FDA給印度生產(chǎn)商Polydrug的警告信內(nèi)容很不可思議

1、FDA 給印度生產(chǎn)商 Polydrug 的警告信 (內(nèi)容很不可思議 )April 14, 2016 Mr. Punit Thakrar, ManagingDirectorPolydrug Laboratories Pvt. Ltd. Corporate OfficeA 201-202, Navbharat Estates, Zakaria Bonder RoadSewri (W)Mumbai -400015Maharashtra, India Dear Mr. Thakrar:From March 16-23, 2015, an investigator from the U.S. Food

2、and Drug Administration (FDA) inspected your drug manufacturing facility, Polydrug Laboratories Pvt. Ltd., PlotN-37, Addl. Ambarnath Industrial Area, MIDC, Anand Nagar,Ambarnath (East), Maharashtra, Mumbai.2015 年 3月 1 6-23日，我們 FDA 的調(diào)查員檢查了你們位于上述地址的生產(chǎn)工廠。We identified significant deviations from curren

3、t good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (API). 我們發(fā)現(xiàn)了嚴(yán)重違反原料藥 生產(chǎn) CGMP 的問題。These deviations cause your drugs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, andCosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(

4、B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.這些問題導(dǎo)致你們生產(chǎn)的藥品根據(jù)聯(lián)邦食品藥品化妝品法 案 501(a)(2)(B)部分 21 U.S.C. 351(a)(2)(B)被認(rèn)定為摻假藥。We have reviewed your A

5、pril 9, 2015, response in detail and acknowledge receipt of your subsequent respo nse.我們已經(jīng)詳細(xì)審核了你們于 2015年4月 9日的回復(fù)，并且告知已收到之后的回復(fù)。Our investigator observed specific deviations during the inspection, including, but not limited to, the following. 我們的調(diào) 查員在檢查期間發(fā)現(xiàn)的具體違規(guī)情況，包括但不限于以下：1. Failure to record and inv

6、estigate all quality-related customer compi aints according to an established p rocedure.未能根據(jù)既定程序記錄和調(diào)查所有與質(zhì)量相關(guān)的客戶投訴。During the inspection our investigator found a torn sheet ofpaper titledProduct Quality Complaints” on the floor of your' s official complaint log' s official complaint log.ware

7、house. We compared it to your firm and discovered that only 2 of the 17 customer complaints on the torn sheet were recorded in your firmFurther, your firm indicated that there may be additional unlogged and/or uninvestigated complaints, but did not provide further explanation. Your firm had not inve

8、stigated the complaints we found on the torn sheet. These uninvestigated complaints reported API that were either sub-potent or containedfilth, including the following problems: 在檢查期間，我們的調(diào) 查員在你們倉庫的地面上發(fā)現(xiàn)了一張被撕毀的表，標(biāo)題是產(chǎn)品質(zhì)量投訴” 。我們將它與你們公司的正式投訴登記本 進(jìn)行了比較，發(fā)現(xiàn)在被撕毀的表上有 17 個投訴，而在公司rH步正式的客訴登記本上只登記了 2 條。還有，你們公司說可能

9、 還有其它沒有登記和 /或沒有調(diào)查的投訴， 但沒有做出進(jìn) 解釋。你們公司沒有對我們在被撕毀的表上發(fā)現(xiàn)的那些投 訴。這些未經(jīng)調(diào)查的投訴報(bào)告了原料藥效價不達(dá)標(biāo)以及受到 污染的情況。low assay value for (b)(4) API 某原料藥含量低 particles and hairs in (b)(4) API 某原料藥發(fā)現(xiàn)顆粒和頭發(fā) an insect and dirt in (b)(4) API 原料藥里發(fā)現(xiàn)昆蟲和臟物 safety goggles in (b)(4)API 原料藥里發(fā)現(xiàn)護(hù)目鏡 (b)(4) scoop in (b)(4) API 原料藥里 發(fā)現(xiàn)料勺Your res

