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FDA 483表:浙江华海(报告原文长达11页)

蒲公英2019-01-20 06:04:14

 翻译:JULIA 来源:Julia法规翻译


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受检公司:Zhejiang Huahai Pharmaceutical Co., Ltd.

受检地址:Coastal Industrial Zone, Chuannan No.1 Branch, Linhai, Zhejiang Province 317016 China

受检身份:生产商

FEI号:3003885745

检查员:CherylClausen/Investigator, Joel Hustedt/Investigator

检查日期:2018-07-23 2018-07-282018-07-30 2018-08-03

签发日期:2018-08-03

发布日期:2018-09-20

 

This document listsobservations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations. And do not represent a final agency determination regarding your compliance if you have an objection regarding an observation, or have implemented, or plan to implement corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA to address above. If you have any questions, please contact FDA at the phone number and address above.

本文件列出了FDA代表在对你工厂检查期间所发现的问题。这些只是检查发现,并不代表FDA对你公司合规性的最终结论。如你们对某一缺陷有异议,或已实施或计划实施纠正措施来纠正某个缺陷,你们在检查期间与FDA代表讨论你们的异议与措施,或通过上述地址向FDA提交资料。如有问题,请通过上述地址电话与FDA取得联系。

 

DURING AN INSPECTIONOF YOUR FIRM WE OBSERVED: 检查你公司期间我们发现

QUALITY SYSTEM 质量体系

OBSERVATION 1 缺陷 1

The change control system to evaluate all changes that may affect the production and control of intermediates or Active Pharmaceutical Ingredients (APIs) is not adequate. Specifically,  评估所有可能影响原料药或中间体的生产和控制的变更控制系统不充分。具体来说

a)     You do not always conduct a formal risk assessment for critical changes to evaluate the potential impact of proposed changes on the quality of intermediates or APIs. Critical Change Request PCRC-11025 was initiated November 27, 2011 and closed November 29, 2011, for the stated purpose of making changes to the (b)(4) manufacturing process to (b)(4) the current (b)(4) ((b)(4)%- (b)(4)%) of the known isomer impurity (b)(4) in the final API and (b)(4) batch yields (current batch yield (b)(4)- (b)(4) per batch).你们未能对关键变更全部执行正式风险评估,以评价所拟变更对中间体API的潜在影响。关键变更申请PCRC-1102520111127启动,于20111129关闭。该变更声称其目的是对XX生产工艺进行变更使得API成品已知异构体杂质XXXXXX%-XX%),并且收率变更为XX(当前收率为XX-XX每批)。

      i)    You did not conduct and document a formal risk assessment for Change Request PCRC-11025 to evaluate the potential impact of proposed changes on the quality of the intermediates or the final API for this critical change to your validated manufacturing process prior to your quality unit approving the change.你们未对变更申请PCRC-11025执行正式风险评估并记录,以在质量部门批准该变更之前评价所拟的对你们已验证工艺的关键变更对中间体或API成品的潜在影响。

      ii)    You hired an outside laboratory to conduct a small labscale research project. Based on the results of a lab scale research project your initiated validation on a commercial scale to change your validated manufacturing process without conducting pilot scale or other small scale batches. Your Deputy Director of Manufacturing stated you have commercial experience and since you only change the (b)(4) there was no need to conduct pilot scale trial batches before instituting critical changes on a commercial scale. 你们聘用外部实验室进行小规模实验室研究项目。基于实验室规模研究项目结果,你们启动了商业规模的验证来变更你们已验证的生产工艺,而未进行中试规模或其它小型批次生产。你们的生产副总声称你们具有商业化经验,并且因为你们只是改变了XX,所以在对商业规模进行关键变更之前不需要进行中试试验。

You initiated validation on a commercial scale without conducting a formal risk assessment to evaluate the potential impact of changes to your validated manufacturing process on the quality of intermediates and APIs. You do not have a quality agreement with the outside laboratory you used to perform a lab scale research project requiring (prior to initiating testing and reporting results): qualification of all instruments used to conduct tests; validation of all software used with qualified instruments to conduct tests; calibration of all applicable measurement devices against traceable standards prior to use; use of official standards as appropriate; if applicable, establishing system suitability prior to testing samples and processing data; and validation of all test methods used for testing. 你们未执行正式风险评估评价改变你们已验证生产工艺对中间体和API质量的潜在影响就启动了商业规模验证。你们与你们用来执行实验室规模研究项目的外部实验室没有签订质量协议要求他们(在启动检测和报告结果之前):确认所有检测用仪器、验证所有确认检测用仪器的软件、使用前采用可追溯标准校正所有使用的测量仪器仪表、使用官方标准(适当时),以及(适当明)在检测样品和处理数据之前确定系统适用性,以及验证所有检测用方法。

b)   You do not have an adequate change control system requiring scientific judgement to determine what additional testing and validation studies are appropriate to justify changes to a validated manufacturing process. You do not always have data to support approval of changes to validated processes. 你们变更控制系统不充分,未要求进行科学判定以确定需要哪些附加检测和验证研究来论证对验证过的生产工艺的变更。你们不是每次都有数据来支持对验证过的工艺的变更批准。

