PMDA 这样检查文件及记录管理

Regarding control of document and record, the inspected site did not control listing of documents into the document list and taking out document from the document storage area based on the procedure, and locations and existence of multiple documents were unknown. There is no assurance that the GMP documents are retained for required retention period, and there is a possibility of losing necessary documents for quality assurance and important technical information. Actually there was an event of missing test record in the past. (Violation of Artucle 20 paragraph 1-3 of GMP ministerial ordinance)关于文件与记录管理：受检现场未按规程要求将文件纳入文件清单统一管控，亦未按规程办理文件自存放区的取出手续，多份文件的存放位置与是否存在均不明确。无法保证 GMP 文件按规定期限保存，存在质量保证所需必要文件及重要技术资料丢失的风险，且既往已实际发生过检验记录丢失事件。（违反 GMP 省令第 20 条第 1～3 项规定）

In addition, the conditions pointed out in the other deficiencies 2 (1), 4 (1) and 8 (1) indicate that the issues of knowlege management and training system became apparent, and the possibilities of insufficient human resources for hand over the tasks or insufficient number of personnel. 此外，其他缺陷项 2 (1)、4 (1) 及 8 (1) 中所指出的情况表明，知识管理与培训体系的问题已凸显，同时存在工作交接所需人力资源不足或人员数量配备不足的可能性。

Taking the above situation into consideration, root cause analysis should be carried out under the involvement of executive managements, and fundamental and adequate corrective and preventive action should be taken. Regarding the corrective actions against the deficiencies of document and record control, at least following actions should be included:鉴于上述情况，应由高层管理人员参与开展根本原因分析，并采取根本性、充分的纠正和预防措施。针对文件与记录管理相关缺陷的纠正措施，至少应包含以下内容：

lConfirm loss or existence of missing GMP documents or records, and all other critical GMP documents for which location confirmation are not done, and report the results.确认已丢失或去向不明的 GMP 文件 / 记录，以及所有其他尚未确认存放位置的关键 GMP 文件的实际存在情况，并上报结果。

lIf loss of any of the GMP documents are confirmed, deviation procedure should be applied and necessary actions should be taken, including analysis of impact to quality assurance and regulatory procedures. 若确认存在 GMP 文件丢失，应执行偏差处理程序，采取必要措施，包括开展对质量保证及法规符合性的影响分析。

A deficiency was observed regarding the retention period of the documents and records of the inspected product (hereinafter referred to as documents). The procedure defined that the manufactuirng instruction and record should be retained for ●years of the shelf life of the product plus 10 years, total ●years. But retantion preiods of other documents than manufacturing instruction and record are defined as ●years of shelf life or one year. Because the inspected product is categorized to biologica drug product, longer document retention period is required to make possible to investigate the cause relationship in the event of occurence of adverse drug event in the patient administered with the biological drug product, the procedure of the inspected site did not comply with this requirement. (Violation of Article 30 paragraph 2 of GMP ministerial ordinance)经查，受检产品的文件与记录（以下简称“文件”）在保存期限方面存在缺陷。规程规定：生产指令及记录的保存期限为产品有效期●年加 10 年，共计 ●年；但生产指令记录以外的其他文件，其保存期限仅规定为产品有效期●年或 1 年。由于受检产品属于生物制品，当使用该生物制品的患者发生药品不良反应时，需要更长的文件保存期限以便开展因果关系调查，而受检现场的规程未满足这一要求。（违反 GMP 省令第 30 条第 2 项）

The procedure should be up-dated, to retain GMP documents for adequate periods based on Article 30 paragraph 2 of GMP ministreal ordinance.应修订相关规程，依据 GMP 省令第 30 条第 2 项，按适宜期限保存 GMP 文件。

