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[其他] 2006年-2018年EDQM检查和缺陷趋势概述

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Certification of Substances Department
PUBLIC DOCUMENT
(LEVEL 1)
English only/Anglais seulement
PA/PH/CEP (18) 56      
Strasbourg, April 2019

Certification of suitability to the Monographs of the European Pharmacopoeia

EDQM Inspection Programme

EDQM inspections and trends of deficiencies
Overview 2006 to 2018

2006年-2018年EDQM检查和缺陷趋势概述


1) INTRODUCTION  概述

All sites involved in the manufacturing of Active Pharmaceutical Ingredients (API) for which a CEP has been requested or granted may be subject to an inspection by the EDQM. A negative outcome of an inspection may result in actions against related CEPs (suspension or withdrawal ofCEPs or closure of CEP applications). Re-inspections are performed either to verify the return tocompliance after a negative inspection outcome, or in the context of
monitoring the sustainabilityof the GMP status.
所有参与生产已申请或批准CEP的活性药物成分(API)的工厂都需要接受EDQM的检查。检查的负面结果可能导致官方对CEP证书采取行动(暂停或撤销CEP或关闭CEP申请)。重新检查的目的是在负面检查结果后,或在监测药品生产12bet管理规范状态的可持续性的背景下,验证是否符合要求。

This document is a review of data from API inspections conducted by the EDQM between 2006 and 2018. It covers:
本文件是对EDQM在2006年至2018年间进行的API检查数据的回顾。它涵盖了:

  • the location of the inspections;  检查地点;
  • whether they were initial or re-inspections;初步检查还是复检查;
  • their outcome;检查结果
  • the distribution of the observed deficiencies to EU Good Manufacturing Practice (GMP) Part II area and criticality;
    观察到的缺陷在欧盟良好12bet网址规范(GMP)第二部分的分布和关键性;
  • the frequency of the findings;
    调查结果的频率
  • issues of data integrity.
    数据完整性问题


The deficiencies observed during EDQM inspections are referenced to EU GMP Part II and therelevant Annexes,or to the corresponding CEP dossiers and the European Pharmacopoeia (Ph.Eur.) in general.
EDQM检查期间发现的缺陷参考欧盟GMP第二部分和相关附件,或相应的CEP档案和欧洲药典(欧洲药典)。

2) REVIEW OF INSPECTIONS BY LOCATION, HISTORY AND OUTCOME
审查检查情况、依据、历史和结果

2.1 The distribution of EDQM inspections by geographical location of inspected sites is given in the followingchart:
下表给出了按受检地点地理位置划分的EDQM检验分布情况:


2.2 The distribution of outcomes of EDQM inspections is given in the following chart:
EDQM检查结果的分布如下图所示:


The chart below displays the total number and ratio of outcomes of EDQM inspections during thereview period:
下表显示了在审查期间EDQM检查结果的总数和比率:


2.3 The distribution of EDQM inspections (initial or re-inspections) is given in the following table:
EDQM检查(初始检查或复检查)的分布如下表所示:


3) DISTRIBUTION OF DEFICIENCIES BY GMP AREA (including compliance with
CEP) & CRITICALITY
按GMP区域划分的缺陷分布(包括符合CEP)和关键性

The deficiencies reported during EDQM inspections are classified as critical, major or other,depending on the risk they may pose to public health and the degree of deviation from EU GMP,the relevant CEP dossier and European Pharmacopoeia (Ph. Eur.).
EDQM检查过程中报告的缺陷可分为关键缺陷、主要缺陷或其他缺陷,具体取决于这些缺陷对公众健康造成的风险以及与 欧盟GMP、相关CEP档案和欧洲药典(欧洲药典)的偏离程度。

For this review, they have been distributed according to the respective chapters of EU GMP PartII as well as compliance with the CEP dossier and the Ph. Eur. Some items group several chapters of the EU GMP Part II.One item gathers all CEP dossier and Ph. Eur. compliance issues.The grouping aims at avoiding the variability linked with the fact that some deficiencies may berelated to different chapters.
在本次审查中,它们是根据欧盟GMP PartII的相关章节以及与CEP档案和欧洲药典的一致性进行划分的。

Only the numbers of the EU GMP Part II chapters are mentioned for each group in the charts; forthe detailed grouping,see Annex I.
图表中只提到了欧盟GMP PartII各章的编号,详细分组见附件一。

3.1 The overall distribution of deficiencies from EDQM inspections between 2006 and 2018 by GMP area and CEP compliance is displayed in the chart below:
下表显示了2006年至2018年EDQM检查中GMP领域和CEP合规性的缺陷总体分布情况