10、ponse stated that you will initiate a corrective action and preventive action (CAPA) plan to include your quality unit 'sassessment of your current p ractices.你們的回復(fù)說你們會啟動CAPA 計(jì)劃，其中會包括你們質(zhì)量部門對現(xiàn)行做法的評估。Your response is inadequate because it is silent on any retrospective investigations conducted for

11、 the 17 complaints that our investigator found on the sheet of paper on your warehouse floor. Your response also did not specify improvements to your complaint handling procedures and documentation practices or efforts to locate and investigate any other unlogged and/or uninvestigated complaints tha

12、t your firm acknowledged could exist .你們的回復(fù)是不充分的，因?yàn)槟銈儗τ谖覀冋{(diào)查員在你們倉庫地面上發(fā)現(xiàn)的表上列出的 17 個投訴的回復(fù)性調(diào)查保 持沉默。你們的回復(fù)也沒有說明對你們投訴處理程序和記錄規(guī)范的改進(jìn)，也沒有努力鎖定其它未登記和/未調(diào)查的投訴，你們公司已知存在的那些投訴。Although the 17 complaints in the unofficial log were not fromU.S. customers, your firm uses shared equipment, personnel, and materials to man

13、ufacture products for multiple markets,' s poor complaintincluding the Un ited States. Your firm handling practices and your inability to prevent and detect product quality defects, such as filth, indicate significant lapsesin your firm's quality system. You are responsible for ensuring that

14、 prior to release your API meet quality and safety requirements and for assuring that any subsequent quality defects are thoroughly investigated. You are also responsible for taking appropriate corrective actions and preventive actions. 雖 然在非正式的登記本上的 17 個投訴并不是來自美國客戶， 但你們公司使用了相同的設(shè)備、人員和物料來生產(chǎn)藥品供給 多個市場，

15、其中包括美國市場。你們公司差勁的客戶投訴處理做法，對防止和發(fā)現(xiàn)產(chǎn)品質(zhì)量缺陷如污染的無能為力，顯 示出你們公司質(zhì)量體系的嚴(yán)重失策。你們有責(zé)任在放行原料藥之前確保其符合質(zhì)量和安全要求，確保隨后的質(zhì)量缺陷受到徹底調(diào)查。你們還有責(zé)任采取適當(dāng)?shù)腃APA。In response to this letter, provide the following: 在回復(fù)此信函 時，請?zhí)峁┮韵聝?nèi)容： a summary of your investigations of all complaints received since 2012, noting whether each complaint is logg

16、ed in your official complaint log and including root cause determinations and CAPA 你們對所有自 2012 年以來收到的投 訴的調(diào)查總結(jié)，注意是否每個投訴都登記在你們的正式投訴登記本上，并且包括了對根本原因的確定以及CAPAyourimproved complaint handling procedure and details of any further controls implemented to ensure that all complaints are logged, documented, and

17、 promptly investigated 你們改善過的 客戶投訴處理程序，你們?yōu)榱舜_保所有投訴都會登記、記錄 和盡快調(diào)查所實(shí)施的所有進(jìn)一步控制方法2. Failure to review and investigate all production deviations. 未 能審核和調(diào)查所有生產(chǎn)偏差Our investigator found a torn page from a batch production record for lot (b)(4) of API(b)(4) in the trash. He noted discrepancies between the disc

18、arded page and the complete batch production record that your firm represented as the official record for that lot. Your firm did not investigate this deviation or the unacceptable practice of discarding a manufacturing record.You did not determine the root cause or assess its effect on drug quality

19、 prior to releasing lot (b)(4). 我們的調(diào)查員在垃圾中發(fā) 現(xiàn)某原料藥某批號批生產(chǎn)記錄上撕下來的一頁。他注意到被 丟棄的頁和你們提供的作為該批次正式記錄的完整批生產(chǎn) 記錄之間有差異。你們公司沒有調(diào)查此偏差，也沒有調(diào)查將 生產(chǎn)記錄丟棄這樣的不可接受的做法。你們在放行該批次之 前，沒有確定根本原因，也沒有評估其對藥品質(zhì)量的影響。Your response states that your quality unit is working on a system to record original data at the time it is generated.Howe

