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嘉峪檢測網(wǎng) 2025-03-19 08:52
根據(jù)21 CFR 211.25要求， 所有從事藥品生產(chǎn)、加工，包裝或倉儲的工作人員應(yīng)具備教育經(jīng)歷/培訓(xùn)經(jīng)歷和工作經(jīng)驗，或者三者的組合，具備能力履行所指派的職責(zé)/配合內(nèi)容應(yīng)包括員工執(zhí)行的特定操作，以及與員工職責(zé)有關(guān)的cGMP要求。cGMP培訓(xùn)應(yīng)有具備資質(zhì)的人員已持續(xù)方式執(zhí)行，其頻次應(yīng)足夠，以確保員工持續(xù)熟悉所適用的cGMP要求。負(fù)責(zé)藥品生產(chǎn)、加工、包裝或貯存的管理人員均應(yīng)受過相應(yīng)教育、培訓(xùn)并具備實踐經(jīng)驗，或具備這些綜合條件，方可從事分配的管理工作，以確保藥品具有所聲稱的或表明擁有的安全性、鑒別、規(guī)格、質(zhì)量和純度。
對于培訓(xùn)的缺陷，F(xiàn)DA在警告信中通常會指出“企業(yè)未能保證從事藥品生產(chǎn)、加工、包裝或貯存的每位員工均受過教育、培訓(xùn)并有實踐經(jīng)驗，能夠履行委派的職責(zé)”（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.）。筆者收集和整理了多份FDA警告信，共計13個常見的培訓(xùn)類缺陷，來自國內(nèi)外各企業(yè)，供企業(yè)參考。
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.
企業(yè)未能確保由有資質(zhì)的人員定期進(jìn)行培訓(xùn)，并至少涵蓋每位員工執(zhí)行的具體操作以及與員工職能相關(guān)的cGMP。
企業(yè)未能確保執(zhí)行cGMP檢驗的實驗室人員接受過現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范要求的充分培訓(xùn)。由企業(yè)的教職人員和研究生開展cGMP檢驗。企業(yè)缺乏足夠的文件記錄來證明實驗室人員接受過各自崗位職能方面的充分培訓(xùn)???????。
在企業(yè)的回復(fù)中以及FDA檢查期間，企業(yè)提供了兩份培訓(xùn)管理規(guī)程，名稱分別為 “GMP與培訓(xùn)”以及“員工培訓(xùn)”，這兩份規(guī)程都是在FDA啟動預(yù)先通知的檢查前大約一周制定的。企業(yè)的回復(fù)不充分，因為在規(guī)程制定之前就開始了cGMP檢驗，并且企業(yè)未對之前的實驗室人員進(jìn)行回顧性評估以證明他們具備專業(yè)知識或受過培訓(xùn)來支持提供給客戶的檢驗結(jié)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.
企業(yè)未能確保從事藥品制造，加工，包裝或暫存的每個人都具已經(jīng)接受教育，培訓(xùn)并具有經(jīng)驗，以使該人能夠履行其委派職責(zé) (21 CFR 211.25(a))。
該企業(yè)未能確保所有人員均具備所進(jìn)行cGMP操作的資質(zhì)。例如，企業(yè)的共同創(chuàng)始人聲稱，他是Magic Heal處方的唯一所有者，完全了解該工藝并執(zhí)行所有生產(chǎn)操作。但是，企業(yè)缺乏證據(jù)證明共同創(chuàng)始人有足夠的經(jīng)驗來履行這些職能，也沒有接受過合適的cGMP培訓(xùn)。
培訓(xùn)對于確保正確履行工作職能至關(guān)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.
企業(yè)未能保證從事藥品生產(chǎn)、加工、包裝或貯存的每位員工均受過教育、培訓(xùn)并有實踐經(jīng)驗，能夠履行委派的職責(zé)。(21 CFR 211.25(a))。
企業(yè)未能確保所有人員都經(jīng)過適當(dāng)?shù)呐嘤?xùn)。管理，生產(chǎn)，質(zhì)量保證和質(zhì)量控制崗位的人員的培訓(xùn)存在缺陷。例如，負(fù)責(zé)某藥品人工目檢的員工未按照SOP要求定期接受培訓(xùn)；負(fù)責(zé)異物（可見微粒）檢驗的分析員沒有按照SOP的要求進(jìn)行資質(zhì)確認(rèn)；有些員工缺少培訓(xùn)記錄。
檢查過程中FDA還發(fā)現(xiàn)實驗室數(shù)據(jù)缺陷，而企業(yè)將這些缺陷歸因于不充分的SOP，軟件和培訓(xùn)。
培訓(xùn)對于確保員工（包括那些監(jiān)督人員和管理人員）正確履行崗位職能是至關(guān)重要的。
在企業(yè)的整改回復(fù)中，企業(yè)表示已經(jīng)針對未按規(guī)定進(jìn)行培訓(xùn)的問題啟動了調(diào)查，并且會更新所有員工的培訓(xùn)匯總表。企業(yè)進(jìn)一步表示將確保按要求提供所有培訓(xùn)。
企業(yè)的回復(fù)不充分。企業(yè)沒有說明監(jiān)督培訓(xùn)計劃失敗的原因，也沒有提供評估培訓(xùn)有效性的詳細(xì)計劃。
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.