3.2 The chart below displays the trends in the deficiencies throughout the years by GMP area and CEP compliance (percentages of the total number of deficiencies for each year):
下表按GMP领域和CEP合规性显示了全年缺陷的趋势(每年缺陷总数的百分比):


The following trends can be seen from the chart:
从图表中可以看出以下趋势:

  • Quality related matters: overall increase until 2015 (up to 45% from 32% in 2006), slight drop since then (down to 40% in 2018);
    12bet相关问题:到2015年总体增长(从2006年的32%上升到45%),此后略有下降(2018年下降到 40%)。


  • Materials management: initially variable, overall stable since 2014 (10-13%);
    物料管理:初始变化无常,2014年以来总体稳定(10-13%)


  • Buildings and equipment:decrease from 2008(35%),overall stable since 2015(19% to 21%);
    建筑和设备:较2008年下降(35%),2015年以来总体稳定(19%至21%)


  • Production: consistent decrease until 2016, increase in 2017-2018 (from 5% to 8%);
    生产:至2016年持续下降,2017-2018年增长(5%至8%)


  • Laboratory controls:generalincrease until 2012 (17%), overall stable since;
    实验室控制:2012年前总体增长(17%),此后总体稳定;


  • Compliance to CEP dossier and Ph. Eur.: regular decrease (from 8% in 2007 down to 1%in 2018)
    CEP档案和药典符合性:有规律下降(从2007年的8%降至2018年的1%)


3.3 For recent inspections (2017-2018) the number of deficiencies by level of criticality(critical, major and other) in each GMP area have been analysed and are presented in thechart below.
对于最近的检查(2017-2018年),每个GMP领域的关键性(关键、主要和其他)级别的缺陷数量已进行了分析,并在下面的图表中列出。


It can be seen from the chart that the largest occurrence of major and critical deficiencies isobserved in Quality related matters, followed by Buildings & Equipment, and by Laboratory controls in third place (details in section 4).
从图表中可以看出,12bet相关问题中出现的主要缺陷和关键缺陷最多,其次是建筑和设备,以及实验室控制排第三(详情见第4节)。

It should be pointed out that the combination of major findings may lead to an overall critical riskfor public health (and therefore a non-compliant inspection outcome without individual critical deficiencies), which is not reflected in the chart.
应当指出的是,主要发现的组合可能会对公众健康造成总体的关键风险(因此,不符合要求的检查结果没有个别的关键缺陷),这在图表中没有反映出来。

4) MOST FREQUENT TYPES OF DEFICIENCIES BY GMP AREA
按GMP领域划分的最常见缺陷类型

The most frequent types of deficiencies identified in each GMP area during EDQM inspections between 2006 & 2018 are listed below.
下面列出了2006年至2018年EDQM检查期间在每个GMP领域发现的最常见缺陷类型。

4.1 Quality related matters  12bet相关问题

Insufficiency and/or ineffectiveness of quality system rendering operations not reliable asevidenced by:
12bet体系的不足和/或无效导致操作不可靠

  • Insufficient oversight of quality unit over GMP activities, e.g.:
    12bet部门对GMP活动的监督不足,例如:

  • failure to effectively control documentation (both paper and electronic);
    未能有效控制文件(纸质和电子文件);
  • inadequate overview of production and laboratory activities;
    生产和实验室活动概述不充分;
  • underreporting and/or insufficient investigation of quality events(complaints,
    deviations, out-of-specification (OOS) results, change controls);
    12bet事件(投诉、偏差、超标(OOS)结果、变更控制)的报告不足和/或调查不足;


  • Fraudulent documentation practices, e.g.
    欺骗性文件,例如:

  • rewriting documents in order to demonstrate acceptable, expected or presentableresults, values or dates;
    重写文件,以证明可接受、预期或可呈现的结果、数值或日期;
  • untimely recording of operations;
    操作记录不及时;
  • unavailability of records;
    记录不可用;
  • use of loose sheets instead of bound logbooks;
    使用活页代替装订的日志;


  • Quality Risk management principles not applied or inadequately implemented in areas such as production activities, deviations, change control, etc.
    12bet风险管理原则在生产活动、偏差、变更控制等方面未得到应用或实施不充分等。


  • Annual quality review not used as a quality tool by companies, e.g.:
    公司未将年度12bet回顾作为12bet工具,例如:

  • not all batches reflected (especially “non-CEP” grade, even though manufactured by same process);
    并非所有批次都反映出来(尤其是“非CEP”级,即使采用相同工艺12bet网址);
  • trends not detected or investigated;
    未发现或调查的趋势;


