根据21 CFR 211.25要求， 所有从事药品生产、加工，包装或仓储的工作人员应具备教育经历/培训经历和工作经验，或者三者的组合，具备能力履行所指派的职责/配合内容应包括员工执行的特定操作，以及与员工职责有关的cGMP要求。cGMP培训应有具备资质的人员已持续方式执行，其频次应足够，以确保员工持续熟悉所适用的cGMP要求。负责药品生产、加工、包装或贮存的管理人员均应受过相应教育、培训并具备实践经验，或具备这些综合条件，方可从事分配的管理工作，以确保药品具有所声称的或表明拥有的安全性、鉴别、规格、质量和纯度。

对于培训的缺陷，FDA在警告信中通常会指出“企业未能保证从事药品生产、加工、包装或贮存的每位员工均受过教育、培训并有实践经验，能够履行委派的职责”（Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions.）。笔者收集和整理了多份FDA警告信，共计13个常见的培训类缺陷，来自国内外各企业，供企业参考。

 

缺陷1

Failure to ensure training is regularly conducted by qualified individuals and covers, at a minimum, the particular operations that each employee performs and CGMP as they relate to the employee's functions.

You failed to ensure that laboratory personnel who performed CGMP testing were adequately trained in current good manufacturing practice requirements. CGMP testing is performed by both faculty members and graduate students at your facility. Your firm lacked the adequate documentation to demonstrate that laboratory personnel were adequately trained in their respective job functions.

In your response, and during our inspection, you provided training procedures entitled "Good Manufacturing Practices & Training" and "Employee Training," both created approximately a week before the initiation of our pre-announced inspection. Your response is inadequate as your firm began CGMP testing prior to the generation of your procedures, and you failed to perform a retrospective assessment of previous laboratory personnel to demonstrate that they had the expertise or training to support the test results provided to your customers.

企业未能确保由有资质的人员定期进行培训，并至少涵盖每位员工执行的具体操作以及与员工职能相关的cGMP。

企业未能确保执行cGMP检验的实验室人员接受过现行药品生产质量管理规范要求的充分培训。由企业的教职人员和研究生开展cGMP检验。企业缺乏足够的文件记录来证明实验室人员接受过各自岗位职能方面的充分培训⁠⁠⁠⁠⁠⁠⁠。

在企业的回复中以及FDA检查期间，企业提供了两份培训管理规程，名称分别为 “GMP与培训”以及“员工培训”，这两份规程都是在FDA启动预先通知的检查前大约一周制定的。企业的回复不充分，因为在规程制定之前就开始了cGMP检验，并且企业未对之前的实验室人员进行回顾性评估以证明他们具备专业知识或受过培训来支持提供给客户的检验结果。

 

缺陷2

Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions (21 CFR 211.25(a)).

You failed to ensure that all personnel are qualified for the CGMP operations they perform. For example, your co-owner stated that he is the sole proprietor of the Magic Heal formulation, had full knowledge of the process, and performed all manufacturing operations. However, you lack evidence that your co-owner has the adequate experience to perform these functions nor has received the appropriate CGMP training.

Training is essential to ensure proper performance of job functions.

企业未能确保从事药品制造，加工，包装或暂存的每个人都具已经接受教育，培训并具有经验，以使该人能够履行其委派职责 (21 CFR 211.25(a))。

该企业未能确保所有人员均具备所进行cGMP操作的资质。例如，企业的共同创始人声称，他是Magic Heal处方的唯一所有者，完全了解该工艺并执行所有生产操作。但是，企业缺乏证据证明共同创始人有足够的经验来履行这些职能，也没有接受过合适的cGMP培训。

培训对于确保正确履行工作职能至关重要。

 

缺陷3

Your firm failed to ensure that all personnel are trained as appropriate. Training deficiencies were noted for personnel operating in management, production, quality assurance, and quality control positions. For example, employees engaged in the manual visual inspection of (b)(4) drug products were not trained at the intervals specified in your SOP; analysts who perform foreign matter (visible particulate) testing were not certified as required by your SOP; and some personnel lacked training records.

We also observed laboratory data deficiencies during the inspection, which you attributed to inadequate SOPs, software, and training.

Training is essential to ensure proper performance of job functions by your firm’s employees, including those responsible for oversight and management of personnel.

In your response, you stated that you had initiated an investigation into the failure to conduct training as specified, and that you would update the training matrices of all employees. You further stated that you would ensure all training is provided as required.

Your response is inadequate. You did not address the reasons for the lapse in oversight of your training program, and you did not provide a detailed plan for assessing the effectiveness of your training.

