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看完缺陷,深深感觉GMP检查报告写出的问题没有最奇葩,只有更奇葩。
官网链接http://www.fda.gov/ICECI/Enforce ... /2016/ucm518540.htm
Warning Letter 320-16-29 Via UPS Return Receipt Requested August 25, 2016
Mr. Kamal Pandya Managing Director and Chairman Pan Drugs Limited 192 G I D C Makarpura Industrial Estate M I Estate, Vadodara 390001 India Dear Mr. Pandya: The U.S. Food and Drug Administration (FDA) inspected yourpharmaceutical manufacturing facility, Pan Drugs Limited, 192 G I D C MakarpuraIndustrial Estate, M I Estate, Vadodara, from November 30 to December 3, 2015. 美国FDA于2015年11月30日至12月3日检查了你们印度的公司。 This warning letter reviews significant violations of current goodmanufacturing practice (CGMP) for finished pharmaceuticals. See 21 CFR, parts210 and 211. 本警告信总结了制剂严重违反CGMP的问题。参见21 CFR, parts 210和 211 Because your methods, facilities, or controls for manufacturing,processing, packing, or holding do not conform to CGMP, your drug products areadulterated 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). 鉴于你们生产、加工、包装和保存的方法、设施或控制不符合CGMP要求,你们的原料药根据FDCA501(a)(2)(B)和21 U.S.C.351(a)(2)(B)规定被判定为掺假药品。 We reviewed your firm’s December 17, 2015, response in detail. 我们详细审核了贵公司于2015年12月17日发出的回复。 During our inspection, our investigators observed specific violationsincluding, but not limited to, the following. 我们的检查人员发现的具体违规情况包括但不仅限于以下: 1. Your firm failed to establish an adequate qualitycontrol unit with the responsibility and authority to approve or reject allcomponents, drug product containers, closures, in-process materials, packagingmaterial, labeling, and drug products (21 CFR 211.22(a)). 贵公司未能建立足够的质量控制部门,具备职责和权力来批准或拒收所有组份、药品容器、密闭器、中控物料、包装材料、标签和药品(21 CFR 211.22(a))。 Your firm’s quality unit allowed the use of adulterated (b)(4) USPAPI, dated May 25–31, 2015, manufactured at the Pan Drugs Ltd. Nandesari facility.The Pan Drugs Ltd. Nandesari facility was placed on FDA import alert 66-40 onMay 5, 2015, for egregious CGMP deviations. Your firm used this API for themanufacture of (b)(4), which were then shipped to the U.S. market fromOctober 7 to November 23, 2015. 贵公司的质量部门允许使用掺假的某USP原料药,日期为2015年5月25-31日,在PAN DRUG的NANDESARI工厂生产的。由于严重CGMP违规,PAN DRUG NANDESARI工厂已于2015年5月5日被FDA发布进口禁令。贵公司使用了此原料药用于某制剂的生产,然后在2015年10月7日至11月23日发往美国销售。 Additionally, your quality unit approved certificates of analysis (COA)for (b)(4) and (b)(4) API, as well as finished products, prior toconducting all quality control and release testing. Your production managerfalsified the documents by signing and dating the “Prepared By” and “CheckedBy” sections of the COA. 另外,你们的质量部门在实施所有质量控制和放行检测之前,就批准了某原料药的检验报告书(COA),以及制剂的COA。贵司生产经理在COA的“制表人”和“审核人”处签字日期从而伪造了文件。 Furthermore, your quality unit failed to identify data integrity issues in11 batch production records reviewed by our investigator. Your productionmanager admitted that he falsified the signatures of other employees in the“Prepared By,” “Reviewed By,” “Approved By,” and “Authorized By” sections. 还有,贵司质量部门未能在我们调查人员审核的11批生产记录中识别出数据完整性问题。贵司生产经理承认他在“制表人”、“审核人”、“批准人”和“授权人”处伪造了其它员工的签名。 According to your response, you recognized that these practices were notadequate. You intended to implement a signature list and revise your SOPs toaddress these failures. However, these actions do not address the quality unitfailures observed. 根据贵司的回复,你们认识到了这些做法都是不好的。你们将实施签名清单,修改你们的SOP来管理此问题。但是,这些措施并没有涉及到发现的质量部门问题。 2. Your firm failed to maintain the buildings used inthe manufacture, processing, packing, or holding of a drug product in a cleanand sanitary condition and to keep them free of infestation by rodents, birds,insects, and other vermin (21 CFR 211.56(a)). 贵公司未能维护药品生产、加工、包装和存贮所用的建筑使其保持洁净和卫生状态,维护其不受啮齿动物、鸟儿、昆虫和其它害虫害兽的侵入(21 CFR 211.56(a))。 For example, our investigators observed mold-like substances on the wallsof your drug processing area, and accumulations of (b)(4) powderthroughout your facility. 例如,我们的调查人员发现在你们药品加工区域的墙面上有霉菌样物质,在整个设施中都看到累积的某粉尘。 