In addition, confirmation should be done whether there are any documents or records related to the manufacturing control and quality control of drug products intended for the Japanese market and the documents and records of process validation related activities, which are already discarded prior to the period required by the GMP ministerial ordinance. And if such discarded document or record is confirmed, evaluation of impact to the product quality or to the product validation by discarding shoud be done.此外，应对以下文件开展核查：面向日本市场的药品，其生产控制、质量控制相关文件与记录，以及工艺验证相关活动的文件与记录，是否存在在 GMP 省令规定期限届满前已被销毁的情况。若确认存在此类已销毁的文件或记录，应对该销毁行为给产品质量及产品验证带来的影响进行评估。

1. As the result of self audit by the inspected manufacturing site revealed records of discrepant opreations from instruction or records that do not reflect actural operation. As a corrective action, this site carried out training of the personnel regarding data integrity total ●times from ●month ●year up to the date of our inspection. But during current on-site inspection, multiple events of compromysing data reliability were observed as follows: (Violation of Article 20 paragraph 2 of GMP ministerial ordinance)受检生产现场自检结果显示，存在操作与规程不符或记录未真实反映实际操作的情况。作为整改措施，自 **●年●月起至本次检查当日，该现场已累计开展●次数据完整性相关人员培训。但本次现场检查中，仍发现多项影响数据可靠性 ** 的问题，具体如下：（违反 GMP 省令第 20 条第 2 项）

(1) Recording.记录填写

1) The procedure for processing of spraying ●to ●and mixing, for the manufacture of ●capsule ●(Batch No. ●) defines that the operation should be recorded each time processing of one bag is completed. But during inspection, even the operation is ongoing and there was an operation that should be recorded as per the procedure, that operation was not recorded.生产●胶囊●（批号●）时，涉及●的喷雾处理与混合操作，规程规定每完成 1 袋处理即应实时记录。但检查发现：即便操作正在进行、且存在规程要求记录的内容，仍未进行记录。

2) ●events of empty record of pre-use cleaning and error check at the start, in the use log of ●, even the test using ●is on-going. In addition, there were ●events of recording post use cleaning even the test is on-going.●设备使用日志中，存在●次设备使用前清洁及开机校验记录空白的情况（即使该设备检测仍在进行）；此外，还存在●次检测尚未结束即提前填写使用后清洁记录的情况。

3) There were ●events of missing record of routine check that should be done before starting the test in the use log of ●, even after the test was completed.●设备使用日志中，存在●次检测已完成，但检测启动前应完成的日常检查记录仍缺失的情况。

4) Samples of multiple lots of multiple products for the tests of ●, ●and ●are heated in crucibles. The procedure of this test defined to record the name of product tested, lot number, test item, identification number of the crucible in the log book of crusible for traceability. But the log book was not recorded even the test is ongoing.开展●、●及●项目检测时，多批次、多产品样品置于坩埚中加热。检测规程规定，为实现可追溯性，应在坩埚使用日志中记录：受试产品名称、批号、检测项目、坩埚编号，但实际检测过程中，该日志未填写。

(2) Issuance of blank record form.空白记录表单发放管理

1) In addition to manufacturing instruction and record, manufacturing unit uses multiple records that are not linked to the procedure such as ●. Blank forms of those records are not controlled for issuance, and the staffs in the manufacuturing unit can freely print out.除生产指令及记录外，生产部门还使用●等未与规程关联的记录。此类记录的空白表单未实施发放管控，生产部门人员可随意打印。

(3) Control of records.记录管理

1) The results of in-process control of tableting process is in-put to a spread sheet, and the print out of the sheet is attached to the manufacturing record. When misstaken of input etc. is found, the procedure defines to cross out the mistake and add the correction. But when such mistake is actually found during record review, the record is removed from the manufacturing record and corrected spread sheet is printed out and attached to the manufacturing record. Multiple original print out of the spread sheets are observed in the trush box in a locker in the office room of manufacturing unit. 压片过程的中控结果录入电子表格后，将打印件附于生产记录中。规程规定：若发现录入错误，应划改错误并补充更正信息。但实际记录审核发现错误时，相关记录被从生产记录中抽出，重新打印更正后的表格再附入；在生产部门办公室储物柜的垃圾桶内，发现多份此类原始打印表格。

