还是有点超出“基本”的范畴，空调设备间是质量管理的盲区这能理解，但发现食物放出蛆有点难接受）

2. （微生物）污染防控不足 21 CFR 211.42(c)(10)(iv)，在警告信数据库出现35次，排名第18；21 CFR 211.113(b) ，在警告信数据库出现75次，排名第12；（环境监测没做，颗粒和微生物都没做）

3. 清洁消毒不足 21 CFR 211.42(c)(10)(v) 在警告信数据库出现9次，排名第43；（清洁验证没做）

4. 工艺规程不足 21 CFR 211.100(a) 在警告信数据库出现186次，排名第2；（没有目检的规程，就单目检规程缺陷，警告信库就出现过8次）

5. 偏差调查不足 21 CFR 211.192 在警告信数据库出现222次，排名第1；（微生物监测偏差的CAPA没有实施）

IPEM的资深讲师Ian Thrussell多次强调，不管是多么特殊的产品和工艺，95%的GMP问题都是基本问题，尤其对先进疗法产品，基本的工作容易被忽视而产生问题。警告信中提到，企业自2023年12月12日起已暂停生产产品，识林法规数据库中显示，CARsgen曾在2022年6月14日，向FDA提交了《CAR-T细胞产品的开发考量（指南草案）》（Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products）的反馈意见，一共7页，细致翔实。识林多次参与和组织国内外的法规意见反馈，深知这类反馈对专业性和资源投入的要求很高，一家中国企业如此重视FDA的指南反馈，并提出有水平的反馈意见，足见公司是认真准备产品在美国上市，令人尊敬。但警告信中这些“基本”的GMP问题，可能就把门关上了。

信中的缺陷翻译如下（完整双语版），若是觉得这些缺陷太基本，自己企业绝对不会出现，就太好了。但若这么觉得的是你公司的管理者，请一定拉他们来学学。

1. Your firm failed to maintain the buildings used in the manufacture, processing, packing, or holding of a drug product in a clean and sanitary condition and to keep them free of infestation by rodents, birds, insects, and other vermin. Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner. [21 CFR 211.56(a)].

Specifically, on July 14, 2023, your Quality Assurance team observed a box of food from June 16, 2023, covered in scuttle fly pupae in the mechanical room which houses the air handling units and failed to remove the box of food until July 31, 2023. After this event, scuttle fly larvae were found in ten environmental and personnel monitoring samples collected in the cleanrooms in July 2023. Additionally, on July 26, 2023, in Suite (b)(4) Clean Room (b)(4) (Grade (b)(4)) a living scuttle fly was observed on the tube rack. Adequate control of insect infestation is needed to ensure product quality and safety.

未能维护药品生产、加工、包装和贮存所用厂房的清洁卫生，保持其不受鼠类、鸟虫以及其它害虫的侵扰。应及时以卫生地方式存放和处置垃圾和有机废物。[21 CFR 211.56(a)]。

具体而言，2023年7月14日，企业质量保证团队在空气处理机组所在的机房发现一盒2023年6月16日生产的食物，上面长满了蚤蝇蛹，直到2023年7月31日才移开食物盒。此事件后，2023年7月在洁净室采集的10份环境和人员监测样本中发现了蚤蝇幼虫。此外，2023年7月26日，在XX车间XX洁净室（XX级）的管架上观察到一只活蚤蝇。需要充分控制昆虫侵扰，以确保产品质量和安全性。

2. Your firm failed to establish an adequate system for preventing contamination and monitoring environmental conditions in aseptic processing areas. [21 CFR 211.42(c)(10)(iv)]. Your firm also failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile. [21 CFR 211.113(b)].For example,

未能建立适当系统来防止无菌工艺区受到污染并监测环境条件。[21 CFR 211.42(c)(10)(iv)]。也未能制订并遵守适当的书面规程来防止无菌药品微生物污染。[21 CFR 211.113(b)]。例如，

a. Non-viable particulate monitoring is not being conducted during open manufacturing manipulations within the Grade (b)(4) utilized as the aseptic processing area for production of Humanized Anti-claudin 18.2 Autologous CAR T Cells (CT041). Non-viable particulate monitoring is critical for the detection of particulates in the manufacturing area as they pose patient harm for products administered intravenously as microorganisms can travel on particulates to contaminate the product.

a.在用于生产人源化抗密蛋白18.2自体CAR T细胞（CT041）的无菌工艺区的XX级区内进行开放式生产操作期间，未进行非活性微粒监测。非活性微粒监测对于检测生产区的微粒至关重要，因为这些微粒会对静脉注射产品的患者造成伤害，微生物可以附着在微粒上污染产品。

b. Viable microbial active air monitoring is not being conducted during open manufacturing manipulations within the Grade (b)(4) utilized as the aseptic processing area for production of your products. Viable microbial active air monitoring is important for the detection of microorganisms in the environment surrounding the product that is exposed to the manufacturing environment.

b.在用于生产产品的无菌工艺区的XX级区内进行开放式生产操作期间，未进行活性空气微生物监测。活性空气微生物监测对于检测暴露于生产环境的产品周围环境中的微生物非常重要。

3. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions. [21 CFR 211.42(c)(10)(v)].