  • Insufficient personnel training, e.g.:
    人员培训不足,例如:

  • no training given to upper management with regard to GMP related matters;
    未对上级管理人员进行与GMP有关的培训;
  • no assessment of training’s efficiency or with limited value;
    未评估培训的效果或培训价值有限;


  • Insufficient validation, e.g.:
    验证不足,例如:

  • processes such as use of recovered solvents, blending or micronisation not always addressed;
    诸如使用回收溶剂、混合或微粉化等过程并不总是被提及;
  • lack of sound knowledge of different approaches regarding cleaning validation.
    对清洁验证的不同方法缺乏足够的了解。


4.2 Materials management 物料管理

  • Insufficient approval and/or management of vendors of key starting materials
    or intermediates (e.g. unreliable on-site audits);
    关键原材料或中间体供应商的批准和/或管理不足(例如不可靠的现场审计);

  • Risk of loss of traceability due to insufficient identification of containers;
    因容器标识不充分而丧失可追溯性的风险;
  • Improper storage conditions (temperature, humidity, non-controlled storage facilities…).
    储存条件不当(温度、湿度、非受控储存设施…)。


4.3 Buildings and equipment  建筑和设备

  • Risks of contamination and/or cross-contamination arising from:
    污染和/或交叉污染的风险来自:

  • mproper design of facilities;
    设施设计不当;
  • oinadequate cleaning of equipment;
    设备清洁不充分;
  • oinsufficient maintenance of equipment.
    设备维护不当。


  • Lack of appropriate user requirement specifications concerning equipment qualification.
    缺乏关于设备确认相关的适当的用户需求规范;


  • Lack of sound scientific approach regarding the management of computerised systems used for material management, production, laboratory controls etc., e.g.:
    用于物料管理、生产、实验室控制等的计算机化系统的管理缺乏健全的科学方法,例如:


  • lack of appropriate user requirement specifications;
    缺乏适当的用户需求规范;
  • insufficient knowledge of validation requirements;
    对验证要求了解不足;
  • no or insufficient management of access levels causing risk of loss of traceability;
    访问级别没有或管理不足,导致可追溯性丧失;
  • insufficient controls to prevent data manipulation;
    控制不足,无法防止数据修改;
  • lack or insufficient review of audit trail;
    缺乏或不充分的审计追踪;


4.4 Production生产

  • Blending of batches without prior appropriate testing;
    在没有经过适当测试的情况下混合批次

  • Lack of control of solvent recovery.
    缺乏对溶剂回收的控制


4.5 Laboratory controls 实验室控制

  • Fraudulent practices regarding testing activities, e.g.:
    有关实验室控制活动的欺骗行为,例如

  • pretesting or “testing into compliance”;
    预测试或“测试合规”
  • deleting OOS results;
    删除OOS结果
  • unreliability of analytical results;
    分析结果不可靠


  • Unreliable microbiological results;
    不可靠的微生物结果

  • Issues with Chemical Reference Standards (CRS):
    关于化学参考标准( CRS)的问题

  • absence of the Ph. Eur. CRS;
    没有欧洲药典,化学参考标准
  • insufficient establishment of secondary standards;
    二级标准制定不足


  • Lack of proper monitoring of potable water.
    缺乏对饮用水的适当监测


4.6 Sub-contracted activities 分包活动

  • No or insufficient review and/or acceptance for such activities (e.g.equipment/instrument calibration, computerised systems validation, further powder processing).
    此类活动(如设备/仪器校准、计算机化系统验证、进一步的粉末加工)没有或不充分的审查和/或验收。

Specific cases of deficiencies related to data integrity
与数据完整性相关的缺陷的具体案例

Most breaches of data integrity occurred in documentation practice and in laboratory controls.Additional issues have been observed, such as absence or gaps of validation and controls on computerised systems.
大多数违反数据完整性的行为发生在文件记录和实验室控制中。还观察到了其他问题,例如验证和控制计算机系统的缺失或差距。

Importantly, 44% of critical and 25% of major deficiencies observed between 2015 and 2018were related to dataintegrity issues.
重要的是,在2015年至2018年间观察到的44%的关键缺陷和25%的主要缺陷与数据完整性问题有关。

