FDA 新版批准前检查手册精华导读 II:数据可靠性的风险信号
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FDA 新版批准前检查手册精华导读 II:数据可靠性的风险信号
笔记 2019-09-10 上周五识林资讯中介绍了FDA 8月13日发布的新版批准前检查手册的第一部分导读,关于三大检查目标的第一个:商业化生产是否准备就绪,另外两个目标是与申报资料的一致性和数据可靠性,这两条本质都是监管机构与企业建立信任的依据,区别是申报资料一致性强调申报资料本身的可信程度,关注于资料和产品;而数据可靠性可能是申报资料未直接覆盖的内容,或者产生申报资料中数据或支持其中论述的依据,更关注整体和体系。 本文介绍在批准前检查中,FDA如何指导其检查员发现和识别可能的数据可靠性问题信号。 Audit the accuracy and completeness of data reported by the facility for the product. Not every CMC data summary must be audited to accomplish this objective. The inspectional strategy may select key data sets from drug development (e.g., formulation development, Stage 1 of process validation) or randomly select data filed in the application. Generally, data on finished product stability, dissolution, content uniformity, and API impurity are good candidates for this audit. 审核设施报告的产品数据的准确性和完整性。不是所有的CMC数据汇总都需要被检查到才可完成这部分目标。检查策略可以是选择关键数据或者随机选择检查申报资料中的数据。一般来说,成品稳定性考察数据,溶出度,含量均一性,API杂质谱等都可以是审计的备查内容。 识林点评:尽管FDA明确指导其检查员不必面面俱到的检查所有数据,但仍列出成品稳定性考察数据,溶出度,含量均一性,API杂质谱四项数据作为可靠性检查的切入点,也是企业自查和风险控制的关键点。 In addition to summary tables, applicants typically submit additional testing for the finished product’s performance and physicochemical attributes. During the inspection, compare raw data—hardcopy or electronic—such as chromatograms, spectrograms, laboratory analyst notebooks, and additional information from the laboratory with summary data filed in the CMC section. Raw data files should support a conclusion that the data/information reported by the site are complete and accurate. Examples of data integrity concerns include failure to scientifically justify not reporting relevant data, such as aberrant test results or absences in a submitted chromatographic sequence. 除了汇总表,申请人一般都会附加对成品特性和理化属性的检测结果。在检查过程中,要将原始数据(纸质的或电子的,比如,色谱图,光谱图,实验室分析人员笔记本,实验室附加信息)与CMC版块中的数据汇总进行对比。原始数据文件应支持该厂区报告的数据/信息是完整和准确的结论。数据完整性问题的例子包括未能科学地论证未报告相关数据,例如异常检测结果或提交的色谱序列缺失。 识林点评:指导检查员用审评员的方式准备检查——首先核对申报资料的自洽性问题:汇总分析表中的数据,是否和附后的原始数据中存在自相矛盾的地方,或者原始数据没有被合理的解释,或被选择性的用于支持某项结论,而不支持该结论的原始数据被忽略或删除了。同样,色谱图,光谱图,实验室分析人员笔记本,实验室附加信息是检查重点和企业自查重点。 When data discrepancies are observed, identify firm personnel involved. Determine which actions or inactions contributed to the data integrity problem and whether corrective actions were or are to be taken. Also determine whether data that should have been reported in the application were not reported. For example, did the firm:
当观察到数据差异时,确定涉及的公司人员。要确定出面对数据可靠性问题时,企业的作为和不作为,以及是否采取过纠正措施或者将要采取的纠正措施。还要确定申报资料中应报告的数据是否未报告。例如,企业是否:
识林点评:integrity本意是诚实、正直,FDA明确要求检查员一但发现这类问题,立刻定位到人和公司体系:不是关注个别产品或者批次,而是整个公司的质量管理体系。无效的OOS从去年已经成为FDA警告信的重灾区【FDA在检查观察项中引用“无效的OOS率”】,如果认为将OOS判定为无效是最省时省力的调查,那要做好充分的准备迎接检查员的挑战和可能的警告信。 Following are possible indications of data integrity problems:
出现下列情况时,可能存在数据可靠性问题:
识林点评:数据可靠性绝命十二条,也是保命十二条,赶紧按照这个单子自查吧。 The investigators should clearly indicate in the EIR whether their findings call into question the reliability of the submitted data. Specific data/information filed in the application should be referenced, when possible. It is essential that the ORA division notify OPF of data reliability concerns promptly to trigger an immediate evaluation of the impact on the application. If such situations are observed, thoroughly document the unreliable data (see III.2.B, Completion of the Establishment Inspection Report). 检查员应在EIR中明确指出他们的发现是否会对所提交数据的可靠性产生疑问。应尽可能援引到申请中提交的具体数据/信息。地区办公室应立即通知OPF(工艺和设施办公室)关于数据可靠性的问题,激活对申请真实性影响的即时评估。如果观察到这种情况,应彻底记录不可靠数据(参见III.2.B,企业检查报告的完成情况)。 识林点评:检查中发现了严重的问题,会影响产品批准的进度,数据可靠性通常被视为这类缺陷。 If a pattern of data reliability issues is identified during a PAI, the investigator should consider expanding the coverage to surveillance of marketed products manufactured in the facility using compliance program 7356.002. If data reliability issues are documented for other products during an expanded inspection, this suggests a broader pattern that implicates all products manufactured at the facility. If so, ORA should consider submitting a recommendation that CDER consider invoking the Application Integrity Policy (AIP) or that a for-cause inspection be planned to further define the scope of the data reliability issues. Contact information and procedures for OC’s Office of Manufacturing Quality (OC/OMQ) are on the AIP website. 如果在PAI期间确定了一类数据可靠性问题,检查员应考虑使用合规性计划7356.002将覆盖范围扩展至监督企业生产的上市产品。如果在扩大检查期间记录了其他产品的数据可靠性问题,表明这类问题更广泛涉及工厂生产的所有产品。如果是这样,ORA应考虑提交CDER考虑援引申请完整性政策(Application Integrity Policy,AIP)的建议,或者计划进行有因检查以进一步明确数据可靠性问题的范围。OC的生产质量办公室(OC / OMQ)的联系信息和规程在AIP网站上。 识林点评:AIP对企业的影响是大而深远的,Ranbaxy因为2009的造假事件,被FDA禁止了新产品的申请(相关识林资讯链接),最终被太阳药业收购。想进一步了解AIP,请登录识林APP或网站,搜索AIP查看主题词。 Related regulations for finished pharmaceuticals: 21 CFR 314.50(d) requires that the CMC section include “data and information in sufficient detail to permit the agency to make a knowledgeable judgment about whether to approve the application.” Several CGMP regulations require laboratory data to be collected and maintained, including 21 CFR 211.160 (General Requirements), 211.165 (Testing and Release for Distribution), 211.166 (Stability Testing), and 211.167 (Special Testing Requirements). 制剂产品相关法规:21 CFR 314.50(d) 要求CMC版块包含的“数据和信息应该足够充分,以保证官方可以对是否可以批准该申请做出一个基于知识的判断”。要求实验室数据收集和保存的相关CGMP法规包括 21 CFR 211.160 (一般要求), 211.165 (发运前的检测和放行), 211.166 (稳定性), 和 211.167(特殊检测要求)。 Related guidance for APIs: Several ICH Q7 sections require laboratory data to be collected and maintained, including XI.A (General Controls) through XI.E (Stability Monitoring of APIs). API相关指南:ICH Q7要求实验室数据收集和保存的要求,包括11.1 (实验室控制 — 一般控制) 至 11.5 (API的稳定性监控)。 作者:识林-枫 参考资料 适用岗位必读建议:
文件适用范围: 文件要点总结:
以上仅为部分要点,请阅读原文,深入理解监管要求。 必读岗位及工作建议:
适用范围: 文件要点总结:
以上仅为部分要点,请阅读原文,深入理解监管要求。 |