美国APP公司警告信-李永康

1、美国APP公司警告信-李永康FDA无菌药品检查风向标2012年2月22日FDA合美国APP公司(无菌药品生产厂)发布了警告信，主 要内容摘译如下。从这个警告信中，我们可以得到FDA对无菌药品生产与控制的关注点与检查新动向，从而不断的自我完善与提升，非常有意义。1) Your firm has not thoroughly investigated any unexplained discrepancy whether or not the batch has already been distributed 21CFR ? 211.192. For example:你们公司没有充分对原因不明的

2、偏差进行调查，包括销售的或未销售的产品批 次。a. In January 2010, your firm identified an insect floating in a waste container in aseptic filling room (b)(4). During your root cause analysis, you stated that the most likely cause was the stopper supplier; however, you did not conduct an audit of the supplier until April 2

3、011. In addition, you stated that there was a pest control program in place, therefore, no corrective action was needed. You continued to find insects in your manufacturing area, in finished product (two vials), and you received a complaint for an insect in a distributed vial. You also stated a pote

4、ntial root cause was the gowning supplier; however, your audit of this supplier was not scheduled to be conducted until December 2011. You did not adequately investigate the original deviation for an insect in the sterile manufacturing area and did not implement appropriate corrective actions to pre

5、vent recurrence.在 2010 年 1 月，贵公司发现一个昆虫浮在某无菌灌装室的废物容器中。在你 们的根源分析说，最大可能原因是供应商 ;然而，直到 2011年 4月你们并没有对 供应商进行审计。此外，你们说已建立了虫害控制程序，但是缺少纠正行动。你们公司持续又发现了昆虫 (2 瓶) ，你们过去已收到过小瓶中发现昆虫的投诉。 你们说潜在的根本原因是服装供应商 ; 然而，直到 2011年 12月你们并没有对 供应商做出审计安排。你们对无菌生产区发现昆虫的偏差没有进行充分的调查， 也没有采取适当的纠正预防行动。b. Your firm has received seven compl

6、aints for vials with missing labels between January 2010 and July 2011. Four of these complaints involve Packaging Line (b)(4); however, in your complaint investigation# (b)(4), you state that this is the only complaint of this type for this lot and no further action is required.从 2010 年 1 月到 2011 年

7、 7 月，你们公司收到 7 次药瓶缺少标签的投诉。其中 4起投诉涉及到该包装线 ; 但是在你们的投诉调查中称 : 该种投诉仅仅这个批次的 第一次，你们没有采取必要的行动。In your response, you describe enhancements to your reserve room procedures and your complaint management procedure; however, you failed to identify a trend in missing labels because your investigation focused on th

8、is lot only. Your response is inadequate because you failed to develop and implement a process that describes how to identify and handle trends.在你们的回复中说要加强贮存室管理和投诉管理 ; 但是你们没有调查标签失踪 的趋势，仅仅调查了这一个批次。你们的回复是不充分的，因为你们缺少一个程 序描述如何去识别与处理趋势。c. Your firm failed to identify an assignable cause for a failing ass

9、ay result for Heparin Lock Flush (OOS# (b)(4) and failed to extend your investigation into other batches of Heparin Lock Flush.你们公司不能确定肝素钠含量 (OOS# (b)(4) 不合格的根源，对肝素钠的调查 未能延伸到其它的批次。In your response, you state investigation (b)(4) was completed to identify the root cause of the out of specification (O

10、OS) results. We cannot evaluate your response since investigation (b)(4) was not included in your response. We are also concerned about a potentially related trend of OOS assay results for other batches of heparin active pharmaceutical ingredient (API) and Lock Flush. Please provide the following in

11、formation or data: 1) A copy of investigation (b)(4) including root cause analysis and corrective actions implemented for this batch; 2) Whether other associated lots may be affected by this issue; 3) Whether you have implemented, for commercial production and release, the new filter and tubing that

12、 was being used when you producedthe failing exhibit batch; and 4) A three-year history of heparin API and Heparin Lock Flush batches that have had OOS results, the testing results obtained, the root cause, and the investigation conclusion.在回复中，你们说 (b)(4) 的根源调查已经完成，但是我们不能评估你们的回 复，因为在你们的回复中没有 (b)(4)

13、的调查内容。我们也关注其它批次的肝素 API 与制剂肝素钠的潜在趋势，请你们提供以下资料或数据 :1) 一份 (b)(4) 调查材料 复印件，包括这一批的根本原因分析和纠正预防措施 ;2) 是否可能影响到其他批 次 ;3) 你们是否已经实施商业化生产和放行，不合格批的生产是否使用了新过 滤器和管道；4)为期三年的历史肝素原料药和肝素钠制剂所有批次的00S结果，测试结果，根本原因和调查结论。d. Your firm has failed to thoroughly investigate several customer complaints. For example, you received

14、 complaint #(b)(4) on March 1, 2010, citing dark particulate matter in a vial of Heparin. You investigated and determined that the particle was most likely due to a vendor issue； however, you did not perform an assessment of the vial supplier.你们公司一直未能彻底调查多个客户的投诉。例如，你们在 2010年3月1日 收到一小瓶肝素钠产品中发现黑色颗粒物的投

15、诉 #(b)(4) 。你们调查和认定黑色 颗粒物很可能是由于供应商的问题 ； 然而你们没有对瓶的供应商进行评估In your response, you state that you have not identified any other defects of this nature. Your response is inadequate since you have not addressed the potential root cause of a vial defect as identified in your investigation.在你们的回复中，你们说你们没有发现任何

16、其他的缺陷。你们回复是不充分 的，因为你们没有叙述潜在的根源调查。2) Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile 21 C.F.R. ? 211.113(b). For example:贵公司没有建立适当的书面程序以防止微生物对无菌药品的污染 21CFR211.113(b) ，例如 :a) Your Process Simulatio

17、n Policy requires incubation of all integral vials. However, the investigator observed integral vials placed in a white pail labeled "to be destroyed," yet your firm did not document the rationale for their destruction. In your firm's attempts to reconstruct the events of this process

18、simulation, you indicated that the operators dropped the vials. This information was not documented on the process simulation records. Inaccurate documentation of, or failure to document the events occurring during the process simulation qualification studies is not acceptable. Although you committe

19、d to revise your procedure, based on the inspectional findings, it appears that further improvements are needed to ensure proper documentation and oversight of your process simulation. For example, please note that itis typical for firms to videotape and have quality staff observe process simulation

20、s.你们的模拟灌装质量装政策要求所有的小瓶均进行培养。然而，调查者发现一 些完整的小瓶放置在一个白色桶内，标为“被销毁”，贵公司没有销毁理由的文 件。你们打算重新进行模拟灌装，原因是操作将这些小瓶倒了。但是，这些信息并 没有记录在模拟灌装记录中。在模拟灌装研究中出现的不正确文件或失败事件是 不可接受的。虽然你们承诺要修改你们的程序，做进一步的改进以确保模拟灌装 的监督和完整记录。请注意要提供质量人员能够进行观察的模拟灌装过程的录像 带。b.During the inspection our investigators noted operators rapidly walking from a

21、 class 10,000 area to a class 100 area and opening the plastic curtains that separate these areas. In addition, the investigators noted an operator excessively shaking the stopper bag while loading the stopper bowl and knocking on the conveyor belt to fix a stuck vial.在检查中我们检查员注意到操作者快速从 10000 区走到 10

22、0 区后打开塑料窗此外，检查员看到操作者过度地摇晃塞包加载输送带固定卡瓶You have had at least (b)(4) media fill failures, and identified that the root cause for (b)(4) of those failures was related directly to aseptic technique.你们至少有 (b)(4) 的模拟灌装失败，其根原是直接源于无菌技术。In your response, you state that you are implementing engineering solution

23、s, reducing the number of required aseptic connections, dedicating Fill Line (b)(4) to liquid product and enhancing your aseptic technique training. Please explain your plan to ensure that these corrective actions will be effective, include how you intend to monitor the effectiveness of the correcti

24、ve actions and what metrics you will use to indicate when additional changes are necessary.在你们的回复中，你们表明要进行工程改造，减少所需的无菌连接，将 (b)(4) 改造成专用线，并强化你们的无菌技术培训。请解释你们的计划，以确保这些纠 正行动是有效的，包括你们打算如何监测纠正措施的效果，你们将使用什么指标 检测出现的附加变化。3) Your firm failed to follow procedures for the handling of all written and oral compla

25、ints regarding a drug product, including specific complaint information or a reason that an investigation was found not to be necessary 21CFR? 211.198. For example:你们公司没有遵循程序来处理所有书面和口头的药品投诉，包括具体的投诉信或理由21CFR?21211.198。比如：Your procedure, Complaint Management Procedure, requires you to perform an initi

26、al impact assessment of all customer complaints; however, your firm failed to perform this assessment on approximately (b)(4) customer complaints received since January 2010 (e.g., particulate matter, leaking vials, and discoloration).你们的投诉管理程序规定你们要对所有的客户投诉进行初步的影响评估，但是 你们公司从 2010年1 月以来就没有对所有客户的投诉进行类

27、似 (b)(4) 的初步影 响评估(例如，颗粒物质，小瓶泄漏和变色 ) 。In your response, you state that you have initiated a deviation investigation to determine the root cause for failure to follow the complaint procedure. In addition, you state that the facility will be in full compliance with the procedural requirements by Septem

28、ber 30, 2011. Please provide a summary of the root cause analysis and any corrective actions you have implemented in your quality system to address the root cause.在你们的回复中，你们声称已起动了偏差调查寻找其根源，为什么没有遵守投 诉管理程序。你们声称到 2011 年 9 月 30 日就能全面符合程序要求。请提供根源析的摘要和从根源上进行纠正的措施4) Your firm does not have adequate written

29、 procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess 21CFR? 211.100(a).你们公司没有足够的生产与过程控制的书面程序，以保证药品生产的鉴别、强 度，质量和/或纯度要求 21CFR? 211.100(a).For example, on

30、June 15, 2011, during the semi-automatic, (b)(4) visual inspection, investigators observed that the visual inspection was performed at a rate of (b)(4) vials per minute (vpm); however, your qualification records do not indicate the rate of inspection during the qualification of your visual inspectio

31、n operators. Upon review of the qualification data, the investigators calculated that employees can inspect approximately (b)(4) vials per minute. In addition, an investigator noticed the visual inspection operator looking away from the vials several times without stopping the inspection machine.例如，

32、在 2011年6 月15日，你们对 (b)(4) 进行半自动化的目视检查，检查员 发现，你们目视检查速度 ( 每分钟多少瓶 ) 并没有在你们的确认文件中找到这个速 度依据。检查员对确认数据进行了审核，发现很多员工是以这样的速度进行目 视检查的。另外，检查员注意到目视检查的操作员即使检查机器不停止的工作， 目视检查这些小瓶也需要数倍的时间。In your response, you state that you are enhancing the qualification program and retraining visual inspection personnel. Please ex

33、plain your plan to ensure that these corrective actions will be effective, including how you intend to monitor the effectiveness of the corrective actions and what ongoing oversight and metrics you will use to indicate when additional improvements are needed.在你们的回复中，你们声称要强化设备确认并重新对目视检查的员工进行再培 训。请解释你

34、们的计划，以确保这些纠正行动是有效的，包括你们打算如何监 测纠正措施的效果，你们将使用什么指标来检测出现的失误以及附加的改进措 施。5) Your firm has failed to follow written responsibilities and procedures applicable to the quality control unit 21CFR?211.22(d). For example, your firm has completed approximately (b)(4) media fill simulations since December 2010; however, you have not completed the reports, and the quality unit has not approved them as per your procedure which requires you to complete all final reports within (b)(4) days of reviewing all of the