欧盟GMP和FDA CGMP

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原创：Julia法规翻译 2018-08-02
01.08.2018
What are the Differences between EU and FDA GMP?
EU和FDA的GMP有什么区别?

While EU and FDA GMP Guidance is very similar, there are also some areas where there are known differences. It is worthwhile being aware of these differences and how to prepare for inspections and interaction with companies and authorities from the"other side".
虽然EU与FDA的GMP指南非常相似，但仍有一些领域是有区别的。了解这些区别，以及了解如何准备检查和公司与药监机构之间从“其它方面”的互动还是很有必要的。
Some examples:
举点例子:
The objective of the FDA "Annual ProductReview" (APR) is to evaluate annually the quality standards of each drug product but also to determine the need for changes inspecifications or manufacturing or control procedures. For this are presentative number of batches is reviewed. The objective of the EU ''Product Quality Review''(PQR) is to concentrate more on the overall manufacturing and quality system and to show that a company consistently produces products with the appropriate quality. But the PQR should include all batches which have been manufactured in the respective period. EU Inspectors are often requesting PQRs in advance of inspections!
FDA“年度产品回顾”（APR）的目的是对每种药品的质量标准进行年度评估，还有确定是否需要对质量标准或生产或控制程序进行修改。为此，需要审核具有代表数量的批次。EU的“产品质量审核”（PQR）的目标更为关注总体的生产和质量体系，显示出一个公司可持续生产出符合适当质量的产品。但是PQR应包括在回顾其是生产的所有批次。EU检查员通常会在检查之前就索取PQR。
Tracking &Trending and Key Process Indicators (KPIs) 追溯&趋势分析以及关键工艺指标（KPI）
According to EU-GMP Chapter 1, "a Pharmaceutical Quality System appropriate for the manufacture of medicinal products should ensure that (…) a state of control is established and maintained by developing and using effective monitoring and control systems for process performance and product quality." It is important touse KPIs to demonstrate a state of control but also to initiate and control potential continuous improvement processes. This should be periodically reviewed by senior management (1.6). Overall, all manufacturing processes should be "clearlydefined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications."
根据EU-GMP第1章“适合于药品生产的PQS应通过开发和使用有效的工艺性能和产品质量监控系统确保建立并保持受控状态”，使用API来证明受控状态是很重要的，但也要启动和控制潜在持续改进程序。高级管理层需要定期对这些进行审核（1.6）。总体来说，所有生产工艺均应“清楚定义，依据经验进行系统的审核，并证明有能力持续生产出所需品质并符合其质量标准的药品”。
So the EU will have an eye on quality metrics data mainly in the course of GMP inspections whereas the FDA has a different approach: The draft "Submission of Quality Metrics Data Guidance for Industry" was issued in November 2016. The FDA wishes that, after it has come into force, manufacturers will submit defined quality metrics to the FDA via an electronic portal. The FDA will use these to calculate specific statistics which are supposed to allow for risk-based inspection planning by the FDA.
所以EU在GMP检查过程中会要看质量量度数据，而FDA则会有不同的方法。FDA于2016年发布了“行业指南：质量量度数据提交”草案。FDA希望在其实施之后，生产商会通过电子端口向FDA提交定义的质量量度。FDA将使得这些来计算特定的统计指标，进而基于风险来规划其现场检查。
Role of the QP QP的职责
In the EU, a named Qualified Person (QP) must certify the GMP compliance for each batch of a drug product, either commercial or investigational (IMPs). The responsibilities of the Qualified Person are defined in Annex 16 to the EU-GMP Guidelines. If commercial productsor IMPs are manufactured or packaged in the US and then imported into the EU, additional analytical testing in the EU is needed. Additionally a successful supplier qualification is needed including initial and periodic compliance audits which are conducted according to the respective EU-GMP Guidance. These audits are performed by the QP or on behalf of the QP. An inspection by a competent authority does not replace the need for an audit. So US companies will still need to face EU audits, even after full implementation of the MRA.