2) Multiple ●in which set values of ●machine are recorded were stored in ●room. Those were recorded from ●year to ●year, but the columns of date of approval and approval stamp by manufacturing process manager remained empty showing that the record left un-approved.记录●设备设定参数的多份●资料存放于●房间，记录时间为●年～●年，但生产工艺负责人批准日期、批准签章栏均为空白，相关记录未经批准即留存。

(4) Retention of record记录保存

1) In room ●a note book named ●note was kept, in which an event of equipment trouble occurred in ●section was recorded. ●note were kept in other manufacturing sections, but the inspected site did not define detailed control procedure including retention period.●房间内存有名为「●笔记」的记录本，其中记录了●工段发生的设备故障。

2) The printout of weighing balance in which sample for ●, ●and ●tests was weighed was put in the pocket of the white laboratory wear of a laboratory personnel without attaching the laboratory record at least from ●month ●date, and this paused a risk of loosing the printout that is used for primary record. Taking such situation into consideration, corrective actions should be taken in accordance with Article 20 paragraph 2 of GMP ministerial ordinance. Such actions should include at lease following points:至少自●年●月●日起，用于●、●及●检测的天平称量打印条，未附于实验室记录，而是存放于实验人员白大褂口袋内，存在作为原始记录的打印条丢失风险。鉴于上述情况，须依据 GMP 省令第 20 条第 2 项采取整改措施，措施至少包括：

a. Check existence of similar deficiencies throughout all the GMP related operations in this manufacturing site.对该生产现场所有 GMP 相关操作进行全面排查，确认是否存在同类缺陷；

b. Confirmation should be done whether the efficacy of the data integrity training was adequately evaluated, and necessary improvements were implemented.确认数据完整性培训的有效性是否得到充分评估，并已落实必要改进。

c. Based on the results of the abeve a. and b., root cause of the failure to conduct Article 20 paragraph 2 compatible operations should be investigated, and based on such investigation results, establish short term and long term remediation plan and implement adequate corrective and preventive actions as a drug manufacturer.基于上述 a、b 项结果，对未能满足 GMP 省令第 20 条第 2 项要求的问题开展根本原因调查，并根据调查结果制定短期及长期整改计划，作为药品生产企业落实充分、有效的纠正和预防措施。

1. The inspected site explained that room ●of ●used for the warehouse of ●do not store documents and records for which control under GMP system (hireinafter referred to as records) is required. But actually multiple GMP records are stored and the location and existence of GMP records were not completely understood. It is unclear whether the retention control of those records are assured for required retention period, and there was a possibility of loosing necessary quality assurance data or critical technical information. 受检现场说明，用于●仓库的●号房间不存放需纳入 GMP 体系管控的文件与记录（以下简称“记录”）。但实际该房间存放了多份 GMP 记录，且 GMP 记录的存放位置与留存状态均未完全掌握。无法确认上述记录是否按规定保存期限实施管控，存在质量保障所需数据或重要技术资料丢失的风险。

Actually there were following events of missing records or records with high probability of missing, even those are within the required retention period. (Violation of Artucle 20 paragraph 1-3 of GMP ministerial ordinance) 事实上，即便在规定保存期限内，已发生以下记录缺失或极有可能缺失的情况。（违反 GMP 省令第 20 条第 1～3 项规定）

Check the control status of GMP records used throughout all the GMP related operations in this site, whether there is other document which is not retained for required period. After that, root cause of the deficiency should be investigated and implement corrective actions. 应对该现场所有 GMP 相关操作所用 GMP 记录的管控情况进行核查，确认是否存在其他未按规定期限保存的文件。核查完成后，应对该缺陷开展根本原因调查并落实纠正措施。