      i)    You did not identify specific parameters and specify acceptance criteria for those parameters prior to implementing changes, as part of critical Change Request PCRC-11025, to use to evaluate if the implemented changes (b)(4) the isomer (b)(4) of (b)(4) and (b)(4) the batch yield. 你们未在实施(作为关键变更申请PCRC-11025的一部分)变更之前识别特定的工艺参数及其可接受标准,使用这些标准评估所实施的变更XX能达成异构体XX以及收率XX

     ii)    Additional testing requirements associated with critical changes are not always based on sound scientific judgement. Change Request PCRC-11025 included changing (b)(4) in your validated manufacturing process. Additional testing requirements associated with these changes were limited to three validation batches and a commitment to conduct additional testing on (b)(4) batches a (b)(4). 与关键变更有关的附加测试要求并不都是基于科学合理的判定。变更申请PCRC-11025包括有更改你们验证过的生产工艺中的XX。对这些变更相关的附加测试要求仅限于3个验证批次,以及承诺会对XX批次执行附加检测的声明。

c)     You do not have an adequate classification procedure for determining the level of testing, validation, and documentation needed to justify changes to a validated process. You do not consistently classify changes. You do not always increase testing, validation, and the documentation required to justify changes to a validated process based on the classification of a proposed change. Amendment to Drug Master File (b)(4) USP (Process (b)(4)) DMF #(b)(4) dated December 10, 2013 indicates the amendment was submitted for minor changes for drug substance manufacturing. Amendment to Drug Master File(b)(4) USP (Process (b)(4)) DMF#(b)(4) contradicts your internal Change Request PCRC-11025 which lists change control classification as critical change. 你们没有充分的分级程序来确定已验证工艺的变更进行论证时所需的检测、验证和文件程度。你们对变更的分级不一致。你们并不是每次都根据所拟变更的分级来增加所需检测、验证和文件以论证对已验证工艺的变更。对DMFXX USP 的修订(工艺XX DMF#XX,日期20131210显示修订是作为原料药生产的轻微变更提交的。对DMFXXUSP(工艺XXDMF#XX的修订与你们内部变更申请PCRC-11025是矛盾的,你们内部变更控制将该变更分级为关键变更。

d)    Written change control procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labeling and packaging materials, and computer software. Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality unit. Your quality unit does not always follow your written procedure for change control. Your written procedure Change Control System SMP-018.05 effective December 30, 2017 section 5.3.6(3) specifies QA shall reject the change if the action cannot meet predetermined expectations. Critical Change Request PCRC-11025 did not include acceptance criteria with predetermined expectations. (b)(4) Product Development Report-01 dated April 13, 2012 Table 8 includes (b)(4) isomer impurity (specification <(b)(4)%) from three batches manufactured according to the validated manufacturing process (results range from (b)(4)%- (b)(4)%) and Table10 includes (b)(4) isomer impurity from the three validation batches manufactured using a different (b)(4) (results range from (b)(4)%- (b)(4)%). The product development report is silent regarding evaluation of the ability of the implemented changes to (b)(4) isomer (b)(4). (b)(4) Product Development Report-01 did not compare the batch weights from batches manufactured immediately before the change to the validated manufacturing process and the first batches manufactured after implementing changes to the manufacturing process. 书面变更控制程序应为原料、质量标准、分析方法、设施、支持系统、设备(包括计算机硬件)、工艺步骤、标签和包材以及计算机软件变更提供识别、文件化、适当审核和批准。所有对GMP相关变更的提议均应由适当的公司部门起草、审核和批准,并经过质量部门审核和批准。你们的质量部门不能每次都遵守你们的书面变更控制程序。你们的书面程序变更控制系统SMP-018.05生效日期201712305.3.63)部分指明如果行动不能达成既定的预期则应拒绝变更。关键变更申报PCRC-11025并未包括有预期接受标准。XX产品研发报告-01日期201204138包括有根据已验证生产工艺生产的3批的XX异构杂质(质量标准<XX%)(结果为XX%-XX%),表10包括有使用不同XX生产的3个验证批次的XX异构杂质(结果在XX%-XX%)。该产品研发报告对变更后XX异构的降低能力并未进行评估。XX产品研发报告-01并未比较变更前后所生产批次的批重量。

OBSERVATION 2 缺陷 2

Validation of production processes, cleaning procedures, analytical methods, and in-process control test procedures are not always adequate. Specifically,  生产工艺、清洁程序、分析方法和中间控制检测方法的验证不完全充分。具体来说

a)    Your manufacturing processes are not always capable of consistently producing final products meeting all product quality specifications. Deviation No. DCB18-17017 was initiated for OOS genotoxic impurity (b)(4) ppm (specification<(b)(4)ppm) in (b)(4) batch (b)(4). Repeat test results included OOS results. As a corrective action you reprocessed (b)(4) batch (b)(4) by (b)(4) the (b)(4) step in your manufacturing process. You did not investigate corrective actions to your manufacturing process or to the manufacturing batch record to improve product consistency and manufacturing reproducibility, and to reduce the level of (b)(4) in the (b)(4) intermediate crude. You did notdevelop a prevent action plan to prevent future OOS (b)(4) levels in the intermediate crude and final API. 你们的生产工艺没有能力保持持续生产出符合所有产品质量标准的成品。偏差编号DCB18-17017由于XX产品XX批号中OOS基因毒性杂质XXppm结果启动(标准<XXppm)。重复检测结果包括有OOS结果。作为纠正措施你们对XX批号采用你们生产工艺中的XX步骤进行了返工。你们并未调查生产工艺或生产批记录的纠正措施以改进产品一致性和生产可重复性,降低XX中间体粗品中的XX水平。你们并未制订预防措施计划来防止未来该中间体粗品和API成品中OOSXX水平。

