FDA483表：印度Liva制药

1、FDA 483 表：Liva Pharmaceuticals 20180910受检公司：Liva Pharmaceuticals Limited受检地址：Survey No. 434-6/B and 434-1/K, Village Jarod, Taluka, Waghodia, Vdodara-Halol Highway, Gjarat, 391510 India受检身份：生产商FEI 号：3013712903检查员：Satheesh Thomas/lnvestigator - Dedicated Drug Cadre 检査日期:2018-08-20 至 2018-08-28签发日期:20

2、18-08-28发布日期:2018-09-10This 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 determi nation regardi ng your compliance if you have an objecti on regarding an observation, or h

3、ave 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

4、 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，你们在检査期间与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 INSPECTIONOF YOUR FIRM WE OBSERVED:检查你公司期间我们发现OBSERVATION 1 缺陷 1Procedures designedto prevent microbiological contamina

5、tion of sterile small volume parental druq products purportinq to be sterile are not followed.未遵守设讣用以防止本应无菌的无菌小容量注射剂药品的微生物污染程序。Specifically,具体来说，SOP entitled: “ The rejection shall be discarded with rationale justification after identifying reasons for obvious breach of container closure integrity &

6、quot;. The same shall be followed by documentation *M. For one of the (b)(4) media fill batch performed between (b)(4) to demonstrate commercial readiness, there is no documentation identifying the reasons for the breach of the container closure integrity of the non-integral vials that were rejected

7、 prior to incubation. A summary is given below:题为"无菌工艺模拟（培养基灌装）”的SOP, QA-00024.版本04,生效日期20180709, 页31,第部分写道“容器有明显容器密闭器完整性问题，如容器开裂、 破损、掉塞/盖则应取出并拒收。拒收者应在识别出完整性问题原因之后进行合理性论 证然后弃除。上述操作要进行记录”。有一个为证明商业准备情况的培养基灌装 批次没有记录下培养询拒收的不完整瓶的容器密闭器完整性问题的原因识别，数据汇总如 下：Medial fill numberNumber of defectsType of defe

8、ctReferenee in Batch培养基灌装编号observed as缺陷类型Master Recordnorvintegral vials during (b)(4) visual inspection 在XX u视检查中发现的 不完整瓶缺陷数量批记录中的索引号(b)(4)0804 vials type of defects not recorded4瓶缺陷类型未记录129-136OBSERVATION 2 缺陷 2Aseptic processing areas are deficient regarding the system for monitoring environment

9、al conditions.无菌加工区域的环境条件监测系统有缺陷。Specifically,具体来说In vestigati ons for the below listed Out of Limits (OOL)for environ mental monitori ng in Suite (b)(4), used in the manufacture of (b)(4) is incomplete.下列用于XX生产的房间XX环境监测的OOL调查是不完整的：OOL NO.GradeType ofResultLimitProductActivity级別monitori ng结果限度manufa

10、cturi ng操作监测类型（yes/No）产品 生产（是/否）M-EM/18/072CActive air(b)N(b)No否Clea ningsampling 主动空气采样cfu/m3cfu/m3淸洁M-EM/18/086CActive air(b)No否Clea ningsampling 主动空气采样cfu/m3淸洁M-EM/18/079c(b)(b)纠b）No否Clea ningcfu/platecfu/plate淸洁M-EM/18/041BPers onnel(b)2(b)mon itori ng 人员监测cfu/platecfu/plateM-EM/18/042BPers onne

11、l mon itori ng 人员监测(b)(4) cfu/plate2(b) cfu/plateM-EM/18/043BPers on nel mon itori ng 人员监测(b)(4) cfu/plate纠b) cfu/plateM-EM/18/050BPerso nnel monitori ng 人员监测(b) cfu/plate纠b) cfu/plateM-EM/18/058BPers onnel mon itori ng 人员监测(b)(4) cfu/plate(b)(4) cfu/plate纠b) cfu/plateM-EM/18/065BPers onnel mon itor

12、i ng 人员监测(b)(4) cfu/plate纠b) cfu/plateM-EM/18/069BPers onnel mon itori ng 人员监测(b)(4) cfu/plate纠b) cfu/plateM-EM/18/073BPers onnel mon itori ng 人员监测(b)(4) cfu/plate2(b) cfu/plateM-EM/18/080BPerso nnel mon itori ng 人员监测(b) cfu/plate纠b) cfu/plateM-EM/18/0481ASettle plate 沉降碟(b) cfu/plate纠b) cfu/plateM-

13、EM/18/068BSurface mon itori ng 表而微生物监测(b)(4) cfu/plateN(b) cfu/plateNo否Cleaning and Sanitization 淸洁消毒No否Cleaning and Sanitizati on 淸洁消毒No否Cleaning andSan itizati on 淸洁消毒No否Cleaning andSan itizati on 淸洁消毒No否Cleaning and Sanitizati on 淸洁消毒No否Cleaning and Sanitizati on 淸洁消毒No否Cleaning and Sanitization

