fda于2018.03.27-04.03，由检察官jose e melendez和ademola o daramola,对辉瑞hospira healthcare india pvt.ltd在印度tamil nadu的sriperrumbudur工厂进行了为期六天的查验，共开出了32页11条缺陷。
近日，fda9778818威尼斯官网挂出针对此工厂的警告信，警告信中可以看出，fda对于qc的检验数据表示很担忧。该缺陷包括如下：
1. 微生物实验室数据完整性：
人员和环境监测培养基结果与实际不符，明显少报。检查员发现培养基实物菌落数与记录数不一致，后该公司员工承认该严重错误。该公司后整改为实际计数结果，但发现环境监测结果急剧增加。
fda评论该厂微生物数据完整性问题使得该厂放行的药品的无菌性无法保证。
fda同时对该厂qc实验室报告的所有结果的有效性的表示严重担忧。
尽管辉瑞高层在fda监管会议上再次与fda沟通该数据完整性的整改问题，但是fda表示，该公司尚没有说明数据报告不准确的范围,以及管理层和员工参与数据造假的程度。
2. 工艺控制不足：
fda检查了该厂灯检不良情况，发现多个批次灯检关键缺陷不良超出规定的限度。
在对该厂的留样的检查期间，fda再次发现了多个外观缺陷样品。
fda评论该厂工艺对灯检关键缺陷的容忍度过高，质量部门未能及时发现生产的不良信息，使得几批有关键质量缺陷的药品进入市场。
3. 化学实验室数据完整性：
fda对几个已经检验合格的批次要求当场进行复测，结果均为oos。
fda发现该厂检验员没有用以记录时间的时钟。
fda表示该厂未确定在相同实验室进行的其它qc实验室检验是否受数据完整性问题影响，也未讨论工厂内数据完整性问题的程度。
为了便于大家理解，这里将2018年此次检查的483缺陷进行列举，（共11条）。主要问题围绕在：
4. 质量体系：质量监管不足
质量部门不能确保所有的生产和实验室操作符合cgmp要求。在fda检查过程中发现的所有缺陷都表明了质量部门没有采取必要措施以确保充分开展分析方法验证/转移，没有分析结果准确性以及对生产或检测过程中发生的所有事件进行了恰当的调查。此外，文件中出现的许多不可接受情况表明人员对确保cgmp数据完整性的重要性认知不足。（2016年检查的重复缺陷）
公司在接收到一批或多批某个产品上市批次不符合注册质量标准的信息后三个工作日内没有递交xxx现场警报报告（far）
5. 实验室控制系统：实验室数据不可靠、异常调查不全面
实验室记录没有包含所有测试、实验和含量检测中获得的完整数据，以确保产品符合已建立的规格标准。微生物实验室数据不可靠，在公司实验室受控的实验室记录中记录的微生物生长计数与培养基碟中观察到的实际计数不一致；
对上市药品的检测和放行没有包括实验室对于制剂产品与最终质量标准、每个活性成分的剂量和鉴别符合一致的放行决定。公司质量控制部化学检测人员篡改检测样品重量从而使多批xx注射剂usp原料药和制剂成品通过xx检测。
无论产品是否被销售，公司都没有对任何原因不明的偏差、产品不合格或其任意成分不符合质量标准的投诉等情况进行全面审核和调查。（2016年检查的重复缺陷）
对于原因不明的偏差，成品不合格或其组分不符合质量标准的书面调查记录并不是都有结论和进一步行动。无法确保公司开展的调查都会包含对偏差的全面评估，采用适当的科学分析方法来查找到可能的根本原因。经由此类调查提出的纠正预防措施，也并不足以或并不能恰当地处理确定的偏差，且未能及时采取进一步预防措施。
没有建立和记录分析方法准确性、灵敏性、专属性和重现性。制剂成品缺乏稳定性指征的测试方法，因此，无法保证使用分析方法产生的数据和结果的可靠性。
仪器没有按照公司文件规定的适当周期校验，文件规定出现准确性和/或精确性限度问题时的补救措施也没有执行。
6. 生产系统：工艺控制不足
没有建立控制程序来监控工艺的收率和验证生产工艺的性能，而这些都会影响到中间体和制剂成品的性质波动和改变。事实显示出，公司缺乏什么是足够的过程控制的认知，其包括必要的关键工艺参数的识别和界定，用于保证成品质量和加强对注射剂生产过程一致性的关注。
没有建立、记录和执行预防无菌药品微生物污染的程序。无法确保开展的工艺模拟实验（培养基灌装）能代表日常无菌小瓶灌装观察到的和/或可能发生的真实情况。实际情况是虽然在培养基灌装过程中操作人员纠正和固有干预是相似的，但是没有明确规定干预频次和持续时间。（此类问题是第五次重复发生了）
在生产操作和过程控制中没有按照书面的生产和过程控制程序规定开展工作并及时记录。
2018.03.27-04.03辉瑞hospira 483表翻译分析
2019.03.12辉瑞hospira警告信
warning letter 320-19-14 march 4,2019
mr.albert bourla,chairman and chief executive officer
mr.albert bourla,主席兼首席执行官
worldwide pfizer,235e 42nd st.,new york,ny 10017
纽约辉瑞总部
dear mr.bourla:
the u.s.food and drug administration(fda)inspected your drug manufacturing facility,hospira healthcare india pvt.ltd.,at plots b3,b4,b5(pt);b6(pt);b11-b18 and b21-b23,sipcot industrial park,irungattukottai,sriperumbudur,kancheepuram district,tamil nadu,india,from march 27 to april 3,2018.
