阿比特龙作为常用的前列腺癌靶向药，与泼尼松联用让患者获益很多，不管是疗效还是安全性都是确切的。 因为经济负担的原因，印度阿比特龙成为国内患者的常用版本，因为需要长期服用，必需性价比高的才能负担的起。 印度阿比特龙主要有两个版本为国内的患者所熟
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
检查员：Christopher S. Keating/Investigator, Ralph H. Vocque/Analyst
检查日期：2019-07-15 至 2019-07-19
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.
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:
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/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/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.
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。
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.
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.
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.
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.
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.
Additionally, your SAP inventory management system is deficient in the following aspects:
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.
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.
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”.
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.
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.
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.
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.
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.
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.
现阶段，印度是世界上最大的仿制药生产国，约占全球仿制药出口总量的20%。 来源/新浪医药 编译/David 印度的制药行业在过去10年中增长迅速，虽然市场规模较世界上的一些主流制药市场（如美国、中国、日本）小了不少，但是印度的一些处于引领地位的制药公司对