FDA警告信中最常见GMP违规情况-----失效调查、供应商确认和稳定性试验不充分

【技术交流】FDA警告信中最常见GMP违规情况-----失效调查、供应商确认和稳定性试验不充分

2014-07-18 蒲公英杂志

                               
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GMP News
16/07/2014

Insufficient failure investigations, supplier qualification, stability testing - the most common GMP violations in the FDA warning letters

FDA警告信中最常见GMP违规情况-----失效调查、供应商确认和稳定性试验不充分

    The analysis of the warning letters issued in the last fiscal year shows no surprise at a first glance: as in recent years the FDA detected an insufficient investigation of unexplained discrepancies and deviations from defined standards and specifications in their inspections. The corresponding paragraph 21 CFR 211.192 requires that the drug maker clarifies the reason for the deviation, takes corrective actions and also creates a complete documentation. In the last 5-year period on average annually about 22 companies received a warning letter listing this GMP deficiency. This fact shows that many quality assurance departments' understanding of deviations handling, failure investigations and corrective actions is frequently fragmentary.

    对2013财年的警告信分析结果显示，最近几年FDA在其检查中，发现对未解释的不符合既定标准和规格的情况及偏差调查不充分。21 CFR 211.192对应的段落要求制药公司说明偏差的原因，采取纠正措施，同时建立完整的文件记录。在过去5年中，每年平均有约22封警告信中列有该缺陷，说明许多公司的质量保证部门对偏差处理、失效调查和纠正措施的理解是不完整的。

    Quite interesting is the detailed study of the warning letters referring to GMP violations with regard to 211.192. These warning letters take into account the drugs' dosage forms. In particular manufacturers of oral dosage forms were addressees of warning letters containing citations with regard to 211.192, followed by parenteral drugs manufacturers, companies in the area of blood/blood products and manufacturers of topical drugs. The respective scenarios are quite different. However, main shortcoming is always the inadequate education and documentation in each incident.

   对警告信中与211.192相关的GMP违规情况研究很有意思。从警告信涉及的药品剂型来看，口服剂型生产商首当其冲，其次是注射剂型生产商，以及血液及血液制品和局部用药产品生产商。当然，主要缺点永远都是对每次事件的教育和记录不充分。

     A rather unexpected finding in the lineup of the most common GMP violations is the high number of citations with regard to 21 CFR 211.84 "Testing and approval or rejection of components, drug product containers, and closures". This quote appears so frequently as never before: 16 out of the 32 companies that received a warning letter in the fiscal year 2013 for violations of part 211 had not implemented the provisions of paragraph 211.84 as expected by the FDA investigators. Interestingly, in this case most of these companies (12 of the 16) are manufacturers of topical products (ointments, creams, etc.).

    在最常出现的GMP违规情况中，令人意外的是引用21CFR 211.84“药品部件、药品容器和密闭器的检测和批准或拒绝接收”的缺陷出现频次很高。该引用出现的频次之高前所未见：在2013财年，32个收到缺陷信的公司中有16个公司，未如FDA检查官期望的那样遵守211.84段落中的条款，其中大部分公司（16家中有12家）生产的是局部用药（膏剂、乳剂等）。

    he formulations in the warning letters in this regard are very similar (in some cases identical) and are usually limited to the following standard wording: "Your firm has not established the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals" or "Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or exampled, as appropriate, and released for use by the quality control unit."

    警告信中关于此的用词公式化地相似（有些案例中完全相同），一般就是下面标准用词：“你公司未在适当的周期内对供应商检验结果进行适当的验证，从而建立对供应商检验的可靠信”或“你公司未能在每批部件、药品容器和密闭器使用前完成取样、检验或与标准比较（适用时），以及经质量控制部门放行使用全过程”。

    Under the addressees of warning letters with quotations in the area of quality control - 21 CFR 211.166 "Stability Testing" and 21 CFR 211.160 "General Requirements" - there are also many of the companies that were already criticised due to non-compliances with regard to 211.84. This is not surprising as the thematic connection of all three paragraphs has a reference to the function of quality control. These two paragraphs 211.166 and 211.160 - just as 211.192 - have been in the top ten of GMP deficiencies for many fiscal years. Main shortcoming relating to 211.166 is the lack of a written stability test programme. Therefore, the following sentence can be read in almost all warning letters: "Your firm does not have an adequate written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates."

     在引用了QC方面章节-----21CFR211.166“稳定性测试”和21CFR211.160“一般要求”----的警告信中，很多公司因为不符合211.84而受到批评。这也不算奇怪，因为这三个章节都共同引用了QC方面的内容。这两个章节，211.166和211.160----与211.192相同----已在之前多个财年被列为GMP缺陷前十位。与211.166相关的主要缺点是缺失书面的稳定性试验方案，因此以下句子几乎出现在所有警告信中“你公司未充分的书面检测方案，以评估药品的稳定性特征，来确定适当的存贮条件和有效期”。

    Information on infringements of 211.160 are more differentiated. Partly some interesting scenarios are described, as, for instance, "inappropriate visual particle inspection" or "switched off audit trail function in the chromatography system".

    Here too Topika makers make the majority of addressees - even though not as clear as in the previous paragraphs of part 211.

Main shortcoming in the implementation of the guidelines in 211.160 is the lack of scientifically sound and appropriate specifications, standards, test plans and test methods for products, intermediates, components etc.

    关于211.160的违规情况有些不同。例如一部分有意思的情况是这样写的，“不适当的目视颗粒检查”或“在色谱系统中关闭了审计追踪功能”。同样，收到警告信最多的还是TOPIKA生产商-----即使这方面的要求并不像211前面的章节那么清楚。对211.160指南最常见的缺点是产品、中间体和部件等缺乏科学合理适当的质量规格、标准、检验计划和检验方法。

     The analysis of the warning letters of last fiscal year has shown that the FDA increasingly focuses on the subject "supplier qualification" and in this context on critically questioning analysis results and certificates of the suppliers. A detailed examination of the warning letters of the current fiscal year will show whether this trend further continues.

    对上一财年的警告信的分析显示，FDA越来越关注“供应商确认”的问题，以及对供应商的分析结果和检验报告的质疑。对本财年警告信的具体分析将揭示是否该趋势会持续。

    A more detailed analysis of the warning letters of the previous fiscal year will be available in the October issue of the GMP Journal.

   对前一财年的警告信更具体的分析将在十月份的GMP杂志上发表。

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