promotion@szsxjh.com  

洁净室整体方案一体化服务商

手机站

关于苏信            苏信产品            信息中心

版权所有 © 苏州市苏信净化设备厂  
备案号:
苏ICP备05019691号-1
业务咨询: 0512-67525878(24小时服务)
E-mail:  promotion@szsxjh.com
地   址:  苏州市工业园区杏林街78号11号厂房B单元
邮   编:  215031

 

资讯详情

案例分析 | 印度某药企收到FDA警告信!

分类:
行业新闻
作者:
发布时间:
2020/03/02 14:46
近日,FDA发布了对印度GPT GPT Pharmaceuticals Pvt. Ltd的警告信,具体问题如下:
1、QU未能确保:
对残留溶剂OOS检测结果进行充分调查;
对含量和杂质检测方法进行验证;
具备充分的记录和报告文件规范,包括文件控制。
2、OOS后复测,获得合格结果,认为原始检测的OOS结果不具有代表性,在没有充分科学论证前提下就忽略了初始的OOS结果。
3、生产设备的产品接触的表面有肉眼可见铁锈、凹痕和刮痕。
4、分析人员使用安捷伦服务账号登录,具有所有管理权限,可以中断HPLC运行,却无法追踪至具体人员。
5、未以适当的时间间隔清洁、维护和(药品属性需要时)消毒和/或灭菌设备和工器具,以防止发生故障或污染从而改变药品的安全性、鉴别、含量、质量或纯度使其超出官方或其它既定要求。
6、未对计算机或相关系统执行适当的控制。
7、HPLC测试删除、中断和单针运行。
问题分析:
1、未能确保对含量和杂质检测方法进行验证。
导致药品不合格的因素有很多,例如自身杂质超标、含量比例不合格、生产过程受到污染等。
企业应该确保洁净室洁净度符合要求,洁净检测仪器的选择也尤为重要。一般来说,洁净室等级要求较高的企业,建议使用吉林洁净度在线监测系统,实时监测洁净室环境。
2、生产设备的产品接触的表面有肉眼可见铁锈、凹痕和刮痕。
(1)生锈的原因可能是环境湿度超过了临界湿度,金属锈蚀的速度加快;
(2)凹痕和刮痕可能是搬移产品时候产生的,并且掉落的金属微粒,可能会对洁净室造成污染。
3、未以适当的时间间隔清洁、维护和(药品属性需要时)消毒和/或灭菌设备和工器具。
洁净室是需要定期进行检测各项指标是否合格,检测仪器也需要进行自检,例如吉林尘埃粒子计数器和吉林浮游菌采样器在使用前都有规定的自检时间。
警告信原文及翻译
Warning Letter 320-20-13
December 17, 2019
Dear Mr. Adityan:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, GPT Pharmaceuticals Pvt. Ltd., FEI 3008311641, at Plot No. 6/3, Road No. 11, Nacharam, Hyderabad, from June 24 to28, 2019.
美国FDA于XXXX年XX月XX日至XX月XX日检查了你们位于XX的XXXX生产场所。
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts210 and 211 (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)被认为是掺假药品。
We reviewed your July 17, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我们已详细审核了你公司XXXX年XX月XX日的回复,并此告知已收到后续通信。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
检查期间,我们的调查人员发现的具体问题包括但不仅限于以下:
1.  Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are incompliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). 
贵公司的质量控制部门未能履行其职责,确保药品生产符合CGMP要求,以及符合既定的鉴别、含量、质量和纯度标准(21 CFR 211.22)。
During the inspection, our investigators observed that your quality unit (QU) did not provide adequate oversight for the manufacturing of bulk (b)(4). For example, your QU failed to ensure thefollowing:
在检查期间,我们的检查员发现你们质量部门(QU)没有对散装XX的生产进行充分的监控。例如你们QU未能确保:
Out-of-specification (OOS) test results for residual solvents were adequately investigated.
对残留溶剂OOS检测结果进行充分调查。
Test methods for assay and impurities were validated.
对含量和杂质检测方法进行验证。
Adequate record and report documentation practices, including document control, were in place.
具备充分的记录和报告文件规范,包括文件控制。
You receive active pharmaceutical ingredients (API) from suppliers and process them into (b)(4). Your QU failed to adequately investigate OOS results for the residual solvent, (b)(4), for API batches (b)(4). You retested the API, obtained passing results, and released these API batches for use in production. You disregarded the initial OOS results without adequate scientific justification.
你们从供应商处接收了API,并将其进行加工至XX。你们的QU未能充分调查API批号XX的残留溶剂的OOS结果。你们复测了该API,获得了合格结果,然后将这些API批次放行用于生产。你们在没有充分科学论证前提下就忽略了初始的OOS结果。
(b)(4) is a (b)(4) solvent and known (b)(4). Solvents in (b)(4) should not be employed in the manufacture of drug substances, excipients, and drug products because of their unacceptable toxicity. However, if the use of (b)(4) solvents, such as (b)(4), is unavoidable in order to produce a drug, then the levels should be restricted. For more information on residual solvents, see FDA’s guidance documentQ3C-Tablesand List at https://www.fda.gov/media/71737/download.
