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The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Yicheng Goto Pharmaceuticals Co., Ltd. at Group 1 Gaokeng, Xiaohe Town, Yicheng City, Hubei Province, from September 11 to 14, 2017.
This warning letter summarizes significant deviations of current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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).
We reviewed your response received on October 13, 2017, in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigators observed specific deviations including, but not limited to, the following.
1.    Failure to adequately validate the process for cleaning and maintenance of equipment.
You have not conducted cleaning validation studies to demonstrate that your cleaning procedures for non-dedicated production equipment are adequate to prevent potential cross-contamination between your API (e.g., (b)(4)), which include (b)(4) drugs. Your firm also processes intermediates on this equipment.
More specifically, you failed to conduct cleaning validation for the majority of the critical non-dedicated production equipment you use to manufacture (b)(4) intermediates and API.
Reactors, (b)(4) are examples of critical multi-use equipment used by your firm.
During the inspection, your staff also stated that it was not required to document equipment cleaning between manufacturing runs. For example, for (b)(4) batch (b)(4), your firm was able to provide a cleaning record for only one piece of equipment (a (b)(4)) to demonstrate that cleaning was performed prior to batch manufacture.
In your response, you state that you will conduct cleaning validation for your non-dedicated equipment. However, you failed to provide your plan to ensure that your equipment is adequately cleaned in the interim.
In response to this letter, provide:
·         Your updated cleaning validation protocol and report for all equipment you use to manufacture drugs including all results and established acceptance criteria. Also, include updated procedures for equipment cleaning and maintenance, with provisions including but not limited to documentation of all cleaning operations.
·         您更新的清洁验证协议和您用于制造药物的所有设备的报告,包括所有结果和既定的验收标准。此外,还包括更新的设备清洁和维护程序,其中包括但不限于所有清洁操作的文档。
·         A risk assessment to determine the effect of inadequate cleaning practices on all potentially affected lots of intermediates and API distributed to the U.S. market. This assessment should include but not be limited to an analysis of retains of all lots at risk for potential cross-contamination.
·         风险评估,以确定不适当的清洁实践对分销到美国市场的所有可能受影响批次的中间体和API造成的影响。该评估应包括但不限于对可能存在交叉污染风险的所有批次的留样进行分析。
·         Your proposed market action plan including customer notifications, retain testing protocol, enhanced complaint monitoring, and recalls, if appropriate, to address all potentially affected lots of intermediates and API in the U.S. supply chain at risk for potential cross-contamination.
·         您提出的市场行动计划包括通知客户,留样检测草案,增强投诉监控以及召回(如果适用),以解决美国供应链中可能受交叉污染风险影响的所有中间体和API。
·         Provide your interim action plan to ensure adequate cleaning before you complete your validation studies, including but not limited to performing cleaning verification testing before change-over to a different API or intermediate to ensure cleaning effectiveness. Also include your acceptance criteria for each API and intermediate.
·         在完成验证研究之前,提供您的临时行动计划以确保充分清洁,包括但不限于在转换到不同的API或中间体之前实行清洁验证测试以确保清洁效果。还包括每种API和中间体的验收标准。
·         A comprehensive, independent review to identify risks of cross-contamination between drugs (API and intermediates) manufactured at your facility. Assess the suitability of your facility and process design to prevent cross-contamination, and include an evaluation of your equipment, material, personnel, and waste flows. Include a detailed corrective action and preventive action (CAPA) plan with systemic remediation and time lines.
·         全面,独立的审查,以确定您工厂生产的药物(API和中间体)之间交叉污染的风险。评估设施和工艺设计的适用性,以防止交叉污染,并包括对设备,材料,人员和废物流向的评估,包括详细的带有系统修复和时间表的纠正措施和预防措施(CAPA)计划。
2.          Failure to ensure that all test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and purity.
You failed to perform adequate analytical tests for (b)(4) API. For example, you conducted assay, related substance, and residual solvent testing without performing system suitability tests and use of standards. In addition, your analysts performed manual integration on chromatograms without a written procedure.
In your response, you state that you have established procedures that require your analysts to use standards, perform system suitability tests, and employ appropriate practices for chromatographic integration. However, you did not provide your procedures on the use of standards and system suitability. Your response also lacked a retrospective assessment of the effect of manual integration on data generated prior to implementing your new procedure.
In response to this letter, provide:
·         An assessment of all test methods used by your firm to ensure they have appropriate instructions, method suitability criteria, and have been appropriately validated to determine whether they are fit for purpose.
