2009－2011年FDA警告信涉及HPLC的内容

情非得已

2009－2011年FDA警告信涉及HPLC的内容

欧盟符合性研究院（ECA）Günter Brendelberger博士在2012年2月28日发布了：2009－2011年FDA警告信中涉及高效液相色谱法的主要问题。内容非常好。

在使用高效液相色谱（HPLC）存在的关键问题包括以下4个方面：

2.校准/确认
3.方法验证
4.系统的适用性/序列

全部译文如下：

            2009–2011年FDA警告信涉及HPLC的内容

1. Raw Data / Protection of Electronic Records 电子记录的原始数据/保护

Your firm lacks systems to ensure that all electronic data generated in your Quality Control laboratory is secure and remains unaltered. All analysts have system administrator privileges that allow them to modify, overwrite, and delete original raw data files … in the High Performance Liquid Chromatography (HPLC) units.贵公司缺乏系统以确保所有的在质量控制实验室产生的电子数据是安全的并保持不变。你们HPLC岗位所有的分析员都具有系统管理员的权限去修改，覆盖并删除原始数据。

There are no procedures that address the security measures in place for generation and modification of electronic data files for these instruments used for raw material, in-process,finished product and stability testing. In addition, your firm's review of laboratory data does not include a review of an audit trail or revision history to determine if unapproved changes have been made. 没有建立一个程序规定如何对原材料、中间控制、成品和稳定性测试的电子文件进行安全保存和修改。贵公司的实验室数据审查并不包括审计跟踪或未经批准修改数据的历史记录审查。

For example,your firm has failed to periodically conduct back-up procedures This server was used to store, back-up, and/or archive raw test data from computer systems (Software:…controlling and monitoring… High-performance liquid chromatography (HPLC) systems in accordance to SOP …”.例如贵公司未能按SOP的要求对服务器上存贮的原始数据进行定期备份。
Your response, however, is inadequate because you fail to adequately address whether you were able to recover the critical data not backed-up between August 2010 and when you first implemented the daily backup process. Your firm has yet to indicate whether HPLC raw data records could be retrieved for the duration of time that the … server was not backing-up the HPLC system data.你们的回复是不适当的，因为你们不能充分叙述2010年8月是否对关键数据进行了备份，2010年8月是你们第一次执行备份程序。贵公司还不能表明能否找到那段时间的HPLC原始数据，…服务器不支持备份HPLC系统数据。

Your firm's laboratory analysts have the ability to access and delete raw chromatographic data located on the … of … used to conduct HPLC testing. Due to this unrestrictive access, there is no assurance that laboratory records and raw data are accurate and valid.贵公司实验室分析员个具有访问和删除原始色谱数据的权力，你们这种不受限制的访问无法保证实验记录和原始数据的准确性和有效性。

You replaced the … HPLC systems operating on … software with … new qualified HPLC units from … software. This validation information will be reviewed at the next inspection. In addition, your response is inadequate because it lacks a retrospective evaluation of the data from the former HPLC units.你们回复说更换了高效液相色谱系统的操作软件......我们将会在下次检查中确认你们进行的验证相关文件。此外，你们的回复是不充足的，因为缺乏对过去PHLC岗位数据的回顾性评价。

For the testing of incoming components, your firm failed to conduct HPLC system qualification using certified standards and validated procedures … . Your laboratory failed to certify … against a primary standard from an ccredited institution and/or to fully characterize the material as a standard.对进厂组份检验，贵公司不能使用权威部门的标准品对HPLC系统进行确认与验证。你们实验室未能证明你们使用的标准品是合法性，或从认可机构购置和/或从用基准标准品标定工作标准品。
Your firm failed to conduct injector and detector performance testing for the … HPLC system. For example, no HPLC injector and detector testing for linearity, accuracy, and precision were conducted, such as: 1) various injection volumes and standard concentration testing; 2) evaluation of detector for noise/drift; and 3) carryover testing to evaluate response at low levels to determine the detection of possible interferences that may affect peaks of interest.贵公司没有对HPLC的注样器和检测器进行性能测试。例如，没有对HPLC注样器和检测器进行线性，准确度，精度度确认。例如：1）不同注射量和标准液的测试；2）对检测器的噪音/漂移评估；3）残留试验，来评估低峰响应时，确定可检测出可能干扰主峰的残留。
Your HPLC calibration lacks a carry over test (sample injection residual test), sample energy (intensity of light source), and lamp use hours determination.你们的HPLC校准缺少进样残留试验，能源（光源强度），灯泡使用时间的测定内容。