XX为XX类溶剂,已知XX。XX中的XX不应用于原料药、辅料和制剂的生产,因为其具有不可接受的毒性。如果使用XX溶剂如XX是某药品生产所不可避免的,则其水平应受到限制。残留溶剂更多信息参见FDA指南文件Q3C—表格与清单。
Your response stated that you retested each of the batches of (b)(4) API for (b)(4) content and all retest results were within specification. Your response also concluded the original failures for residual (b)(4) were not representative and did not compromise product quality. However, your response failed to provide justification to disregard the initial OOS results or a plan for how your QU will ensure OOS results are adequately investigated. You also did not provide adequate corrective action to ensure appropriate documentation of testing performed as part of your OOS investigations.
你们的回复声称你们复测了XX API的所有批次中XX含量,所有复测结果均在标准范围内。你们的回复还得出结论说原始检测的残留XX结果不具有代表性,对产品质量没有影响。但是,你们的回复未提交忽略初始OOS结果的论证,亦未提交你们QU要如何确保OOS结果会受到充分调查的计划。你们亦未提交充分的纠正措施,以确保适当记录所执行的检测,作为你们OOS调查的一部分。
For more information about handling failing,out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production athttps://www.fda.gov/media/71001/download.
处理失败、OOS、OOT或其它非预期结果和你们调查文件的更多信息,参见FDA指南文件“药品OOS结果调查”。
In response to this letter, provide a comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but notbe limited to:
在回复本函时,请提交一份全面评估和补救计划,以确保你们QU被授予权限和提供资源可有效履责。该评估亦应包括但不限于:
Residual solvents test of retains samples of API you received, as well as (b)(4) you distributed. If such testing reveals substandard quality drugs, take rapid corrective actions, such as notifying customers and product recalls.
对你们已收到的API和你们已销售的XX的留样的残留溶剂检测。如果检测发现药品质量不合格,应即刻采取措施,如通知客户和召回产品。
A list of all residual solvents used in your facility or at your suppliers, and your risk-based plans to strictly limit (or discontinue) any (b)(4) solvents in raw materials you receive and drugs you produce. Include specifications for all residual solvents used in API you receive.
一份你们工厂或你们供应商所用所有残留溶剂的清单,以及你们基于风险的严格限制(或中断)你们接收的原料和你们生产的药品中的所有XX溶剂的计划。包括在你们接收的API中所有残留溶剂的标准。
A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for U.S. drugs, irrespective of whether the batch was ultimately distributed in the U.S. and a report summarizing the findings of the     analysis, including the following for each OOS:
一份对所有宣布无效美国药品(无论该批次是否最终销售至美国)OOS的独立回顾审核(包括中控和放行/稳定性测试)结果,以及一份分析所发现问题的总结报告,包括每个OOS的以下内容:
Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error
确定宣布无效的OOS结果相关的科学论证和证据是否能得出结论,显示有实验室错误导致这些结果
For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation
如果调查中发现有可得出结论的实验室根本原因,请提交理由,并确保所有受相同或类似根本原因影响的其它实验室方法被识别出来进行补救
For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production: batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability,  deviation history, complaint history, batch failure history. Summarize  potential manufacturing root causes for each investigation, and any manufacturing operation improvements 
如果回顾性审核中发现有OOS结果不能得出结论,或未发现实验室根本原因,则包括一份对生产批次生产记录、生产步骤充分性、设备/设施适用性、原料波动性、工艺能力、偏差历史、投诉历史、批失败历史的彻底审核。总结每个调查所发现的可能生产根本原因,以及所有生产操作改进措施。
A comprehensive review and remediation plan for your OOS result investigation systems. The corrective action and preventive action (CAPA) plan should include but not be limited to the following:
一份对你们OOS结果调查系统的全面审核和补救计划。CAPA计划应包括但不仅限于:
Quality unit oversight of laboratory investigations
质量部门对实验室调查的监管
Identification of adverse laboratory control trends
识别不良实验室控制趋势
Resolution of causes of laboratory variation
实验室变动原因的解决方案
Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
在未识别出可归因的实验室原因时,对可能的生产原因启动彻底调查
Adequately scoping of each investigation and its CAPA