20、ver, your response is inadequate because you failed to indicate whether you intend to retrospectively investigate theextent to which your firm's manufacturing records are unreliable,determine root causes, and take necessary corrective actions.Further, you did not note whether your quality unit w

21、ill conduct a thorough review of all batch production records for accuracy and investigate any discre pancies.你們的回復(fù)中聲稱你們質(zhì)量部門有一個體系可以在數(shù)據(jù)產(chǎn)生時記錄原始數(shù)據(jù)。但是，你 們的回復(fù)是不充分的，因?yàn)槟銈儧]有說明你們是否準(zhǔn)備進(jìn)行 回顧性調(diào)查，延伸至你們公司生產(chǎn)記錄不可靠的情況，確定 根本原因，采取必要的糾正措施。還有，你們沒有說明你們質(zhì)量部門是否準(zhǔn)備對所有批生產(chǎn)記錄進(jìn)行準(zhǔn)確性審核，調(diào)查 所有差異?；貜?fù)中，請?zhí)峁┮韵聝?nèi)容：In response to this letter,

22、 provide the following: 在對此信函的a summary of your retrospective investigation of the duplicate batch production records for lot (b)(4) 你們對某批次雙份批生記錄的回顧性調(diào)查總結(jié)retrospective review of all batch production records for lots within expiry, including an evaluation of the effect of any discrepancies on API batc

23、h quality 你們對尚在有效期內(nèi)的所 有批次的生產(chǎn)記錄進(jìn)行回顧性審核，包括所有差異對原料藥 批質(zhì)量影響評估 your CAPA plan describing actions and controls to ensure accuracy and retention of all records including original batch production records 你們的 CAPA 計(jì)劃， 其中說明為了確保所有記錄，包括原始批生產(chǎn)記錄，的準(zhǔn)確 性和保存所采取的措施和控制方式 documentation that your employees are adequately

24、 trained to complete batch production records contemporaneously and accurately, to investigate production record discrepancies, and to understand the connection between accurate recordkeeping and product quality你們員工受到充分培訓(xùn)，在生產(chǎn)同時同步并準(zhǔn)確完成批生產(chǎn) 記錄，調(diào)查生產(chǎn)記錄差異，以及理解準(zhǔn)確記錄保存和產(chǎn)品質(zhì) 量之間關(guān)聯(lián)的培訓(xùn)文件記錄3. Failure of computeri

25、zed systems to have sufficient controls to p revent unauthorized access or changes to data 計(jì)算機(jī)化系統(tǒng) 沒有充分的控制，無法防止未經(jīng)授權(quán)的進(jìn)入以及更改數(shù)據(jù)Your firm 's computer system for entering test results and storing certificates of analysis (CoA), which document whether a drug meets specifications, does not have sufficie

26、nt controls to prevent unauthorized changes to a CoA after quality unit approval. 你們 公司用于輸入檢測結(jié)果和存貯 COA 的計(jì)算機(jī)系統(tǒng)，其中記錄了藥品是否符合質(zhì)量標(biāo)準(zhǔn)，沒有充分的控制來防止在質(zhì)量部門批準(zhǔn)之后，未經(jīng)授權(quán)對COA 的改動。During the inspection, our investigator reviewed (b)(4) CoA stored on computer #16, all of which were approved by the quality unit. A manager

27、 demonstrated for our investigator how results on an already finalized CoA could be manipulated after the formal quality unit approval. Also, the quality unit electronic signatures on these CoA were uncontrolled images of signatures rather than certificate-based electronic signatures.在檢查期間，我們調(diào)查員審核存貯

28、于 16 號計(jì)算機(jī)的某 COA 時，所有 COA 均經(jīng)過質(zhì)量部門批準(zhǔn)。一個經(jīng)理向我們調(diào)查員演 結(jié)果進(jìn)行篡改。還有，質(zhì)量部門在這些 COA 上的電子簽名 是非受控的簽字圖形，而不是經(jīng)過認(rèn)證的電子簽名。示在正式的質(zhì)量部門批準(zhǔn)之后，如何對已經(jīng)定稿的COA 的Your response states that your firm plans to implement an enterprise resource planning system. Your response is inadequate because you did not provide sufficient detail about