5) CONCLUSION 结论
From the geographical distribution of EDQM inspections (see 2.1), it is clear that manufacturing sites in India and China are the ones mostly visited, which is in line with the share of these two countries in the repartition of CEP manufacturers outside Europe (82% in March 2017). On theother hand, inspections in the European Economic Area (EEA) have
practically dropped to zero,due to the monitoring of the compliance status of European sites being a responsibilityof therespective National Competent Authorities.
从EDQM检查的地理分布来看(见2.1),很明显印度和中国的生产基地是检查最多的。这与这两个国家在欧洲以外CEP12bet网址商再分配中所占的份额一致(2017年3月为82%)。另一方面,欧洲经济区(EEA)的检查由于对欧洲各业务点的合规状况进行监测,这一点实际上降至零,这是各国家主管当局的责任。

Regarding the trends of inspection outcomes, the high level of non-compliances observed in thefirst few yearsafter implementation of the EDQM inspection programme (especially between2009 and 2013) is considered to demonstrate the ability of the EDQM to detect sites at risk froma GMP point of view. Since 2014, the relatively stable and comparatively low rate of non-compliance observed is seen as a result of the manufacturers’ efforts
to adapt and comply withregulatory & GMP requirements, promoted by the EDQM’s continuous presence in the field of inspections (see 2.2).
关于检查结果的趋势,在实施EDQM检查计划后的最初几年(特别是在2009年至2013年之间)观察到的高水平的不合规情况被认为是证明EDQM能够检测出GMP风险的能力。自2014年以来,观察到相对稳定且相对较低的不合规率,这是由于12bet网址商努力调整并符合监管和GMP要求,由EDQM在检查领域的持续存在所推动(见2.2)。

An overall decline in findings related to buildings, equipment and materials management over theyears (see 3.2) is considered as an achievement resulting from raising the companies’ awareness in these fields. This improvement in the status of the majority of the facilities consequently allowed the inspectors to focus more on quality systems and subsequently identify more quality related issues, as shown by them consistently occupying the first place in the distribution of deficiencies in recent years.
这些年来,与建筑、设备和物料管理相关的调查结果总体下降(见3.2)被认为是公司在这些领域的意识提高所取得的成就。大多数设施的这种状态的改进使检查员能够更多地关注12bet体系,并随后识别出更多与12bet相关的问题,正如他们近年来在缺陷分布中始终占据第一位所显示的那样。

A significant portion of the issues resulting in GMP non-compliance (critical and major deficiencies) arerelated to data integrity.
导致GMP不合规(关键缺陷和主要缺陷)的大部分问题与数据完整性有关。

Another result of the review is the low level of discrepancies to the CEP dossier (see 3.2), which demonstrates the increased efforts of companies to comply with their commitments and the conditions under which their CEPs were granted throughout their lifecycle.
审查的另一个结果是, CEP档案(见3.2)的差异程度较低,这表明公司越来越努力遵守其承诺,以及在其生命周期内授予CEP的条件。

Annex I 附录I

Detailed grouping of chapters of EU GMP part II:
欧盟GMP第二部分章节的详细分组:

  • Quality related matters  12bet相关问题
    Quality management (chapter 2)12bet管理(第2章)
    Personnel (chapter 3)人员(第3章)
    Documentation (chapter 6)文件(第6章)
    Validation (chapter 12)验证(第12章)
    Change control (chapter 13)变更控制(第13章)
    Complaints and recalls (chapter 15)投诉与召回(第15章)
    Contract manufacturers (chapter 16)委托12bet网址企业(第16章)

  • Materials management 物料管理
    Materials management (chapter 7)物料管理(第7章)
    Storage and distribution (chapter 10)贮存和流通(第10章)
    Packaging (chapter 9)包装(第9章)
    Distribution (chapter 17)流通(第17章)


  • Buildings and facilities / Process equipment 建筑和设施/工艺设备
    Buildings and facilities (chapter 4)建筑和设施(第4章)
    Process equipment (chapter 5)工艺设备(第5章)

  • Production 生产
    Production and in-process control (chapter 8)
    生产和中间控制(第8章)
    Rejection and reuse of materials (chapter 14)物料拒收和再利用(第14章)


  • Laboratory controls 实验室控制
    Laboratory controls (chapter 11)
    实验室控制(第11章)


  • Specific group: Compliance to CEP dossier and Ph. Eur.
    Compliance of process to CEP dossier
    工艺符合CEP档案
    Compliance of analytical specifications and methods to CEP dossier Compliance to Ph. Eur.general methods and general monographs
    符合CEP档案的分析规范和方法,符合欧洲药典一般方法和一般专著





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honker  同问  详情 回复 发表于 2019-6-20 16:04
honker  同问  详情 回复 发表于 2019-6-20 16:04
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药徒
5#
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感谢分享!
药徒
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同问,求分享!
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这个必须还是学习一下
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