2009－2011年FDA警告信涉及HPLC的內(nèi)容
歐盟符合性研究院（ECA）GünterBrendelberger博士昨天（2012年2月28日）發(fā)布了：2009－2011年FDA警告信中涉及高效液相色譜法的主要問(wèn)題。內(nèi)容非常好，我快速進(jìn)行了翻譯。
在使用高效液相色譜（HPLC）存在的關(guān)鍵問(wèn)題包括以下4個(gè)方面：
1.電子記錄的原始數(shù)據(jù)/保護(hù)2.校準(zhǔn)/確認(rèn)3.方法驗(yàn)證4.系統(tǒng)的適用性/序列
原文鏈接： Go here to access the complete list of FDAfindings regarding HPLC.
全部譯文如下：
2009–2011年FDA警告信涉及HPLC的內(nèi)容
1.Raw Data / Protection of Electronic Records 電子記錄的原始數(shù)據(jù)/保護(hù)
Yourfirm lacks systems to ensure that all electronic data generated in your QualityControl laboratory is secure and remains unaltered. All analysts have systemadministrator privileges that allow them to modify, overwrite, and deleteoriginal raw data files … in the High Performance Liquid Chromatography (HPLC)units.貴公司缺乏系統(tǒng)以確保所有的在質(zhì)量控制實(shí)驗(yàn)室產(chǎn)生的電子數(shù)據(jù)是安全的并保持不變。你們HPLC崗位所有的分析員都具有系統(tǒng)管理員的權(quán)限去修改，覆蓋并刪除原始數(shù)據(jù)。
Thereare no procedures that address the security measures in place for generationand modification of electronic data files for these instruments used for rawmaterial, in-process,finished product and stability testing. In addition, yourfirm's review of laboratory data does not include a review of an audit trail orrevision history to determine if unapproved changes have been made. 沒(méi)有建立一個(gè)程序規(guī)定如何對(duì)原材料、中間控制、成品和穩(wěn)定性測(cè)試的電子文件進(jìn)行安全保存和修改。貴公司的實(shí)驗(yàn)室數(shù)據(jù)審查并不包括審計(jì)跟蹤或未經(jīng)批準(zhǔn)修改數(shù)據(jù)的歷史記錄審查。
Forexample,your firm has failed to periodically conduct back-up procedures Thisserver was used to store, back-up, and/or archive raw test data from computersystems (Software:…controlling and monitoring… High-performance liquidchromatography (HPLC) systems in accordance to SOP …”.例如貴公司未能按SOP的要求對(duì)服務(wù)器上存貯的原始數(shù)據(jù)進(jìn)行定期備份。
Yourresponse, however, is inadequate because you fail to adequately address whetheryou were able to recover the critical data not backed-up between August 2010and when you first implemented the daily backup process. Your firm has yet toindicate whether HPLC raw data records could be retrieved for the duration oftime that the … server was not backing-up the HPLC system data.你們的回復(fù)是不適當(dāng)?shù)?，因?yàn)槟銈儾荒艹浞謹(jǐn)⑹?010年8月是否對(duì)關(guān)鍵數(shù)據(jù)進(jìn)行了備份，2010年8月是你們第一次執(zhí)行備份程序。貴公司還不能表明能否找到那段時(shí)間的HPLC原始數(shù)據(jù)，…服務(wù)器不支持備份HPLC系統(tǒng)數(shù)據(jù)。
Your firm's laboratory analysts have theability to access and delete raw chromatographic data located on the … of …used to conduct HPLC testing. Due to this unrestrictive access, there is noassurance that laboratory records and raw data are accurate and valid.貴公司實(shí)驗(yàn)室分析員個(gè)具有訪(fǎng)問(wèn)和刪除原始色譜數(shù)據(jù)的權(quán)力，你們這種不受限制的訪(fǎng)問(wèn)無(wú)法保證實(shí)驗(yàn)記錄和原始數(shù)據(jù)的準(zhǔn)確性和有效性。
2.Calibration / Qualification 校準(zhǔn)/確認(rèn)
