2014诺化仕无锡FDA警告信.doc

FDA警告信-诺化仕(无锡)制药有限公司公司名称：Novacyl Wuxi Pharmaceutical Co., Ltd.受检地址：8 Guang Shi Xi Road Wuxi, Jiangsu, 214185, China检查日期：2013年10月14-18日违规发现：原料药：CGMP违规1. 对化验室管理控制不充分，无法保证符合已建立的规范，防止数据缺失我们的检查发现你们文件规范严重违规，包括原始数据缺失。你们质量部门的基本任务是保证你公司保留有支持性原始数据来证明你们的原料药符合既定预期的质量标准。例如，在检查中，我们检查员在垃圾中发现某产品相关的原料药色谱图，日期为2013年10月15日，在与标准图比较时，发现其中报告了一个多出来的色谱峰。在检查期间，你们公司声称化验员丢弃这张色谱图是因为它是一张空白图，但是，化验员未能在系统中找出所谓的“空白图谱”，因为该“空白图谱”已被后面的进针所覆盖。另外，检查记录了你们公司在杂质检测中对积分参数进行了改变，但没有适当的文件记录和论证。在你们抽屉里发现，你们公司在色谱图上贴了手工书写的便条记录该变更。另外，你公司实施了此变更，但没有开启审计追踪，该审计追踪本来可以追溯到变更日期以及变更人的。在你们化验室系统发现的其它重大缺陷包括：(1)尽管经常使用手动积分，但未建立手动积分的书面程序(2)未能给每个可以使用化验室系统的化验员设立单独的密码(3)在你们化验室使用了不受控的记录表来记录原始分析数据(4)在一个抽屉里发现有许多不受控的色谱图、记录表，以及不知来源的便条方法实施缺乏控制，采集的数据积分缺乏充分控制，带来的问题是你们生产的原料药的品质和数据缺乏可信度。你公司在2013年11月06日的回复中，声明你公司将对所有未受控计算机系统创建一个验证程序，创建一份新的操作规程(SOP)，重新培训所有化验员操作分析检测。但是，我们在最近检查中发现关于你们HPLC系统不充分缺陷使得我们怀疑你们是否有能力来实施持续的纠正的预防措施，是否能如你们之前所承诺的满足官方要求。请提交更为详细的执行计划时间表，以及你们的详细计划如何来实施适当的纠正措施。我们也鼓励你们将进展以月报形式提交给官方。作为你们回复的一部分，请提交一份完整的化验室计算机系统验证计划。该计划应包括一份审计追踪功能和其它适当的控制来防止数据删除和改写。另外，包括一份仍在有效期内的已销售的原料药的分析数据和批记录的回顾性审核，与对可能支持药品申报和所有DMF的数据的评估一起。该调查应包括一份对所有在你们场所生产的原料药的调查。另外，提交防止这些缺陷再次发生的系统性纠正措施的细节。制剂成品：CGMP违规2. 你公司未能适当记录或调查OOS和其它不符合事项(21 CFR211.192)例如，检查记录OOS调查#1203，关于某产品中发现金属颗粒，未能找到污染的根本原因，或解释为什么某步骤未能防止该污染。3. 你公司未能建立化验室控制，包括科学合理和适当的规范、质量标准、取样计划和检测程序，用以保证药品成分、药品容器、密闭物、中控物、贴标以及药品符合适当的鉴别、剂量、质量和纯度标准(21CFR211.160(b);以及4. 你公司未在CGMP活动发生当时记录这些活动。缺乏CGMP活动文件记录的同时增加了记录错误数据的可能性(21CFR211.188)。例如，你们公司未能保证检验文件的完整性和准确性。例如，在2013年10月15日，我们检查发现化验员采用了未经标识的试管进行某产品的紫外可见光测试。在向UV光谱仪输入数据时，化验员在每个样品识别项下均输入“未知”，这里应该是输入各样品的批号的。另外，检查2013年9月2日的紫外可见光测试发现，化验员在每个样品识别项下无输入“未知”。后来，我们注意到分析工作表自从2013年9月2日起，均有适当的样品识别，但是，工作表中的原始数据并不能与样品制备进行适当的链接。在你们的回复中，你们指出化验员记得样品制备的顺序，将样品管按序放置在样品管架上的。我们担心你们依赖于你们雇员的记忆力，而不是实际的支持性文件记录。CGMP的基本原则是在活动进行的当时进行记录，以保证复杂的活动和关键步骤是根据书面程序进行的。检测过程中的样品识别是保证分析完整性的基本要求。另外，我们检查记录了多个例子，化验员在样品制备过程中未能记录原料批号，使得无法将所用原料链接至适当的检验工作表。这使得我们担心你们化验室检测产生的数据的可信度。你们公司回复声明你们会修订相关的检测记录和SOP，对这些修订进行培训。你们描述的纠正措施不足以保证你们可以决定你们CGMP缺陷的程度及其对产品质量的影响。他们也不足以防止这些缺陷操作的再次发生。在本警告信中引用的偏差和违规行为并不是你们工厂存在的全部偏差和违规的清单。你们有责任对所发现的偏差进行调查，决定偏差原因，防止已发现偏差的再次发生，以及发生其它偏差。以下为机器翻译：Novacyl 无锡制药股份有限公司 14/12/19健康和人类服务部 logoDepartment 健康与人类服务部公共卫生服务食品和药物管理局银泉，MD 20993警告信力宏： 320-15-04挂号信回执2014 年 12 月 19 日Yonhui (William) 刘总经理Novacyl 无锡制药股份有限公司8 广石西路江苏省无锡市 214185，中国亲爱的刘先生：期间我们 2013 年 10 月 14 日至 10 月 18，2013年检验的药品生产设施，Novacyl 无锡制药股份有限公司位于江苏省广石溪路无锡 8 市 214185，中国，调查员从美国食品和药物管理局 （FDA）确定显著偏离现行良好制造规范 （CGMP） 制造的活性药物成分 (Api) 和重大违反行为的 CGMP 法规对完成的药品210 和 211 部分标题 21，联邦法规。这些偏差和侵犯行为导致您的 Api 和药物掺假所指的一节的联邦食品、 药品和化妆品法案（法案），21 u.s.c.351(a)(2)(B)，501(a)(2)(B)，在这中，使用的方法或设施或控件用于产品、 它们的制造、加工、 包装、 或持有不符合或不操作或符合 CGMP 管理。我们检查注意到贵公司生产 （卡尔费休合成 （api 和 （卡尔费休 (卡尔费休 （卡尔费休和赋形剂）。（被定义为标题 21、联邦法规、 节 210.3(b)(9) 下的成品的药产品过程中材料的卡尔费休，因此符合 CGMP 法规在 21 CFR 211 我们已详细检讨过贵公司的响应日 2013 年 11 月 6 日，并注意到它缺乏足够的纠正措施。我们的调查人员具体缺陷检查中发现的 API 的制造设施，包括但不是限于以下内容：API： CGMP 偏差1.未能管理实验室系统有足够的控制，以确保符合建立的质量标准，并防止遗漏的数据。我们检查显示有关您文件的做法，包括缺少原始数据的严重缺陷。它是一个基本的责任，你的质量单位，以确保贵公司保留演示它们的规格的本意是拥有你的 Api 满足所支持的原始数据。例如，在视察时，我们的调查人员发现色谱图有关的 （卡尔费休，API 在垃圾桶里，日 2013 年 10 月 15 日，向标准报告相比其他色谱峰。在视察中，贵公司说，分析师丢弃色谱图，因为它是空白的注射液中存在。然而，分析师是无法从系统中检索的空白的色谱图，因为它被随后又注射了覆盖。此外，检查记录贵公司作出更改集成参数的杂质不适当的文件或理由的情况下测试。您的公司依赖手写笔记对色谱图在实验室的抽屉里发现了作为此更改的文档。此外，贵公司实施此更改，恕不审计线索，将捕获更改的日期和谁进行了更改。注意到在您的实验室系统中其他重大不足之处包括：a) 未能有一个书面的程序进行手动集成尽管其患病率。b） 未能使用单独的密码，每个分析师前往实验室系统。c） 不受控制的工作表用于原始分析数据在您的实验室。d） 存在很多不受控制的色谱图、 电子表格和注释在抽屉里找到的来历不明。缺乏对方法的性能控制和缺乏对数据的完整性控制收集的真实性和可靠性，您的数据及您生成的 Api 的质量的提高问题。贵公司的响应日 2013 年 11 月 6 日，说明贵公司将创建的所有不受控制的计算机系统的验证程序，创建新的标准作业程序 （SOP）和再培训的所有分析师都进行分析测试。然而，观察您的高效液相色谱法系统不足的最新检验中发现引发疑问你能够实现可持续的纠正和预防措施，该机构以前的承诺未被履行。