(1) Record of trainig carried out ●month ●day ●year is missing at the time of inspection. Regarding the periodical training for all the personnel in this site, training records in the manufacturing unit were retained, but the training records in the quality unit were not retained.检查时发现，●年●月●日开展的培训记录缺失。针对该现场全体人员的定期培训，生产部门的培训记录已留存，但质量部门的培训记录未留存。

(2) Monitoring by sedimentation test was carried out in ●as an investigation for a complaint. There was a description indicating the existence of an attachment describing the monitoring locations for the sedimentation test, in the note column of ●for this monitoring, but the attachment was missing at the time of inspection.. 为开展某投诉调查，在●区域开展了沉降法监测工作。该项监测的●备注栏中记载有沉降试验监测点位相关附件，但检查时该附件已缺失。

2. Following deficiencies were observed regarding failure to the reliability of records. Additional deficiencies in records were observed as described in other deficiencies 1 and 8. In addition, the inspected site did not assign the responsible person ensuring reliability of records, as defined in Article 20 paragraph 2 of GMP ministerial ordinance. (Violation of Article 20 paragraph 2 of GMP ministerial ordinance)经查，存在记录可靠性失效的相关缺陷，其他缺陷项 1 和 8 中亦发现额外的记录类缺陷。此外，受检现场未按照 GMP 省令第 20 条第 2 项规定指定确保记录可靠性的责任人。（违反 GMP 省令第 20 条第 2 项规定）

(1) An incomplete batch manufacturing instruction and record of ●tablet ●(Lot No.: ●) was retained in a personal letter case of ●. On the other hand, official batch record of this lot was separately kept. As the result of comparison of those two records, discrepancies in the time of start of operation, weight of intermediate product after ●process, and yield of this process.●片●（批号：●）的不完整批生产指令及记录存放在●的个人文件柜中，而该批次的正式批记录另行存放。对两份记录比对后发现：操作开始时间、●工序后中间产品重量及该工序收率均存在不一致。

(2) Manufacturing records of multiple lots of ●granule recorded the weighed amount of active ingredient ●as ●kg for all the lots. The site personnel explained that they compare the amount indicated in the instruction and the reading of the weighing balance, and confirm there is no significant difference, then record as ●kg for all of them. This practice indicate that they don’t record accurate reading of weighing balance and there is a possibility that the weighed amount of active ingredient do not reflect the amount of marketing authorization. 多批次●颗粒的生产记录中，活性成分●的称量值全部统一记录为●kg。现场人员解释称：其仅比对规程规定量与天平读数，确认无显著差异后，即统一记录为●kg。该做法表明其未记录天平真实读数，存在活性成分实际称量值未反映上市许可载明量的风险。

(3) Cleaning of ●room after completion of manufacturing of ●tablet ●(Lot No.: ●) was on-going, but the hygine control record was already recorded that the cleaning was completed and the signature of confirmation was done.●片●（批号：●）生产结束后，●房间的清洁工作仍在进行中，但卫生管控记录已预先填写清洁完成并签署确认签名。

(4) The dissolution test of the sample of ●th year in the stability monitoring of ●granule ●(Lot No.: ●) was not completed at the time of inspection, but the report of product quality review (hereinafter referred to as APQR) descrubed results of all the test including dissolution test and concluded that all the test results were within the specifications.●颗粒●（批号：●）稳定性监测中第●年样品的溶出度试验在检查时尚未完成，但 ** 产品质量回顾报告（APQR）** 中已记载包含溶出度试验在内的全部检测结果，并判定所有结果均符合标准。

Taking those situations into consideration, and in accordance with the provision of Article 20 paragraph 2, take necessary actions to assure the reliability of records. In taking the actions, at least following points should be included:鉴于上述情况，须依据 GMP 省令第 20 条第 2 项规定，采取必要措施确保记录可靠性，措施至少包含以下内容：

a. Assign a personnel who has an enough knowledge for assurance of reliability as the responsible person, and define the duties and responsibilities of such person in the document defined in Article 6 paragraph 4 of GMP ministerial ordinance.指定具备充足记录可靠性保障知识的人员作为责任人，并在 GMP 省令第 6 条第 4 项规定的文件中明确其职责与权限。

b. Confirm whether similar deficiencies in the recording practices, and if such event is confirmed, investigate the root cause, evaluate tie impact and implement adequate CAPA. 排查是否存在同类记录填写缺陷，若确认存在，应开展根本原因调查、评估影响，并落实充分的纠正和预防措施（CAPA）。

