PDATR80《制药实验室数据完整性管理体系》(中英文对照版).doc

PDA TR 80《制药实验室数据完整性管理体系》（中英文对照版）
原标题：PDA TR 80《制药实验室数据完整性管理体系》（中英文对照版）
PDA TR 80《制药实验室数据完整性管理体系》现已全文翻译完毕，大家可以点击文末“阅读原文”链接下载中英文对照版全文。由于微信篇幅关系，这里只放出微生物实验室数据完整性的内容：
5.0 Data Integrity in the Pharmaceutical Microbiology Laboratory
5.0 微生物实验室的数据完整性
5.1 General Considerations and Risks
一般原则及风险
The approaches used to investigate the occurrence of suspected data integrity issues that h recently occurred in a pharmaceutical microbiology laboratory can be challenging and, in some cases, may be very different than those used to evaluate similar occurrences in an analytical chemistry laboratory, Many microbiological methods are performed manually;
subsequently, the recorded results are often based on the visual observations by an individual scientist performing the tests.
制药企业微生物实验室对可疑数据完整性问题的调查方法，越来越成为一个挑战，并且在一些情况下，与同样发生可疑数据的化学分析实验室的调查方法完全不同。很多微生物测试方法都是手动操作，以及所有的测试结果都由微生物测试人员人工检查并记录。
Listed below are a few examples of regulatory observations, Warning Letters, or other institutional accounts that note data integrity problems associated with microbiological laboratory records. These are only examples and are not intended to be an all-inclusive list of concerns:
以下是一些官方检查项，警告信，或其他官方检查关于微生物实验室记录数据完整性问题的情况列举，这些仅是举例并不完全代表所有与微生物实验室数据完整性相关的问题：
●Company failed to record and report reliable and accurate data for the environmental monitoring (EM) results; for example, contamination in Grade A rooms were recorded and reported as having no viable microorganisms present when, in fact, microbial contamination was present. Specifically, the settle agar plates used in these areas were felsely reported as having “ no colonies present” but were found to contain 16 colony-forming units (CFU), more than could be reasonably overlooked.
●公司未记录和报告真实准确的环境监测结果数据；例如，A级区实际存在微生物污染但实际记录和报告为零。特别是A级区沉降菌报告为“无菌落生长”，但实际上发现沉降菌结果为16cfu，可能会有更多类似的情况被掩盖。
●Company failed to implement an adequate quality assurance system as evidenced by: product sterility test failures that occurred and were not reported, investigated, or documented; five batches of viral harvests that were rejected due to contamination，yet no reports were initiated；and a company practice that product sterility test failure(s) were investigated only if more than one test jar per batch of the first or second harvests failed for sterility.
●公司质量保证体系未有效执行，具体表现为：产品无菌测试失败未报告，调查或记录；5批次产品由于病毒污染而被拒绝放行，但没有任何调查报告被发起，以及某些公司仅在第二次无菌失败或同一批次超过一瓶出现无菌样品失败的情况下，才会发起无菌调查
●Company used a contract laboratory to perform microbiological testing; however, the company audit checklist used to evaluate the suitability of this laboratory was completed by the contract laboratory, not the company, with no follow-up verification.
●公司存在委托实验室进行微生物检测的情况然而，对委托实验室符合性审计的主体是由该委托实验室进行而非公司，且并未进行任何确认。
●Private testing laboratory claimed to have conducted microbiological testing, yet it did not have the laboratory equipment (i.e., incubators) and/or media necessary to perform the analysis.
●公司声称内部进行微生物实验测试，但实验室并没有实验相关的设备（如培养箱）和/或测试所必须使用的培养基。
●Company used an “ unofficial” notebook to record microbial contamination in the plant’s water system; however, there was no official investigation or documentation regarding the water system contamination with a known pathogen (Pseudomonas aeruginosa).[Comment: This type of observation relates to both the microbiology laboratory and operators’ behaviors. Periodically, deceptive individuals will use the same technique to mislead, misrepresent, and/or obscure emerging microbial problems in manufacturing equipment that can impact product quality.]