Between December 16, 2016 and August 22, 2017 you initiated 17 OOS investigations for (b)(4) impurity in (b)(4). Of the 17 OOS investigations initiated for (b)(4) impurity in (b)(4) you attributed 13 OOS results to lab related errors, 5 OOS results to production errors, and 2 OOS results to a combination of lab and production errors. You reprocessed all 17(b)(4) batches you investigated for OOS (b)(4) impurity.20161216-20170822期间,你们启动了17XXXX杂质的OOS调查。在这17OOS调查中,你们将13OOS结果归因于化验室相关错误,5OOS结果归因于生产错误,2OOS结果归因于化验室与生产共同错误。你们将所有这17XX杂质OOS调查的产品进行了返工。

b)    Written validation protocols are not always adequate. 有的书面验证方案不充分。

      i)    Your process Validation Protocol for (b)(4) process(b)(4) Workshop (b)(4) CNVP-11-075 and Process Validation Protocol for Crude(b)(4) Step (b)(4) PVC-18012(P) do not include the specific parameters with acceptance criteria to establish your manufacturing process is not only consistent and reproducible but able to fulfill the purpose for changing your validated manufacturing process. 你们的XX车间XX工艺的工艺验证方案XXCNVP-11-075XX粗品XX步骤工艺验证方案PVC-18012(P)未包括特定的工艺参数及其可接受标准用以建立你们的生产工艺不仅一致可重复而且能达成改变你们已验证生产工艺的目的。

      ii)    Neither Process Validation Protocol for (b)(4) Process (b)(4) Workshop (b)(4) CNVP-11-075 nor Process Validation Protocol for Crude (b)(4) Step (b)(4) PVC-18012 (P) specified the number of manufacturing batches to be manufactured as part of validation of your manufacturing process or discussed the number of validation batches to manufacture based on the complexity of the process or the magnitude of the process change. XX车间XX工艺的工艺验证方案XXCNVP-11-075XX粗品XX步骤的工艺验证方案PVC-18012P)均未指明要生产的批数,将其作为你们生产工艺验证的一部,亦未根据工艺复杂性或工艺变更严重性讨论要生产的验证批数。

     iii)    Neither Process Validation Protocol for (b)(4) Process (b)(4) Workshop CNVP-11-075 nor Process Validation Protocol for Crude (b)(4) Step (b)(4) PVC-18012(P) included a sampling plan designed to demonstrate the consistency and reproducibility of your manufacturing process through batch uniformity data. XX车间XX工艺的工艺验证方案XXCNVP-11-075XX粗品XX步骤的工艺验证方案PVC-18012P)均未包括设计用以通过批均匀性数据证明你们生产工艺的一致性和可重复性的取样计划。

c)     You do not always initiate investigations during process validation. (b)(4) process validation batch (b)(4) test results for Diastereo-isomer (b)(4)% ( specification <(b)(4)%) were OOT (Out-of-Trend) compared to the other (b)(4) validation batches with Diasterio-isomer results ranging from (b)(4)% to (b)(4)%. You did not initiate an investigation to identify the CPP (s) (Critical Process Parameter), non-critical process parameter(s), raw material(s), or other influences which could impact Diastereo-isomer results in an effort to improve the quality and consistency of(b)(4) (the product from the (b)(4) synthesis step in the manufacture of (b)(4)). 你们在工艺验证时不是每次都启动调查。XX工艺验证批次XX的非对映异构体XX检测结果为XX%(标准<XX%),相比其它XX验证批非对映异构体(结果为XX%-XX%))为OOT结果(超趋势)。你们并未启动调查来识别CPP(关键工艺参数)、非关键工艺参数、原料药或其它可能影响非对映异构结果的因素以努力提高质量和XXXX生产中XX合成步骤的产品)一致性。

d)   You do not have sufficient data to demonstrate your in-house test methods, used for Assay and Related Substance testing of (b)(4) are at least equivalent to USP Monograph test methods. (b)(4) USP Method and In-house Method Qualification Comparison Research Report VLDor-10-099(R) version 2 effective August 29, 2014 does not include data showing you tested known concentrations of (b)(4) and spiked (b)(4) samples and then compared the results from your in-house test method with results from tested known concentrations of (b)(4) and spiked (b)(4) samples using the USP method to verify your in-house test results at least meet the acceptance criteria of the USP methods. 你们没有足够的数据证明你们用于XX产品的含量和有关物质检测的内控检测方法至少等同于USP各论检测方法。XXUSP检测方法和内控检测方法确认对比研究报告VLDor-10-099R)版本2生效日期20140829并不包括数据显示你们使用内控方法检测的已知浓度XX与加标XX样品,与采用USP方法检测已知浓度XX和加标样品所得结果进行比较,确认你们内控检测方法至少符合USP方法的可接受标准。

