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[其他] 2006年-2018年EDQM检查和缺点趋势概述

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宣布于 2019-6-18 12:38:30 | 只看该作者 |只看大图 回帖奖赏 |倒序阅览 |阅览形式
本帖最终由 东玲miffy 于 2019-6-18 12:38 修正

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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检查和缺点趋势概述


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.
一切参加出产已请求或同意CEP的活性药物成分(API)的工厂都需求承受EDQM的检查。检查的负面成果或许导致官方对CEP证书采纳举动(暂停或吊销CEP或封闭CEP请求)。从头检查的意图是在负面检查成果后,或在监测药品出产明升体育88办理标准状况的可继续性的布景下,验证是否契合要求。

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检查数据的回忆。它涵盖了:

  • the location of the inspections;  检查地址;
  • whether they were initial or re-inspections;开始检查仍是复检查;
  • their outcome;检查成果
  • the distribution of the observed deficiencies to EU Good Manufacturing Practice (GMP) Part II area and criticality;
    调查到的缺点在欧盟杰出制作标准(GMP)第二部分的散布和要害性;
  • the frequency of the findings;
    查询成果的频率
  • issues of data integrity.
    数据完好性问题


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检查期间发现的缺点参阅欧盟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
检查检查状况、依据、前史和成果

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址地理位置区分的EDQM查验散布状况:


2.2 The distribution of outcomes of EDQM inspections is given in the following chart:
EDQM检查成果的散布如下图所示:


The chart below displays the total number and ratio of outcomes of EDQM inspections during thereview period:
下表显现了在检查期间EDQM检查成果的总数和比率:


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)的散布如下表所示:


3) DISTRIBUTION OF DEFICIENCIES BY GMP AREA (including compliance with
CEP) & CRITICALITY
按GMP区域区分的缺点散布(包含契合CEP)和要害性

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检查进程中陈述的缺点可分为要害缺点、首要缺点或其他缺点,详细取决于这些缺点对大众健康形成的危险以及与 欧盟GMP、相关CEP档案和欧洲药典(欧洲药典)的违背程度。

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.
在本次检查中,它们是依据欧盟GMP PartII的相关章节以及与CEP档案和欧洲药典的共同性进行区分的。

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:
下表显现了2006年至2018年EDQM检查中GMP范畴和CEP合规性的缺点整体散布状况


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范畴和CEP合规性显现了全年缺点的趋势(每年缺点总数的百分比):


The following trends can be seen from the chart:
从图表中能够看出以下趋势:

  • Quality related matters: overall increase until 2015 (up to 45% from 32% in 2006), slight drop since then (down to 40% in 2018);
    明升体育88相关问题:到2015年整体增加(从2006年的32%上升到45%),尔后略有下降(2018年下降到 40%)。


  • Materials management: initially variable, overall stable since 2014 (10-13%);
    物料办理:初始变化无常,2014年以来整体安稳(10-13%)


  • Buildings and equipment:decrease from 2008(35%),overall stable since 2015(19% to 21%);
    修建和设备:较2008年下降(35%),2015年以来整体安稳(19%至21%)


  • Production: consistent decrease until 2016, increase in 2017-2018 (from 5% to 8%);
    出产:至2016年继续下降,2017-2018年增加(5%至8%)


  • Laboratory controls:generalincrease until 2012 (17%), overall stable since;
    实验室操控:2012年前整体增加(17%),尔后整体安稳;


  • Compliance to CEP dossier and Ph. Eur.: regular decrease (from 8% in 2007 down to 1%in 2018)
    CEP档案和药典契合性:有规矩下降(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.
关于最近的检查(2017-2018年),每个GMP范畴的要害性(要害、首要和其他)等级的缺点数量已进行了剖析,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).
从图表中能够看出,明升体育88相关问题中出现的首要缺点和要害缺点最多,其次是修建和设备,以及实验室操控排第三(概况见第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,首要发现的组合或许会对大众健康形成整体的要害危险(因而,不契合要求的检查成果没有单个的要害缺点),这在图表中没有反映出来。

4) MOST FREQUENT TYPES OF DEFICIENCIES BY GMP AREA
按GMP范畴区分的最常见缺点类型

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范畴发现的最常见缺点类型。

4.1 Quality related matters  明升体育88相关问题

Insufficiency and/or ineffectiveness of quality system rendering operations not reliable asevidenced by:
明升体育88体系的缺少和/或无效导致操作不可靠