1. Following events were observed related to reliability of records, including the cases of recording different information from the facts, or cases of absence of required record (Violation of Article 20 paragraph 2 of GMP ministerial ordinance)经查，发现多起涉及记录可靠性的问题，包括记录内容与实际情况不符、应记录内容未记录等情形。（违反 GMP 省令第 20 条第 2 项规定）

In addition, other deficiencies related to the reliability of reords were observed, as indicated by other deficiencies 1(2), 1 (3), 3, 9, 11, 12 and 15 (1).此外，如其他缺陷项 1 (2)、1 (3)、3、9、11、12 及 15 (1) 所述，本次检查还发现其他与记录可靠性相关的缺陷。

(1) In the cleaning record of each work room within clean area on the date of inspection, ●day ●month ●year, the check boxesof ●which indicate those rooms were cleaned were checked. The cleaning record indicated a cleaning method which uses drinking water, purified water and 75% ethanol as sanitizer. But preparation record of the ethanol sanitizer could not found. The operator explained that they did not use ethanol during cleaning, and a record different from the actual operation was recorded.检查当日（●年●月●日）洁净区各操作间的清洁记录中，标示对应房间已完成清洁的●勾选框均已勾选。清洁记录记载的清洁方式为使用饮用水、纯化水及 75% 乙醇作为消毒剂，但乙醇消毒剂配制记录无法查到。操作人员自述清洁过程中未使用乙醇，该记录与实际操作不符。

(2) There was a record in ●(●day ●month ●year) that 75% ethanol was prepared by diluting 95% ethanol with water. The procedure for preparation of this sanitizing solution defined to use 95% ethanol. But this site did not purchase 95% ethanol since ●year, instead, purchased absolute ethanol. According to the explanation by this site, they recorded that 95% ethanol was used according to the instruction by the procedure instead of actually used absolute ethanol. The record shown to the inspector described different record from the actual operation,（●年●月●日）的记录显示，系将 95% 乙醇加水稀释配制成 75% 乙醇。该消毒剂配制规程规定使用 95% 乙醇，但该现场自●年起未采购 95% 乙醇，实际采购使用的为无水乙醇。据现场人员解释，其未按实际使用的无水乙醇记录，而是按规程要求虚假填写使用了 95% 乙醇，向检查人员出示的记录与实际操作不符。

(3) The procedure defined that the equipment used in the clean area should be sanitized before and after using for manufacturing operation. But from ●month ●year up to the the time of current inspection, the available preparation records for sanitizing agent for equipment were only those descrubed in the above (2), and this suggest that the preparation records of sanitizer for equipment did not adequately recorded for about a half year. In addition, the status label for ●vessel used for ●described date and time of cleaning, but a record to be recorded at the time of cleaning was not prepared.规程规定，洁净区内使用的生产设备应在生产操作前后进行消毒。但自●年●月起至本次检查时，设备消毒剂的有效配制记录仅上述 (2) 中所述内容，表明近半年内设备消毒剂配制记录未完整填写。此外，用于●的●容器状态标识中标注了清洁日期与时间，但未建立清洁操作时应同步填写的对应记录。

(4) During inspection on ●day ●month ●year, a training record titled as ●was stored in the office room of manufacturing unit. The columns of lecturer, date of training, items for training, method of training, method of evaluation of training efficacy, were not filled but the column of recording trainee described that ●trainees were participated among ●candidates and there were signatures of the participants. The lecturer of this training explained that the training was done on ●day ●month ●year, but there was no supporting evidence to confirm this.●年●月●日检查时，生产部门办公室内存放一份题为《●》的培训记录。该记录中讲师、培训日期、培训项目、培训方式、培训效果评估方式等栏目均为空白，但参训人员栏记载●名候选人中●人参训，且有参训人员签名。该培训讲师称培训于●年●月●日开展，但无相关佐证材料可证实。