e)     You do not have validated cleaning procedures. Cleaning procedures for (b)(4)-203-1 and (b)(4) 204-3 in workshop (b)(4) used in the manufacture of crude (b)(4) are not validated in that you do not have data to demonstrate the cleaning procedure is effective following manufacture of (b)(4) consecutive batches. The most recent cleaning validation study, CVD-18015(R), approved in July 2018, is based on (b)(4) consecutive batches. The 2016 equipment use log for (b)(4)-203-1 shows (b)(4) consecutive batches were manufactured before cleaning. Your Quality Assurance Director verbally confirmed no rinse samples were analyzed following either of these cleanings. 你们的清洁方法未经验证。XX车间XX粗品生产所用XX-203-1XX204-3的清洁程序未经过验证,你们没有数据证明在连续XX批次生产之后的清洁程序是有效的。最近的清洁验证研究CVD-18015R)批准日期201807,是基于XX个连续批次。2016年设备XX-203-1使用日志显示在清洁之前连续生产了XX批。你们的QA总监口头确认说在这些清洁之后并没有检测淋洗样品。

OBSERVATION 3 缺陷 3

The system for managing quality to ensure confidence that the API will meet its intended specification for quality and purity is not adequate in that your quality unit lacks written procedures and the authority and responsibility to ensure all critical deviations are thoroughly investigated. Specifically,  管理质量以确保API符合其既定质量标准中质量和纯度可信度的体系不充分,因你们质量部门缺少书面程序和权力及职责确保彻底调查所有关键偏差。具体来说

a)     You released finished APIs manufactured from crude intermediates with OOS levels of genotoxic impurities without conducting a thorough investigation. Deviation No. DCB18017025 initiated December 13, 2017 and closed April 16, 2018 was initiated for OOS (b)(4) impurity (b)(4) ppm (specification <(b)(4) ppm) in (b)(4) batch (b)(4). You identified the root cause as an equipment failure which impacted intermediate crude (b)(4) batch (b)(4) during (b)(4). You reprocess (b)(4) batch (b)(4) Intermediate crude(b)(4) batch (b)(4) was also used in (b)(4) API final batch (b)(4). You did not reprocess batch (b)(4) made from OOS intermediate crude (b)(4) batch (b)(4). You did not open an investigation, or conduct additional testing on batch (b)(4). Your QA Director stated batch (b)(4) met the product release specification for Related Substance (b)(4). 你们放行了使用OOS水平基因毒性杂质的中间体粗品所生产的API成品,而未进行彻底调查。偏差DCB1801702520171213启动,20180416关闭,启动原因是XX产品XX批号XX杂质OOS结果XXppm(标准<XXppm)。你们识别根本原因为设备故障影响了XXXX产品XX批号的中间体粗品。你们将XXXX中间体粗品返工,然后用于XXAPI成品的生产。你们并未返工采用OOS中间体粗品XX批次生产的XX批号。你们未启动调查,或对XX批次进行附加检测。你们的QA总监声称批次XX的有关物质XX符合产品放行标准。

b)   Major Deviation DD (b)(4) 17003 was initiated August 2, 2017 and closed September 11, 2017 for (b)(4) batch (b)(4) and (b)(4) with OOS results for unknown impurity (specification<(b)(4)%). You confirmed OOS results for (b)(4) batches (b)(4) single unknown impurity (b)(4)%, and (b)(4) single unknown impurity (b)(4)%. 主要偏差DD XX 1700320170802启动,于20170911关闭,启动原因是XX批和XX批未知杂质OOS结果(标准<XX%)。你们确认了XXXX单个未知杂质OOS结果XX%,以及XX单个未知杂质XX%

       i.    You did not identify a root cause for the single unknown impurity results in batches (b)(4) and (b)(4). You stated the root cause was probably due to occasional fluctuation in your manufacturing process. You did not attempt to identify this single unknown impurity. You did not attempt to identify the source of fluctuations in your manufacturing process for (b)(4). 你们未识别出XX批次和XX批次中单个未知杂质结果超标的根本原因。你们声称根本原因可能是你们生产工艺的偶然波动。你们并未试图识别此单个未知杂质。你们并未试图找出你们XX生产工艺波动的来源。

      ii.    You did not develop an adequate Corrective Action and Preventive Action (CAPA) plan. The CAPA you listed on Deviation Investigation Report Form for Deviation DD (b)(4) 17003 included: discarding both batches and following-up on the next (b)(4) batches to see if a similar issue occurs. You did not review your manufacturing process and manufacturing batch records to determine if your manufacturing process and manufacturing batches records could be revised to reduce process variation. You did not interview employees to determine if employees consistently and reproducibly follow your manufacturing instructions.你们未制订充分的CAPA计划。你们在偏差调查报告表DD XX17003中所列的CAPA包括:弃用这2批,跟踪下XX批查看是否有类似问题发生。你们并未回顾你们的生产工艺和批生产记录以确定你们的生产工艺和批生产记录是否可进行修订以降低工艺波动。你们并未与员工面谈以确定员工是否一致和重复地遵守你们的生产指令。