企业未能保证从事药品生产、加工、包装或贮存的每位员工均受过教育、培训并有实践经验，能够履行委派的职责。(21 CFR 211.25(a))。

企业未能确保所有人员都经过适当的培训。管理，生产，质量保证和质量控制岗位的人员的培训存在缺陷。例如，负责某药品人工目检的员工未按照SOP要求定期接受培训；负责异物（可见微粒）检验的分析员没有按照SOP的要求进行资质确认；有些员工缺少培训记录。

检查过程中FDA还发现实验室数据缺陷，而企业将这些缺陷归因于不充分的SOP，软件和培训。

培训对于确保员工（包括那些监督人员和管理人员）正确履行岗位职能是至关重要的。

在企业的整改回复中，企业表示已经针对未按规定进行培训的问题启动了调查，并且会更新所有员工的培训汇总表。企业进一步表示将确保按要求提供所有培训。

企业的回复不充分。企业没有说明监督培训计划失败的原因，也没有提供评估培训有效性的详细计划。

 

缺陷4

You perform microbiological testing activities without qualified staff.

Your firm has (b)(4) employees. (b)(4) conducts microbiological testing, and (b)(4) reviews the test data. (b)(4) has appropriate qualifications to perform microbiology testing nor adequate training in CGMP regulations, as is evident by the deficiencies cited in this letter. This lack of staff qualification in microbiology was further demonstrated by your firm’s failure to use basic microbiological laboratory equipment such as an operational microscope and typical reagents used for Gram staining. You stated that you were not aware of the last time your firm conducted Gram stain testing for identification.

由没有资质的员工开展微生物检验。

企业有XX名员工。XX人执行微生物检验，XX人审核检验数据。XX人具备执行微生物检验的适当资质或接受了充分的CGMP培训，此警告信所引用的缺陷可证实这一点。企业未使用基本的微生物实验室设备，例如，显微镜和革兰氏染色法的典型试剂，这也进一步证明了企业的微生物学员工缺乏资质。企业表示不清楚上一次使用革兰氏染色法进行菌种鉴定是什么时候。

 

缺陷5

Your firm was unable to provide any CGMP-related training documentation. Your firm’s senior management further stated that no CGMP-related training has ever been provided to employees.

企业未能提供任何cGMP相关的培训记录。企业高层还说，从来没有给员工提供任何cGMP相关的培训。

 

缺陷6

Failure to maintain training records of employees involved in the manufacture of intermediates or API.

Our investigator found that your employees' CGMP training records contained numerous discrepancies that raise doubts regarding their authenticity. For example, the inspection documented that 10 of 11 training records contained identical handwritten responses. Our investigator also found incomplete training assessment forms for two employees. The forms indicated that the employees had not been evaluated as required in your procedures, yet the employees’ training files stated that they had been evaluated as “very good” for the skills in question.

该企业未能保留参与中间体或原料药生产的员工的培训记录。

我们的检查人员发现，该企业的员工CGMP培训记录有多处缺陷，这让我们怀疑该记录的真实性。例如，检查中发现11个培训记录中有10个完全一样的手写答复。我们的检查人员还发现，有两个员工的培训评估表格不完整。这些表格说明员工并没有根据程序要求进行评估，但是员工的培训档案上却写到他们技能“优”。

 

缺陷7

Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions (21 CFR 211.25(a)).For example, you did not train your contract employees in CGMP or in job-specific procedures. In addition, CGMP documents, including procedures and batch records, apparently could not be fully comprehended by many of the contract employees. Your contract employees conducted critical CGMP operations for your finished drug products such as visual inspection of filled capsules, (b)(4) sealing, 100% verification of sealed bottles, final label quality inspection, outsert pasting on bottle caps, and the final packing in boxes. CGMP training is essential to ensure employees are qualified to perform all operations in compliance with good manufacturing practice.

We acknowledge your commitment to amend training procedures for your contract employees to ensure that you adequately train all of them.

企业未能保证从事药品生产、加工、包装或贮存的每位员工均受过教育、培训并有实践经验，能够履行委派的职责(21 CFR 211.25(a))。

企业没有对合同制员工进行cGMP培训，或岗位相关规程的培训。另外，很明显，有多份合同制员工不能完全理解cGMP文件，包括规程和批记录。合同制员工完成了多次成品的关键cGMP操作，例如，目检胶囊填充、封装、已封装瓶的100%确认、最终标签质量检查、瓶盖外贴和最后装箱。要保证员工有资质进行符合GMP要求的操作，cGMP培训是基本要求。

企业回复：承诺修订合同员工的培训管理规程，以保证对他们进行充分的培训。

 

缺陷8

You failed to assure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training or experience, or any combination thereof, to enable that person to perform the assigned functions （21 CFR 211.25(a)）.For example:

a. Our investigators discovered a water bottle under one of the labeling tables in the product labeling room. As per SOP #P-PB-052, "It is prohibited to eat, drink and smoke in the plant, only drinking is allowed outside the manufacturing areas (corridors)."

b. investigation confirmed that an analyst assigned to run the (b)(4) active air sampler did not set up and run the air sampler correctly, but labeled and incubated the plates anyway. Visual inspection of the incubated plates on January 16, 2014, did not show evidence of exposure in the (b)(4) active viable air sampler.