Novacyl Wuxi Pharmaceutical Co., Ltd. 12/19/14Warning LetterWL:320-15-04CERTIFIED MAILRETURN RECEIPT REQUESTEDDecember 19, 2014Yonhui (William) Liu, General ManagerNovacyl Wuxi Pharmaceutical Co. Ltd.8 Guang Shi Xi RoadWuxi, Jiangsu, 214185, ChinaDear Mr. Liu:During our October 14, 2013 through October, 18, 2013inspection of your pharmaceutical manufacturing facility, Novacyl Wuxi Pharmaceutical Co. Ltd. located at 8 Guang Shi Xi Road Wuxi, Jiangsu, 214185, China, an investigator from the U.S. Food and Drug Administration (FDA) identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs) and significant violations of the CGMP regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These deviations and violations cause your APIs and drug products to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.Our inspection noted that your firm produces(b)(4)synthesized(b)(4)API and(b)(4)(a(b)(4)of(b)(4)and excipients).The(b)(4)is by definition an in-process material for a finished drug product under Title 21, Code of Federal Regulations, section 210.3(b)(9), and therefore subject to the CGMP regulations at 21 CFR 211.We have conducted a detailed review of your firms response dated November 06, 2013, and note that it lacks sufficient corrective actions.Our investigator observed specific deficiencies during the inspection of the API manufacturing facility, including, but not limited to, the following:API: CGMP DEVIATION1. Failure to manage laboratory systems with sufficient controls to ensure conformance to established specifications and prevent omission of data.Our inspection revealed serious deficiencies related to your documentation practices, including missing raw data.It is a basic responsibility of your quality unit to ensure that your firm retains the supporting raw data that demonstrates your APIs meet specifications that they are purported to possess.For example, during the inspection, our investigator found a chromatogram related to(b)(4), API in the trash, dated October 15, 2013, which reported an additional chromatographic peak when compared to the standard.During the inspection, your firm stated that the analyst discarded the chromatogram because it was present in the blank injection.However, the analyst was unable to retrieve the blank chromatogram from the system because it was overwritten by a subsequent injection.In addition, the inspection documented that your firm made changes to integration parameters for the impurities test without appropriate documentation or justification.Your firm relied upon hand written notes on a chromatogram discovered in a drawer at the laboratory as the documentation for this change.Furthermore, your firm implemented this change without an audit trail that would have captured the date of the change and who made the change.Other significant deficiencies noted in your laboratory system include:a)Failure to have a written procedure for manual integration despite its prevalence.b)Failure to use separate passwords for each analysts access to the laboratory systems.c)Use of uncontrolled worksheets for raw analytical data in your laboratory.d)Presence of many uncontrolled chromatograms, spreadsheets and notes of unknown origin found in a drawer.The lack of controls on method performance and inadequate controls on the integrity of the data collected raise questions as to the authenticity and reliability of your data and the quality of the APIs you produce.Your firms response, dated November 06, 2013, stated that your firm will create a validation program for all uncontrolled computer systems, create a new standard operating procedure (SOP), and retrain all analysts performing analytical tests.However, observations found during the most recent