PIC/S指南PI 040-1 GMP缺陷分级 20190101

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PIC/S GUIDANCE ON CLASSIFICATION OF GMP DEFICIENCIES

PIC/S GMP缺陷分级指南

PI 040-1

3 Appendices

1 January 2019

1.    DOCUMENT HISTORY 文件历史

Adoption by Committee of PI 040-1	25 September 2018
由PI 040-1委员会采纳	2018年9月25日
Entry into force of PI 040-1	1 January 2019
PI 040-1生效	2019年1月1日

2.    INTRODUCTION 前言

2.1   This guidance is intended to provide a tool to support the risk based classification of GMP deficiencies from inspections and to establish consistency amongst Inspectorates.

本指南意在提供工具支持基于风险的GMP检查缺陷分级，保持不同检查员之间的一致性。

2.2   This guidance will enable Industry to be informed of the principles used to classify GMP deficiencies and also provide examples of the classification of different types of deficiencies. This approach is not binding as the classification takes also into account the context of the finding and the quality history of the site. It does not remove the responsibility of the company in assessing the impact of the finding on the products already on the market and/or on their quality system.

本指南让企业了解GMP缺陷分级原则，亦提供不同类型缺陷级别的例子。此方法并非与级别本身绑定，它同时还要考虑发现缺陷的情形以及该场所的质量历史。分级并不会免除企业评估该缺陷对已销售产品和/或其质量体系所产生影响的责任。

2.3   Consistency of classification of GMP deficiencies will assist in the following:

GMP缺陷统一分级标准有助于：

a)    Improve inter-agency consistency in reporting and

提高药监机构之间报告统一性，促进检查员之间的沟通；

b)    Harmonise inspectorate response and management of deficiencies classified as “Critical”, “Major” and “Other”;

统一检查员对分级为“关键”、“主要”和“其它”的缺陷的响应与管理；

c)    Provide transparency in how the deficiencies are classified; and

使得缺陷分级透明化，以及

d)    Simplify international deficiency trendanalysis based on harmonised reporting of GMP deficiencies from different inspectorates.

基于不同检查员对GMP缺陷的统一报告而简化国际缺陷趋势分析。

3.    PURPOSE AND SCOPE 目的与范围

3.1   The purpose and scope is the harmonisation of the classification of GMP deficiencies to facilitate harmonised reporting of GMP deficiencies from inspections across inspectorates.

目的与范围是统一GMP缺陷的分级，促进不同检查员检查缺陷的报告方式。

3.2   Harmonisation will help ensure that there isa consistent view across inspectorates of what constitutes a “Critical” deficiency and what constitutes a “Major” deficiency. Risk management principles will be applied to the categorisation of these deficiencies dependent on the type of product manufactured or process. The reference in the relevant code of Good Manufacturing Practice or local legislation should be established for each deficiency to ensure that a reported deficiency has are gulatory basis and is accurately applied.

统一将有助于确保不同检查员之间在何者构成“关键”缺陷以及何者构成“主要”缺陷方面达成共识。风险管理原则将被用于根据所生产产品或工艺类型不同对这些缺陷所做的分类。应为每个缺陷建立对GMP或当地法律中相关代码的引用，确保所报告的缺陷具备法规依据，并准确适用。

3.3   This guidance is also intended to:

本指南亦旨在：

a)    provide actions to be taken by inspectorates in response to the reporting of critical and major deficiencies;

为检查员对关键和主要缺陷报告响应提供应采取的措施；

b)    enhance communication, information sharing and scientific exchange to promote increased consistency and predictability inregulatory assessments and decisions and the rapid exchange of safety and quality information regarding manufacturers.

改进沟通、信息共享和科学交流，以促进法规评估和决策方面进一步统一化和可预见性，促进生产商安全和质量信息的快速交换。

4.    DEFINITIONS 定义

4.1   Critical Deficiency (See Appendix 3 for examples of Critical deficiencies)

关键缺陷（参见附录3关键缺陷举例）

A deficiency which has produced, or leads to a significant risk of producing either a product which is harmful to the human or veterinary patient or a product which could result in a harmful residue in a food producing animal.

已造成或将导致生产出对人体或动物患者有害的产品，或导致食用动物具有有害残留的产品的严重风险的缺陷。

A “Critical” deficiency also occurs when it is observed that the manufacturer has engaged in fraud, misrepresentation or falsification of products or data.

在发现生产商伪造、歪曲或篡改药品或数据时亦成为“关键”缺陷。

A “Critical” deficiency may consist of several related deficiencies, none of which on its own may be “Critical”, but which may together represent a ”Critical” deficiency, or systems’ failure where a risk of harm was identified and should be explained and reported as such.