在EU，指定的QP必须对每批（商业化或临床试验用）药品的GMP合规情况进行认证。QP的职责在EU-GMP指南附录16中已有定义。如果商业化药品或IMP是在美国生产或包装，然后进口至EU，则在EU需要进行额外的分析检测。此外还需要有正面的供应商确认，包括有依据相应的EU-GMP指南执行的初次和定期合规审计。这些审计要由QP或其代表人执行。由药监机构执行的检查并不能取代审计的需要。因此即使是在MRA全面实施之后，美国公司仍需要面对EU审计。
In the US, the Quality Control Unit is responsible for conducting a production record review according to CFR Part 211.192 and for ensuring contractors meet GMPs (211.22a).
在美国，质量部门负责根据CFR第211.192部分执行生产记录审核，并确保委托生产商符合GMP要求(211.22a)。
Validation 验证
There is growing conformity between the FDA Process Validation Guideline and the revised Annex 15 ("Qualification and Validation"). A better match with the FDA Guideline was also one of the reasons for the revision of EU-GMP Guide Annex 15.
FDA工艺验证指南与修订后的附录15（验证与确认）现在是越来越接近了。与FDA指南更为接近也是修订EU-GMP指南附录15的理由之一。
As one difference the Annex 15 asks to also list non-critical attributes and parameters in the validation protocol. The FDA Process Validation Guideline only requires the specification of critical quality attributes and critical process parameters.The FDA sees another difference in the number of validation batches. Annex 15 refers to the minimum number of three, whereas the FDA Process Validation Guideline does not mention a number. For the FDA there is another difference interms of process validation approaches. In Annex 15 three approaches are mentioned (traditional, continuous process verification, hybrid), while the FDA Process Validation Guideline makes no distinction. Further, the requirements for statistics also differ in the two documents. This topic is emphasized morein the FDA Process Validation Guideline. The FDA even recommends that as tatistician should create the data collection plans and should also be consulted with regard to the use of statistical methods. The FDA also sees differences regarding the subject of sampling in stage 3 of the process validation life cycle (continued/ongoing process verification) and demands a higher number of samples - at least until sufficient data exist to assess variability. There is no such demand for an increased number of samples in the ongoing process verification in Annex 15.
有一个差异是附录15还要求在验证方案中列出非关键属性和参数。FDA的工艺验证指南只要求关键质量属性和关键工艺参数标准。在验证批数方面也有区别。附录15指出最少批次为3批，而FDA工艺验证指南则并未提及此数据。对于FDA，在工艺验证方法上也有差异。在附录15中提到了3种验证方法（传统方法、持续工艺确认和混合），而FDA工艺验证指南则未作出区别。另外，对统计的要求也有区别。在FDA工艺验证指南中对此有着更多的强调。FDA甚至建议统计师要创建数据集计划，还应咨询使用何种统计方法。FDA中关于工艺验证生命周期第3阶段取样方面也有差异（持续工艺核查），要求取样更多---至少直到有足够的数据用于评估波动性，而在附录15的持续工艺核查中则没有要求增加样品数量。
EU Specifics EU特有
Contamination Control 污染控制
The 2015 revision of EU-GMP Guide Chapter 3 and Chapter 5 put a lot of focus on contamination control. The main changes in the new Chapter 3 "Premises and Equipment" concern measures to prevent cross-contamination. The changes are closely associated with the revision of Chapter 5 ("Production") and with the EMA-Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA/CHMP/CVMP/SWP/169430/2012). The new text asks for arisk-based assessment on the basis of toxicological data. This means that dedicated facilities are only required if the identified risks can not be controlled using adequate technical or organisational measures.
