PICS PI 045 辅料的GMP风险评估

半窗疏影

PICS PI 045 辅料的GMP风险评估


作者：Skyla Sun
来源：OurGMP


　　TABLE OF CONTENTS


　　目录


　　1. Document history文件历史


　　2. Introduction简介


　　3. Scope范围


　　4. Determination of appropriate GMP based on type and use of excipient


　　基于类型和使用的辅料，合理选择GMP


　　5. Determination of excipient manufacturer’s risk profile


　　辅料生产商对风险预测的决定


　　6. Confirmation of application of appropriate GMP


　　确认采用的GMP的合理性


　　7. Revision History 修订历史


　　1. DOCUMENT HISTORY 文件历史

　　2. INTRODUCTION 简介


　　The present PIC/S Guidelines are based on EC document 2015/C 95/02, which has been drafted by the EMA GMDP IWG and transposed for PIC/S purpose by the PIC/S Sub-Committee on the Harmonisation of GM(D)P.


　　目前的PIC/S指南，基于EC文件 2015/C 95/02，此文件由EMA GMDP IWG起草，并由PIC/S的GM(D)P协调分委员会转换。


　　These guidelines have been adopted by PIC/S as a guidance document. It is up to each PIC/S Participating Authority to decide whether it should become a legally-binding standard.


　　上述指南已由PIC/S采用，作为其指南文件。每个PIC/S成员机构决定其是否应成为具有法律约束的标准。


　　The manufacturing authorisation holder is required to ensure that the excipients are suitable for use in medicinal products by ascertaining what the appropriate good manufacturing practice (GMP) is.


　　生产许可持有方应通过确定适用的GMP是什么，来确保辅料适用于药品。


　　The appropriate GMP for excipients of medicinal products for human use shall be ascertained on the basis of a formalised risk assessment in accordance with these guidelines.


　　根据依照本指南进行的正式风险分析，来确定人用药辅料的适宜GMP。


　　The risk assessment shall take into account requirements under other appropriate quality systems as well as the source and intended use of the excipients and previous instances of quality defects.


　　风险分析应考虑到其它相关质量系统的要求，以及辅料的来源、预期用途和先前的质量缺陷情况。


　　The manufacturing authorisation holder shall ensure that the appropriate GMP ascertained is applied. The manufacturing authorisation holder shall document the measures taken.


　　生产许可持有方应确保采用的GMP是适合的。生产许可持有方应记录采取的措施。


　　The excipient risk assessment/risk management procedure should be incorporated in the pharmaceutical quality system of the manufacturing authorisation holder.


　　辅料风险分析/风险管理规程应并入生产许可持有方的制药质量体系。


　　Manufacturing authorisation holders should have the risk assessment/management documentation for appropriate GMP for excipients available on site for review by GMP inspectors. Consideration should be given to sharing relevant information from the risk assessment with the excipient manufacturer to facilitate continuous improvement.


　　生产许可持有方应有适用于辅料GMP的风险分析/管理文件，且能供GMP检查官于现场查阅。应考虑与辅料制造商分享风险评估的相关信息，以促进持续改进。


　　A risk assessment as set out in these guidelines should be carried out for excipients for authorised medicinal products for human use in accordance with provisions established by applicable national competent authorities.


　　应根据国家职能部门制定的适用规定，对已获得许可的人用药品的辅料进行本指南规定的风险分析。


　　3. SCOPE 范围


　　3.1 These guidelines apply to the risk assessment for ascertaining the appropriate GMP for excipients for medicinal products for human use. An excipient is any constituent of a medicinal product other than the active substance and the packaging material.


　　此指南适用于风险评估，以确定适合于人用药所用辅料的GMP。 辅料是除活性物质和包装材料外的药品的任何成分。


　　3.2 These guidelines do not cover substances added to stabilise active substances that cannot exist on their own.


　　本指南不包含加入无法独立存在的活性物质的稳定剂。


　　4. DETERMINATION OF APPROPRIATE GMP BASED ON TYPE AND USE OF EXCIPIENT


　　基于辅料的类型和用途的适当的GMP决策


　　4.1 In PIC/S PE 009 Guide to Good Manufacturing Practice for Medicinal Products Annex 20, principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality, including excipients, can be found.


　　在PIC/S PE 009 药品GMP指南 附录20中，可以找到适用于药品质量不同方面(包括辅料)的质量风险管理的原则和工具实例。


　　4.2 These quality risk management principles should be used to assess the risks presented to the quality, safety and function of each excipient and to classify the excipient in question, e.g. as low risk, medium risk or high risk. Quality risk management tools such as those listed in Annex 20 (e.g. hazard analysis and critical control points — HACCP) should be used for this purpose.