充分划定每个调查及其CAPA的范围
Revised OOS investigation procedures with these and other remediations 
修订后的OOS调查程序,包括这些和其它补救措施
Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
QU批准所有操作以评估是否遵守适当规范的条款
Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all drugs you manufacture.
监管和批准调查,履行所有其它QU职责,以确保你们生产的所有药品的鉴别、含量、质量和纯度
2.  Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipmentand utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR211.67(a)). 
你公司未以适当的时间间隔清洁、维护和(药品属性需要时)消毒和/或灭菌设备和工器具,以防止发生故障或污染从而改变药品的安全性、鉴别、含量、质量或纯度使其超出官方或其它既定要求(21 CFR 211.67(a))。
Our investigator observed that your dedicated equipment such as the (b)(4) and (b)(4) used to manufacture (b)(4) had visible rust, dents, and scratches on product contact surfaces.
我们的调查员发现你们用于生产XX的专用设备如XX和XX与产品接触的表面有肉眼可见铁锈、凹痕和刮痕。
Your response stated that you did not verify the cleanliness of all surfaces because the manufacturing area and entire equipment train is dedicated. You also stated that your Quality Unit would verify equipment cleaning. However, your response did not provide a plan for ensuring routine maintenance of your facility, including equipment maintenance, repairs, and replacement.
你们的回复声称你们并未核查所有表面的清洁情况,因为生产区域和整个设备链是专用的。你们还声称你们QU会核查设备的清洁情况。但是你们的回复并未提交一份确保对你们设施进行定期维保的计划,包括设备维护、维修和更换。
In response to this letter, provide:
在回复本函时请提交:
Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
你们执行日常、预警操作管理对设施和设备进行监管的CAPA计划。该计划应能确保(除其它事情外)快速发现设备/设施性能问题、有效执行维修、遵守适当的预防性维保计划、及时更新设备/设施基础设施,以及改进系统进行持续管理审核。
A CAPA plan, based on the retrospective assessment, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.
一份基于回顾评估制订的CAPA计划,其中包括对你们清洁程序和规范的适当补救,以及完成时间表。提交一份关于你们的设备清洁生命周期管理流程中的弱点的详细总结。说明你们清洁程序的改进,包括改进清洁效果、改进后的所有产品和设备执行适当清洁的持续确认,以及所有需要的补救措施。
3.  Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)). 
你公司未对计算机或相关系统执行适当的控制,以确保只有经过授权的人员方可对主生产和检验记录或其它记录进行修改(21 CFR 211.68(b))。
Our investigator observed your laboratory equipment lacked appropriate controls. For example, from January 1, 2018, to June 25, 2019, audit trails from (b)(4) Agilent 1260 Infinity Series II high-performance liquid chromatography (HPLC) instruments showed a pattern of aborted runs and single run entries for testing (b)(4). Single run entries included analyses of multiple peaks or split peaks without documented investigations or adequate scientific justifications. Your employees used the Agilent Service Account login, with full administrative privileges, to abort HPLC testing runs without being attributable to a specific individual.
我们调查人员发现你们的实验室设备缺乏适当控制。例如,2018年1月1日至2019年6月25日,安捷伦1260 Infinity 系列II HPLC审计追踪显示有运行中断和XX检测单针运行记录。单针运行记录包括多峰或裂峰分析,但没有调查记录或足够的科学论证。你们的员工使用了安捷伦服务账号登录,具有所有管理权限,可以中断HPLC运行,却无法追踪至具体人员。
Your response identified the number of deleted, aborted, and single runs during your HPLC testing. However, your response did not provide adequate investigations or evidence of corrective actions put in place to prevent these data integrity issues from recurring.
你们的回复说找出了你们HPLC测试中删除、中断和单针运行的数量。但是你们的回复并未提交足够的调查或制订的纠正措施证据,以防止这些数据完整性问题重复发生。
Data Integrity Remediation
数据完整性补救措施
Your quality system does notadequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance documentData Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.
你们的质量体系不能充分确保数据的准确性和完整性,无法支持你们生产的药品的安全性、有效性和质量。参见FDA指南文件“数据完整性和药品GMP合格”指导建立和遵守CGMP合格数据完整性规范。
We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements.
我们知悉你们正聘用顾问对你们的操作进行审计并协助你们符合FDA要求。
In response to this letter,provide the following:
在回复此函时请提交以下信息:
A. A comprehensive investigation into the extent of the inaccuracies in data records and     reporting. Your investigation should include: 
一份对数据记录和报告不准确性程度的全面调查。你们的调查应包括
A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
详细的调查方案和方法学,所有实验室、生产操作和评估所覆盖的系统的总结,如有除外部分请论证
Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
对现有和已离职员工进行面谈,找出数据不准确的程度、范围和根本原因。我们建议这些面谈由有资质的第三方进行。
An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
你们工厂数据完整性缺陷的程度的评估。识别出省略、修改、删除、记录销毁、不同步记录填写和其它缺陷。说明你们已发现的数据完整性问题所涉及的工厂操作。
A comprehensive retrospective evaluation of the nature of the testing and manufacturing data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.
一份对检测和生产数据完整性缺陷情况的全面回顾性评估。我们建议由具备在已发现可能有问题的领域的专业能力的有资质的第三方对所有数据完整性问题进行评估。
B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations. 你们药品质量中所发现的不合格情况的潜在影响的当前风险评估。你们的评估应包括由于受到数据完整性问题影响的药品放行导致的患者风险的分析,以及持续运营所具有的风险。
C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include: 
你们公司的管理策略,包括你们全球CAPA计划详细情况。你们的策略应包括:
A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.
详细的CA计划,描述你们准备如何确保你们生成的所有数据的可靠性和完整性,包括分析数据、生产记录和所有提交给FDA的数据。
A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
一份对你们数据完整性问题根本原因的全面描述,包括当前行动计划的范围和深度与调查和风险评估发现相称的证据。说明负责数据完整性的人员是否还有能力影响你公司与CGMP有关或药品申报数据。
Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
临时措施,描述你们已采取或将采取用来保护患者和确保你们药品质量的措施,如通知你们的客户、召回产品、执行额外检测、增加批次至稳定性计划以确保稳定性、药品申报措施和加强投诉监测。
Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
长期措施,其中描述所有对用以确保你们公司数据完整性的程序、流程、方法、控制、系统、管理监管和人力资源(例如培训、员工提高)的弥补和提升。
A status report for any of the above activities already underway or completed.
上述活动已开展或已经完成的状态报告。
Concerns with Drug Suppliers
对药品供应商的担忧
You previously sourced (b)(4) API from (b)(4) who refused FDA inspection and was placed on Import Alert (b)(4) on (b)(4). Accordingly, FDA placed your firm on Import Alert 99-32 until you no longersourced drugs from (b)(4) and you committed to revise your API supplier qualification program.
你们之前从XX处采购XX API,该公司拒绝了FDA的现场检查要求,已于XX日被放置于进口禁令中。相应地,FDA已将你公司放置于进口禁令99-32中,直到你们不再从XX处采购药品,你们已承诺会修订你们的API供应商确认程序。
Conclusion 
结论
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility.You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.
此函中所引用的违规并不是全部。你们有责任对这些偏差进行调查,确定原因,防止其再次发生,防止你们设施内其它偏差的发生。
If you are considering an action that is likely tolead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C.356C(b). This also allows FDA to consider, as soon as possible, what actions,if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
如果你们在考虑要采取的措施可能会导致你们工厂所生产的药品供应中断,FDA要求你立即联系CDER药品短缺负责人员,这样FDA可以与你们一起采用最为高效的方式引导你们的操作符合法规要求。联系药品短缺负责人员还能让你满足依据21 U.S.C. 356C(b)你可能必须报告你们药品中止或中断的义务,让FDA尽快考虑是否需要采取何种措施来避免短缺,保护依赖于你们药品的患者健康。
FDA placed your firm on Import Alert 66-40 on December 16, 2019.
FDA已于2018年8月1日将你公司置于进口禁令66-40中。
Until you correct all violations completely and weconfirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.
在贵公司未能完成所有偏差纠正并且由我们确认你们符合CGMP之前,FDA可能会搁置所有将你公司列为药品生产的新申报和增补申报的批准。
Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at GPT Pharmaceuticals Pvt. Ltd., FEI 3008311641, at Plot No. 6/3, Road No. 11, Nacharam, Hyderabad into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).
未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21 U.S.C. 381(a)(3)拒绝接受在上述地址生产的产品进入美国。
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
在收到此函后,请在15个工作日内回复至本办公室。在回复中说明自从检查后,你们做了哪些工作来纠正你们的偏差,防止其再次发生。如果不能在15个工作日内完成纠正措施,说明延迟的原因以及完成计划。
 

信息中心

相关产品

暂时没有内容信息显示
请先在网站后台添加数据记录。