     iii.    You did not conduct a thorough risk assessment. Your risk assessment consisted of answering (b)(4) generic questions: yes, no, or NA (Not Applicable). Deviation DD (b)(4) 17003 investigation did not include documentation showing a more thorough risk assessment was conducted by your risk management team. Your written procedure for Quality Risk Management SMP-023.03 effective November 1, 2017 section 7.1.3 specifies a risk management team should be established when solving major risk issues, and section 7.1.5 of the same procedure specifies to select different tools according to the risk category. Quality Risk Management SMP-023.03 section 8.3 specifies allactivities should be defined and documented. Quality Risk Management SMP-023.03 does not specify which risk management methods and tools to use in association with specific deviation categories. 你们未进行深入的风险评估。你们的风险评估是由对XX个一般性问题的回答所组成的:是、否或NA(不适用)。偏差DD XX 17003调查并不包括显示由你们风险管理小组执行更为深入风险评估的文件。你们的书面程序“质量风险管理”SMP-023.03生效日期201711017.1.3部分说在解决主要风险问题时应组成一个风险管理小组,同一程序的7.1.5部分说要根据风险类别选择不同的工具。“质量风险管理”SMP-023.038.3部分说应定义并记录所有活动。“质量风险管理”SMP-023.03并未说明对于特定的偏差分类要使用何种风险管理方法和工具。

c)    You do not always thoroughly document investigations. Your written procedure Deviation Investigation Management System SMP-017.05 effective January 1, 2018 section 6.4.2 specifies the investigation should be well documented including the quality risk assessment (the same specification as included in version SMP-17.04 effective May 30, 2016). Deviation Investigation Management System SMP-017.05 like SMP-017.04 does not specify which risk management methods and tools to use in association with specific deviation categories. 你们未能记录所有调查。你们的书面程序“偏差调查管理体系”SMP-017.05生效日期201801016.4.2部分说应好好记录所有调查包括质量风险评估(与20180530生效的版本SMP-017.04中所包括的标准相同)。“偏差调查管理体系”SMP-017.05SMP-017.04一样并说明对于特定的偏差类别要使用何种风险管理方法和工具。

d)   You do not always thoroughly investigate deviations before closing the deviation. Deviation DCB02-17002 was initiated October 10, 2017 and closed February 1, 2018 for single unknown impurity (specification <(b)(4)%) (b)(4) intermediate (b)(4) batches (b)(4) ((b)(4)%) and (b)(4) ((b)(4)%). The Deviation Investigation Report states unspecified impurity at RRT (Relative Retention Time) (b)(4) is an in process impurity observed in other batches but at levels not more than (b)(4)%.You did not identify a root cause. Your corrective action plan included: use LC-MS to identify the impurity, conduct further investigations once the impurity is identified, and conduct a lab trial study to determine if reprocessing removes the impurity. You did not develop a preventive action plan. You did not identify the single unknown impurity. You reprocessed (b)(4) intermediate (b)(4) batches (b)(4) and (b)(4) and assigned the reprocessed batches final API batch numbers (b)(4) and (b)(4). You then closed the investigation without identifying the single unknown impurity. 你们未在所有偏差关闭之前对其进行彻底调查。偏差DCB02-1700229171010启动,于20180201关闭,启动原因是XX中间体未知杂质XX批(XX%)和XX批(XX%)(标准<XX%)超标。偏差调查报告声称RRT(相对保留时间)XX的非特定杂质为在其它批准中发现的过程杂质,但处于不超过XX%的水平。你们并未找出根本原因。你们的纠正措施计划包括:使用LC-MS识别杂质,在识别出杂质之后进行进一步调查,并且进行实验室试验研究以确定返工是否能清除该杂质。你们并未制订预防措施计划。你们并未识别出该单个未知杂质。你们返工了XX中间体XX批号XXXX,并为返工后的API成品批给定了批号XXXX。然后你们没有识别出此单个未知杂质就关闭了此调查。

e)     You do not always follow your written procedures. Returned Products Management Procedure SMP-012.02 effective October 30, 2013 defines a quality-related issue as any non-compliance to physical, chemical or microbiological feature. You classified Return No. RC-18006 as not quality related for (b)(4) batches (b)(4) and (b)(4) returned for not complying with customer PSD specifications, a physical feature. The Treatment Record sectionand closure date on Return No. RC-18006 were left blank. 你们未能保持遵守你们的书面程序。“退货管理程序”SMP-012.02生效日期20131030将质量相关问题定义为不符合物理化学或微生物属性。你们将退货单RC-18006XX批号XXXX因不符合客户PSD标准(一个物理特性)退货分类为非质量相关问题。退货单RC-18006的处理记录部分和关闭日期还是空白的。

 

OBSERVATION 4 缺陷 4

The quality unit doesnot always fulfill the responsibilities of the quality unit to release or reject all APIs. Specifically, (b)(4) batch (b)(4) (b)(4) (designates the batch was (b)(4)) did not meet your customer’s specification for PSD (Particle Size Distribution (b)(4)-(b)(4)um). The actual PDS values were not reported on the CoA (Certificate Analysis) for the batch. The quality unit did not complete a Product Release Form rejecting the batch for not meeting the customer’s PSD specification with instructions for handling the batch,  质量部门未能始终履行其放行或拒收所有API的职责。具体来说,XX批次XX不符合你们客户的PSD(粒径分布XX-XXum)质量标准。实际的PSD值在该批次COA上没有报告。质量部门未完成产品放行单拒收该不符合客户PSD标准的批次以及下达该批次处理指令。