Following actions should be taken to remediate the above deficiencies.须采取以下措施整改上述缺陷：

a. Investigate the root cause of continued practice of preparing records that are different from the actual operation, necessary records were not prepared and this situation was not detected by the responsible personnel, and the recoreds were not done contemporaneously.针对持续存在记录与实际操作不符、应建记录未建立、该问题未被责任人发现、记录未同步填写等情况，开展根本原因调查；

b. Check existence of similar deficiencies in other operations.排查其他操作环节是否存在同类缺陷；

c. Based on the results of above a. and b., impact of identified defficiencies to the product quality should be evaluated.根据上述 a、b 项调查结果，评估已发现缺陷对产品质量的影响。

d. Based on the results of above a. and b., establish short term, middle term and long term remediation plan to assure reliability of records, and take adequate corrective actions according to such plan.基于上述 a、b 项结果，制定短期、中期及长期整改方案以保障记录可靠性，并按方案落实充分的纠正措施。

The documents and records related to the inspected product need to be retained for the duration of the shelf life plus 30 years, in accordance with Article 30, Item 1 of the GMP Ministerial Ordinance. The Manufacturing Site specified the retention period for these documents and records as X years as a general rule. On the other hand, the retention period of temperature records was established separately. The retention period for the temperature records of the storage cabinet X was specified as X years, while the retention period for all other temperature records was uniformly specified to be X years. These records were discarded after the retention period expired. Review and revise the the written procedures to ensure that the temperature records of the inspected product are retained for the period specified in the GMP Ministerial Ordinance.根据GMP省令第30条第1项的规定，与检查产品相关的文件和记录需要保留至产品保质期结束后的30年。制造地点通常规定这些文件和记录的保留期限为X年。另一方面，温度记录的保留期限是单独设定的。存储柜X的温度记录的保留期限被指定为X年，而所有其他温度记录的保留期限则统一规定为X年。这些记录在保留期限结束后被丢弃。审查并修订书面程序，确保检查产品的温度记录按照GMP省令规定的期限进行保留。

The document retention and management procedures required the production batch records of products for the Japanese market (records of X, X, X, and X) to be retained for the longer of the product shelf life plus 1 year or 5 years. However, the inspection found that a wide range of records had been discarded, including X records of QC, X records of X of X, and usage records of X and X. Ensure that all necessary documents and records are retained for the required period as specified in Article 20 of the GMP Ministerial Ordinance.文件保存和管理程序要求为日本市场生产的产品批次记录（X、X、X和X的记录）保留至产品保质期加1年或5年中较长的一个期限。然而，检查发现，包括QC的X记录、X的X记录、X和X的使用记录在内的大量记录已被丢弃。确保所有必要的文件和记录按照GMP法令第20条的规定保留所需的期限。

2. Reconciliation and related records of working standards used for product release test, including use date, used amount are not recorded. (Violation of Article 11 paragraph 1-2 of GMP ministerial ordinance)用于产品放行测试的工作标准的核对及相关记录，包括使用日期、使用量未被记录。(违反GMP省令第11条第1-2款)

Control procedure for analytical standards should be established to make possible to trace back that adequate standards are used for laboratory tests, and record the reconciliation according to such procedure.应建立分析标准的控制程序，以便能够追溯实验室测试中使用了适当的标凈，并根据该程序记录核对。