“关键”缺陷可包含几个相关缺陷，其中任何一个可能单独时都不是“关键”，但合在一起则成为“关键”缺陷；或者是当发现一个系统有受损风险，理当如此解释并报告时亦成为“关键”缺陷。

4.2   Major Deficiency (See Appendix 3 for examples of Major deficiencies)

主要缺陷（参见附录3主要缺陷举例）

A deficiency that is not a “Critical” deficiency, but which:

并非“关键”缺陷，但具有以下性质的缺陷：

-      has produced or may produce a product which does not comply with its Marketing Authorisation, Clinical Trial Authorisation, product specification; pharmacopoeia requirements or dossier;

已生产或可能生产出不符合其上市许可、临床试验批件、药品质量标准、药典要求或注册资料的产品；

-      does not ensure effective implementation of the required GMP control measures;

不能确保有效实施所需GMP控制措施；

-      indicates a major deviation from the terms of the manufacturing authorisation;

显示严重偏离生产许可的条款；

-      indicates a failure to carry out satisfactory procedures for release of batches or (within PIC/S) failure of the authorised person to fulfil his/her duties;

显示批放行或（在PIC/S内）未能执行令人满意的程序，或授权人未能履行其职责；

-      consists of several “Other” related deficiencies, none of which on its own may be “Major”, but which may together represent a “Major” deficiency or systems failure and should be explained and reported as such.

包括几个“其它”相关缺陷，其中任何一个单独可能都不是“主要”，但在一起则成为“主要”缺陷，或者是系统失败且应按“主要缺陷”解释或报告。

4.3   Other Deficiency 其它缺陷

A deficiency that is not classified as either “Critical” or “Major”, but indicates a departure from Good Manufacturing Practice (GMP).

一个缺陷不能分级为“关键”或“主要”，但显示出偏离GMP要求。

A deficiency may be judged as “Other” because there is insufficient information to classify it as “Critical” or “Major”.

如果没有足够的信息将一个缺陷分级为“关键”或“主要”，则可能判定为“其它”。

4.4   Comment 建议

One-off minor discrepancies are usually not formally considered deficiencies, but are brought to the attention of the manufacturer as comments.

一次性轻微偏差通常并不会正式成为缺陷，但会作为建议提醒生产商注意。

5.    MANAGEMENT TOOL TO SUPPORT CONSISTENT AND OBJECTIVE CATEGORISATION OF GMP DEFICIENCIES IN ACCORDANCE WITH RISK MANAGEMENTPRINCIPLES 依据风险管理原则支持GMP缺陷统一客观分类的管理工具

5.1   When classifying a deficiency as “Critical”, inspectors should determine if there is clear evidence by considering risk of harm as in the definition. An example is provided in the flow chart found in Appendix 1, Figure 1.

在将一个缺陷分级为“关键”时，检查员应考虑定义中伤害风险从而确定是否有明确的证据。在附录1图1中流程图中可找到举例。

5.2   When a “Critical” deficiency is not clearly evident, the deficiency may be rated as “Critical”, “Major” or “Other”. A determination on the classification should be made for which the following guidance may be followed:

如果一个“关键”缺陷没有明确的证据证明，则该缺陷可能会被定级为“关键”、“主要”或“其它”。应依据以下指南来确定其级别：

5.2.1       Perform a detailed evaluation of the deficiency to determine an initial classification as per Appendix 1, Figures2-5; then

按附录1图2-5对缺陷进行详细评估，初步确定其级别，然后

5.2.2       Perform an evaluation of factors that would either increase or reduce the risk regardless of the initial classification as described in Appendix 2; then

无论初始分级如何，按附录2对可能会提升或降低风险的因素进行评估，然后

5.2.3       Make a decision as to whether the initial risk classification may be as described in Appendix 1, Figure 1:

按附录1图1中所述，决定初步风险分级是否

-      upgraded due to effects that increase the risk, i.e. risk-increasing effects,

因影响会增加风险而升级，即风险增加影响

-      maintained, or

维持原级

-      downgraded due to effects that reduce the risk, i.e. risk-reducing effects.

因影响会降低风险而降级，即风险降低影响

5.3   Deficiency classification examples (a non-exhaustive list) are provided in Appendix 3 which can be used to assist in the classification determination if required.

附录3给出了一份缺陷分级举例（非穷尽清单），可用于协助分级决策（需要时）。

5.4   The format of how deficiencies are written and grouped can also be a factor affecting the classification of the deficiency.

缺陷书写和组合的格式亦可能成为影响缺陷分级的一个因素。

6.    ACTIONS TO BE TAKEN BY INSPECTORATES IN RESPONSE TO THE REPORTING OF CRITICAL AND MAJOR DEFICIENCIES 检查员应对关键和主要缺陷报告所需采取的措施

6.1   Compliance and enforcement measures are dependent upon a number of factors, including significance of violations suchas a “Critical” deficiency and a large number of “Major” deficiencies, history of the site, potential risks to products, and assessment of the manufacturer’s proposed corrective actions. Where appropriate, this may include assessment of interim risk mitigating actions while long term remediation continues.

合规和强制措施取决于一系列因素，包括违规的严重性，如“关键”缺陷和大量“主要”缺陷、工厂历史、对产品的潜在风险，以及对生产商所拟纠正措施的评估。适当时，如果需要长期补救时，可能会包括对临时风险降低措施的评估。

6.2   The clinical impact of the deficiencies on specific ‘at risk’ groups (e.g. children or immunocompromised patients) as aresult of the observed quality or regulatory failures should be considered separately, and used to inform quality defect decisions and market actions such as recall. When assessing the clinical impact of observed deficiencies, expert advice such as medical and toxicological input should be sought.

缺陷对具体“处于风险中的”组（例如儿童或免疫功能低下患者）产生的临床影响应作为所发现的质量或注册失败结果进行单独考量，并用于通知质量缺陷决策和市场行动如召回。在评估所发现缺陷的临床影响时，应寻求专家建议如药性和毒性建议。

6.3   If the findings are linked to patient safety, immediate action needs to be taken.

如果缺陷与患者安全相关联，则需要立即采取措施。

6.4   Additional factors that should be considered include:

应考虑的其它因素包括：

a)    the risk to health and safety;

对健康和安全的风险；

b)    compliance history of the manufacturer;

生产商的合规历史；

c)    whether the manufacturer acted within difference or premeditation;

生产商是否不在乎或有预谋；

d)    the degree of co-operation offered;

所提供合作的程度；

e)    the likelihood that the same problem will reoccur;

同样问题重复发生的可能性；

f)     the likelihood of the enforcement action being effective.

强制措施生效的可能性。

6.5   Typically the first steps could include aletter of warning/cautionary letter or a re-inspection or reassessment inspection for which failure to address risk with repeat deficiencies may result in a non-compliance or similar rating.

一般来说，第一步可包括警告信/警示函或重新检查或重新评估检查，检查中发现未能解决重复缺陷的风险则会导致不合规或类似分级。

6.6   Depending upon the severity of the deficiency the inspectorate will determine if appropriate inspectional or regulatory actions are needed.

根据缺陷严重程度不同，检查员会决定是否需要采取适当的检查或法规行动。

6.7   The actions that can be taken may include:

可采取措施包括：

a)    compliance related communications which alert the manufacturer to the inspectorate’s concern, and possibility for future regulatory action if remedial action is not effective;

合规有关沟通，警示生产商检查员关切所在，以及如果补救措施无效可能导致的强制措施；

b)    regulatory action against the site authorisation or GMP approval (refusal, suspension or amendment of an establishment licence);

对工厂批文或GMP批准采取的强制措施（拒绝、搁置或工厂许可修改）；

c)    market actions  such  as recall  (voluntary  or mandated  by  the regulatory authority);

市场措施如召回（主动或药监机构强制）；

d)    prohibition of supply / importation;

禁止供应/进口；

e)    prosecution;

起诉；

f)     communications to the public using public warning/public advisory or information updates;

利用公众警示/公众建议或信息更新与公众沟通；

g)    suspension or cancellation of Marketing Authorisation/Product Licence;

搁置或撤销上市许可/产品批文；

h)    health product label or packaging changes.

卫生产品标签或包装修改。

7.    ENHANCING COMMUNICATION, INFORMATION SHARING AND SCIENTIFIC EXCHANGE TO PROMOTE INCREASED CONSISTENCY AND PREDICTABILITY INREGULATORY ASSESSMENTS AND DECISIONS AND THE RAPID EXCHANGE OF SAFETY AND QUALITY INFORMATION REGARDING MANUFACTURERS 增进沟通、信息共享和科学交流，提高法规评估和决策一致性和可预见性，促进生产商的安全和质量信息快速交流

7.1   In the global pharmaceutical supply chain, GMP non-compliance of a manufacturer can impact many different markets. Although the inspecting authority’s primary focus is ensuring the quality of medicines for their population, the impact of possible regulatory actions on supply to other markets should also be considered.

在全球药品供应链中，生产商的GMP不合规可能会影响多个不同市场。尽管检查当局的初衷是确保其民众的药品质量，但亦应考虑可能的法规措施对其它市场供应的影响。

7.2   The sharing of non-compliant inspection findings between trusted partners, particularly when regulatory action may follow, may help authorities in other territories to prepare risk mitigating market actions.

在互信伙伴间共享检查不合规缺陷，尤其是在后续可能采取法规行动时，将有助于其它领土的药监机构制订市场风险降低措施。

7.3   Maintaining close communication between affected inspectorates facilitates coordinated supply chain actions to avoid shortage of essential medicines. This also ensures that external notifications to healthcare professionals and patients are consistent and published at a timewhich is compatible with the actions in other territories.

保持受影响检查员之间的紧密沟通有助于协调供应链行动，避免基本药物短缺。这亦将确保对卫生专业人员和患者的外部通知与其它国家/地区的行动保持统一和同步。

8.    REVISION HISTORY 修订历史

Date 日期	Version number 版本号	Reasons for revision 修订理由

转自[url=]Julia法规翻译[/url]

syhorchid

了解一下

xqliu

学习一下啦，谢谢提供分享

qcl1236

谢谢分享，学习了。如果能有附录看看具体的操作就更好了。楼主能再发个附录吗？

huazhang

学习 学习，谢谢提供分享！

宋超1

非常好的资料

小金库

非常感谢分享