(b)(4) batch (b)(4) was (b)(4) a (b)(4) time and the batch number was changed to batch (b)(4) ((b)(4) μm). The quality unit completed a Product Release Form and identified the batch as released without further instructions for handling the batch. Yet (b)(4) batch (b)(4) was (b)(4)a (b)(4) time. After (b)(4) batch (b)(4) was (b)(4) a (b)(4) time PSD results were (b)(4) μm. The quality unit completed a Product Release Form releasing the batch a second time. XX产品XX批号XX了时间然后该批号改为批号XXXXμm)。质量部门完整填写了产品放行表认可放行该批次而无处理该批次的进一步指令。而XX批次XXXX时长。在XXXXXX时长之后PDS结果为XXμm。质量部门完整填写了产品放行单第二次放行了该批次。

 

FACILITIES AND EQUIPMENT SYSTEM 设施和设备系统

OBSERVATION 5 缺陷 5

Cleaning procedures do not contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. Specifically, your cleaning procedures are inadequate in that three of the three (b)(4) examined during the inspection contained visible residue or apparent foreign material. (b)(4) 102-1 contained apparent white particulate matter and what appeared to be a red-colored metallic particle. (b)(4) 102-2 contained apparent white residue.(b)(4) II-250 also contained apparent white residue along the length of the (b)(4).,  清洁程序不够详细,无法让操作工以可重复和有效方式清洁每种设备。具体来说,你们有3个设备清洁程序不够充分,在检查期间发现有可见残留或明显的异物。XX102-1有明显的白色颗粒物和貌似红色金属颗粒,XX102-2有明显白色残留,XXII-250亦有明显的XX长的白色残留。

 

OBSERVATION 6 缺陷 6

Equipment used in themanufacture of intermediates and APIs should be of appropriate design andadequate size, and suitably located for its intended use, cleaning, andmaintenance. This is a repeat observation. Specifically, 用于中间体和API生产的设备应具备适当的设计,有足够的尺寸,并适当安装以符合其既定用途、清洁和维护。此为重复缺陷。具体来说

a)     You do not maintain equipment in a good state of repair. Theend of the (b)(4) consists of (b)(4) different colored unidentified materials:(b)(4). Your Engineering Supervisor stated the (b)(4) material is the (b)(4)repair material and the (b)(4) material is the (b)(4) of the same repairmaterial. Only a small portion of the (b)(4) covered the repaired area. Thedurability of the (b)(4) in the absence of the (b)(4) is unknown. The (b)(4)material is unknown. 你们未将设备保持在良好的维修状态。XX的尾端包括XX不同颜色未经识别的物料XX。你们工程主管声称XX材料是XX维修材料,并且XX材料是相同维修材料的XX。只有小部分XX覆盖在维修后的区域。没有XXXX的耐用性是未知的。XX物料是未知的。

b)    You do not have adequate lighting in (b)(4) to inspect (b)(4) after cleaning to ensure no visible residue remains. 你们在XX没有充足的照明检查清洁后的XX以确保没有可见残留。

c)    You do nothave an adequate (b)(4) sealing machines to seal (b)(4) API (b)(4) bags. (b)(4) sealing machines (b)(4)-811 does not have sufficient controls for pressure and time to ensure proper sealing. You do not conduct leak tests to check bag seals prior to final product approval and release. 你们没有足够XX的封口机用以密封XX APIXX袋。XX封口机XX-911没有足够的压力和时长控制确保进行适当的密封。你们并未在成品批准放行之前进行泄漏测试检查袋子密封情况。

 

OBSERVATION 7 缺陷 7

Schedules and procedures for preventive maintenance of equipment are not adequate or do not exist. Specifically, 设备预防性维保计划和程序不充分或不存在。具体来说

a)     You do not have a written procedure describing how to conduct a (b)(4) test to verify the integrity of the interior surface of the (b)(4) in your manufacturing workshops. (b)(4) are used in the manufacture of crude (b)(4) in workshops (b)(4) and (b)(4). 你们没有书面程序描述如何进行XX测试以确定你们生产车间的XX内表面的完整性。XX用于XX车间XXXX的粗品生产。

b)   You do not have a written procedure describing how to perform repairs to the interior surfaces of (b)(4). Repairs to interior surfaces of (b)(4) are made by your employees without written instructions for how to make those repairs.  你们没有书面程序描述如何对XX内表面进行维修。XX内表面的维修是由你们员工执行的,但没有书面程序指导如何进行这些维修。

c)    You do not have a record showing a (b)(4) test was performed immediately following a repair to the (b)(4) of the (b)(4) in (b)(4)II-250. (b)(4)II-250 is used in themanufacture of crude (b)(4). 你们没有记录显示在XX粗品生产所用XXII-250里的XX维修之后立即进行了XX检测。

 