2. Storage and reconciliation of the starting material are controlled and recorded using a manufacturing control system. But the reconciliation of raw material ●described as the active ingredient in the marketing authorization dossier and the materials used in the manufacture are not recorded. (Violation of Article 10 paragraph 6 of GMP ministerial ordinance)To be able to trace that adequate raw materials and packaging materials are used for manufacture, establish a control procedure of them, and record of reconciliation of those materials.2. 使用制造控制系统控制和记录起始物料的存储和核对。但是，营销授权档案中描述为活性成分的原材料●和在制造过程中使用的材料的核对未被记录。(违反GMP省令第10条第6款)为了能够追踪到生产过程中使用了足够的原材料和包装材料，应建立对它们的控制程序，并记录这些材料的核对。

We checked a copy of a manufacturing record for ●(Lot: ●) submitted on ●day ●month ●year prior to the inspection, and calcucrated the actual loading amount of water in the ●process from the recorded amount of the flow meter and obtained the result of ●kg which exceeded ●kg to the instructed ●kg. On the other hand, when we checked the original record in the manufacturing site during inspection, the record of flow meter was revised to align with the instructed amount of ●kg on ●day ●month ●year. As the result of checking adequacy of this record, multiple deficiencies having an impact to the reliability of records were observed as follows; (Violation of Article 20 paragraph 2 of GMP ministerial ordinance)我们核查了检查前 **●年●月●日提交的●（批号：●）生产记录复印件，根据记录的流量计数值计算●工序的实际加水量，结果为●kg**，较规程规定的 **●kg超出●kg**。而本次现场检查中核查该生产记录原件时发现，流量计记录已于 **●年●月●日被修改，与规程规定的●kg保持一致。经对该记录合规性核查，发现多项影响记录可靠性 ** 的缺陷，具体如下：（违反 GMP 省令第 20 条第 2 项规定）

(1) When we requested an explanation for the discrepancy between the copy of a manufacturing rocord submitted as pre inspection documents and the original record, the inspected site acknowleged the back dated revision of the record.当要求对预提交的生产记录复印件与原件之间的差异进行说明时，受检现场承认对记录进行了倒签修改。

(2) A QA personnel in charge of document storage found the discrepancy between the instructed loading amount of ●and the actually loaded amount early in ●month ●year and reported to the manufacturing manager. The manufacturing manager interviewed the operator involved in the process at the time of the event, and speculated that the excess loading may result in decreased product yield. The manufacturing manager judged that the actually loaded amount was correct and instructed to revise the record. But there was no record of the interview and the instruction to revise the record by the manufacturing manager. Investigation of the root cause of incorrect record and CAPA for such event were not done. They explained that the record of flow meter was revised by reverse calculation to make the loaded amount of ●as ●kg, but the objective evidence to prove absence of the over loading of ●kg, and correct loading of ●kg was not shown. QA 文件保管负责人已于 **●年●月上旬发现●规程加水量与实际加水量存在差异 **，并向生产部经理汇报。生产部经理对事发时该工序操作人员进行了问询，推测过量加料可能导致产品收率下降；生产部经理判定实际加料量正确，并指令修改记录，但无问询记录及生产部经理下达修改指令的记录。未对该错误记录开展根本原因调查，亦未针对该事件实施 CAPA。现场解释称，流量计记录系通过倒推计算修改为●kg 加水量，但未提供可证明未发生●kg 过量加料、实际准确加入●kg 的客观证据。

(3) The personnel in charge of document storage in QA unit acknowleged that when the revised manufacturing record was returned from the manufacturin unit, the person stored the record without confirming adequacy of the revision.QA 部门文件保管负责人承认：生产部门交回修改后的生产记录时，其未确认修改的合规性即予以归档保存。

(4) As the result of reviewing record for data integrity (hereinafter referrd to as DI) training, such training was done only to the managers and super visors of each unit and there was no record of DI training to the operators, and it is unclear that adequate DI training was done.经核查 ** 数据完整性（以下简称 DI）** 培训记录，此类培训仅针对各部门经理及主管开展，无操作人员的 DI 培训记录，无法确认已对操作人员实施充分的数据完整性培训。