●公司使用“非正式”的记录本以记录工厂内水系统的微生物污染情况；然而，当发现水系统中存在已知控制菌（铜绿假单胞菌污染时，公司并未针对此污染情况发起任何正式的调查或记录。<备注：此类型的污染与微生物实验室及人员操作污染相关。隐瞒人员会定期使用相同的技术来误导、歪曲和/或掩盖生产设备中出现的微生物问题, 从而影响产品质量。>
●Company recorded results that the growth promotion test on the media used for simulation studies supported growth meeting the standard set by USP Chapter <71> Sterility Tests when, in fact, the microorganisms did not grow (30). In another case, filamentous fungi were seen growing in all five spiked media tubes, indicating contamination, yet laboratory records claimed that all five distinct species of microorganisms were actually growing per the USP standard.
●公司记录用于培养基模拟灌装的培养基促生长测试结果符合USP<71>无菌检测章节的标准菌种生长要求，然而事实上，XX（30）微生物并未生长。另一个情形中检查人员发现，真菌菌丝在5管液体培养基试管中生长，显示了污染，但实验室记录却显示按照USP标准5管试验管中显示各测试菌种生长良好。
Again, while this list is not exhaustive, it does present actual inspection observations made by several regulatory auditors during their documentation of data integrity anomalies in pharmaceutical microbiology laboratories.
虽然以上显示的清单并不详尽，但却来源于多次官方审计检查中微生物实验室存在的缺陷检查记录清单。
5.1.1 Interviewing Analysts
问询分析人员
One critical element in conducting an audit for data integrity problems in a microbiological laboratory is interviewing the individuals who perform the QA/QC tests, in particular, the laboratory analysts or technicians. When reviewing analytical results reconded on worksheets or data printouts from the LIMS, for example, it is extremely difficult to detect data that should have been recorded but was not. Much of what analysts learn comes from on-the-job training, yet unofficial dialogue with cowokers or supervisors is rarely captured or documented. For instance, when a senior analyst instructs a junior analyst on how to handle the appearance of “unwanted” microorganisms found growing on analytical petri plates (such as“write the numerical count of the suspected colonies on the lid of the petri dish but don’t record it on the official worksheet until the supervisor has a chance to review it.”)，this “unofficial” practice will not be found in the company’s standard operating procedures（SOPs）. An auditor can best assess the potential for inappropriate practices first, by verifying the acceptance criteria described in SOPs and，then，by inquiring of the analysts or technicians if they have been instructed to adjust or modify data or divert from the laboratory SOPs in any form. Without conducting such foce-to-face interviews, this kind of microbiological data manipulation would be extremely difficult to detect.
对微生物实验室数据完整性问题的审计一项重要的基本要素是问询执行微生物测试的QA/QC人员，特别是实验室的分析师和技术人员。当审核记录于工作表或从LIMS系统中打印的分析结果时，很难发现本应被记录而未被记录的数据。大部分分析人员的知识来源于在岗培训，因此同事间的或与主管间的非正式谈话就很难被捕捉或记录。例如，当一个高级技术员指导新员工进行培养皿微生物计数，当发现培养皿上“不好的”（或“非预期生长的”）微生物时（例如，在主管审核结果之前将计数结果写在培养皿上而不是记录表格中），这种“非正式”的操作就不会出现在公司SOP描述中。审核员可以评估潜在不当做法的最佳方式是，确认sop中描述的验收标准，然后，通过询问分析员或技术人员，去分析他们是否被指示调整或修改数据或以任何形式从实验室sop转移。如果不进行这种面对面的面谈，这种微生物数据操纵将极其难以察觉。如果没有面对面的这种沟通，这种类型的微生物实验室数据操作将很难被发现。
5.1.2 On-site Laboratory and Sampling Review
公司内实验室和取样环节审核
There are several procedural steps when handling, shipping» and storing microbiological samples that can dramatically and negatively impact final analytical results. Specific examples of managing samples that can diminish recovery of microbiological or endotoxin results and, thus, should be avoided through procedures and adequate employee training, are listed below:
文件中有很多关于微生物样品取样，运输，储存的步骤会对最终微生物测试结果存在显著的、不良的影响。为避免影响微生物及内毒素测试结果应当包括完善的管理文件和足够的人员培训，例子包括：
●Collecting in-process product or water samples in an inappropriate container that may bind (or remove) a bacterial endotoxin from the sample may later reduce the true level of bacterial endotoxins within that test portion.
使用不合适的容器取中间产品样品或水的样品可能会弱化（或去除）样品中的细菌内毒素水平，随后可能减少被测试样品中真正的内毒素水平。
● The excessive use of disinfectants to spray the sampling port(s) prior to taking the sample may result in the disinfectant dripping into the sample bottle and reducing the actual bioburden of the product sample. Sampling from the sample ports should closely simulate the common practices performed during routine production operations.