Our investigators also observed gaps and holes in the walls of yourfacility around piping and air ducts. These gaps and holes were open to thesurrounding environment and allowed pests to enter your facility. During the inspection,we observed a lizard exiting one of the holes, and evidence of other pestactivity. For example, our investigators observed what appeared to be rodentdroppings within three feet of (b)(4) bags purported to hold (b)(4)drug product. 我们的调查人员还发现你们墙上工厂里管道和排气管留有间隙和洞。这些间隙和洞向周围环境敞开,使得虫鼠可以进入你们工厂。在检查期间,我们发现有一只蜥蜴从洞里出去,还有其它虫害活动的证据。例如,我们调查人员发现用于存贮某药品的某袋子3英尺内有一些啮齿动物的粪便样的东西。 3. Your firm failed to clean, maintain, and, as appropriatefor the nature of the drug, sanitize and/or sterilize equipment and utensils atappropriate intervals to prevent malfunctions or contamination that would alterthe safety, identity, strength, quality, or purity of the drug product beyondthe official or other established requirements (21 CFR 211.67(a)). 贵公司未能根据药品的特性要求按适当的时间间隔清洁、维护和消毒和/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、剂量、质量或纯度使其不符合官方或其它既定要求 (21 CFR 211.67(a))。 For example, our investigators observed rust, dirt, and lubrication leakson and around your shared drug manufacturing equipment. Your processing (b)(4)for the production of (b)(4) and (b)(4) had non-food-gradeoil on and around the equipment. We also observed black particles in the (b)(4)used in manufacturing drug products. You told our investigator that your firmhad no cleaning procedure for the equipment or facility. 例如,我们调查人员发现你们共用的药品生产设备上及其周围有生锈、污渍和润滑油泄漏。你们生产某产品的设备使用了非食用级油品。我们还发现在药品生产所用的某设备上有黑色颗粒物。你们告诉我们调查人员贵司没有设备或设施的清洁程序。 Your equipment was observed to be in poor operating condition. Forexample, we observed a warped lid on your “(b)(4)” that prevented properclosure. 贵司设备处于不良运行状态。例如,我们发现某设备上有一个盖子变形了,无法关闭。 In response to this letter, provide details of the plan you stated youwill develop for facility upgrades and corrections, including photographicevidence that demonstrates that the entire facility meets CGMP requirements.Your response should also include your plan to ensure your facility andequipment will be proactively maintained in such a way that your product iscontinually manufactured under CGMP conditions. 在回复此函时,请提供详细的计划,说明你们将如何对设施进行升级和改造,包括图片证据证明整个设施符合CGMP要求。你们的回复还应包括你们确保你们会对你们的设施和设备进行主动维护的计划,保证你们的药品持续在CGMP条件下生产。 4. Your firm failed to exercise appropriate controls overcomputer or related systems to assure that only authorized personnel institutechanges in master production and control records, or other records (21 CFR211.68(b)). 贵公司未能对计算机或相关系统进行适当的控制,以确保只有经过授权的人员才能修改主生产和检验记录,以及其它记录(21 CFR 211.68(b))。 For example, the computer in your quality unit area did not have controlsto restrict access and prevent unauthorized changes to data files and folders.All employees had access to your Annual Product Review (APR) spreadsheet. Thedesktop computer containing the APR was not locked. 例如,你们质量部门区域的计算机并没有控制来限制进入,防止未经授权地修改数据文件和文件夹。所有员工都可以登录你们的年度质量回顾(APR)工作表。保存APR的台式计算机没有锁定。 In your response, you committed to “reassessing the GMP” requirements forcomputer-based systems; you stated the systems would be “evaluated, checked andvalidated.” You did not include a timeline or specify a plan to review releasedbatches and determine the impact of the deficiency. 在你们的回复中,你们承诺会“重新评估GMP”对基于计算机系统的要求,你们声称系统会被“评估、检查和验证”。你们没有包括一份时间表,也没有说明你们审核已放行批次确定缺陷造成影响的计划。 Data Integrity Remediation 数据完整性问题弥补 Your quality system does not adequately ensure the accuracy and integrityof data to support the safety, effectiveness, and quality of the drugs youmanufacture. We acknowledge that you are using a consultant to audit youroperation and assist in meeting FDA requirements. In response to this letter,provide the following. 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。我们知道你们聘请了顾问来审计你们的操作,协助符合FDA要求。在回复此函时,提供以下资料: A. A comprehensive investigation into the extent of the inaccuraciesin 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;对评估所覆盖的所有化验室、生产操作和系统的总结,以及对你们意在排除的操作中所有部分的论证。
- 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.
- 与现有的和已离职的员工进行面谈,找出数据不准确的表现、范围、根本原因。我们建议这些面谈由一个有资质的第三方来实施。
- 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。描述你们工厂操作中发现数据完整性问题的所有部分。
- 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 batches were identified evaluate all data integrity lapses.
- 一份对数据完整性缺陷状况的全面回顾性评估。我们建议由一个有资质的第三方里具有该领域专业水平的专家评估所有数据完整性问题。
B. A current risk assessment of the potential effects of theobserved failures on the quality of your drugs. Your assessment should include analysesof the risks to patients caused by the release of drugs affected by a lapseof data integrity, and risks posed by ongoing operations. 对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 ofyour global corrective action and preventive action plan. Your strategy shouldinclude: 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 of 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 data at your firm.
- 一份完整的描述你们数据完整性问题的根本原因的描述,包括认定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。说明是否对数据完整性问题承担责任的个人仍有能力对你公司对CGMP相关或药物应用数据产生影响。
- 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,描述你们已采取的行动,或即将采取用以保护患者确保你们药品质量的努力,例如通知你们的客户、召回产品、实施额外测试、向稳定性试验计划中增加批次以确保稳定性、药品申报行动以及加强投诉监测。
- 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,描述所有对程序、工艺、方法、控制、系统、管理监管和人力资源(例如,培训、员工提升)的弥补措施和改善措施,以确保你们公司数据的完整性。
- A status report for any of the above activities already underway or completed.
- 对上述活动已开展或已经完成的状态报告。
Access to Information during Inspection 检查期间信息获取情况 Your firm attempted to delay the start of the inspection, and some recordswe requested during the inspection were not provided. 贵公司试图拖延检查开始,在检查期间我们索取的一些记录并没有提供。 On November 30, 2015, our investigator observed your warehouse supervisortearing out pages from your firm’s annual report and placing the pages into hispocket. Eventually, the supervisor provided the pages to our investigator. 在2015年11月30日,我们调查人员发现你们的仓库主管撕毁你们公司年度报告的几页,并放进了自己的口袋。最后,主管给我们的调查人员提供了那几页文件。 On December 1, 2015, our investigator requested printed chromatograms fromyou HPLC and GC. You failed to provide them. 在2015年12月1日,我们调查人员索取你们HPLC和GC里打印出的色谱图。你们没有提供。 When an owner, operator, or agent delays, denies, limits, or refuses aninspection, the drugs may be adulterated under section 501(j) of the FD&CAct. We recommend that you review FDA’s guidance for industry, Circumstancesthat Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM360484.pdf 当所有者、运营商或代理延误、否决、限制或拒绝检查,则根据FDCA 501(j)的规定将其生产的药品判定为掺假药品。我们建议你们查看FDA行业指南“延误、否决、限制或拒绝药品检查的情形”。 Conclusion Violations cited in this letter are not intended as an all-inclusive list.You are responsible for investigating these violations, for determining thecauses, for preventing their recurrence, and for preventing other violations. FDA placed your firm on Import Alert 66-40 on December 8, 2015. Until you correct all violations completely and we confirm your compliancewith CGMP, FDA may withhold approval of any new applications or supplementslisting your firm as a drug product manufacturer. Failure to correct these violations may also result in FDA continuing torefuse admission of articles manufactured at Pan Drugs Limited, 192 G I D CMakarpura Industrial Estate, M I Estate, Vadodara into the United States undersection 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority,articles may be subject to refusal of admission, in that the methods andcontrols used in their manufacture do not appear to conform to CGMP within themeaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B). After you receive this letter, respond to this office in writing within 15working days. Specify what you have done since our inspection to correct yourviolations and to prevent their recurrence. If you cannot complete correctiveactions within 15 working days, state your completion date and reasons fordelay. Carla Norris Compliance Officer U.S. Food and Drug Administration White Oak Building 51, Room 4359 10903 New Hampshire Avenue Silver Spring, MD 20993 USA Please identify your response with FEI 3010532174. Sincerely, /S/ Francis Godwin Acting Director Office of Manufacturing Quality Office of Compliance Center for Drug Evaluation and Research
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