  • Insufficient oversight of quality unit over GMP activities, e.g.:
    明升体育88部门对GMP活动的监督缺少,例如:

  • failure to effectively control documentation (both paper and electronic);
    未能有用操控文件(纸质和电子文件);
  • inadequate overview of production and laboratory activities;
    出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);
    明升体育88事情(投诉、误差、超支(OOS)成果、改变操控)的陈述缺少和/或查询缺少;


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

  • rewriting documents in order to demonstrate acceptable, expected or presentableresults, values or dates;
    重写文件,以证明可承受、预期或可出现的成果、数值或日期;
  • untimely recording of operations;
    操作记载不及时;
  • unavailability of records;
    记载不可用;
  • use of loose sheets instead of bound logbooks;
    运用活页替代装订的日志;


  • Quality Risk management principles not applied or inadequately implemented in areas such as production activities, deviations, change control, etc.
    明升体育88危险办理准则在出产活动、误差、改变操控等方面未得到运用或施行不充分等。


  • Annual quality review not used as a quality tool by companies, e.g.:
    公司未将年度明升体育88回忆作为明升体育88东西,例如:

  • not all batches reflected (especially “non-CEP” grade, even though manufactured by same process);
    并非一切批次都反映出来(尤其是“非CEP”级,即便选用相同工艺制作);
  • trends not detected or investigated;
    未发现或查询的趋势;


  • Insufficient personnel training, e.g.:
    人员训练缺少,例如:

  • no training given to upper management with regard to GMP related matters;
    未对上级办理人员进行与GMP有关的训练;
  • no assessment of training’s efficiency or with limited value;
    未评价训练的作用或训练价值有限;


  • Insufficient validation, e.g.:
    验证缺少,例如:

  • processes such as use of recovered solvents, blending or micronisation not always addressed;
    比如运用收回溶剂、混合或微粉化等进程并不总是被提及;
  • lack of sound knowledge of different approaches regarding cleaning validation.
    对清洁验证的不同办法缺少满足的了解。


4.2 Materials management 物料办理

  • Insufficient approval and/or management of vendors of key starting materials
    or intermediates (e.g. unreliable on-site audits);
    要害原材料或中心体供货商的同意和/或办理缺少(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损失可追溯性的危险;
  • Improper storage conditions (temperature, humidity, non-controlled storage facilities…).
    储存条件不妥(温度、湿度、非受控储存设备…)。


4.3 Buildings and equipment  修建和设备

  • Risks of contamination and/or cross-contamination arising from:
    污染和/或穿插污染的危险来自:

  • mproper design of facilities;
    设备规划不妥;
  • oinadequate cleaning of equipment;
    设备清洁不充分;
  • oinsufficient maintenance of equipment.
    设备保护不妥。


  • Lack of appropriate user requirement specifications concerning equipment qualification.
    缺少关于设备承认相关的恰当的用户需求标准;


  • Lack of sound scientific approach regarding the management of computerised systems used for material management, production, laboratory controls etc., e.g.:
    用于物料办理、出产、实验室操控等的核算机化体系的办理缺少健全的科学办法,例如:


  • lack of appropriate user requirement specifications;
    缺少恰当的用户需求标准;
  • insufficient knowledge of validation requirements;
    对验证要求了解缺少;
  • no or insufficient management of access levels causing risk of loss of traceability;
    拜访等级没有或办理缺少,导致可追溯性损失;
  • insufficient controls to prevent data manipulation;
    操控缺少,无法避免数据修正;
  • lack or insufficient review of audit trail;
    缺少或不充分的审计追寻;


4.4 Production出产

  • Blending of batches without prior appropriate testing;
    在没有通过恰当测验的状况下混合批次

  • Lack of control of solvent recovery.
    缺少对溶剂收回的操控


4.5 Laboratory controls 实验室操控

  • Fraudulent practices regarding testing activities, e.g.:
    有关实验室操控活动的诈骗行为,例如

  • pretesting or “testing into compliance”;
    预测验或“测验合规”
  • deleting OOS results;
    删去OOS成果
  • unreliability of analytical results;
    剖析成果不可靠


  • Unreliable microbiological results;
    不可靠的微生物成果

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

  • absence of the Ph. Eur. CRS;
    没有欧洲药典,化学参阅标准
  • insufficient establishment of secondary standards;
    二级标准拟定缺少