企业未能保证从事药品生产、加工、包装或贮存的每位员工均受过教育、培训并有实践经验，能够履行委派的职责(21 CFR 211.25(a))。例如，

a. 《SOP #P-PB-052》规定，禁止在车间内吃喝吸烟，只允许在生产区之外（走廊）喝水；但是检查员在贴签室的贴签桌下发现一瓶水；

b. 企业的调查结果确认，派去运行某浮游菌空气取样器的检验员，没有正确安装和运行空气取样器，但仍用此进行标记和培养。2014年1月16日的培养皿目检，没有显示某活性浮游菌空气取样器暴露的证据。

 

缺陷9

Employees are not adequately trained.For example:

a. An employee dressed in an animal control uniform walked through the production gowning area without stopping to gown, and sidestepped three “antibacterial adhesive rugs” as he walked through the gowning area. He failed to follow SOP #P-PB-052, Plant Access Control, section D4.

b. An operator working in the fractionation Area had his facemask pulled down while having a conversation with another operator in the area. All employees must wear masks while working in the fractionation area as required by SOP P-PB-052.

员工未得到充分的培训。例如：

a. 一个员工穿着动物管理的衣服穿过生产区的更衣区，而没有停下来换衣服，在他通过更衣区时横跨了3个抗菌黏附地毯。他没有遵守《SOP #P-PB-052 工厂访问控制规程》的D4部分。

b. 隔离区工作的一位员工和该区域另一位员工说话时，摘下自己的面罩。然而，《SOP P-PB-052》要求所有员工在的隔离区工作时，必须带面罩

 

缺陷10

Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions (21 CFR 211.25(a)).

Your firm performs microbiological testing activities related to your aseptic processing operations without including any qualified staff with microbiology background. Specifically, production personnel with no microbiology background perform environmental monitoring and evaluate the samples collected for microbial growth. Production personnel also perform in-process testing for bioburden. In addition, the media from media fills are evaluated by packaging employees.

In your response, you indicate that a consultant educated in microbiology will train your operators every (b)(4) to perform and evaluate viable environmental monitoring samples and bioburden test samples of in-process materials. In addition, you commit to (b)(4) have a consultant train packaging personnel to evaluate media fills. Your proposal is inadequate in that training exercises alone cannot replace the appropriate combination of education, training, and experience necessary to perform these critical microbiological activities that monitor the aseptic operation.

企业未能保证从事药品生产、加工、包装或贮存的每位员工均受过教育、培训并有实践经验，能够履行委派的职责(21 CFR 211.25(a))。企业针对无菌工艺操作进行的微生物检验，并未安排具有微生物学背景的有资质员工。例如，由没有微生物背景的生产人员，进行环境监测并评价采集用来评价微生物生长的样本。生产人员还进行了微生物污染水平的中间过程检验。此外，培养基模拟灌装用培养基由包装人员评价。

"企业回复：企业指出将请一名拥有微生物教育背景的顾问培训操作员，来执行并评价微生物环境监测样本，以及中间过程物料微生物污染水平检验的取样。此外，企业承诺有顾问培训包装人员评价培养基模拟灌装。 FDA认为，这些整改措施是不充分的，在这些监测无菌操作的关键微生物学监测活动中，培训不能取代教育、培训、经验等综合能力。

 

缺陷11

Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions (21 CFR 211.25(a)). For example, on March 18, 2013, FDA investigators identified the presence of incomplete training "Questionnaire" records. Per your training procedures, these questionnaire forms must be completed following each training to assess the individual's competence. The inspection documented over 40 instances of incomplete training records for three of your staff members. In each case, the trainee and trainer names were left blank on the questionnaires, but were pre-filled with the answers. Incomplete training records were found for critical GMP activities, including:

• Handling of sterilized materials and materials to be sterilized

• Handling and transfer of media fill vials

• Line clearance for the manufacturing, filling, washing and sealing areas, sanitized container storage area and sanitization area

• Replacement of filters and integrity testing frequency

• Operation of filter integrity tester

• Qualification of personnel for aseptic area

Your response indicates that these are not GMP documents and that the FDA investigators' concerns were limited to the department-specific training. Your response did not include a review of all other training documents to determine whether assessments had been appropriately completed and assessed.