美国fda于2018年3月27日至4月3日检查了你们位于印度的hospira healthcare india pvt.ltd.生产场所。
this warning letter summarizes significant violations of current good manufacturing practice(cgmp)regulations for finished pharmaceuticals.see 21 cfr,parts 210 and 211.
本警告信总结了制剂生产严重违反cgmp的行为。参见21cfr第210与211部分。
because your methods,facilities,or controls for manufacturing,processing,packing,or holding do not conform to cgmp,your drug products are adulterated within the meaning of section 501(a)(2)(b)of the federal food,drug,and cosmetic act(fd&c act),21 u.s.c.351(a)(2)(b).
由于你们的制剂生产、加工、包装或保存的方法、场所或控制不符合cgmp要求，你们的药品根据fdca的501(a)(2)(b)以及21 u.s.c.351(a)(2)(b)被认为掺假。
we reviewed your april 24,2018,response in detail and acknowledge receipt of subsequent correspondence.
我们已详细审核了你公司2018年4月24日的回复。
during our inspection,our investigators observed specific violations including,but not limited to,the following.
检查期间，我们的检查人员发现的具体问题包括但不仅限于以下：
1.your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards(21 cfr 211.194(a)).
贵公司未能确保实验室记录包含从所有用以确保符合既定标准的测试中获得的完整数据(21 cfr 211.194(a))。
your microbiology laboratory did not accurately report test results.on march 27,2018,during a walk-through of your laboratory,our investigator observed microbial growth on(b)(4)personnel/environmental monitoring media plates associated with(b)(4)aseptic processing lines.however,our review of laboratory records found that analysts had recorded a result of“nil”(no growth)for each of these plates.on the same day,our investigator also observed that your microbiologist had significantly underreported microbial results for three(b)(4)samples.
你们的微生物实验室没有准确地报告检验结果。2018年3月27日,在你们的实验室检查过程中，我们的检查人员发现了与(b)(4)无菌生产线相关的(b)(4)人员环境监测培养基碟上有微生物生长。然而,我们对实验室记录的审查发现,分析人员对这些碟子记录的结果为"零"(无生长)。同一天,我们的检查人员还发现，你的微生物人员对3个(b)(4)样品的微生物结果明显少报。
during the inspection,your staff confirmed that laboratory records did not accurately reflect the actual microbial growth observed on plates.
在检查过程中,你们员工确认,实验室记录没有准确反映在碟子上观察到的实际微生物结果。
your written response acknowledged the significance of these microbial growth count discrepancies.your firm also stated that,after implementing extra plate-reading oversight in the microbiology laboratory,a notable increase in counts emerged in environmental monitoring results,with a particularly“sharp”increase in personnel monitoring excursions across the facility.