Youreplaced the … HPLC systems operating on … software with … new qualified HPLCunits from … software. This validation information will be reviewed at the nextinspection. In addition, your response is inadequate because it lacks aretrospective evaluation of the data from the former HPLC units.你們回復(fù)說(shuō)更換了高效液相色譜系統(tǒng)的操作軟件......我們將會(huì)在下次檢查中確認(rèn)你們進(jìn)行的驗(yàn)證相關(guān)文件。此外，你們的回復(fù)是不充足的，因?yàn)槿狈?duì)過(guò)去PHLC崗位數(shù)據(jù)的回顧性評(píng)價(jià)。
For the testing of incoming components,your firm failed to conduct HPLC system qualification using certified standardsand validated procedures … . Your laboratory failed to certify … against aprimary standard from an ccredited institution and/or to fully characterize thematerial as a standard.對(duì)進(jìn)廠(chǎng)組份檢驗(yàn)，貴公司不能使用權(quán)威部門(mén)的標(biāo)準(zhǔn)品對(duì)HPLC系統(tǒng)進(jìn)行確認(rèn)與驗(yàn)證。你們實(shí)驗(yàn)室未能證明你們使用的標(biāo)準(zhǔn)品是合法性，或從認(rèn)可機(jī)構(gòu)購(gòu)置和/或從用基準(zhǔn)標(biāo)準(zhǔn)品標(biāo)定工作標(biāo)準(zhǔn)品。
Yourfirm failed to conduct injector and detector performance testing for the … HPLCsystem. For example, no HPLC injector and detector testing for linearity, accuracy,and precision were conducted, such as: 1) various injection volumes andstandard concentration testing; 2) evaluation of detector for noise/drift; and3) carryover testing to evaluate response at low levels to determine thedetection of possible interferences that may affect peaks of interest.貴公司沒(méi)有對(duì)HPLC的注樣器和檢測(cè)器進(jìn)行性能測(cè)試。例如，沒(méi)有對(duì)HPLC注樣器和檢測(cè)器進(jìn)行線(xiàn)性，準(zhǔn)確度，精度度確認(rèn)。例如：1）不同注射量和標(biāo)準(zhǔn)液的測(cè)試；2）對(duì)檢測(cè)器的噪音/漂移評(píng)估；3）殘留試驗(yàn)，來(lái)評(píng)估低峰響應(yīng)時(shí)，確定可檢測(cè)出可能干擾主峰的殘留。
YourHPLC calibration lacks a carry over test (sample injection residual test),sample energy (intensity of light source), and lamp use hours determination.你們的HPLC校準(zhǔn)缺少進(jìn)樣殘留試驗(yàn)，能源（光源強(qiáng)度），燈泡使用時(shí)間的測(cè)定內(nèi)容。
Your firm also fails to maintain raw dataassociated with the re-qualification and calibration of your laboratoryinstruments. During the inspection the investigators were informed that theannual re-qualification and calibration of your laboratory equipment (e.g.,HPLC, GC, polarimeter, and analytical balance) is performed by the … . However,you were unable to provide raw data or documentation regarding thequalification and calibration of your instruments and data to demonstrate thatyour quality unit reviewed and approved the work performed by your contractor. 貴公司不能對(duì)實(shí)驗(yàn)室儀器進(jìn)行重新確認(rèn)和校準(zhǔn)來(lái)維護(hù)原始數(shù)據(jù)。在考察期間調(diào)查員要求你們要對(duì)實(shí)驗(yàn)室設(shè)備進(jìn)行年度重新確認(rèn)和校準(zhǔn)（例如，高效液相色譜儀，氣相色譜，旋光儀，分析天平），然而你們無(wú)法提供重新確認(rèn)和校準(zhǔn)的原始數(shù)據(jù)或文件和質(zhì)量部門(mén)審核文件，和承包商審查的批準(zhǔn)文件。
3.Method Validation 方法驗(yàn)證
Yourfirm failed to generate and document chromatographic data to support thevalidation of the analytical method .. used for the determination of Urea inUrea Cream 40%. In addition, your firm failed to generate a and documentchromatographic data to support stress studies …to demonstrate that the methodis suitable for determining stability.貴公司沒(méi)有色譜數(shù)據(jù)來(lái)支持分析方法的驗(yàn)證......該方法用于40％尿素霜的測(cè)定。此外，貴公司沒(méi)有色譜數(shù)據(jù)來(lái)支持降解實(shí)驗(yàn)研究和該方法是否適用于穩(wěn)定性研究。