OBSERVATION 8 缺陷 8

Substances associated with the operation of equipment, such as lubricants, heating fluids or coolants are not always food grade lubricants and oils. Specifically, you use (b)(4) in all of your (b)(4) reactors in Workshop (b)(4). You do not test (b)(4) prior to release for use for (b)(4) a potential toxic contaminant. Rather than preventing potential finished API contamination from (B)(4) by testing (b)(4) for (B)(4) prior to approval and release, your QA Director stated you periodically monitor your finished product APIs for (B)(4) contamination, 与设备操作有关的物质如润滑剂、导热油或冷却剂并不都是食品级润滑剂或润滑油。具体来说,你们在XX车间所有XX反应釜上使用了XX。你们在放行其使用之前未对XX检测可能的毒性污染物。你们未在批准和放行XX之前检查XX防止API成品受到可能的XX污染,你们QA总监声称你们定期检查你们的API成品中的XX污染情况。

 

LABORATORY SYSTEM 化验室系统

OBSERVATION 9 缺陷 9

Sampling plans, and test procedures are not always scientifically sound and appropriate to ensure raw material, intermediates and APIs conform to established standards of quality.  取样计划和检测方法并不全是科学合理并合适于确保原料、中间体和API符合既定的质量标准。

a)    You do not always have scientifically sound reasons for invalidating OOS results for lab related reasons. This is a repeat observation. Complaint No. CC-16008 received September 13, 2016 for (b)(4) batches (b)(4) ((b)(4)ppm (b)(4) impurity) and(b)(4) ((b)(4)ppm (b)(4) impurity) failing to meet (b)(4) impurity specification <(b)(4)ppm identifies the complaint as a quality complaint for product quality attribute. Your Vice President of Analytical Operations stated a Single Quadrupole LC-MS is not as sensitive as a Triple Quadrupole LC-MS and sometimes it gives false positive results. Your customer tested (b)(4) batches (b)(4) and (b)(4) using a Triple Quadrupole LC-MS. You sent samples of (b)(4) and (b)(4) to an outside laboratory to test using a Triple Quadrupole LC-MS. Your customer provided you with their LC-MS test method. The outside laboratory used a Triple Quadrupole LC-MS but did not follow the test method provided by your customer. 并不是所有因化验室相关原因宣布OOS无效均有科学有效的理由。此为重复缺陷。投诉CC-1600820160913收到,原因是XX批次XXXX杂质XXppm)和XXXX杂质XXppm)不符合XX杂质标准<XXppm,该投诉为产品质量属性有关的质量投诉。你们的分析运营副总裁声称单四极杆LC-MS不如三重四极杆LC-MS灵敏,有时单四极杆LC-MS会得到假阳性结果。你们的客户使用的是三重四极杆LC-MS检测的XX批次XXXX,你们则将XXXX样品送至一个外部实验室使用三重四极杆LC-MS检测。你们的客户给你们提供了他们的LC-MS检测方法,而外部实验室使用了三重四极杆LC-MS但没有按你们客户提供的方法进行检测。

You do not have a quality agreement with this outside laboratory requiring all equipment used for testing is qualified, any software used with the instrument is validated, and the test method used is validated prior to reporting results. You used results from this outside laboratory for (b)(4) batches (b)(4) and (b)(4) to invalidate the OOS results reported by your customer. After your customer returned (b)(4) batches (b)(4) and (b)(4) you reprocessed the batches and assigned the reprocessed batches new batch numbers (b)(4) and (b)(4) Finished API batches (b)(4) and (b)(4) were then sold to other customers. 你们与该外部实验室没有质量协议要求所有用于检测的设备经过确认,要求所有仪器所用的软件经过确认,并且在报告结果之前所有方法均经过验证。你们使用了此外部实验室的XX批次XXXX的结果用以宣布你们客户报告的OOS结果无效。在你们的客户退回了XX批次XXXX产品后,你们对这些批次进行了返工,对返工批次给定了新批号XXXX。成品批次XXXX后来被卖给了其它客户。

b)   You do not have scientifically sound sampling plans. 你们没有科学合理的取样计划

       i)    Sampling Procedure for API Raw Material QC-026-9 effective September 30, 2017 includes sampling instructions designed to obscure non-homogenous raw material batches. As an example, section 5.6 specifies to sample the (b)(4) of (b)(4) compartment in the tanker and (b)(4) thecompartment sample and then (b)(4) the (b)(4) samples from (b)(4) the compartments. You do not have data establishing inter-batch and intra-batch homogeneity for key starting material. API原料取样程序”QC-026-9生效日期20170930包括有取样指导,设计用以阻止不均匀的原料批次。例如,第5.6部分说要在罐的XX取样,然后将XX中取的样XX。你们没有数据建立关键起始物料的批内和批间均匀性。

     ii)    Sampling procedures lack sufficient details describing how to collect samples to ensure the sampling procedure is consistently and reproducibly followed. Sampling Procedure for APIs QA-005-5 effective August 30, 2017 is silent regarding which drums to sample or how to collect samples from the sampled drums. 取样程序对如何采集样品以确保能一致可重复地遵守取样程序描述不够详细。“API取样程序”QA-005-5生效日期20170830未说明要从哪个桶取样或如何从桶中采集样品。

c)    You do not have data to support reduced testing for genotoxic and other impurities. during process validation for (b)(4) you committed to testing the final API validation batches for elemental impurities and residual solvents, (b)(4). After the three (b)(4) validation batches you test (b)(4) batches (b)(4) for elemental impurities and residual solvents. During process validation for (b)(4) you tested the finished API validation batches for potential genotoxic impurity (b)(4). After the validation batches you test (b)(4) batches (b)(4) for potential genotoxic impurity (b)(4). 你们没有数据支持对基因毒性杂质和其它杂质降低检测频次。在XX工艺验证中,你们承诺会检测API验证批次成品的元素杂质和残留溶剂XX。在3XX验证批次后,你们检测了XX批次XX的元素杂质和残留溶剂。在XX工艺验证中,你们检测了验证批次的API成品潜在基因毒性杂质XX。在验证批次之后,你们检测了XX批次XX的潜在基因毒性杂质。