你们的书面回复承认了这些微生物计数的严重错误。贵公司还表示,在对微生物计数实施额外的监督后,环境监测结果出现了明显的数量剧增,尤其是整个工厂的人员监测结果"急剧"增加。
accurate microbiological data is fundamental to evaluating and maintaining the state of control of an aseptic processing operation.awareness of microbial excursions in an aseptic processing operation is essential to trigger prompt actions that maintain environment control.your failure to report accurate data compromised the sterility assurance of drug products released from the facility and may have increased risks to patients.
准确的微生物数据是评估和保持无菌处理操作控制状态的基础。在无菌处理操作中发现微生物偏离对于及时触发行动维持环境控制至关重要。你们未能报告准确数据，使得从该工厂放行的药品的无菌性无法保证,并可能增加患者的风险。
the critical data integrity breaches identified in our inspection also raise serious concerns regarding the validity of all results reported by your quality control laboratory.we acknowledge your decision during the inspection to suspend release of drug products until the data integrity issues were thoroughly investigated.we also note that during the fda regulatory meeting held on may 8,2018,your management further acknowledged the significant data integrity problem identified in the inspection and discussed a comprehensive plan to address root causes.
在我们的检查中发现的严重数据完整性问题也会引发我们对你们的qc实验室报告的所有结果的有效性的严重担忧。检查期间我们收到你们暂停放行药品直到数据完整性问题得到彻底调查的决定。我们还注意到,在2018年5月8日举行的fda监管会议上,你们的管理层进一步谈到检查中发现的严重数据完整性问题,并讨论了解决根本原因的全面计划。
your response included adding corporate and third-party oversight of microbiology laboratory tests and data reporting,and several other remediation measures.however,your response did not describe the scope of inaccurate reporting of data,and the extent of management and staff involvement with data manipulation.
你们的回复包括增加对微生物实验室测试和数据报告进行内部和第三方监督,以及其他一些补救措施。然而,你们的回复没有说明数据报告不准确的范围,以及管理层和员工参与数据造假的程度。
in your response to this letter,include:
回复此函,请包括:
a final report on corrective actions and preventive actions(capa)that were implemented to assure that aseptic processing operations are maintained in a state of control,including fully requalifying personnel involved in these operations.
一份为确保无菌操作保持在控制状态而实施的纠正措施和预防措施的最终报告，包括对参与这些操作的人员进行全面再确认。
the final report on changes implemented in the site’s quality control (qc) laboratories to enhance procedures,training,and cgmp documentation practices observed during the inspection and as a result of post-inspection assessments.
工厂qc实验室所实施的用以强化程序、培训，以及针对检查期间发现的和检查后评估发现的cgmp文件记录缺陷所做的变更的最终报告。
a comprehensive,retrospective review of reliability of all microbiology laboratory data,including but not limited to data relating to water system control and environmental monitoring(personnel,surfaces,air).assess all batches within expiry and distributed in the united states.
一份对所有微生物实验室数据可靠性进行全面回顾审核，包括但不仅限于与水系统控制和环境监测（人员、表面、空气）相关的数据。评估所有销售至美国仍在效期内的批次。
2.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 has already been distributed(21 cfr 211.192).
贵公司未能彻底调查所有已销售和未销售批次及其组分的偏差或不符合其质量标准情况（21 cfr 211.192）。
your firm failed to adequately investigate poor control and critical defects in your(b)(4)manufacturing process.
贵公司未能充分调查在你们xx生产工艺中的不良控制和关键缺陷。
our inspection found that you initiated multiple investigations because batches exceeded critical defect limits for visual inspection.for example,during four months in 2017,three batches yielded excessive critical defect rates ranging from(b)(4)%to(b)(4)%.the limit is no more than(b)(4)%.
我们的检查发现由于批次超出目视检查关键缺陷限度，你们发起了多个调查。例如，在2017年4个月间，有3批关键缺陷率超出范围（xx%-xx%，限度≤xx%）。
manufacturing investigations indicated that high rates of significant(b)(4)appearance defects were caused by power failures and(b)(4)that disrupted the(b)(4).these events delayed reaching appropriate(b)(4)during the(b)(4),leading to insufficient and non-uniform(b)(4).however, your investigations did not sufficiently determine the root cause of recurring batches with significant(b)(4)defects when no power interruptions and cycle deviations were documented.your process control problems permitted excessive(b)(4)to remain in finished product units and caused persistent defects.the(b)(4)caused by these(b)(4)process control difficulties were found to lead to quality attribute specification failures including impurities,assay,or(b)(4).