14、淸洁消毒No否Cleaning andSan itizatio n 淸洁消毒No否Cleaning andSan itizati on 淸洁消毒No否Assembling 装配No否Cleaning and Sanitizati on 淸洁消毒OBSERVATION 3Employees engaged in the manufacture, processing and packing of a sterile small volume parental druq product, lack the training and experience required to perform th

15、eir assiqned functions.从事一个无菌小容量注射剂药品的生产、加工和包装的员丄缺乏执行其指定丄作的培训和经验。Specifically,具体来说a) Per SOP entitled: "Qualification and requalification of Visual inspectors", PK-002-00 Effective: 01/12/2017, the acceptance criteriafor qualifying a visual inspector is listed below. During the inspection

16、on 08/20/2018, I had randomly picked a qualified visual inspector with initials (b)(4) to perform visual inspection of the visual inspection test kit containing a sample set of (b)(4) vials, used to qualify visual inspectors However, the aforementioned visual inspector failed to meet the below liste

17、d acceptance criteria that is required to qualify visual inspector.根据题为“LI检员资质确认与再确认” SOP PK-002-00,生效日期20170112, LI检员资 质确认的可接受标准列出如下。在20180828的检查期间，我随机抽取了一个具备资质的 名为XX的L1检员对用于确认LI检员资质的LI检标样系列进行LI检。但是，前述LI检员未 能达到下述U检员确认所需的可接受标准。Acceptance criteria 可接受标准Result结果Total Quantity of Defective Containers (

18、Not Less than (NLT) (b)(4)(b)(4)缺陷容器总数（不得低于XX）XXTotal Quantity OF Good Containers (NLT (b)(4)(b)(4)好容器总数（不得低于XX）XXAcceptance Criteria NLT (b"4)% (Critical Defect)(b)(4)%可接受标准NLT XX% （关键缺陷）XX%Acceptance criteria 事(b)% of total defects (other than critical)(b)(4)%可接受标准事总缺陷数XX% （关键项除外）XX%False rej

19、ect rate W(b"4)% (Good Vial)(b)(4)%错误拒收率WXX% （好瓶）XX%b) Per SOP entitled: "Manual Visual Inspection of filled andsealed containers", SOP Number: PK-004-00, Effective Date: 01/10/2017, defects such as “(b)(4) and black particles" for small volume parental, liquid vial (b)(4), are c

20、lassified as critical defects Per the current SOP entitled: MManuaMsual Inspection of filled and sealed containers Document Number: 2261 -SOP-PK-00005, Version 2.0, Effective Date: 03/19/2018, for small volume parental, liquid vial (b)(4), black particles is classified as critical defects and (b)(4)

21、 Particles has been re-classified as a major defect. The re-classification of (b)(4) particles in the current SOP, is not scientificallyto meet acceptance criteria for being qualified visual inspector (see aforementioned Observation 3-a).根据题为“已灌装密封容器的人工LI检”的SOP PK-004-00,生效日期20170110,缺陷 如小容量注射剂的“XX与

22、黑色颗粒”、液体瓶XX,均归类为关键缺陷。根据现行SOP “已 灌装密封容器的人工目检”，文件编号2261-PK-00005,版本2.0,生效日期20180319, 对于小容量注射液，液体瓶XX、黑色颗粒归类为关键缺陷，且XX颗粒重新分类为主要缺 陷。该现行SOP中XX颗粒的重新分类无法科学地达到LI检员资质确认的可接受标准(参 见前述缺陷3-a) oOBSERVATION 4 缺陷 4Failure to follow established and approved Standard Operating Procedures未遵守已制订且批准的SOP。Specifically,具体来说SO

23、P entitled:M Procurement, receipt, storage, and handling of (b)(4) microbial cultures and re-hydrating fluid”，Document Number:2261 -SOP-QC-00090, Effective Date: 05/10/2018, Version 2.0, Section 6.0 (G) reads in parts: * (b)(4) received lot of (b) culture shall be checked for its purity, which is to

24、 be done by colony morphology and characteristics, gram staining and microbial identification through (b)(4) as per SOP No.: 2261 -SOP-QC-00121*M. However, all microbial cultures used for the growth promotion test has not been verified for its purity.题为“XX微生物培养和补水液的采购、接收、存贮和处理” SOP,文件编号 2261-SOP-QC-

25、00090,生效日期20180510,版本号2.0,第6.0 (G)部分写道“XX 培养基XX的接收批次应按SOP2261-SOP-QC-00121采用菌落形态和特征、革兰氏染色 和微生物鉴别来检查纯度”。但是，用于促生长试验的所有的微生物培养基均未确认 其纯度。OBSERVATION 5 缺陷 5Investigati on in validating an Out of Specificati on (OOS) during the real-time stability studies is not scientifically justified.调查宣布实时稳定性研究中的OOS结果没有经过科学论证。Specifically,具体来说For (b)(4), Lot number (b)(4), (b)(4), there wa