Via UPS??????????????????????????????????????????Warning Letter 320-17-39

June 22, 2017

Mr. Liu Jian Hua

Professor and Director

Shandong Analysis and Test Center

19 Keyuan Road

Jinan, Shandong, China 250014

Dear Mr. Liu Jian Hua:

　　The U.S. Food and Drug Administration (FDA) inspectedyour drug manufacturing facility, Shandong Analysis and Test Center at 19Keyuan Road, Jinan, Shandong, from January 16–18, 2017.

　　美國FDA于2017年1月16-18日檢查了你們位于山東省濟南市歷下區(qū)科院路19號的藥品生產(chǎn)場所---山東省分析檢測中心。

　　This warning letter summarizes significant deviationsfrom current good manufacturing practice (CGMP) for active pharmaceuticalingredients (API).

　　本警告信總結(jié)了原料藥生產(chǎn)嚴重違反CGMP的行為。

　　Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, your APIare 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).

　　由于你們的原料藥生產(chǎn)、加工、包裝或保存的方法、場所或控制不符合CGMP要求，你們的原料藥根據(jù)FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被認為是摻假藥品。

　　We reviewed your February 20, 2017 response indetail.

　　我們詳細審核了你們公司2017年2月20日的回復(fù)。

　　During our inspection, our investigators observedspecific deviations including, but not limited to, the following.

　　檢查期間，我們的調(diào)查人員發(fā)現(xiàn)的具體問題包括但不僅限于以下：

　　1. Failure to ensure thattest procedures are scientifically sound and appropriate to ensure that yourAPI conform to established standards of quality and/or purity.

　　未能確保檢測程序科學(xué)合理適當，無法確保你們的API符合既定的質(zhì)量和/或純度標準。

　　Your site is a contract testing lab that analyzessamples of heparin and heparin-related drugs for the presence of over-sulfatedchondroitin sulfate (OSCS) using Nuclear Magnetic Resonance (NMR)spectroscopy.

　　你們的場所是肝素和肝素相關(guān)藥品樣品分析的委托化驗室，提供多硫酸軟骨素(OSCS)項目核磁共振(NMR)檢測服務(wù)。

　　You failed to routinely establish system suitabilitywhen testing samples for OSCS.

　　你們在檢測樣品的OSCS項目時，日常檢測未運行系統(tǒng)適用性。

　　Furthermore, on December 26, 2014, you conducted asystem suitability test that failed. You did not investigate why your equipmentfailed system suitability for detection of OSCS, or determine the reliabilityof other OSCS tests conducted prior to the date of the system suitabilityfailure.

　　另外，2014年12月26日，你們運行了系統(tǒng)適用性，但系統(tǒng)適用性失敗。你們未調(diào)查為什么儀器的OSCS檢測用系統(tǒng)適用性會失敗，也沒有確定該系統(tǒng)適用性失敗之前其它OSCS檢測結(jié)果是否可靠。

　　In your response, you acknowledge that your laboratoryperformed system suitability infrequently, noting that “the heparin standards(USP) and OSCS were detected at least (b)(4).” You committed toroutinely establish system suitability before analyzing batch samples in thefuture.

　　在你們的回復(fù)中，你們說你們化驗室很少運行系統(tǒng)適用性，因為你們看到“肝素標準品(USP)和OSCS至少在XX中檢出”。你們承諾會在將來進行樣品分析之前常規(guī)運行系統(tǒng)系統(tǒng)性。

　　Your response is inadequate because you did notinvestigate the validity of all test results for OSCS in heparin orheparin-related drugs during the period in which you failed to conduct systemsuitability in coordination with sample analyses.

　　你們的回復(fù)是不充分的，因為你們沒有調(diào)查你們未運行系統(tǒng)適用性期間樣品分析中肝素或肝素相關(guān)藥物中OSCS所有檢測結(jié)果的有效性。

　　System suitability testing determines whetherrequirements for precision are satisfied and ensures the NMR spectrometer isfit for the intended testing before analyzing samples. It is critical that yoursystem be demonstrated as suitable for detecting OSCS contamination in heparinto avoid the possibility of samples erroneously passing when an instrument isnot working properly.

　　系統(tǒng)適用性檢測決定了精密度是否滿足要求，在開始樣品分析之前確保NMR儀器適合既定檢測。證明系統(tǒng)適合于檢出肝素中的OSCS污染，避免儀器不正常工作時使得樣品錯誤地通過檢測是非常重要的。

　　For further reference regarding heparin, see theguidance for industry Heparin for Drug and Medical Device Use: MonitoringCrude Heparin for Quality at　　關(guān)于肝素的更多參考資料，參見行業(yè)指南：藥用和醫(yī)療器械用肝素：監(jiān)測肝素粗品的質(zhì)量。

　　2. Failure to prevent unauthorizedaccess or changes to data, and to provide adequate controls to preventmanipulation and omission of data.