生产调查显示高频次严重xx外观缺陷是因为断电和xx中断引起的。这些事件延误了在xx期间达到适当的xx，导致xx不足和不均匀。但是你们的调查并未充分确定在没有记录任何断电和循环偏差的情况下，批次仍反复出现严重xx缺陷的根本原因。你们的工艺控制问题允许制剂单元保持超出xx，导致了持续缺陷。这些xx工艺控制困难导致的xx被发现会导致不符合质量属性标准，包括杂质、含量或xx。
the extent of these critical drug quality defects was further revealed when examination of reserve samples identified many(b)(4)appearance defects,although the lots had undergone the required 100%visual inspection and had met aql sampling criteria.
在检查留样时发现许多xx外观缺陷，进一步暴露了这些药品关键质量缺陷的程度，尽管这些批次经过了所要求的100%灯检且符合aql取样标准。
the investigations did not include a timely capa plan to address(b)(4)design deficiencies and inappropriately high tolerances for critical defects such as(b)(4).you also did not adequately address the need to highly scrutinize variances in pressure control in your(b)(4)equipment,including better triggers for investigation.
检查并未包括及时的capa计划，用以解决xx设计缺陷和关键缺陷（如xx）的不恰当的过高的容忍度。你们亦未说明是否需要充分仔细检查在你们xx设备的压力控制中的变量，包括更好地触发调查。
excessive defects and major manufacturing deviations are both signals of unacceptable manufacturing variation and the need for thorough investigation into the sufficiency of process design and controls.the failure of your firm’s operations and quality departments to promptly detect adverse signals in manufacturing permitted the conditions that allowed several batches with critical quality defects to be distributed.
过多的缺陷和主要生产偏差都是不可接受的生产波动的信号，需要彻底调查工艺设计和控制的充分性。你们的运营和质量部门未能及时发现生产的不良信息，使得几批有关键质量缺陷的药品进入市场。
we acknowledge your decision to recall all batches of(b)(4)injection usp(b)(4) and (b)(4)within expiry in the u.s.market,after your testing of retain samples showed subpotent test results.
我们知悉你们在检验了留样并得到效价过低的检验结果后，决定召回所有销售至美国在效期内的xx注射剂批次。
in your response,you committed to enhance process understanding and control.you stated that you would improve and validate a modified(b)(4)process and remediate deficiencies in the visual inspection program.your response was inadequate in that:
在你们的回复中，你们承诺会加强工艺理解和控制。你们说你们会改进和验证修订后的xx工艺，修复目视检查程序的缺陷。你们的回复在以下方面是不充分的：
it did not include a reassessment of the adequacy of your capa to address handling out-of-specification(oos)(b)(4)results obtained by your laboratory.
未包括重新评估你们的capa是否足以处理你们的实验室获得的oos(b)(4)结果。
it lacked sufficient details on the evaluation of additional(b)(4)products produced with the same manufacturing equipment used for the(b)(4)injection(b)(4)and(b)(4).
其中对在xx注射剂和xx所用相同生产设备中生产的其它xx产品的评估不够详细
in your response to this letter,provide:
回复此函，请提交：
your final report on the improvements needed to ensure that(b)(4)processes will reproducibly meet required quality attributes.
你们确保xx工艺能重复符合所需质量属性所需的改进的最终报告
an evaluation of the design and state of control of each(b)(4)cycle used to produce drug products for u.s.supply.include a retrospective assessment of all investigations(e.g.,process deviations,failures,complaints)related to(b)(4)drug products not recalled from the u.s.market.summarize the root causes assigned for identified defects,the adequacy of the capa,and any further steps needed.
用于生产美国市场药品的每个xx周期的设计和受控状态的评估，包括对所有与未从美国市场召回的xx药品有关的调查的回顾性评估（例如工艺偏差、不合格、投诉）。总结所发现缺陷归结的根本原因，capa的充分性和所需的更多步骤。
your capa for routine,vigilant operations management oversight of facilities and equipment to assure prompt detection of equipment performance issues,execution of repairs,completion of preventive maintenance,upgrades to equipment and facilities,and other appropriate actions.