Your firm has not verified that thepreservatives and API test methods using the … System is adequate for itsintended use. The … system is different from the previously used … HPLC systemin make, model, and column. In addition, your analysis of … in finished productdoes not identify the maximum adjustment in mobile phase to obtain a suitableresolution between peaks … .貴公司沒(méi)有確認(rèn)因使用不同HPLC儀器、型號(hào)、柱子時(shí)測(cè)定防腐劑和API方法是否適當(dāng)。此外，對(duì)某制劑的分析方法沒(méi)有確認(rèn)流動(dòng)相的最大調(diào)整量從而獲得合適的分離度。
Youfailed to include testing for method precision and ruggedness in your HPLCAssay Method Validation … . We are concerned that you have not established thedegree of reproducibility or repeatability of the analytical procedure undernormal operating conditions. In addition, you failed to establish adequatesystem suitability parameters to ensure that the complete testing system(including instrument, reagents, columns, and analysts) continues to operatesuitably for the intended application.在HPLC分析方法驗(yàn)證中，你們沒(méi)有包括精度度和耐用性驗(yàn)證....我們關(guān)注的是你們不能建立在正常條件下重復(fù)性或重復(fù)性限度要求。此外，你們還沒(méi)有建立足夠的系統(tǒng)適用性參數(shù)來(lái)確保該測(cè)試系統(tǒng)（包括儀器，試劑，柱和分析師）符合預(yù)期的用途。
Yourfirm failed to include the following characteristics: accuracy, robustness,ruggedness and specificity in your validation of the HPLC assay method … usedfor the analysis of Pyridoxine Hydrochloride (Vitamin B6), Riboflavin 5' PhosphateSodium (Vitamin B2) and Thiamine Hydrochloride (Vitamin B1) in Poly-VitaminDrop products.在你們的HPLC分析方法驗(yàn)證中缺少準(zhǔn)確度，耐用性，再現(xiàn)性和專(zhuān)屬性的驗(yàn)證，該方法用于測(cè)定在聚維滴劑產(chǎn)品中維生素B6、核黃素維生素B2、維生素B1的測(cè)定。
4.System Suitability / Sequences系統(tǒng)的適用性/序列
YourGC and HPLC analyses for both finished products and raw materials lackappropriate system suitability determinations. Your SOP … each specify threestandard solution injections. Both methods are used for testing of drugproducts at batch release and during stability study.你們的GC和HPLC在成品和原料的測(cè)定中缺乏適當(dāng)?shù)南到y(tǒng)適用性實(shí)驗(yàn)，這兩種方法都用于藥品的放行檢測(cè)和穩(wěn)定性研究。
Ourconcern is that you may not be evaluating the signal to noise ratio duringsystem suitability. Evaluation of the signal to noise ratio during systemsuitability is a normal laboratory practice when testing low level impuritiesor degradant content by HPLC.我們關(guān)注的是你們可能未在系統(tǒng)適應(yīng)性中評(píng)估信噪比。當(dāng)用HPLC 檢測(cè)低含量的雜質(zhì)和降解產(chǎn)物時(shí)，通常在系統(tǒng)適應(yīng)性中評(píng)估信噪比。
Failure to ensure that approved testprocedures for …. HPLC are followed. For example, the inspection found noscientific justification for the current sequence of chromatographic injectionsperformed, which is different to the sequence included in the approvedanalytical method.沒(méi)有遵守已批準(zhǔn)的HPLC程序要求進(jìn)行檢測(cè)，例如在檢查中發(fā)現(xiàn)操作者使用沒(méi)有任何科學(xué)道理的色譜進(jìn)樣序列，也跟批準(zhǔn)的分析序列不同。
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