由沒有資質(zhì)的員工開展微生物檢驗。
企業(yè)有XX名員工。XX人執(zhí)行微生物檢驗，XX人審核檢驗數(shù)據(jù)。XX人具備執(zhí)行微生物檢驗的適當(dāng)資質(zhì)或接受了充分的CGMP培訓(xùn)，此警告信所引用的缺陷可證實這一點。企業(yè)未使用基本的微生物實驗室設(shè)備，例如，顯微鏡和革蘭氏染色法的典型試劑，這也進(jìn)一步證明了企業(yè)的微生物學(xué)員工缺乏資質(zhì)。企業(yè)表示不清楚上一次使用革蘭氏染色法進(jìn)行菌種鑒定是什么時候。
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.
企業(yè)未能提供任何cGMP相關(guān)的培訓(xùn)記錄。企業(yè)高層還說，從來沒有給員工提供任何cGMP相關(guān)的培訓(xùn)。
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.
該企業(yè)未能保留參與中間體或原料藥生產(chǎn)的員工的培訓(xùn)記錄。
我們的檢查人員發(fā)現(xiàn)，該企業(yè)的員工CGMP培訓(xùn)記錄有多處缺陷，這讓我們懷疑該記錄的真實性。例如，檢查中發(fā)現(xiàn)11個培訓(xùn)記錄中有10個完全一樣的手寫答復(fù)。我們的檢查人員還發(fā)現(xiàn)，有兩個員工的培訓(xùn)評估表格不完整。這些表格說明員工并沒有根據(jù)程序要求進(jìn)行評估，但是員工的培訓(xùn)檔案上卻寫到他們技能“優(yōu)”。
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.
企業(yè)未能保證從事藥品生產(chǎn)、加工、包裝或貯存的每位員工均受過教育、培訓(xùn)并有實踐經(jīng)驗，能夠履行委派的職責(zé)(21 CFR 211.25(a))。
企業(yè)沒有對合同制員工進(jìn)行cGMP培訓(xùn)，或崗位相關(guān)規(guī)程的培訓(xùn)。另外，很明顯，有多份合同制員工不能完全理解cGMP文件，包括規(guī)程和批記錄。合同制員工完成了多次成品的關(guān)鍵cGMP操作，例如，目檢膠囊填充、封裝、已封裝瓶的100%確認(rèn)、最終標(biāo)簽質(zhì)量檢查、瓶蓋外貼和最后裝箱。要保證員工有資質(zhì)進(jìn)行符合GMP要求的操作，cGMP培訓(xùn)是基本要求。
企業(yè)回復(fù)：承諾修訂合同員工的培訓(xùn)管理規(guī)程，以保證對他們進(jìn)行充分的培訓(xùn)。
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.
企業(yè)未能保證從事藥品生產(chǎn)、加工、包裝或貯存的每位員工均受過教育、培訓(xùn)并有實踐經(jīng)驗，能夠履行委派的職責(zé)(21 CFR 211.25(a))。例如，
a. 《SOP #P-PB-052》規(guī)定，禁止在車間內(nèi)吃喝吸煙，只允許在生產(chǎn)區(qū)之外（走廊）喝水；但是檢查員在貼簽室的貼簽桌下發(fā)現(xiàn)一瓶水；
b. 企業(yè)的調(diào)查結(jié)果確認(rèn)，派去運行某浮游菌空氣取樣器的檢驗員，沒有正確安裝和運行空氣取樣器，但仍用此進(jìn)行標(biāo)記和培養(yǎng)。2014年1月16日的培養(yǎng)皿目檢，沒有顯示某活性浮游菌空氣取樣器暴露的證據(jù)。
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.
員工未得到充分的培訓(xùn)。例如：
a. 一個員工穿著動物管理的衣服穿過生產(chǎn)區(qū)的更衣區(qū)，而沒有停下來換衣服，在他通過更衣區(qū)時橫跨了3個抗菌黏附地毯。他沒有遵守《SOP #P-PB-052 工廠訪問控制規(guī)程》的D4部分。
b. 隔離區(qū)工作的一位員工和該區(qū)域另一位員工說話時，摘下自己的面罩。然而，《SOP P-PB-052》要求所有員工在的隔離區(qū)工作時，必須帶面罩
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.
企業(yè)未能保證從事藥品生產(chǎn)、加工、包裝或貯存的每位員工均受過教育、培訓(xùn)并有實踐經(jīng)驗，能夠履行委派的職責(zé)(21 CFR 211.25(a))。企業(yè)針對無菌工藝操作進(jìn)行的微生物檢驗，并未安排具有微生物學(xué)背景的有資質(zhì)員工。例如，由沒有微生物背景的生產(chǎn)人員，進(jìn)行環(huán)境監(jiān)測并評價采集用來評價微生物生長的樣本。生產(chǎn)人員還進(jìn)行了微生物污染水平的中間過程檢驗。此外，培養(yǎng)基模擬灌裝用培養(yǎng)基由包裝人員評價。
"企業(yè)回復(fù)：企業(yè)指出將請一名擁有微生物教育背景的顧問培訓(xùn)操作員，來執(zhí)行并評價微生物環(huán)境監(jiān)測樣本，以及中間過程物料微生物污染水平檢驗的取樣。此外，企業(yè)承諾有顧問培訓(xùn)包裝人員評價培養(yǎng)基模擬灌裝。 FDA認(rèn)為，這些整改措施是不充分的，在這些監(jiān)測無菌操作的關(guān)鍵微生物學(xué)監(jiān)測活動中，培訓(xùn)不能取代教育、培訓(xùn)、經(jīng)驗等綜合能力。
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.