你们监管设施和设备用以确保及时发现设备性能问题、执行修理、完成预防性维护、设备和设施升级以及其它适当措施的常规、警戒操作管理capa
3.your firm failed to have,for each batch of drug product,appropriate laboratory determination of satisfactory conformance to final specifications for the drug product,including the identity and strength of each active ingredient,prior to release(21 cfr 211.165(a)).
你们公司未在放行前对每批药品进行适当的实验室检测，确定其符合药品的最终质量标准，包括每种活性成分的鉴别和剂量（21 cfr 211.165(a)）。
from february 16 to march 20,2018,you tested(b)(4)batches of(b)(4)api for(b)(4).all results were reported as passing.however,during the fda inspection on march 28,2018,we requested retesting the same batches under our observation.all retest results were oos.
从20180206至02180320，你们检验了xx批次xx用xx原料药。所有结果均报告为合格。但是20180328在fda检查期间，我们要求在我们观察下复测相同的批次，所有结果均为oos。
a batch of(b)(4)finished product,initially tested on may 25,2017,was also retested on march 28,2018,and found to be oos.
一批xx成品，初测时间为20170525，亦在20180328进行了复测，结果为oos。
further,on april 2,2018,your management informed our investigator that the(b)(4)test for(b)(4)batch(b)(4)raw material was repeated and that all(b)(4)replicates failed to meet the specification.
20180402，你们高级管理层通知我们调查人员说xx批次xx原料的xx检测正在重复，所有xx平行结果均不符合质量标准。
our investigators noted that your analysts did not have a timer to indicate the start and end of(b)(4)reported in your laboratory record of analysis.it was unclear if analysts were(b)(4)the(b)(4)samples for the full(b)(4)required.
我们的检查员注意到你们的化验员并没有计时器来指示你们实验室分析记录中所报告的xx开始和结束时间。不太清楚化验员是否xx样品用于所需的全部xx。
in your response,you indicated that your investigation had revealed data integrity issues related to reporting(b)(4)test results.you also indicated that your investigation,still in progress,has identified laboratory equipment failure as a probable root cause for the failing(b)(4)results.more specifically,inefficient removal of(b)(4)from the(b)(4)is considered to be the cause of incomplete(b)(4)of the sample.
在你们的回复中，你们说你们的调查显示xx检验结果报告有数据完整性问题。你们还说你们调查仍在进行中，将实验室设备失败作为不合格xx结果可能的根本原因。更为具体地说，未能有效从xx中清除xx被认为是样品不完全xx的原因。
we acknowledge your decision to suspend all(b)(4)testing.however,you did not include an assessment to determine whether other qc laboratory tests performed in the same laboratory were compromised by data integrity issues.your response also fails to discuss the extent of data integrity breaches in your facility.
我们知悉你们决定暂停所有的xx检测。但是，你们并未确定在相同实验室进行的其它qc实验室检测是否受数据完整性问题影响。你们的回复亦未讨论你们工厂内数据完整性问题的程度。
in a field alert report(far)of july 20,2018,regarding oos(b)(4)results,you indicated that“analysts performing the(b)(4)test did not perform the analysis in accordance with procedures and did not record the data accurately in the past.”also,“there may be instances where testing results for the karl fisher test,gas chromatography,infrared spectroscopy and ultraviolet spectroscopy were not recorded accurately.”
在20180720的far中，关于oos xx结果，你们说“过去执行xx检测的化验员并未根据程序进行检验，且未准确记录数据”。还有，“可能有时kf水分检测、气相、红外光谱和紫外光谱均有记录不准确的情况”。
in your response to this letter,include:
回复此函，请包括：
a comprehensive capa to ensure all batches of(b)(4)finished product intended for the u.s.market meet all established specifications.include your results from testing reserve samples of all drugs(active ingredient and finished drug product)that remain within retest period or expiry in the u.s.market.
一份全面capa，确保所有准备销往美国的xx成品批准符合既定质量标准。包括你们对所有销售往美国仍在效期内或复验期内药品（活性成分和制剂成品）留样的检测结果。
your market action plan for all batches with reserve sample testing found to be oos or inaccurately reported(e.g.,as identified by your independent third party).
你们对留样检验为oos或不准确报告（例如，你们独立第三方所发现的）的所有批次的市场行动计划
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