For example, you have not validated the cleaning process for the (b)(4) used in the production of your products purported to be sterile. Your Senior Vice President of Quality stated that your firm has not conducted a cleaning validation to ascertain that your cleaning process for manufacturing your products can adequately remove contamination from your manufacturing equipment and cleanroom. Cleaning validation is used to establish cleaning conditions effective against the removal of microorganisms commonly found in your manufacturing environment that pose a contamination risk to your sterile products.

未能建立适当的系统来清洁和消毒房间和设备，以产生无菌条件。[21 CFR 211.42(c)(10)(v)]。

例如，企业未对声称无菌产品生产中使用的XX的清洁工艺进行验证。企业质量部高级副总裁表示，企业没有进行清洁验证，以确定生产产品的清洁工艺能够充分去:除生产设备和洁净室中的污染物。清洁验证用于建立有效的清洁条件，以去除生产环境中常见的对无菌产品造成污染风险的微生物。

Your responses dated December 28, 2023, March 1, 2024, April 15, 2024 and May 23, 2024, are acknowledged. Your cleaning gap assessment, cleaning validation protocol and revisions to SOPs have been reviewed. While you indicate the cleaning program will assess the effective removal of bacteria and fungi from surfaces through a disinfectant efficacy study, you have failed to provide any results from this study. Without this information, it is unclear whether your disinfection process is effective for the removal of microorganisms that may contaminate your product.

FDA收悉企业2023年12月28日、2024年3月1日、2024年4月15日和2024年5月23日的回复。并已审查了企业的清洁差距评估、清洁验证方案和SOP修订。虽然企业表示清洁计划将通过消毒剂有效性研究评估表面细菌和真菌的有效去除，但企业未提供任何该研究的结果。由于没有这些信息，尚不清楚企业的消毒工艺是否能有效去除可能污染产品的微生物。

4. Your firm failed to establish 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)].

For example, there was no procedure for 100% visual inspection of the final drug product to ensure that it is essentially free from visible particulates, which is necessary to ensure quality and purity prior to intravascular administration.

未能制订生产和工艺控制的书面规程，以保证所生产药品具有声称的或表明拥有的鉴别、规格、质量和纯度。[21 CFR 211.100(a)]。

例如，没有对成品制剂进行100%目检的规程，以确保其基本不含可见微粒，这在血管内给药前确保质量和纯度是必要的。

5. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch had already been distributed. [21 CFR 211.192].

For example, there were excursions of the action limit associated with microbial monitoring of personnel in the Grade (b)(4) environment where your products are manufactured. During the investigation of these excursions, CAPAs were proposed but never implemented. Since that time, additional excursions for microbial monitoring of personnel action limit within Grade (b)(4) during manufacturing of your products have occurred. Your products have been released following these excursions. Appropriate CAPAs are to be identified and implemented in a timely manner to prevent recurrence of excursions.

未能彻底调查任何不明原因的偏离或任一批次的失败或原辅料不符合其任一质量标准，不管该批次是否已经放行销售。[21 CFR 211.192]。

例如，在生产产品的XX级环境中，与人员微生物监测相关的行动限出现了偏离。在调查这些偏离期间，提出了CAPA，但从未实施。从那时起，在产品生产期间，XX级内的人员行动限微生物监测发生了额外偏离。企业产品在这些偏离后被放行。应确定并及时实施适当的CAPA，以防止再次发生偏离。

It is noted in your response dated April 15, 2024, that "CARsgen RTP site Deviation and CAPA SOPs (NC-SOP-QA-0006, NC-SOP-QA-0007 respectively)" became effective on January 31, 2024. Appropriate control mechanisms have been added to the CAPA SOP to ensure both implementation of CAPAs and verification of effectiveness checks are in place." However, the updated SOPs have not been provided for review to determine suitability of the response in addressing this violation and providing for appropriate corrective action.

企业在2024年4月15日的回复中指出，“CARsgen RTP场地偏差和CAPA SOP（分别为NC-SOP-QA-0006，NC-SOP-QA-0007）”已于2024年1月31日生效。已在CAPA SOP中增加了适当的控制机制，以确保CAPA的实施和有效性检查的确认。”但是，尚未提供更新后的SOP以供审查，以确定回复是否适用解决此违规行为并提供适当的纠正措施。

The nature of your above-listed violations demonstrates that you have failed to ensure that your firm manufactures drug products that meet established specifications for identity, strength, quality, and purity.

企业上述违规行为的性质表明，企业未能确保所生产的药品符合鉴别、规格、质量和纯度的既定质量标准。

We have reviewed your correspondences dated December 28, 2023, March 1, 2024, April 15, 2024, and May 23, 2024, which respond to the Form FDA-483 and set forth your corrective actions. We acknowledge you have paused manufacturing your products as of December 12, 2023, notified clinics not to administer previously released drug products to patients, and have plans for disposition of products that remain in your control. As noted above in response to specific violations, you have not provided sufficient detail to assess the adequacy of your proposed corrective actions; for all other violations, FDA may need to verify your proposed corrective actions during an inspection of your facility.

FDA已审核了企业2023年12月28日、2024年3月1日、2024年4月15日和2024年5月23日对FDA-483的回复，并列出了企业的纠正措施。FDA知悉，企业自2023年12月12日起已暂停生产产品，通知诊所不要给患者服用之前放行的药品，并计划处置了仍在企业控制范围内的产品。如上文所述，针对具体违规行为，企业没有提供足够的细节来评估拟定的纠正措施的充分性；对于所有其它违规行为，FDA可能需要在工厂检查期间核实拟定的纠正措施。

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