29、 how this system will prevent unauthorized access or data manipulation, nor did you indicate your timeframe for installing and validating the system. In addition, you failed to review and confirm authenticity of CoA data for products you have already released under the deficient conditions described

30、 above.你們的回復(fù)中說， 你們公司計(jì)劃實(shí)施一個 ERP 系統(tǒng)。你們的回復(fù)是 不充分的，因?yàn)槟銈儧]有提供足夠細(xì)節(jié)說明此系統(tǒng)如何防止 非法進(jìn)入和數(shù)據(jù)篡改，也沒有說明你們安裝和驗(yàn)證此系統(tǒng)的 時間框架。另外，你們沒有審核和確認(rèn)你們已經(jīng)在上述有缺 陷的條件下放行的 COA 數(shù)據(jù)的權(quán)威性。In response to this letter, provide the following: 在回復(fù)此信函 時，請?zhí)峁┮韵聝?nèi)容： a CAPA plan for controlling access to computer systems for all laboratory and manufacturi

31、ng records and equi pm ent 一份CAPA計(jì)劃，說明如何控制所有化驗(yàn)室、 生產(chǎn)記錄和設(shè)備用計(jì)算機(jī)系統(tǒng)的權(quán)限 your firm 's plan to establish, issue, and strictly control access to your manufacturing and laboratory systems 你們的公司建立、簽發(fā) 和嚴(yán)格控制你們生產(chǎn)和實(shí)驗(yàn)室系統(tǒng)權(quán)限的計(jì)劃 a detailed summary of your steps to train personnel on the proper use ofcomputerized s

32、ystems 一份詳細(xì)的總結(jié)， 說明你們培訓(xùn)員工正 確使用計(jì)算機(jī)化系統(tǒng)的步驟4. Failure to have appropriate test procedures to ensure that API conform to established standards of quality and/or purity. 沒有適當(dāng)?shù)臏y試程序來確保原料藥符合既定的質(zhì)量和/或純度標(biāo)準(zhǔn)。Our investigator found numerousinvalid ” moisture contentresults while reviewing data from the Karl Fischer

33、Potentiometer (Tiamo 2.3 software). These results, generated from July 2012 to March 2015, indicate either a quality problem or an inadequate moisture content test method. Correctly measuring water content is especially important because excess moisture in your API can lead to quality defects such a

34、s chemical degradation and/or microbial growth. 我們的調(diào)查員在 審核 KF 滴定儀（ TIAMO2.3 軟件）的數(shù)據(jù)時發(fā)現(xiàn)大量“無效”水份含量結(jié)果。這些結(jié)果產(chǎn)生于2012 年 7 月至 2015 年3 月期間，要是顯示是質(zhì)量有問題，要么是水分測試方法不 充分。正確測定的水分結(jié)果尤其重要，因?yàn)槟銈冊纤幹谐?量的水份可能會導(dǎo)致質(zhì)量缺陷，如化學(xué)降解和 /或微生物滋生。During the inspection and in your written response, you referredto the invalid assay results

35、asout of specification” (OOsay that your staff failed to report the invalid results becausethey were not aware of the reporting and documentation requirements. You also say that you are revising your OOSP rocedure.在檢查期間以及在你們書面回復(fù)中，你們將無效的 含量結(jié)果稱為“超標(biāo)（00S）”結(jié)果。你們說你們員工沒有 將無效結(jié)果報(bào)告上來，因?yàn)樗麄儾幻靼讏?bào)告和記錄的要求。你們還說你們正在修訂你們的 00S 程序。Your response is inadequate because, although you conducted a failure investigation, you did not provide us with sufficientinvalid ” resultdetail about your investigation or its findings, such as whether your firm retrospectively investigated the took necessary corrective actions. These