本文通过警告信的案例，介绍了FDA、EMA和NMPA对GMP咨询顾问的要求，最后简要介绍了警告信的内容。

The FDA's CGMP guidelines provide instructions on this in 21 CFR 211.34:

"Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained. Records shall be maintained stating the name, address, and qualifications of any consultants and the type of service they provide."

Fortunately, the EU GMP Guideline Part I includes almost the same requirements in chapters 2.23 and 2.24:

• Consultants should have adaquate education, training and experience, or any combination thereof, to advise on the subject, for which they are retained.

• 顾问应具有足够的教育、培训和经验，或以上任何组合，以便就相应的主题提供咨询意见。

• Records should be maintained stating the name, adress, qualification, and type of service providide by these consultants.

• 应保存记录，说明这些顾问的名称、地址、资质和提供的服务类型。

So far, so good. However, in a recent warning letter, the FDA explicitly points out that even if a consultant who meets the aforementioned requirements (21 CFR 211.34) is employed, the company itself is still responsible for GMP compliance.

The warning letter particularly and explicitly mentions the executive management as being responsible for dealing with all deviations and deficiencies in order to comply with CGMP.

Interestingly, the FDA recommends that the consultant should audit the company according to the 6-system audit system. This 6-system audit system was once intended as an inspection model for FDA inspections as described in the 2006 Quality Systems Approach to Pharmaceutical CGMP Regulations. To date, this model has not been widely adopted for FDA inspections. It is therefore all the more surprising that it is now recommended for clarification of GMP deficiencies.

第三百零八条：应当由企业指定人员进行独立、系统、全面的自检，也可由外部人员或专家进行独立的质量审计。

第三百一十二条（十七）供应商：指物料、设备、仪器、试剂、服务等的提供方，如生产商、经销商等。

2023版GMP指南《质量管理体系》第276页4.7.1章节《自检》提到：自检的实施需要有足够的有资质的人员参加，企业委派外部人员或专家进行内部审计，应通过书面协议明确双方的权利 义务，并对相关人员的资质进行书面确认。

以下是警告信缺陷的主要内容：

公司名称:Diora Kimya Sanayi ve Ticaret Limited Sirketi

检查日期:2024年5月27日至31日

警告信签发日期:2024年10月17日

• 该公司未能对药品生产中使用的来料进行充分的鉴别测试，仅依赖供应商的COA，而没有在适当的时间间隔内验证这些证书的可靠性。药品中含有易被二甘醇（DEG）和乙二醇（EG）取代的甘油等成分（潜台词是未能检测甘油中乙二醇和二甘醇杂质的含量）。

• 药品放行前没有对产品进行适当的检测。将XX和甘油的成分检测结果从供应商的COA中直接转录到成品COA中。

• 未能充分验证药品生产中使用的生产和工艺控制，没有完成非专用设备的工艺验证和清洁验证研究。缺乏文件证明用于生产药品的设备是经过确认的，适合其预期用途。也没有确认水系统，该水系统提供XX作为药品中使用的组分。