  • Lack of proper monitoring of potable water.
    缺少对饮用水的恰当监测


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、核算机化体系验证、进一步的粉末加工)没有或不充分的检查和/或检验。

Specific cases of deficiencies related to data integrity
与数据完好性相关的缺点的详细事例

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.
大多数违背数据完好性的行为发生在文件记载和实验室操控中。还调查到了其他问题,例如验证和操控核算机体系的缺失或间隔。

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年间调查到的44%的要害缺点和25%的首要缺点与数据完好性问题有关。

5) CONCLUSION 定论
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检查的地理散布来看(见2.1),很明显印度和我国的出产基地是检查最多的。这与这两个国家在欧洲以外CEP制作商再分配中所占的比例共同(2017年3月为82%)。另一方面,欧洲经济区(EEA)的检查因为对欧洲各事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职责。

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).
关于检查成果的趋势,在施行EDQM检查方案后的开始几年(特别是在2009年至2013年之间)调查到的高水平的不合规状况被认为是证明EDQM能够检测出GMP危险的才能。自2014年以来,调查到相对安稳且相对较低的不合规率,这是因为制作商尽力调整并契合监管和GMP要求,由EDQM在检查范畴的继续存在所推进(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,与修建、设备和物料办理相关的查询成果整体下降(见3.2)被认为是公司在这些范畴的认识进步所获得的成果。大多数设备的这种状况的改善使检查员能够更多地重视明升体育88体系,并随后识别出更多与明升体育88相关的问题,正如他们近年来在缺点散布中一直占有第一位所显现的那样。

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(要害缺点和首要缺点)的大部分问题与数据完好性有关。

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.
检查的另一个成果是, CEP档案(见3.2)的差异程度较低,这表明公司越来越尽力恪守其许诺,以及在其生命周期内颁发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  明升体育88相关问题
    Quality management (chapter 2)明升体育88办理(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)改变操控(第13章)
    Complaints and recalls (chapter 15)投诉与召回(第15章)
    Contract manufacturers (chapter 16)托付制作企业(第16章)

  • Materials management 物料办理
    Materials management (chapter 7)物料办理(第7章)
    Storage and distribution (chapter 10)储存和流转(第10章)
    Packaging (chapter 9)包装(第9章)
    Distribution (chapter 17)流转(第17章)


  • Buildings and facilities / Process equipment 修建和设备/工艺设备
    Buildings and facilities (chapter 4)修建和设备(第4章)
    Process equipment (chapter 5)工艺设备(第5章)

  • Production 出产
    Production and in-process control (chapter 8)
    出产和中心操控(第8章)
    Rejection and reuse of materials (chapter 14)物料拒收和再利用(第14章)


  • Laboratory controls 实验室操控
    Laboratory controls (chapter 11)
    实验室操控(第11章)


  • Specific group: Compliance to CEP dossier and Ph. Eur.
    Compliance of process to CEP dossier
    工艺契合CEP档案
    Compliance of analytical specifications and methods to CEP dossier Compliance to Ph. Eur.general methods and general monographs
    契合CEP档案的剖析标准和办法,契合欧洲药典一般办法和一般专著





药生
沙发
宣布于 2019-6-18 19:22:19 来自手机 | 只看该作者

点评

honker  同问  概况 回复 宣布于 2019-6-20 16:04
honker  同问  概况 回复 宣布于 2019-6-20 16:04
honker  同问  概况 回复 宣布于 2019-6-20 16:04
东玲miffy  知药出品,必属精品  概况 回复 宣布于 2019-6-20 09:12
板凳
宣布于 2019-6-19 09:01:51 | 只看该作者
药徒
地板
 楼主| 宣布于 2019-6-20 09:12:23 | 只看该作者
药徒
5#
宣布于 2019-6-20 15:47:25 | 只看该作者
感谢共享!
药徒
6#
宣布于 2019-6-20 16:04:12 | 只看该作者
药徒
7#
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药徒
8#
宣布于 2019-6-20 16:04:18 | 只看该作者
9#
宣布于 2019-6-22 10:48:04 | 只看该作者
同问,求共享!
药徒
10#
宣布于 2019-6-24 19:19:51 | 只看该作者
药徒
11#
宣布于 2019-6-25 07:54:28 | 只看该作者
这个有必要仍是学习一下
12#
宣布于 2019-6-25 10:44:18 | 只看该作者
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