1、FDA 483 表：Liva Pharmaceuticals 20180910受檢公司：Liva Pharmaceuticals Limited受檢地址：Survey No. 434-6/B and 434-1/K, Village Jarod, Taluka, Waghodia, Vdodara-Halol Highway, Gjarat, 391510 India受檢身份：生產商FEI 號：3013712903檢查員：Satheesh Thomas/lnvestigator - Dedicated Drug Cadre 檢査日期:2018-08-20 至 2018-08-28簽發日期:20

2、18-08-28發布日期: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代表在對你工廠檢查期間所發現的問題。這些只是檢查發現，并不代表 FDA對你公司合規性的最終結論。如你們對某一缺陷有異議，或已實施或計劃實施糾正措 施來糾正某個缺陷，你們在檢査期間與FDA代表討論你們的異議與措施，或通過上述地址 向FDA提交資料。如有問題，請通過上述地址電話與FDA取得聯系。DURING AN INSPECTIONOF YOUR FIRM WE OBSERVED:檢查你公司期間我們發現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.未遵守設訃用以防止本應無菌的無菌小容量注射劑藥品的微生物污染程序。Specifically,具體來說，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:題為"無菌工藝模擬（培養基灌裝）”的SOP, QA-00024.版本04,生效日期20180709, 頁31,第部分寫道“容器有明顯容器密閉器完整性問題，如容器開裂、 破損、掉塞/蓋則應取出并拒收。拒收者應在識別出完整性問題原因之后進行合理性論 證然后棄除。上述操作要進行記錄”。有一個為證明商業準備情況的培養基灌裝 批次沒有記錄下培養詢拒收的不完整瓶的容器密閉器完整性問題的原因識別，數據匯總如 下：Medial fill numberNumber of defectsType of defe

8、ctReferenee in Batch培養基灌裝編號observed as缺陷類型Master Recordnorvintegral vials during (b)(4) visual inspection 在XX u視檢查中發現的 不完整瓶缺陷數量批記錄中的索引號(b)(4)0804 vials type of defects not recorded4瓶缺陷類型未記錄129-136OBSERVATION 2 缺陷 2Aseptic processing areas are deficient regarding the system for monitoring environment

9、al conditions.無菌加工區域的環境條件監測系統有缺陷。Specifically,具體來說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生產的房間XX環境監測的OOL調查是不完整的：OOL NO.GradeType ofResultLimitProductActivity級別monitori ng結果限度manufa

10、cturi ng操作監測類型（yes/No）產品 生產（是/否）M-EM/18/072CActive air(b)N(b)No否Clea ningsampling 主動空氣采樣cfu/m3cfu/m3淸潔M-EM/18/086CActive air(b)No否Clea ningsampling 主動空氣采樣cfu/m3淸潔M-EM/18/079c(b)(b)糾b）No否Clea ningcfu/platecfu/plate淸潔M-EM/18/041BPers onnel(b)2(b)mon itori ng 人員監測cfu/platecfu/plateM-EM/18/042BPers onne

11、l mon itori ng 人員監測(b)(4) cfu/plate2(b) cfu/plateM-EM/18/043BPers on nel mon itori ng 人員監測(b)(4) cfu/plate糾b) cfu/plateM-EM/18/050BPerso nnel monitori ng 人員監測(b) cfu/plate糾b) cfu/plateM-EM/18/058BPers onnel mon itori ng 人員監測(b)(4) cfu/plate(b)(4) cfu/plate糾b) cfu/plateM-EM/18/065BPers onnel mon itor

12、i ng 人員監測(b)(4) cfu/plate糾b) cfu/plateM-EM/18/069BPers onnel mon itori ng 人員監測(b)(4) cfu/plate糾b) cfu/plateM-EM/18/073BPers onnel mon itori ng 人員監測(b)(4) cfu/plate2(b) cfu/plateM-EM/18/080BPerso nnel mon itori ng 人員監測(b) cfu/plate糾b) cfu/plateM-EM/18/0481ASettle plate 沉降碟(b) cfu/plate糾b) cfu/plateM-

13、EM/18/068BSurface mon itori ng 表而微生物監測(b)(4) cfu/plateN(b) cfu/plateNo否Cleaning and Sanitization 淸潔消毒No否Cleaning and Sanitizati on 淸潔消毒No否Cleaning andSan itizati on 淸潔消毒No否Cleaning andSan itizati on 淸潔消毒No否Cleaning and Sanitizati on 淸潔消毒No否Cleaning and Sanitizati on 淸潔消毒No否Cleaning and Sanitization

14、淸潔消毒No否Cleaning andSan itizatio n 淸潔消毒No否Cleaning andSan itizati on 淸潔消毒No否Assembling 裝配No否Cleaning and Sanitizati on 淸潔消毒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.從事一個無菌小容量注射劑藥品的生產、加工和包裝的員丄缺乏執行其指定丄作的培訓和經驗。Specifically,具體來說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.根據題為“LI檢員資質確認與再確認” SOP PK-002-00,生效日期20170112, LI檢員資 質確認的可接受標準列出如下。在20180828的檢查期間，我隨機抽取了一個具備資質的 名為XX的L1檢員對用于確認LI檢員資質的LI檢標樣系列進行LI檢。但是，前述LI檢員未 能達到下述U檢員確認所需的可接受標準。Acceptance criteria 可接受標準Result結果Total Quantity of Defective Containers (

18、Not Less than (NLT) (b)(4)(b)(4)缺陷容器總數（不得低于XX）XXTotal Quantity OF Good Containers (NLT (b)(4)(b)(4)好容器總數（不得低于XX）XXAcceptance Criteria NLT (b"4)% (Critical Defect)(b)(4)%可接受標準NLT XX% （關鍵缺陷）XX%Acceptance criteria 事(b)% of total defects (other than critical)(b)(4)%可接受標準事總缺陷數XX% （關鍵項除外）XX%False rej

19、ect rate W(b"4)% (Good Vial)(b)(4)%錯誤拒收率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).根據題為“已灌裝密封容器的人工LI檢”的SOP PK-004-00,生效日期20170110,缺陷 如小容量注射劑的“XX與

22、黑色顆粒”、液體瓶XX,均歸類為關鍵缺陷。根據現行SOP “已 灌裝密封容器的人工目檢”，文件編號2261-PK-00005,版本2.0,生效日期20180319, 對于小容量注射液，液體瓶XX、黑色顆粒歸類為關鍵缺陷，且XX顆粒重新分類為主要缺 陷。該現行SOP中XX顆粒的重新分類無法科學地達到LI檢員資質確認的可接受標準(參 見前述缺陷3-a) oOBSERVATION 4 缺陷 4Failure to follow established and approved Standard Operating Procedures未遵守已制訂且批準的SOP。Specifically,具體來說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.題為“XX微生物培養和補水液的采購、接收、存貯和處理” SOP,文件編號 2261-SOP-QC-

25、00090,生效日期20180510,版本號2.0,第6.0 (G)部分寫道“XX 培養基XX的接收批次應按SOP2261-SOP-QC-00121采用菌落形態和特征、革蘭氏染色 和微生物鑒別來檢查純度”。但是，用于促生長試驗的所有的微生物培養基均未確認 其純度。OBSERVATION 5 缺陷 5Investigati on in validating an Out of Specificati on (OOS) during the real-time stability studies is not scientifically justified.調查宣布實時穩定性研究中的OOS結果沒有經過科學論證。Specifically,具體來說For (b)(4), Lot number (b)(4), (b)(4), there wa