Your firm also fails to maintain raw data associated with the re-qualification and calibration of your laboratory instruments. During the inspection the investigators were informed that the annual 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 the qualification and calibration of your instruments and data to demonstrate that your quality unit reviewed and approved the work performed by your contractor. 贵公司不能对实验室仪器进行重新确认和校准来维护原始数据。在考察期间调查员要求你们要对实验室设备进行年度重新确认和校准（例如，高效液相色谱仪，气相色谱，旋光仪，分析天平），然而你们无法提供重新确认和校准的原始数据或文件和质量部门审核文件，和承包商审查的批准文件。

3. Method Validation 方法验证

Your firm failed to generate and document chromatographic data to support the validation of the analytical method .. used for the determination of Urea in Urea Cream 40%. In addition, your firm failed to generate a and document chromatographic data to support stress studies …to demonstrate that the method is suitable for determining stability.贵公司没有色谱数据来支持分析方法的验证......该方法用于40％尿素霜的测定。此外，贵公司没有色谱数据来支持降解实验研究和该方法是否适用于稳定性研究。

Your firm has not verified that the preservatives and API test methods using the … System is adequate for its intended use. The … system is different from the previously used … HPLC system in make, model, and column. In addition, your analysis of … in finished product does not identify the maximum adjustment in mobile phase to obtain a suitable resolution between peaks … .贵公司没有确认因使用不同HPLC仪器、型号、柱子时测定防腐剂和API方法是否适当。此外，对某制剂的分析方法没有确认流动相的最大调整量从而获得合适的分离度。
You failed to include testing for method precision and ruggedness in your HPLC Assay Method Validation … . We are concerned that you have not established the degree of reproducibility or repeatability of the analytical procedure under normal operating conditions. In addition, you failed to establish adequate system suitability parameters to ensure that the complete testing system (including instrument, reagents, columns, and analysts) continues to operate suitably for the intended application.在HPLC分析方法验证中，你们没有包括精度度和耐用性验证....我们关注的是你们不能建立在正常条件下重复性或重复性限度要求。此外，你们还没有建立足够的系统适用性参数来确保该测试系统（包括仪器，试剂，柱和分析师）符合预期的用途。

Your firm failed to include the following characteristics: accuracy, robustness, ruggedness and specificity in your validation of the HPLC assay method … used for the analysis of Pyridoxine Hydrochloride (Vitamin B6), Riboflavin 5' Phosphate Sodium (Vitamin B2) and Thiamine Hydrochloride (Vitamin B1) in Poly-Vitamin Drop products.在你们的HPLC分析方法验证中缺少准确度，耐用性，再现性和专属性的验证，该方法用于测定在聚维滴剂产品中维生素B6、核黄素维生素B2、维生素B1的测定。

情非得已

4. System Suitability / Sequences系统的适用性/序列

Your GC and HPLC analyses for both finished products and raw materials lack appropriate system suitability determinations. Your SOP … each specify three standard solution injections. Both methods are used for testing of drug products at batch release and during stability study.你们的GC和HPLC在成品和原料的测定中缺乏适当的系统适用性实验，这两种方法都用于药品的放行检测和稳定性研究。
Our concern is that you may not be evaluating the signal to noise ratio during system suitability. Evaluation of the signal to noise ratio during system suitability is a normal laboratory practice when testing low level impurities or degradant content by HPLC.我们关注的是你们可能未在系统适应性中评估信噪比。当用HPLC 检测低含量的杂质和降解产物时，通常在系统适应性中评估信噪比。

Failure to ensure that approved test procedures for …. HPLC are followed. For example, the inspection found no scientific justification for the current sequence of chromatographic injections performed, which is different to the sequence included in the approved analytical method.没有遵守已批准的HPLC程序要求进行检测，例如在检查中发现操作者使用没有任何科学道理的色谱进样序列，也跟批准的分析序列不同。
We remain concerned about current laboratory practices, in that not all injection results are being reported. For example, the assay test for lots … failed to include all the injection results performed as part of the chromatographic run. Your response provides no explanation regarding why analytical results are selectively reported. 我们仍然关注目前你们实验室还存在没有被发现的其它做法。例如很多含量测试没有包括实际运行进样的所有色谱结果。你们的回复也没有解释为什么选择性使用色谱分析结果。

Your system suitability test requires that … injections of standard be performed and that a Relative Standard Deviation (RSD) of … % be met in order for the test to be acceptable. This acceptance criterion is contrary to the USP requirement chapter <621>. During our inspection, you were unable to provide validation data to support your current RSD criteria. Your response is inadequate in that you failed to provide scientific rationale to justify the change in your analytical method for system suitability requirements. In response to this letter, please provide a valid % RSD and the analytical data to support it.你们的系统适用性实验要求…注射标准液计算RSD以符合接受标准，这个接受标准与USP通用要求<621>相反。在我们检查期间，你们不能提供验证数据来支持你们当前的RSD接受标准。你们的回复是不充分的，没有提供科学的依据证明变更方法的系统适用性实验要求。在这个回复信中请你们提供有效证的RSD和分析数据来支持。

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