Taking the above situation into consideration, necessary actions to ensure reliability of records should be taken in accordance with the requirement of Article 20 paragraph 2 of GMP ministerial ordinance. Please note that at least following information should be included to the corrective action report;鉴于上述情况，须依据 GMP 省令第 20 条第 2 项规定，采取确保记录可靠性的必要措施。请注意，纠正措施报告中至少应包含以下内容：

1) Root cause of the situation in which the date of revision of record have to be back dated, and CAPA for the situation.记录被倒签修改的根本原因调查及对应 CAPA；

2) Root cause investigation for the incorrect recording, and root cause of the situation that CAPA was not implemented for the incorrect recording.错误记录的根本原因调查，以及未针对该错误记录实施 CAPA 的根本原因调查；

3) Root cause investigation for the incorrect recording, and CAPA for the situation that CAPA was not implemented for the incorrect recording. 错误记录的根本原因调查，以及未针对该错误记录实施 CAPA 的根本原因调查；

4) Root cause investigation for the failure of QA unit to detect back dated correction of record by manufacturing unit, and CAPA was not implemented for such situation.QA 部门未能发现生产部门倒签修改记录、且未针对该情况实施 CAPA 的根本原因调查及对应 CAPA；

5) Result of checking of existence of similar deficiencies throughout the inspected site, or detailed plan to do such check. (Including the record to be reviewed, the time period in which reviewed records were prepared, explanation of adequacy of review method, etc.)）对受检现场全范围同类缺陷的排查结果，或详细排查方案（含需审核的记录、记录覆盖的时间段、审核方法的合理性说明等）；

6) Carry out DI training to all the personnel involved in record preparation or reviwing, and submit the record for such training.对所有参与记录填写及审核的人员开展数据完整性培训，并提交培训记录；

7) Objective evidence supporting the explanation that the over loading of ●kg was actually not done and ●kg was exactly loaded.支持“实际未发生●kg 过量加料、准确加入●kg” 这一说明的客观证据；

8) Evaluation of impact to the product quality, if the over loading of ●kg was actually occurred.若实际发生●kg 过量加料，对产品质量的影响评估；

Wheter there is an existing supporting data or not, to the explanation of lowered product yield if the loading amount of ●exceed the instructed amount. (If yes, submit the data.)针对“若●加料量超出规程规定量会导致产品收率下降” 的说明，是否存在支持性数据（如有，请提交该数据）。

1. The inspected site did not establish a document corresponding to the manufacturing instruction required in GMP ministerial ordinance. In addition, the manufacturing record did not describe instructions in the manufacturing process, and special notes and precautions to be followed. (Violation of Article 10-1 of GMP ministerial ordinance) For example, following instructions were not described in the master batch record. Batch manufacturing instruction or master batch manufacturing instruction and record describing necessary instructions and other necessary items should be established and carry out manufacturing operations according to such document.受检现场未制定与 GMP 省令中要求的生产工艺规程相对应的文件。此外，生产记录中未记载生产过程的操作指令，以及应遵守的专项说明和注意事项。（违反 GMP 省令 第 10 条之 1 规定）例如，总批记录中未记载以下操作指令。应制定包含必需操作指令及其他必要内容的批生产规程或总批生产规程与记录，并严格按照该类文件执行生产操作。

(1) Carry out re-●in the ●process.●工序应进行的再●操作要求

(2) Calculation method of ●to be added in the ●process, ●to be added in the ●filtration process, ●to be added in the ●process.) ●工序中需加入的●的计算方法、●过滤工序中需加入的●、●工序中需加入的●

(3) Stirring method to make the mixture uniform after addition of ●in the ●filtration process.●过滤工序中加入●后，使混合物料均匀的搅拌方式

(4) Filtration pressure in the ●filtration process.●过滤工序的过滤压力

(5) Duration of concentration by filtration of ●.●过滤浓缩的时长

(6) Conditions of stirring and stand still after addition of ●in the ●process.●工序中加入●后的搅拌与静置条件

(7) Loading pattern of ●containing trays in the lyophylizer.冻干机内装载含●托盘的方式