April 14, 2016
Mr. Punit Thakrar, Managing Director
Polydrug Laboratories Pvt. Ltd. Corporate Office
A 201-202, Navbharat Estates, Zakaria Bonder Road
Sewri (W)
Mumbai – 400015
Maharashtra, India
Dear Mr. Thakrar:
From March 16-23, 2015, an investigator from the U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Polydrug Laboratories Pvt. Ltd., Plot N-37, Addl. Ambarnath Industrial Area, MIDC, Anand Nagar, Ambarnath (East), Maharashtra, Mumbai.
2015年3月16-23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 current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (API).
我們發(fā)現(xiàn)了嚴重違反原料藥生產(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, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(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)被認定為摻假藥。
We have reviewed your April 9, 2015, response in detail and acknowledge receipt of your subsequent response.
我們已經(jīng)詳細審核了你們于2015年4月9日的回復，并且告知已收到之后的回復。
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 investigate all quality-related customer complaints according to an established procedure.
未能根據(jù)既定程序記錄和調(diào)查所有與質(zhì)量相關的客戶投訴。
During the inspection our investigator found a torn sheet of paper titled “Product Quality Complaints” on the floor of your warehouse. We compared it to your firm’s official complaint log and discovered that on
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行了比較，發(fā)現(xiàn)在被撕毀的表上有17個投訴，而在公司正式的客訴登記本上只登記了2條。還有，你們公司說可能還有其它沒有登記和/或沒有調(diào)查的投訴，但沒有做出進一步解釋。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)查的投訴報告了原料藥效價不達標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)護目鏡
(b)(4) scoop in (b)(4) API
原料藥里發(fā)現(xiàn)料勺
Your response stated that you will initiate a corrective act
你們的回復說你們會啟動CAPA計劃，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 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 that your firm acknowledged could exist.
你們的回復是不充分的，因為你們對于我們調(diào)查員在你們倉庫地面上發(fā)現(xiàn)的表上列出的17個投訴的回復性調(diào)查保持沉默。你們的回復也沒有說明對你們投訴處理程序和記錄規(guī)范的改進，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 from U.S. customers, your firm uses shared equipment, personnel, and materials to manufacture products for multiple markets, including the United States. Your firm’s poor complaint handling practices and your inability to prevent and detect product quality defects, such as filth, indicate significant lapses in your firm’s quality system. You are responsible for ensuring that 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備、人員和物料來生產(chǎn)藥品供給多個市場，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)量體系的嚴重失策。你們有責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。你們還有責任采取適當?shù)腃APA。
In response to this letter, provide the following:
在回復此信函時，請?zhí)峁┮韵聝?nèi)容：
a summary of your investigations of all complaints received since 2012, noting whether each complaint is logged 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CAPA
your improved complaint handling procedure and details of any further controls implemented to ensure that all complaints are logged, documented, and 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)查所實施的所有進一步控制方法
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 discarded 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 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 da
你們的回復中聲稱你們質(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，你們的回復是不充分的，因為你們沒有說明你們是否準備進行回顧性調(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)量部門是否準備對所有批生產(chǎn)記錄進行準確性審核，調(diào)查所有差異。
In response to this letter, provide the following:
在對此信函的回復中，請?zhí)峁┮韵聝?nèi)容：
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)
a retrospective review of all batch production records for lots within expiry, including an evaluation of the effect of any discrepancies on API batch quality
你們對尚在有效期內(nèi)的所有批次的生產(chǎn)記錄進行回顧性審核，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，的準確性和保存所采取的措施和控制方式
documentation that your employees are adequately 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，在生產(chǎn)同時同步并準確完成批生產(chǎn)記錄，調(diào)查生產(chǎn)記錄差異，以及理解準確記錄保存和產(chǎn)品質(zhì)量之間關聯(lián)的培訓文件記錄