取样前对取样口使用消毒剂过度喷洒可能导致消毒剂滴落在取样瓶中导致降低所取样品中真正的微生物负载水平。从取样口取样应当正常模拟日常生产时使用该取样点的情况。
● When using in-line sample collection manifolds for collecting intermediate-stage product manufacturing, the manifold needs to cool down after heat sterilization so it does not kill the microbes collected for laboratory testing.
采用在线样品收集管道抽取中间体产品时，收集管道在加热灭菌后需要冷却，以免杀死供实验室检测用样品中收集到的微生物。
● Product sample collection bags should not be held directly under a UV light within a storage cabinet. Exposure to UV light will kill the microbes present before the sample collection bags are delivered to the laboratory for testing.
取样瓶不应该直接放在有UV紫外灯的传递窗中。样品瓶传递至实验室之前暴露在UV紫外灯下将杀灭取样器中的微生物
● Microbiological sample bags should not be stored in a freezer or extremely cold refrigerator, which may injure or stress indigenous microbes. Microbial samples should be placed within a controlled environment to preclude any harmful or deleterious impact on the samples; then, analyses should commence as soon as reasonably possible.
微生物取样瓶不应该储存于冰箱或超低温冰箱中以免使样品中微生物受损或阻碍生长。微生物样品应当被放置在受控的环境中排除任何对样品有害的影响；否则，分析人员应当立即进行测试
Finished products or in-process samples that are undergoing sterility testing in a Class 100 clean room (or isolator) should be disinfected using an antimicrobial solution and a validated contact time. Disinfectant vapors or solution passing through the product packaging or container-closure and into or onto the product prior to sample analysis may prevent or kill microbes in the media-enrichment test environment, which may inhibit recovery of product contaminants. For example, if the product sample was contaminated prior to the package disinfection step, a vulnerable container-closure system prepared with excessive disinfectant would likely result in false negative data. The sample container disinfection process should be included in laboratory qualification studies and the suitability tested to ensure that residual disinfection solution does not alter the integrity of the sample results.
100级房间（或隔离器）中进行成品或中间产品的无菌测试，应当使用消毒剂及经验证的接触时间对样品表面进行消毒。在样品检验前消毒剂喷雾或溶液如果穿透待检品包装或容器密封系统进入或覆盖在包装外则会阻止或杀灭充满培养基的环境，从而阻碍产品中微生物生长。例如，在包装消毒步骤前产品取样遭到污染，那么过度的消毒将容易透过容器密封系统产生假阴性的结果。样品包装容器消毒程序应当包含在实验室确认研究工作以及方法适用性监测中，确保残留的消毒剂不会改变样品微生物结果的完整性。
Because microbiological results are not captured in a chromatograph, as with HPLC or GC analysis, opportunities to directly review any anomalies between the raw and recorded data are few. One way to verify the accuracy of the test data documentation is to set aside all available microbial petri plates, broths，identification strips，etc., in a secure area or refrigerator just after they have been removed from the incubator and analysis is complete. A careful review of the raw data against the analytical worksheets or LIMS data entries should reveal any discrepancies and provide an opportunity to catch any problems with either personnel training or equipment recording, and thus improve, laboratory procedures.
由于微生物测试不像高效液相和气相测试那样通过色谱仪进行分析，因此能够直接审核出原始数据和所记录的数据之间异常情况的几率很小。确认测试数据准确性的一种方法是，在待检验工作完成后将用于测试的微生物培养皿、营养肉汤、鉴定条等从培养箱中取出，将它们放在安全区域或冰箱中，然后仔细核对检验工作表或LIMS数据。可以发现任何不符之处，并提供机会发现人员培训或设备记录方面的任何问题，从而改进实验室程序。
Another technique may prove effective in checking data from samples stored in refrigerators and freezers. The ordinal test vessels from completed analyses of all positive samples (in-process or finished product bioburden test results, sterility test results, water testing, EM, personnel, etc.) usually contain microbial isolates. Conducting an inventory of the stored samples can provide a starting point to determine if there are differences between what was actually recovered during sample analysis and the data recorded on worksheets or in the LIMS. While taking inventory of samples stored in freezers and refrigerators，be sure to note the product name, lot numbers, tracking numbers, microbial identification, etc., marked on the exterior of test tubes and petri dishes. This collected information will provide a list that can later be compared to the results recorded on batch records, worksheets, and LIMS. The information gathered from reviewing the stored sample plates and tubes can indicate whether a company’SOPs are effective or if the analysts are following procedures correctly when there are objectionable microorganisms that need to be investigated. If the number and types of actual microbial isolates found from the stored samples do not match those in the company’s quality control records, these data integrity issues maybe due to intentional misreporting of the data.