·         一份企业使用的所有检测方法的评估,以确保它们有适当的说明、方法适用性标准,并经过适当验证,以确定它们是否适合用途。
·         A reanalysis plan for all batches within retest date that were analyzed using methods lacking system suitability or standards.
·         一份重新测试日期内所有批次的再分析计划,这些批次是使用缺乏系统适用性或标准的方法进行分析的。
·         A comprehensive review of all instances of chromatographic manual integration. Provide scientific justification for the manual integration parameters you used for analysis. For integrations that lacked scientific justification, provide your plan for reintegration with appropriate reintegration parameters. Assess whether reintegration results comply with your established API acceptance criteria. If you identify out-of-specification (OOS) results, describe actions, such as customer notification and recalls, you have taken or will take to ensure the quality of marketed products and to protect patients.
·         一份对所有手动积分的实例进行的全面审核。为您用于分析的手动积分参数提供科学的依据。对于缺乏科学依据的积分,提供您使用合适的积分参数进行重新积分的计划。评估重新积分的结果是否与设定的API接收标准相符。如果您发现了OOS结果,则描述所采取或将要采取的措施,例如通知客户和召回,以确保上市产品的质量以及保护患者。
·         Provide a comprehensive, independent review of your laboratory practices, methods, equipment, and analyst competencies. Based on this review, provide a detailed CAPA plan to fully remediate your laboratory system. Elements of your CAPA should include, but not be limited to, measures you will take to strengthen quality assurance oversight of review and approval of method validation and test results. Your plan should also include your process for evaluating the effectiveness of the implemented CAPA. 
·         提供对您实验室实践、方法、设备和分析能力的完整的、独立的审核。基于该审核,提供详细的CAPA计划,以完整的修复您的实验室系统。您的CAPA应当包含但不限于以下元素:您将采取的措施,以加强质量保证监督审查和批准方法验证和测试结果。您的计划还应包括评估已实施CAPA有效性的流程。
3.          Failure to design a documented stability program to monitor the stability characteristics of API and to use the results to confirm appropriate storage conditions and retest or expiry dates.
For example, you do not have stability data to support the (b)(4) retest date assigned to your (b)(4) API. You also have not performed ongoing annual stability monitoring of API.
In your response, you state that you plan to initiate stability monitoring of (b)(4) API during their next manufacturing campaign. You failed to provide justification for the (b)(4) retest date in the interim.
In response to this letter, provide your plan of action with timelines to develop and implement a complete drug stability program for API manufactured for the U.S. market. Your program should be designed to support all assigned retest dates and process hold times for each API. Assess the stability of all API currently distributed to the U.S. market.
4.          Failure to demonstrate that your manufacturing process can reproducibly manufacture an API meeting its predetermined quality attributes.
Your firm failed to conduct process performance qualification for several API. For other API, you conducted partial process performance qualification as you did not adequately evaluate significant variables (e.g., parameters) in your manufacturing processes for those API. In addition, you do not have an on-going program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document, Process Validation: General Principles and Practices, for approaches that FDA considers appropriate elements of process validation, at http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf.
In your response, you state that you will complete process validation for your API. However, your response is inadequate because you failed to specify how you will ensure that your API are manufactured reproducibly. You also did not provide a retrospective review of your manufacturing processes to identify whether drug quality was adversely affected.
在您的回复中,您声明您将完成API的工艺验证。 但是,您的回复是不充分的,因为您未能说明如何确保您的API可重复生产。您也没有对您的制造工艺进行回顾性审查,以确定药品质量是否受到不利影响。
In response to this letter, provide your validation protocols and reports. Also provide an update on the status of process performance qualification for your manufacturing processes for all API distributed to the U.S. market and your program for ensuring an ongoing state of control of your manufacturing processes.
Repeat Observations at Facility
FDA cited similar CGMP observations during inspections we conducted from September 12 to 15, 2011; and September 1 to 4, 2014. You proposed specific remediation for these observations in your responses. These repeated failures demonstrate that your management’s oversight and control over the manufacture of intermediates and API is inadequate.
CGMP Consultant Recommended
Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations and to assist your firm in meeting CGMP requirements. We also recommend that the third party perform a comprehensive audit of your entire operation for CGMP compliance and, and evaluate the completion and effectiveness of any corrective actions and preventive actions you have implemented before you pursue resolution of your firm’s compliance status with FDA.
Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
您使用顾问并不能免除您企业遵守CGMP的义务。 贵企业的实行管理层仍然有责任全面解决所有缺陷并确保持续的CGMP合规性。
Deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations.
FDA placed your firm on Import Alert 66-40 on January 10, 2018.
Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.
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