 

OBSERVATION 10 缺陷 10

Your on-going testing program to monitor the stability characteristics of APIs to confirm appropriate storage conditions and retest dates is not adequate. Specifically,  你们监测API稳定性特性以确认适当的存贮条件和复验期的持续检测计划不充分。具体来说。

a)    You subjected (b)(4) API sample to conditions expected to cause degradation (forced degradation). You did not conduct full product release testing on those forced degradation samples, using validated test methods, to identify the specific product release test(s) that are stability indicating. Instead you included forced degradation samples in three HPLC test method validations for Related Substance, Assay and (b)(4) impurity. Not all potential product degradants can be identified by HPLC test methods. Product release tests for (b)(4) include tests for identification of Residual Solvents by GC-FID. You did not test forced degradation samples for Residual Solvents by GC-FID. 你们将XXAPI样品放在产生降解(强降解)的条件下。你们并未对这些强降解样品使用验证过的检测方法执行全面放行检测,以识别出具有稳定性指示性的特定产品放行测试。相反,你们在HPLC有关物质、含量和XX杂质3个检测方法验证中包括了强降解样品。并不是所有潜在产品降解物均可使用HPLC检测方法识别的。XX产品放行检测包括采用GC-FD鉴别残留溶剂的测试。你们并未采用GC-FID检测样品中的残留溶剂。

b)    You do not always appropriately add stability study samples to your stability study program. Deviation investigation DCB02-17002 was initiated for (b)(4) intermediate (b)(4) batches (b)(4) signle unknown impurity (b)(4)% (specification <(b)(4)%) and (b)(4) single unknown impurity (b)(4)%. You reprocessed the batches. You assigned the following batch numbers to the finished APIs made from the aforementioned (b)(4) intermediate (b)(4) batches: (b)(4) and (b)(4). You did not add batches (b)(4) and (b)(4) your stability study program. 你们未能保持适当地将稳定性研究样品加入你们的稳定性研究计划。偏差调查DCB02-17002启动原因为XX中间体XX批次单个未知杂质XX%(标准<XX%)和XX单个未知杂质XX%。你们将这些批次进行了返工。你们将使用前述中间体XX批次所生产的API成品给定了以下批号:XXXX。你们未将批次XXXX加入你们的稳定性研究计划。

 

PRODUCTION SYSTEM 生产系统

OBSERVATION 11 缺陷 11

Production deviations are not always reported and evaluated and critical deviations are not always investigated and the conclusions recorded. Specifically,  未报告和评估所有生产偏差,未对所有关键偏差进行调查并记录结论。具体来说。

a)    Your production operators do not always follow batch production instructions for critical processing parameters. At approximately (b)(4) on July 24, 2018, the temperature monitor for (b)(4) II-201 used in the manufacture of (b)(4) crude (b)(4) batch (b)(4) displayed (b)(4) degrees C. The manufacturing batch recordfor (b)(4) crude (b)(4) showed the manufacturing process for intermediate (b)(4) from chemical synthesis (b)(4) step was at step (b)(4) in the manufacturing process. The batch record identifies the parameters for this step as (b)(4) °C-(b)(4)°C maintained for (b)(4). The batch record also identifies this (b)(4) time duration as critical. The previous batch record entry recorded at (b)(4) listsa temperature of (b)(4)°C. The temperature for step (b)(4) is controlled by a manual (b)(4). 你们的生产操作员未能始终遵守关键工艺参数的批生产指令。20180724XX时,XX粗品XX批次生产所用XXII-201的温度监测显示为XX摄氏度。XX粗品XX的批生产记录显示中间体XX的生产工艺为生产工艺XX步骤的化学合成XX步骤。批记录识别此步骤的参数为保持XX°C-XX°CXX时长。批记录还识别此XX时长为关键。之前的XX批记录数据列出温度为XX°C。步骤XX的温度是由手动XX控制的。

b)    On July 25, 2018 in workshop (b)(4) a production employee was observed recording a value of (b)(4) liters for the amount of (b)(4) at step (b)(4) in the batch manufacturing record during the production of crude (b)(4) batch (b)(4). The flowmeter for the (b)(4) displayed a value of (b)(4). A production operator in Workshop (b)(4) stated (b)(4) equates to (b)(4) liters. The specification for (b)(4) at step (b)(4) in the batch manufacturing record for crude (b)(4) is (b)(4) +/- (b)(4)L. 

20180725,在XX车间XX粗品XX批次生产中看到有一个生产人员正在批生产记录上记录XX步骤的XX数量为XX升。XX流量计显示值为XXXX车间里一名生产操作工声称XX等于XX升。粗品XX批记录里XX步骤的XX标准为XX+/-XX升。


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