企业未能保证从事药品生产、加工、包装或贮存的每位员工均受过教育、培训并有实践经验，或其组合，能够履行委派的职责(21 CFR 211.25(a))，例如：2013年3月18日，FDA检查员发现了不完整的培训问卷记录。按照企业的《培训管理规程》，这些问卷表格必须在每次培训后完成，来评估个人的能力。这次检查发现了3位员工约40个不完整记录。每个情况，在问卷上，培训学员与培训讲师的名字是空白的，但是答案是预先填好的。在关键的GMP活动中，发现了不完整的培训记录，包括：

• 已灭菌物料和待灭菌物料的处理

• 培养基模拟灌装瓶子的处理

• 生产、灌装、清洁、封口区的在线清洁，容器贮存区和清洗区的卫生

• 过滤器的替换和完整性检测频率

• 过滤器完整性检测

• 无菌区的人员资质

企业回复说，这些不是GMP文件，FDA检查员关注的是车间部门特定的培训。企业的回复没有包括所有其他培训文件的审核，来确定是否已完成评估。

 

缺陷12

You failed to assure each person responsible for supervising the manufacture, processing, packing, or holding of a drug product has the education, training or experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess （[21 CFR 211.25(b)）. For example:

a. During a review of retention samples for Complaint #QC-13-002 regarding missing lot numbers and expiration dates on two product packages of Anascorp® lot (b)(4), the analyst, at the direction of the supervisor, documented that “no missing batch #'s or expiration dates have been located within these samples.” However, your investigation confirmed that there are no retention samples for this lot at your firm.

b. Sterility testing records for Anascorp® Bulk lots (b)(4) and Anascorp® Final Filled lots (b)(4) all show negative results for each day of the (b)(4) day incubation period. However, no analysts work on weekends and plates are only read Monday –Friday. An investigation revealed that microbiology personnel are instructed to record Saturday and Sunday results as negative if Monday's results are negative as well.

c. Four different company personnel performed a secondary signoff on environmental monitoring records that had no documented results.

未能保证每位监督药品生产、加工、包装或贮存的负责人，具备相应的教育、培训并有实践经验，或其组合，能够履行委派的职责，以提供对药品所声称的或表明拥有的安全性、成分、规格、质量和纯度的保证。(21 CFR 211.25(b))。

a. 投诉调查报告（编号：QC-13-002）中描述， 某批Anascorp®的两个包装没有批号和有效期，在对留样的检查中，分析员在主管指示下，记录“这些的留样没有缺失批号和有效期”。但是，该企业的调查确认了该企业对这批没有留样；

b. Anascorp®散装(b)(4)批的无菌检测结果表明在Anascorp®最终灌装(b)(4)批次培养期间，每天的结果都是阴性。但是没有分析员在周末上班，培养皿只在工作日观察⁠⁠⁠⁠⁠⁠⁠。检查员发现微生物人员被告诉，如果周一是阴性结果的话，就记录周末阴性结果

c. 4个不同的企业人员对没有记录结果的环境监测报告确认签字。

 

缺陷13

Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions, and that training in current good manufacturing practice is conducted by qualified individuals (21 CFR 211.25(a)).

During interviews with our investigators, your contract employee who trains other contract employees on good documentation practices was unable to explain the material he was required to present during training. In addition, while a significant number of your contract employees do not speak English, you only provided English training materials to these employees.

We also found an employee’s failing equipment qualification training assessment form in the trash, yet that employee’s official file showed passing results. According to your company policies, personnel with failing scores must be retrained, but your firm was unable to provide evidence of retraining in the employee’s official record.

According to your response of September 22, 2014, department heads are now responsible for training their contractors. Your response is inadequate, as you failed to assess how critical operations were affected by unqualified personnel.

You have not demonstrated that you have provided employees with appropriate resources and training to make sure that they are qualified for the operations they performed. Falsification and manipulation of employee training records is unacceptable.

未能保证从事药品生产、加工、包装或贮存的每位员工均受过教育、培训并有实践经验，或其组合，能够履行委派的职责，并且未能由有资质的人员指导CGMP培训。(21 CFR 211.25(a))

在检查员面谈时，该公司负责培训其他合同工良好文件管理规范的员工不能对培训材料给出解释。并且，该公司的很多员工不会说英语，但该公司只提供英语培训材料。

检查员在垃圾中发现了员工设备资质培训不合格的评估，但是该员工的正式文件是通过的。按照公司的政策，分数不合格的员工须再培训，但是该公司不能提供员工再培训的的证据。

该公司在2014年9月22日的483回复中说，部门领导负责该部门的合同工培训。该企业回复不充分，没有评估资质不合格的人员是怎样影响关键操作的。

该公司没有证明给员工提供了恰当的资源和培训，以确保员工的资质符合各自进行的操作。员工培训记录的造假和操纵是不可接受的。

 

 

来源：Internet

关键词： FDA警告信 培训管理类缺陷