inspection regarding the inadequacy of your HPLC system raises questions regarding your ability to implement sustainable corrective and preventive actions, as previous commitments made to the agency were not fulfilled. Please provide specific milestones and your detailed plan on how you intend to implement the appropriate corrective actions. We will also encourage you to submit monthly reports to the agency of your progress.As part of your response,provide a complete validation plan for your laboratory computerized systems.This plan should include an audit trail component and other appropriate controls to prevent deletion and overwriting of data.In addition, include aretrospective review of the analytical data and batch records for all of the APIs distributed that remain within expiration, along with an evaluation of data that may have been generated to support a drug application, including any Drug Master File.This investigation should include a review of all APIs manufactured at your site.Furthermore, provide details of the systemic corrective actions taken to prevent recurrence of these deficiencies.Please note that a guidance document entitled “Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients” (ICH CGMP guidance), prepared under the auspices of the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, describes current good manufacturing practice (CGMP) for the manufacture of APIs.The guidance is intended to help ensure that all APIs meet the standards for quality and purity they purport or are represented to possess.FDA considers the expectations outlined in ICH Q7, as well as alternatives intended to accomplish the same goals and provide an equivalent level of quality assurance, in determining whether a firms APIs have been manufactured, processed, packed, and held according to current good manufacturing practice under section 501(a)(2)(B) 21 USC 351(a)(2)(B) of the Act.To obtain the ICH CGMP guidance document for your reference, please refer to the following page of FDAs website:/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073497.pdf.FINISHED PRODUCT: CGMP VIOLATIONS2. Your firm did not properly document or investigate out-of-specifications (OOS) and other discrepancies(21 CFR 211.192).For example,the inspection documented that OOS Investigation #1203, related to the presence of metal particles in(b)(4), failed to determine the root cause of the contamination or explain why the(b)(4)step was unable to prevent the contamination.3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b); and,4. Your firm did not record all CGMP activities at the time these were performed. The lack of contemporaneous documentation of CGMP activities increases the likelihood of recording erroneous data(21 CFR 211.188).For example,your firm failed to ensure testing documentation was complete and accurate.For example, on October 15, 2013, our inspection revealed analysts working with unlabeled tubes reportedly of(b)(4)to perform the(b)(4)UV-Vis test.When entering the data onto the UV Spectrophotometer, the analyst entered “unknown” in the sample identification column for each sample where the lot number and sample number should have been recorded.In addition, examination of the(b)(4)UV-Vis test from September 02, 2013, revealed that the analyst had entered “unknown” in the sample identification column for each sample.Later, we noted that the analytical worksheet from September 02, 2013, had appropriate sample identifiers; however, the raw data on the worksheet cannot be properly linked to the sample preparations.In your response, you indicate that the analyst