企業(yè)未能保證從事藥品生產(chǎn)、加工、包裝或貯存的每位員工均受過教育、培訓(xùn)并有實踐經(jīng)驗，或其組合，能夠履行委派的職責(zé)(21 CFR 211.25(a))，例如：2013年3月18日，F(xiàn)DA檢查員發(fā)現(xiàn)了不完整的培訓(xùn)問卷記錄。按照企業(yè)的《培訓(xùn)管理規(guī)程》，這些問卷表格必須在每次培訓(xùn)后完成，來評估個人的能力。這次檢查發(fā)現(xiàn)了3位員工約40個不完整記錄。每個情況，在問卷上，培訓(xùn)學(xué)員與培訓(xùn)講師的名字是空白的，但是答案是預(yù)先填好的。在關(guān)鍵的GMP活動中，發(fā)現(xiàn)了不完整的培訓(xùn)記錄，包括：
• 已滅菌物料和待滅菌物料的處理
• 培養(yǎng)基模擬灌裝瓶子的處理
• 生產(chǎn)、灌裝、清潔、封口區(qū)的在線清潔，容器貯存區(qū)和清洗區(qū)的衛(wèi)生
• 過濾器的替換和完整性檢測頻率
• 過濾器完整性檢測
• 無菌區(qū)的人員資質(zhì)
企業(yè)回復(fù)說，這些不是GMP文件，F(xiàn)DA檢查員關(guān)注的是車間部門特定的培訓(xùn)。企業(yè)的回復(fù)沒有包括所有其他培訓(xùn)文件的審核，來確定是否已完成評估。
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.
未能保證每位監(jiān)督藥品生產(chǎn)、加工、包裝或貯存的負(fù)責(zé)人，具備相應(yīng)的教育、培訓(xùn)并有實踐經(jīng)驗，或其組合，能夠履行委派的職責(zé)，以提供對藥品所聲稱的或表明擁有的安全性、成分、規(guī)格、質(zhì)量和純度的保證。(21 CFR 211.25(b))。
a. 投訴調(diào)查報告（編號：QC-13-002）中描述， 某批Anascorp®的兩個包裝沒有批號和有效期，在對留樣的檢查中，分析員在主管指示下，記錄“這些的留樣沒有缺失批號和有效期”。但是，該企業(yè)的調(diào)查確認(rèn)了該企業(yè)對這批沒有留樣；
b. Anascorp®散裝(b)(4)批的無菌檢測結(jié)果表明在Anascorp®最終灌裝(b)(4)批次培養(yǎng)期間，每天的結(jié)果都是陰性。但是沒有分析員在周末上班，培養(yǎng)皿只在工作日觀察???????。檢查員發(fā)現(xiàn)微生物人員被告訴，如果周一是陰性結(jié)果的話，就記錄周末陰性結(jié)果
c. 4個不同的企業(yè)人員對沒有記錄結(jié)果的環(huán)境監(jiān)測報告確認(rèn)簽字。
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.
未能保證從事藥品生產(chǎn)、加工、包裝或貯存的每位員工均受過教育、培訓(xùn)并有實踐經(jīng)驗，或其組合，能夠履行委派的職責(zé)，并且未能由有資質(zhì)的人員指導(dǎo)CGMP培訓(xùn)。(21 CFR 211.25(a))
在檢查員面談時，該公司負(fù)責(zé)培訓(xùn)其他合同工良好文件管理規(guī)范的員工不能對培訓(xùn)材料給出解釋。并且，該公司的很多員工不會說英語，但該公司只提供英語培訓(xùn)材料。
檢查員在垃圾中發(fā)現(xiàn)了員工設(shè)備資質(zhì)培訓(xùn)不合格的評估，但是該員工的正式文件是通過的。按照公司的政策，分?jǐn)?shù)不合格的員工須再培訓(xùn)，但是該公司不能提供員工再培訓(xùn)的的證據(jù)。
該公司在2014年9月22日的483回復(fù)中說，部門領(lǐng)導(dǎo)負(fù)責(zé)該部門的合同工培訓(xùn)。該企業(yè)回復(fù)不充分，沒有評估資質(zhì)不合格的人員是怎樣影響關(guān)鍵操作的。
該公司沒有證明給員工提供了恰當(dāng)?shù)馁Y源和培訓(xùn)，以確保員工的資質(zhì)符合各自進(jìn)行的操作。員工培訓(xùn)記錄的造假和操縱是不可接受的。
來源：Internet