3. Failure of computerized systems to have sufficient controls to prevent unauthorized access or changes to da
計算機化系統(tǒng)沒有充分的控制，無法防止未經(jīng)授權(quán)的進入以及更改數(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 sufficient 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的計算機系統(tǒng)，其中記錄了藥品是否符合質(zhì)量標準，沒有充分的控制來防止在質(zhì)量部門批準之后，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 demonstrated for our investigator how results on an already finalized CoA could be manipulated after the formal quality unit approval. Also, the quality unit’s 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)查員審核存貯于16號計算機的某COA時，所有COA均經(jīng)過質(zhì)量部門批準。一個經(jīng)理向我們調(diào)查員演示在正式的質(zhì)量部門批準之后，如何對已經(jīng)定稿的COA的結(jié)果進行篡改。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)過認證的電子簽名。
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 how this system will prevent unauthorized access or da
你們的回復中說，你們公司計劃實施一個ERP系統(tǒng)。你們的回復是不充分的，因為你們沒有提供足夠細節(jié)說明此系統(tǒng)如何防止非法進入和數(shù)據(jù)篡改，也沒有說明你們安裝和驗證此系統(tǒng)的時間框架。另外，你們沒有審核和確認你們已經(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:
在回復此信函時，請?zhí)峁┮韵聝?nèi)容：
a CAPA plan for controlling access to computer systems for all laboratory and manufacturing records and equipment
一份CAPA計劃，說明如何控制所有化驗室、生產(chǎn)記錄和設備用計算機系統(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)和嚴格控制你們生產(chǎn)和實驗室系統(tǒng)權(quán)限的計劃
a detailed summary of your steps to train personnel on the proper use of computerized systems
一份詳細的總結(jié)，說明你們培訓員工正確使用計算機化系統(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?shù)臏y試程序來確保原料藥符合既定的質(zhì)量和/或純度標準。
Our investigator found numerous “invalid” moisture content results while reviewing da
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，因為你們原料藥中超量的水份可能會導致質(zhì)量缺陷，如化學降解和/或微生物滋生。
During the inspection and in your written response, you referred to the invalid assay results as “out of specification” (OOS). You say that your staff failed to report the invalid results because they were not aware of the reporting and documentation requirements. You also say that you are revising your OOS procedure.
在檢查期間以及在你們書面回復中，你們將無效的含量結(jié)果稱為“超標（OOS）”結(jié)果。你們說你們員工沒有將無效結(jié)果報告上來，因為他們不明白報告和記錄的要求。你們還說你們正在修訂你們的OOS程序。
Your response is inadequate because, although you conducted a failure investigation, you did not provide us with sufficient detail about your investigation or its findings, such as whether your firm retrospectively investigated the “invalid” results or took necessary corrective actions. These problems have persisted for approximately three years without adequate resolution.
你們的回復是不充分的，因為盡管你們實施了失敗調(diào)查，但你們沒有給我們提供關于你們調(diào)查的細節(jié)和調(diào)查所發(fā)現(xiàn)的問題，例如，是否你們公司對“無效”結(jié)果進行了回顧性調(diào)查，以及有沒有采取必需的糾正措施。這些問題持續(xù)了近三年都沒有充分地解決掉。
In response to this letter, provide the following:
在對本信函的回復中，請?zhí)峁┮韵聝?nèi)容：
an evaluation of all laboratory methods to determine their suitabitily and copies of all validation reports for methods you will continue to use
對所有化驗室方法的評估，以確定其適用性，提供所有你們將要持續(xù)使用的方法的驗證報告的副本
an action plan to replace any method found to be unsuitable for its intended use
一份替換所有發(fā)現(xiàn)不適合于其既定用途的方法的行動計劃
all original and retest results for moisture content for all API lots within expiry and distributed since 2012
所有仍在有效期內(nèi)的以及自2012年開始銷售的原料藥所有批次水分的原始結(jié)果和復測結(jié)果
your actions to ensure all laboratory discrepancies, including any OOS or “invalid” results for any API lot within expiry, have been fully documented, investigated, and resolved
你們確保所有化驗室差異，包括所有仍在有效期內(nèi)的原料藥批次的所有OOS或“無效”結(jié)果，已經(jīng)充分記錄、調(diào)查和解決的措施
your actions to ensure that any future laboratory discrepancies, including OOS or “invalid” results, will be adequately documented and resolved prior to API release for distribution
你們確保所有未來的化驗室差異，包括OOS或“無效”結(jié)果，在原料藥放行銷售之前將被充分記錄和解決的措施
Conclusion
Deviations cited in this letter are not intended to be an all-inclusive list. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations.
Your quality system does not securely and reliably retain your manufacturing da
來源：Julia Blog，感謝朱玉姣老師。
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