remembered the order in which the samples were prepared and placed into the test tube rack.We are concerned that you rely on the memory of your employees, rather than on actual supporting documentation.A basic principle of CGMP is to record activities at the time of performance to ensure that complicated activities and critical steps are performed according to written procedures.Identifying samples under test is essential to the integrity of the analysis.In addition, our inspection documented multiple instances where the analysts did not record raw material lot numbers during sample preparation, making it impossible to link the raw materials used to the appropriate test worksheet.This raises concerns about the authenticity of the data that your laboratory testing generates.Your firms response states that you will revise relevant test records and SOPs, and conduct training on these revisions.Your described corrective actions are insufficient to ensure that you can determine the extent of your CGMP deficiencies and their effect on product quality. They are also insufficient to prevent recurrence of the deficient practices.The deviations and violations cited in this letter are not intended to be an all-inclusive list of deviations and violations that exist at your facility.You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations.SUMMARYThe above examples are serious CGMP deficiencies and violations demonstrating that your quality system does not adequately ensure the accuracy and integrity of the data generated and available at your facility to support the safety, effectiveness, and quality of the APIs and drug products you manufacture.We strongly recommend that you hire a qualified third party auditor/consultant with experience in detecting data integrity problems to assist you with coming into compliance with CGMP regulations and statutory authorities. In your response to this letter, provide the following to the Agency:1. A comprehensive evaluation of the extent of the deletion and destruction of records. Aspart of your comprehensive evaluation, provide a detailed action plan to investigate the extent of the deficient documentation practices;2. A risk assessment regarding the potential effect on the quality of APIs and drug products. As part of your risk assessment, determine the effects of your deficient documentation practices on the quality of the API and drug product released for distribution; and3. A management strategy for your firm that includes details of your global corrective action and preventive action plan.a)As part of your corrective action and preventive action plan, describe thecorrectiveactions you will take, such as contacting your customers, recalling product, conducting additional testing and/or adding lots to your stability programs to assure stability, monitoring of complaints, or other steps to assure the quality of the product manufactured under the deficient and violative conditions discussed above.b)In addition, as part of your corrective action and preventive action plan, describe thepreventiveactions you will take, such as revising procedures, implementing new controls, training or re-training personnel, or other steps to prevent the recurrence of CGMP violations, including breaches of data integrity.If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDERs Drug Shortages Program immediately, as you begin your internal discussions, at so that we can work with you on the most effective way to bring your operations into compliance with the law.Contacting the Drug Shortages Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect