FDA 483表：印度Cipla -Virgonagar工厂 20190730_印度

受检公司：Cipla, Ltd-Virgonagar Site

受检地址：Old Madras Road, Virgonagar, Bangalore, Kamataka, 560049, India

受检身份：API Manufacturer 原料药生产商

FEI号：3002806691

检查员：Christopher S. Keating/Investigator, Ralph H. Vocque/Analyst

检查日期：2019-07-15 至 2019-07-19

签发日期：2019-07-19

发布日期：2019-07-30

This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations. And do not represent a final agency determination regarding your compliance if you have an objection regarding an observation, or have implemented, or plan to implement corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA to address above. If you have any questions, please contact FDA at the phone number and address above.

本文件列出了FDA代表在对你工厂检查期间所发现的问题。这些只是检查发现，并不代表FDA对你公司合规性的最终结论。如你们对某一缺陷有异议，或已实施或计划实施纠正措施来纠正某个缺陷，你们在检查期间与FDA代表讨论你们的异议与措施，或通过上述地址向FDA提交资料。如有问题，请通过上述地址电话与FDA取得联系。

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED: 检查你公司期间我们发现

1.    Investigations into out-of-specification (OOS) QC analytical results,related to finished API product quality failures, are not adequate..与API成品质量不合格有关的QC OOS结果调查不充分。

Specifically, your investigations do not always determine root causes for API drug substance failures. Review of several OOS investigations revealed that your personnel conducting the investigations are not always adequately assessing the analytical data to evaluate/eliminate all possible sources of the OOS results. Examples include, but are not limited to:

具体来说，你们的API原料药不合格调查有时未确定根本原因。对几个OOS调查的审核发现你们执行调查的人员有时未评估分析数据从而确定/消除所有可能OOS结果来源。例子包括但不仅限于：

• 1021_LAB1/INV/10/18/05-(b)(4) Lots: (b)(4) and (b)(4).Investigation reports OOS for “any other individual impurity around RRT (b)(4)”during 36 month long-term stability testing. The root cause for the OOS was determined as “the higher temperature and humidity conditions are not favorable to retain the original characteristics of the (B)(4) USP material”. Review of the overlays of the chromatographic data for 0-36 months stability testing for Lots: (b)(4) and (b)(4) shows that the main (b)(4) peak shifts from around (b)(4) minutes to around (b)(4) minutes for both lots during the 0-36 month period. However, you do not evaluate why the main (b)(4) peak shifts significantly between stability pulls, or compare it to the USP reference standard. Note that these lots of (b)(4) USP are validation batches, and the key starting material is (b)(4) where you do not control or monitor the critical (b)(4) step of (b)(4) at the specified rate of (b)(4) L/hr during the manufacture of the API intermediate (b)(4).

• 1021_LAB1/INV/10/18/05-XX批号：XX与YY：为36个月长稳实验“RRTXX单杂”超标的调查报告。OOS根本原因确定为“温湿度太高不利于保存XX USP物料的原始特性”。对2个批号的0-36个月稳定性试验色谱数据叠加显示2批号主峰在0-36个月期间从约XX分钟漂移至约XX分钟，但你们未评估为何主峰会在稳定性测试或相比于USP对照品中有严重漂移。这些XX USP批次为验证批，关键起始物料为XX，你们在API中间体XX生产过程中未控制或监测关键XX步骤使其保持在指定速率XXL/小时。

• 1021_LAB1/INV/10/18/02-(b)(4) Lot: (b)(4). (Same as aboveOOS)

• 1021_LAB1/INV/10/18/02-批号：XX（与上述OO相同）

• 1021_LAB1/OOS/02/19/09-(b)(4) USP Lot: (b)(4). Investigation reports OOS for “description” during 60 month long-term (25C/60%R.H.) stability testing. The root cause for the OOS was determined as “exposure to atmosphere and heat, undergoes colour change, hence material by nature is not stable at higher temperature beyond 12 months at any temperature exceeding 25C.”.However, you do not adequately explain the failure at 25C/60%R.H. compared to the explanation of the same description failures at intermediate (30C/(b)(4)%R.H.) and accelerated (40C/75%R.H.). Furthermore, many of the stability lots of (b)(4) USP used for comparative analysis are packaged under (b)(4) and (b)(4) which you do not adequately explain/justify why you can compare the results when the container/closure systems are not the same or that (b)(4) are not part of the commercial packaging process.

• 1021_LAB1/OOS/02/19/09-XXUSP批号：XX，为60个月长稳（25C/60%R.H.）“性状”OOS结果调查报告。公司判定该OOS的根本原因是“暴露于大气和热，颜色变化，因此该物料在温度超出25C时超过12个月不稳定”。但是你们并未将25C/60%R.H.不合格结果与中间体外观不合格（30C/(b)(4)%R.H.）和加速（40C/75%R.H.）不合格进行比较解释。多批用于比较分析的XX USP批次采用XX和XX包装，你们未充分解释/论证为何你们采用不同容器/密闭系统或不是商业包装工艺一部分的XX的结果进行比较。

• 1021_LAB1/OOS/01/18/04-(b)(4) Lot: (b)(4). Investigation reports OOS for (b)(4) content during residual solvent analysis. Your retest confirmed the original OOS result, where you performed the original sample test on the original GC instrument/column in duplicate. You retested the lot using a fresh sample on a different GC instrument/column. However, you did not perform any retesting of the fresh sample on the original GC instrument/column to evaluate if the original sample may have been contaminated due to preparation/handling error in the lab.

• 1021_LAB1/OOS/01/18/04-XX批号：XX为残留溶剂分析XX含量OOS调查报告。你们进行了复测，确认了原始OOS结果。原始检测使用的是原始样品在原GC仪器/色谱柱平行检测，而复测使用的新样品，使用了不同的GC仪器/柱子。你们并未在原GCP仪器/色谱柱上对新样品进行复测，以评估原始样品是否可能因化验室制备/处理错误造成污染。

• Equipment used to control and monitor critical process parameters identified in the manufacture of APIs and API intermediates is not adequately designed, installed or qualified.  用于控制和监测API及其中间体生产关键工艺参数的设备设计、安装或确认不够。

Specifically, 具体来说

a)     Your designs of the (b)(4) installed on (b)(4) E4(b)(4)-04 and E3-(b)(4)-19 do not exist. You could not provide any detailed design schematics for the (b)(4) which were installed on the (b)(4) after the equipment was originally qualified. No re-qualification of the (b)(4) was performed after the (b)(4) were fabricated and installed into the (b)(4) of which you could not provide any work orders or documentation as to when the(b)(4) were installed into the (b)(4). Furthermore, you have not conducted avalidated study to show that the (b)(4) was designed in a manner that consistently adheres to the critical process parameter (b)(4) rate L/hr) for the (b)(4) during the manufacture of (b)(4) API intermediate, which is further manufactured into APIs (b)(4) and (b)(4) Currently you use a (b)(4) system for(b)(4) during step in the BMR for both E4(b)(4)-04 and E3(b)(4)-19, but havenever demonstrated that the (b)(4) the (b)(4) is consistent with the (b)(4) rate by validating it against a (b)(4). Note that this (b)(4) is (b)(4) and can easily form undesired side (b)(4) products if the (b)(4) rate deviates from (b)(4)L/hr. Note that during the inspection we observed several OOS events for APIs (b)(4) and (b)(4) where (b)(4) is used as the key starting material for both APIs.

你们对XX和XX上安装的XX没有设计。你们无法提供设备初始确认之后安装在XX上面的XX的任何详细的设计图纸。在XX制成并安装至XX之后，你们未进行再确认，你们不能提供任何工作指令或文件说明何时安装的。另外，你们未进行验证研究证明其设计方式能保持API中间体XX生产中符合关键工艺参数XXL/小时。该中间体后续生产成为APIXX和XX。目前你们在XX和XX的BMR步骤中使用XX系统，但从来未通过验证证明XX速度保持一致。注意到XX为XX，如果XX速度偏离XXL/小时则易形成不想要的副产物。检查期间我们发现有几起API XX和XX的OOS亊件都是采用XX作为关键起始原料。

b)    The equipment used in the manufacture (b)(4) steps) of your APIs and API intermediates is manually monitored for temperature during that particular stage of manufacturing, by having the production operator read the temperature on the display and record in the batch record. However, review of the batch records shows that (b)(4)/processing time temperatures are only monitored and recorded in the batch records at the start and stop times of(b)(4) or during periodic intervals (b)(4) etc.) during (b)(4). You do not have any alarm system monitoring the temperature probes which would identify if any temperature excursions occur in critical manufacturing steps.

你们API和API中间体XX生产步骤所用设备采用人工监测温度，由操作员读取显示温度，记录在批记录上。但是对批记录的审核显示XX/处理时间温度仅在XX开始和结束时有监测和记录于批记录，或以XX时间间隔记录。你们没有警报系统监测探头温度，以发现关键生产步骤中温度超标。

c)     Your sensor panel for (b)(4) E3-(b)(4)-19 is not workingas intended-for-use. During the facility tour on 07/15/19, we observed that the sensor for the (b)(4) line was not illuminated during the (b)(4) step (b)(4) during the manufacture of (b)(4) Lot: (b)(4). The sensor indicates whether the (b)(4) line to the (b)(4) is open or closed. A (b)(4) is a required critical process parameter for the (b)(4) during Step (b)(4). Note that none of your staff could identify if the (b)(4) line was open or closed, since the light did not appear to be in working order.

你们XX的探头面板无法按预定用途进行工作。在20190715参观现场时，我们发现XX线的探头在XX批号XX步骤生产期间不亮。该探头显示的是XX线至X是开还是关，是XX步骤中XX的关键工艺参数。由于灯不能显示，因此你们员工无法判定XX线是开还是关。

别再说FDA不重视设备设施系统了-CIPLA GOA基地最新483解读

3.     Preventative controls over your electronic inventory and warehousing management systems are not effectively established to prevent product mix-ups and ensure traceability for the life cycle of the material. 你们电子库存预防性控制和仓库管理系统不能有效防止产品混淆，无法确保物料生命周期追溯性。

Specifically, you did not appropriately qualify/validateyour SAP inventory management system in accordance with ICH and Part 11 requirement for validation of electronic systems. You did not effectively develop the validation protocol with the required challenges of your warehouse management system to demonstrate that the system would perform in a first-in/first-expiry/first-out (FI/FE/FO) manner, or that a reconciliation of materials challenge was performed by reconciling the quantities from your goods issue slip with the consumption bill of materials with any leftover returned raw materials, since you do not always returned all raw materials specific to a batch production order to the warehouse.

具体来说，你们没有对你们的SAP库存管理系统根据ICH和第11部分对电子系统验证的要求进行恰当确认/验证。你们未制订有效验证方法，在其中挑战你们的仓库管理系统，证明系统能够按先进先出/先到效期先出（FIFO/FEFO），或通过对你们物料发放单与消耗物料单中载明数量和退回物料数量进行数量平衡挑战，因为你们有时并不会将一个批次生产订单中所有原料返回给仓库。

During the inspection, your SAP validation team conceded that they did not perform the required negative challenges to the system in the raw material product warehouses to ensure the system would reject a material ifit was incorrectly selected for a bill of material/pick list in a FI/FE/FO fashion, or that any raw materials reconciliation was performed, where difference between quantities listed on the SAP-generated goods issuance sheets and the consumption bill of materials were challenged against excess returned raw materials not consumed in the production processes.

检查期间，你们的SAP验证组承认他们没有对原料产品库的系统做反而挑战，确保系统在没有按FIEO/FEFO方式选择物料时会拒绝物料，或者是对原料进行数量平衡，挑战SAP生成物料发放单与物料消耗单之间差异是否和生产剩余退库原料数量相等。

Additionally, your SAP inventory management system is deficient in the following aspects:

另外，你们的SAP库存管理系统在以下方面有缺陷：

• You do not attach the SAP-generated goods issue slips(Proposed work order for API), which your warehouse personnel use to pick the specific raw materials in your batch production order, to the batch production records. As such, your QA department has no way to verify during final batch record review if the raw materials listed on the goods issue slip match the materials which were picked from the warehouse and weighed/dispensed for batch production.

• 你们没有在批生产记录中附入SAP生成的物料发放单（API拟工单），你们仓库人员用该发料单挑选批生产指令中的指定原料。这样你们的QA部分就无法在最终批记录审核中核对发料单上所列原料是否与仓库为批生产所选/称重/分料的物料相同。

• You do not perform raw material reconciliation, where any excess material not used in production are returned the warehouse by the production staff and reconciled by the warehouse personnel. Additionally, you identify certain materials issued from the raw materials warehouse as “non-dispensed”, despite that they are not utilities or solvents from the (b)(4). However, you could not provide an adequate explanation/justification as to why these materials are not returned to the warehouse after use in the production process. Subsequently, the warehouse personnel are not performing a final reconciliation, where excess raw materials are accounted for against the consumption bill of materials and checked back into the warehouse.

• 你们未对原料进行数量平衡，如果在生产过程中多余物料未使用完，生产人员退回仓库，由仓库人员进行数量平衡。另外，你们把原料仓库发放的一些物料识别为“未分料”的，但有些物料实际未使用的或是来自XX的溶剂。但你们未能提供足够的解释/论证说明为什么这些物料在生产工艺使用完毕之后没有返回给仓库。因此仓库人员并未进行最终数量平衡，而超出数量的原料是通过与物料消耗单比较后退回给仓库的。

• You do not returned all issued raw materials to the storage warehouse after production is completed. During the inspection, we observed raw materials staged in the dispensed material staging area which were not part of the production lots identified in the staging area. only 2 lots were identified; however, we discovered additional raw materials from three other production lots which were identified as either “not yet consumed” or “not yet dispensed”.

• 你们在生产完成之后没有把所有已发放的原料退回给仓库。在检查期间，我们发现分料区的原料并不是生产区域所标示的生产批号的一部分。生产区只有2批，但我们发现有3个生产批次的物料，这些物料标示为“未消耗”或“未分料”。

• You do not perform line clearances for the non-dedicated production staging area, where all traces of raw materials specific to a production lot are removed from the area and returned to the warehouse.

• 你们对非专用生产区域未进行清场，将所有前一生产批号的物料从区域里清除并退回给仓库。

• You often stage non-dispensed materials (normally held in warehouse) in the dispensed material staging areas for long periods of time (>(b)(4)), despite that you have no validated study or scientific evidence to support that the long-term storage in these production areas affect the quality, potency, purity, and strength of the raw materials during long-term storage outside of the warehouse.

• 你们经常将未分的原料（通常保存在仓库）放在分料区很久（大于XX时长），但你们并没有经过验证，或科学证据支持物料在仓库以外的这些生产区域长期保存不会影响原料的质量、效价、纯度和含量。

• Your SAP-generated “Proposed work order for API” issuance sheets have a design/validation flaw where the “proposed work order date” is populated with the date when the sheets are printed/reprinted from SAP, and donot reflect the actual work order date.

• 你们SAP生成的“API拟工作订单”发放表设计/验证有瑕疵，其中的“拟工作订单日”为从SAP中打印/重新打印的日期，而不是实际的工作订单日期。

4.    Process validation of API intermediates are not designedand executed in a manner consistent with the original change control proposals,using all equipment specified in the change control. API中间体的工艺验证设计与执行与原始变更控制提议不一致，未使用变更控制中所指定的所有设备。

Specifically, you did not adequately perform the process validation for the manufacture of (b)(4) in API (b)(4) block as described in Change Control: 1024-P-18-00012. You did not perform an appropriate comparative analysis of all proposed manufacturing equipment, you did not perform all process validation manufacturing using only the equipment in API-(b)(4) Block, and you did not place all API lots manufactured (using the (b)(4) API intermediate process validation lots) on stability monitoring.

具体来说，你们未按变更控制1024-P-18-00012所述对XX API生产进行充分的工艺验证。你们未对所有拟用生产设备进行比较分析，你们不是仅使用API-XX区的设备进行工艺验证生产，你们未将所有验证批次API（使用XX的API中间体工艺验证批次）放入稳定性监测。

5.     Stability studies performed to determine the expiry dates for finished APIs are not conducted in the same container closure system as the packaging procedure specified in the batch records. 用于确定API成品有效期的稳定性研究不是按批记录中所述包装程序包装在相同容器密闭系统中。

Specifically, your stability protocol for (b)(4) USP API (Protocol: SP/BL/DS/(b)(4)0001) states that the (b)(4) USP stability samples are to be packaged in (b)(4) and (b)(4) bags which contain (b)(4) and (b)(4) and placed in (b)(4) drums. This is not in accordance with the batch packaging records for (b)(4) USP, where the API material is packaged without (b)(4) and not (b)(4). You are not conducting long-term and accelerated stability studies for (b)(4) USP in the same container closure systems as which you package the material for shipment. Your projected shelf life is (b)(4) based on the studies conducted with (b)(4) and (b)(4) despite that it is not commercially packaged in the same manner. Note that your firm has several confirmed OOS failures for long-term stability at 30+/-2C and (b)(4)+/-5%R.H., which have been attributed to “exposure to atmosphere and heat, undergoes colour change, hence material by nature is not stable at higher temperature beyond 12 months at any temperature exceeding 25C.”

具体来说，你们的XX原料药稳定性方案（方案号SP/BL/DS/(b)(4)0001）说XX USP稳定性样品包装在XX和XX袋，其中有XX和XX，然后放在XX桶内。该描述与批包装记录所述不符合，批包装记录写的是该API包装没有XX没有XX。你们未采用与发运物料包装相同的容器密闭系统进行长期和加速稳定性试验。你们所拟货架期为XX，是基于XX所执行的研究，却与商业化包装并不相同。注意到你公司有几个30+/-2C和 (b)(4)+/-5%R.H长期稳定性OOS不合规情况，你们将之归因于“暴露于大气和热环境中，颜色发生变化，因此物料在温度超出25C时超过12个月不稳定”。

6.     Written procedures for packaging operations are not established. 未制订包装操作书面程序。

Specifically, your batch manufacturing record for (b)(4) states that packaging of the intermediate must be performed in a dry environment and packaged (b)(4). You do not have a detailed written procedure for packaging (b)(4), or identify the (b)(4) line used for packaging in the batch manufacturing record. Furthermore, your firm management informed us during the inspection that the packaging rooms are not controlled or monitored for temperature and humidity. As such, you have not way to identify or confirm if personnel are performing packaging of the intermediate under the specified conditions. Note that (b)(4) intermediate is temperature, moisture, and oxygen sensitive and can easily form degradation/decomposition products upon exposure to these conditions.

具体来说，你们XX批生产记录说中间体包装必须在干燥环境包装。你们对XX包装没有详细的书面程序，或在批生产记录中写明包装使用XX线。另外，你们公司的管理层在检查期间告诉我们包装间的温湿度不受控亦未进行监测。这样的话你们没有办法知道或确认该中间体是否在指定条件下包装。注意XX中间体对温湿度和氧气均敏感，在暴露于这些条件中时易降解/分解。

7.     Records not made readily available during an FDA inspection.FDA检查期间记录不易获取。

Specifically, you were not able to provide the requested photographs of raw materials located in the AP (b)(4) dispensed material staging areas and the control panel display for (b)(4) E3-(b)(4)-19 in API-(b)(4)-Block manufacturing area. Because of explosion-prove conditions in production areas and warehouses, we allowed your personnel to collect photographs, which your staff explained were to be taken with explosion-proof cameras. You did not capture all requested photographs in real time and did not verify all photos before rearranging items which we wanted captured. Additionally, all ofthe photographs collected by your staff were acquired using a normal camera with a flash option, despite your instruction to us that we were not allowed to have cellular phones or our own cameras in those areas where photos were collected.

具体来说，你们未能提供所要求的XX分料区的原料照片，和原料药XX生产区控制面板显示。由于生产区域和仓库有防爆要求，我们允许由你们的人员采集照片，你们员工解释说会采用防爆照相机拍照。你们并未实时拍摄所要求的所有照片，亦未核查所有照片，之后才重新安排拍摄了我们想要的照片。另外，你们员工拍摄的所有照片均采用普通带闪光照相机拍摄，而你们却对我们说我们不能使用手机或自己的照相机在这些区域内拍照。