　　未能防止未經(jīng)授權(quán)進入和修改數(shù)據(jù)，未能提供足夠的控制以防止數(shù)據(jù)修改和刪除。

　　Your quality control unit did not have basic controlsto prevent changes to your electronically-stored laboratory data. During ourinspection, we requested that you display original electronic data for analysisof heparin and heparin-related drug samples. Your analyst was unable to retrieverequested data, and explained that he deletes older data to make space fornewly acquired data.

　　你們質(zhì)量控制部門沒有基本的控制用以防止對你們電子存貯實驗室數(shù)據(jù)的修改。在我們的檢查期間，我們要求你們顯示肝素和肝素相關(guān)藥物樣品分析的原始電子數(shù)據(jù)。你們的化驗員未能恢復(fù)所要求展示的數(shù)據(jù)，還解釋說他刪除了舊數(shù)據(jù)，給新產(chǎn)生的數(shù)據(jù)騰出空間。

　　In your response, you committed to revise proceduresregarding analyst computer permission levels, but did not address the data thatwas deleted.

　　在你們的回復(fù)中，你們承諾說要修訂化驗室計算機許可水平的程序，但沒有說明數(shù)據(jù)刪除的問題。

　　Access to information during inspection檢查期間信息獲取

　　During the inspection, you provided a document listingthe names of (b)(4) customers for which you performed testing. However,you only provided additional requested information, such as sample informationand test results, regarding (b)(4) of these customers. You stated thatyou would not provide data related to testing performed for other customersuntil you obtained their prior consent.

　　在檢查期間，你們提供了一份文件，其中列出了你們受委托進行檢測的客戶名稱。但是，你們只是提供了我們要求查看的與這些客戶的XX有關(guān)的其它信息，如樣品信息和檢測結(jié)果。你們說你們不能提供為其它客戶所檢測的樣品數(shù)據(jù)，除非獲得其許可。

　　For example, you failed to provide informationpertaining to samples analyzed for (b)(4), a firm that produces heparinand heparin-related drugs for the U.S. supply chain.

　　例如，你們未能提供包含有為XX客戶所檢測的樣品的信息。該公司為美國供應(yīng)鏈生產(chǎn)肝素和肝素有關(guān)藥品。

　　When an owner, operator, or agent delays, denies,limits, or refuses an inspection, the drugs manufactured, processed, packed, orheld in the facility may be deemed adulterated under section 501(j) of theFD&C Act. See FDA’s guidance document, Circumstances thatConstitute Delaying, Denying, Limiting, or Refusing a Drug Inspection, at　　當一個場所的所有人、操作員或代理延誤、否決、限制和拒絕檢查時，在該場所生產(chǎn)、加工、包裝和存貯的藥品根據(jù)FDCA的501(j)會被作為摻假藥。參見上述指南。

　　Conclusion結(jié)論

　　The deviations cited in this letter are not intendedas an all-inclusive list. You are responsible for investigating the deviations,for determining the causes, for preventing their recurrence, and for preventingother deviations.

　　在此函中所引用的偏差并不是全部。你們有責(zé)任對這些偏差進行調(diào)查，確定原因，防止其再次發(fā)生，防止其它偏差的發(fā)生。

　　Until you correct all deviations completely and weconfirm your compliance with CGMP, FDA may withhold approval of any newapplications or supplements listing your firm as a drug manufacturer.

　　在貴公司未能完成所有偏差糾正并且由我們確認你們符合CGMP之前，F(xiàn)DA可能會擱置所有將你公司列為藥品生產(chǎn)的新申報和增補申報的批準。

　　Failure to correct these deviations may also result inFDA refusing admission of articles manufactured at Shandong Analysis and TestCenter at 19 Keyuan Road, Jinan, Shandong, into the United States under section801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority,articles may be subject to refusal of admission, in that the methods andcontrols used in their manufacture do not appear to conform to CGMP within themeaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

　　未能糾正這些偏差可能還會導(dǎo)致FDA依據(jù)FDCA第801(a)(3)條和21 U.S.C. 381(a)(3)拒絕接受在上述地址生產(chǎn)的產(chǎn)品進入美國。

　　After you receive this letter, respond to this officein writing within 15 working days. Specify what you have done since ourinspection to correct your deviations and to prevent their recurrence. If youcannot complete corrective actions within 15 working days, state your reasonsfor delay and your schedule for completion.

　　在收到此函后，請在15個工作日內(nèi)回復(fù)至本辦公室。在回復(fù)中說明自從檢查后，你們做了哪些工作來糾正你們的偏差，防止其再次發(fā)生。如果不能在15個工作日內(nèi)完成糾正措施，說明延遲的原因以及完成計劃。

　　Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.govor mail your reply to:

　　請將你們的電子回復(fù)發(fā)送至上述郵箱或者以下地址：

Rokhsana Safaai-Jazi

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3011060456.

Sincerely,

/S/

Thomas J. Cosgrove, J.D.

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

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