另一个可能证明有效的手段是检查储存在冰箱或超低温冰箱中的样品数据。保存所有原始的阳性测试结果的测试容器（中间产品或成品的微生物限度测试、无菌检查、水测试，环境测试，人员表面微生物测试等）通常都包含微生物菌落。检查被存储的阳性样品可以从最开始的数据检查检验记录单或LIMS系统与实际数值之间是否存在差异。如果要将阳性样品储存起来，应当确保在试管壁和培养皿外表面注明产品名称，批号，追踪号，微生物鉴定结果等信息。收集这些信息是用于提供足够信息用于与检验记录结果，批记录，表格和LIMS系统中的数据核对。对于这些搜集信息的审核是为了考察公司SOP规定的是否完善以及分析人员是否正确按照规程执行操作，对有任何可疑菌落生长发起必要的调查。如果被储存起来的冻存管，培养皿等观察到的信息与QC报告的数据不一致，则显示有故意为之的嫌疑而造成微生物数据完整性不符合要求。
5.1.3 Worksheet Review
检验记录的审核
Microbiology data often relies on less automated recordkeeping that can be manipulated, often without clear traceability to the original record, when recording forms and worksheets are not well controlled or reconciled. In order to cross-check and confirm data in worksheets, entries in linked documentation should be reviewed (e.g., logbooks of equipment, batch records). Control over the issuance of original paper records, forms or worksheets should provide mechanisms that allow the original records to be distinguished from copies and reconciled. An expert microbiologist recommends reviewing analytical worksheets carefully during an inspection for the following indications of possible falsification: (a) lab reports containing more tests than can reasonably be run per day or per week or by an individual analyst; (b) backlogged sample worksheets reviewed and approved as a batch at the end of the month; (c) worksheets completed by personnel not present in the lab the day of the tests; (d) worksheets reviewed and approved by some other than an authorized reviewer/approver; (e) changes in handwriting signatures; (f) changes in reporting format, e.g” <1 CFU being replaced by zero; (g) results with counts reported as merely meeting specifications; (h) a change in frequency of OOS result reporting; (i) perfectly filled-out worksheets, indicating a risk that they are a second copy; (j) use of media before it passes growth promotion; (k) missing worksheets or worksheets out of numerical order; (l) discrepancies between investigation reports and worksheets; and (m) results from a single batch reported twice (31)»
微生物数据记录通常无自动记录装置依靠手工操作，如果记录本和台账未良好受控或管理，这样通常会导致很难可清晰追溯至原始记录数据。为了能够对记录表格中原始数据进行交叉审核，在录入相关文件记录时应当对其录入的数据进行审核（例如：设备使用日志，批记录）。实验室原始记录和表格应当有受控发放机制，以区分原始记录和复印件及受控件的区别。一位微生物学专家建议在审核实验员检验记录时应当关注以下可能出现的数据造假：（a）实验室某个实验员出具的检验记录数量远远超过理论上一个单独实验员一天或一周正常的数量；（b）月底开始集中审核和批准积压的一批次样品检验记录；（c）检测记录上签字的人员在检测当天并未在岗；（d）未授权的记录审核员；（e）书写或签名处有涂改；（f）报告形式变更，例如用0替代＜1cfu；（g）报告的结果几乎接近标准值；（h）OOS结果报告周期的变更；（i）刚好填满一整张记录，可能显示为重新誊抄的记录；（j）在培养基适用性检查之前就使用该培养基；（k）记录表格丢失或表格编号不连续；（l）记录表和调查报告之间存在差异；以及（m）同一批次报告2次结论（31）。
5.1.4 Contract Laboratories
合同实验室
Companies that do not have the laboratory space, specialized equipment, or capacity to conduct highvolume microbiological analyses may outsource this type of testing to contract laboratories. In such cases, the company is responsible for thoroughly investigating the reputation and quality control pe