2015年，修订后的EU-GMP指南第3章和第5章对污染控制关注颇多。在新的第3章“设施与设备”中的主要变化是防止交叉污染的相关措施。该变化是与第5章（生产）的修订以及EMA关于设定共用设施中不同药品和平中风险识别所用基于健康暴露限设定指南（EMA/CHMP/CVMP/SWP/169430/2012）紧密相关的，新的内容要求以毒性数据为基础进行基于风险的评估。这意味着如果使用技术或组织措施无法控制所识别的风险时，则需要使用专用设施。
This is also supported by EMAs Toxicological Guideline, mentioned above. It has been valid since 1 June 2015 and describes a risk assessment based on the toxicological evaluation of the products manufactured in the shared facilities/production areas. The revised chapter 5 "Production" also has a high focus on the technical and organisational measures to prevent cross-contamination.
这也受到上述EMA毒性指南的支持。该指南自2015年6月1日起生效，其中描述了基于共用设施/设备区域中所生产药品的毒性评估的风险评估。修订后的第5章“生产”亦高度关注防止交叉污染的技术和组织措施。
Overall, a documented Contamination Control Strategy is required and QRM principles should be used to assess and control the risks of contamination & cross contamination.
总体来说，需要有文件记录的污染控制策略，并应使用QRM原则评估和控制污染&交叉污染的风险。
Supply ChainTraceability 供应链追溯
The qualification of (all) suppliers is a legal obligation of the marketing authorisation holder (MAH). Already when applying for a marketing authorisation (MA), the respective API suppliers need to be audited (and qualified) by the manufacturer. And this is the start of an ongoing qualification.
对（所有）供应商进行确认对于上市许可持有人MAH来说是法定义务。在申报MA时，相应的API供应商就需要由生产商进行审计（和确认）。这是持续确认的开始。
Article 46 of EU-Directive 2001/83/EC requires that (to comply with the GMP guidelines) the product manufacturer shall verify compliance of the API manufacturer it uses by conducting audits at manufacturing and distribution premises. For excipient suppliers, a formalised risk assessment is the minimum (see next paragraph).
EU指令2001/83/EC第46条要求（符合GMP指南）药品生产商应通过对生产和销售设施进行审计以核查其所用API生产商的合规性。对于辅料供应商，则至少应进行正式的风险评估（参见下一段）。
Chapter 7 of the EU-GMP Guide ("Outsourced Activities") then requires that "the Contract Giver is responsible for assessing the legality, suitability and the competence of the Contract Acceptor to carry out successfully the outsourced activities" prior to outsourcing activities [7.5] and that "the Contract Giver should monitor and review the performance of the Contract Acceptor (…)"[7.7].
EU-GMP指南第7章（外包活动）要求在委托活动之前“委托方有义务评估受托方成功执行外包活动的合法性、适当性以及其资格”【7.5】，并且“委托方应监管和审核受托方的表现（……）”【7.7】。
According to Annex 16 of the EU-GMP Guide, the QP has to ensure that "all audits of sites involved in the manufacture and the testing of the medicinal products and in the manufacture of the active substance have been carried out and that the audit reports are available to the QP performing the certification."[1.7.3]
根据EU-GMP指南附录16的要求，QP必须确保“已审计了药品生产和检测所有相关场所，以及API生产场所，并且执行认证的QP应可以获得这此审计报告”【1.7.3】。
GMP for Excipients 辅料GMP
In the EU, there is GMP Guidance for pharmaceutical excipient suppliers: Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use. The expectation is that Manufacturing Authorisation Holders perform a risk assessment to evaluate any risk associated with the excipient manufacturer/ supplier to further define appropriate GMP controls and a classification of the manufacturer's risk profile for the supplier qualification.
在EU，有一份药用辅料供应商的GMP指南“2015年3月19日，确定人用药辅料GMP适当性的正式风险评估指南”。要求是生产许可持有人执行风险评估以评价与辅料生产商/供应商有关的所有风险，进一步定义适当的GMP控制，对生产商的风险概况进行分级用于供应商确认。

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麦田.守望 发表于 2021-4-17 22:47
2点：1.一个叫欧盟，一个叫FDA；2.一个没有C，一个有C。

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