　　上述质量风险管理原则应用来评估每种辅料的质量、安全和功能方面的风险，并对辅料进行分类，如低风险、中等风险或高风险。质量风险管理工具，例如附录20中所列出的(如：HACCP)应该用于此目的。


　　4.3 For each excipient from each manufacturer used, the manufacturing authorisation holder should identify the risks presented to the quality, safety and function of each excipient from its source — be that animal, mineral, vegetable, synthetic, etc. — through to its incorporation in the finished pharmaceutical dose form. Areas for consideration should include, but are not limited to:


　　对于每家生产商的每种辅料，生产许可持有方应从其来源(动物、矿物、植物、合成等)直到其结合进成品剂型，识别每种辅料的质量、安全和功能方面的风险。需要考虑的方面应包括，但不限于：


　　(a) transmissible spongiform encephalopathy;


　　传染性海绵状脑病(TSE);


　　(b) potential for viral contamination;


　　病毒污染的可能性;


　　(c) potential for microbiological or endotoxin/pyrogen contamination;


　　微生物或内毒素/热原污染的可能性;


　　(d) potential, in general, for any impurity originating from the raw materials, e.g. aflatoxins or pesticides, or generated as part of the process and carried over, e.g. residual solvents and catalysts;


　　通常，原物料产生任何杂质的可能，如黄曲霉毒素或农药，或作为工艺一部分产生和带入的杂质，如残留溶剂和催化剂;


　　(e) sterility assurance for excipients claimed to be sterile;


　　声称无菌的辅料的无菌保证;


　　(f) potential for any impurities carried over from other processes, in absence of dedicated equipment and/or facilities;


　　不使用专用设备和/或设施的情况下，其它生产带来杂质的可能;


　　(g) environmental control and storage/transportation conditions including cold chain management, if appropriate;


　　环境控制和仓储/运输条件，包括冷链管理(如适用);


　　(h) supply chain complexity;


　　供应链的复杂性;


　　(i) stability of excipient;


　　辅料的稳定性;


　　(j) packaging integrity evidence.


　　包装完整性证据;


　　4.4 Additionally, with respect to the use and function of each excipient, the manufacturing authorisation holder should consider:


　　另外，考虑到每种辅料的用途和功能，生产许可持有方应考虑：


　　(a) the pharmaceutical form and use of the medicinal product containing the excipient;


　　含有辅料的药品的用途和剂型;


　　(b) the function of the excipient in the formulation, e.g. lubricant in a tablet product or preservative material in a liquid formulation, etc.;


　　制剂中辅料的作用，如片剂产品中的润滑剂或液体制剂中的防腐剂等;


　　(c) the proportion of the excipient in the medicinal product composition;


　　辅料在药品成分中所占的比例;


　　(d) daily patient intake of the excipient;


　　患者每日摄入的辅料的剂量;


　　(e) any known quality defects/fraudulent adulterations, both globally and at a local company level related to the excipient;


　　全球范围或当地公司范围与辅料有关的所有已知的质量缺陷/造假情况


　　(f) whether the excipient is a composite;


　　辅料是否为一种组分;


　　(g) known or potential impact on the critical quality attributes of the medicinal product;


　　对药品关键质量属性的已知或潜在的影响;


　　(h) other factors as identified or known to be relevant to assuring patient safety.


　　确定或已知与确保患者安全有关的其他因素。


　　4.5 Having established and documented the risk profile of the excipient, the manufacturing authorisation holder should establish and document the elements of the PIC/S PE 009 Guide to Good Manufacturing Practice for Medicinal Products that he/she believes are needed to be in place in order to control and maintain the quality of the excipient, e.g. Annex 1 or/and Annex 2; Guide to Good Manufacturing Practice for Medicinal Products Part II: Basic Requirements for Active Pharmaceutical Ingredients.


　　建立并记录辅料的风险预测后，生产许可持有人应建立并记录PIC/S PE 009 药品GMP指南中企业认为控制并维持辅料质量所必须的要素，如附录1和/或附录2;药品GMP指南 部分II：API的基本要求。


　　4.6 These elements will vary depending on the source, the supply chain and the subsequent use of the excipient, but as a minimum the following high level GMP elements should be considered by the manufacturing authorisation holder:


　　这些要素会根据辅料的来源、供应链和随后的使用而不同，但生产许可持有方至少应考虑下述高水平GMP要素：


　　(a) establishment and implementation of an effective pharmaceutical quality system;


　　有效制药质量体系的建立和运转;


　　(b) sufficient competent and appropriately qualified personnel;


　　人员具备足够的能力和适当的资质;


　　(c) defined job descriptions for managerial and supervisory staff responsible for manufacturing and quality activities;


　　负责生产和质量活动的监管人员的职责描述;


　　(d) training programmes for all staff involved in manufacturing and quality activities (included but not limited to cleaning, engineering, laboratory, maintenance, materials management, safety, and technical services);


　　所有涉及生产和质量活动的员工的培训方案(包括但不仅限于：清洁、工程、实验室、维护、物料管理、安全、和技术服务);


　　(e) training programmes related to health, hygiene and clothing as identified as necessary to the intended operations;


　　健康、卫生和更衣相关的培训方案，应确认其对于既定操作是必要的;


　　(f) provision and maintenance of premises and equipment appropriate to the intended operations;


　　厂房设施和设备的设计和维护适合于其既定操作;


　　(g) documentation system(s) covering all processes and specifications for the various manufacturing and quality operations;


　　文件系统涵盖所有生产和质量操作的工艺流程和质量标准;


　　(h) systems for coding and identifying starting materials, intermediates and excipients to allow full traceability;


　　起始物料、中间体和辅料的编码和识别系统可以进行全程追踪;


　　(i) qualification program of suppliers;


　　供应商资质确认项目;


　　(j) system for quality control of the excipient and a responsible person independent from production to release the batches;


　　用于辅料质量控制的系统和独立于生产进行批放行的负责人;


　　(k) retention of records for incoming materials and excipients and retention of samples of excipients for the periods required by PIC/S Guide to Good Manufacturing Practice for Medicinal Products, Part II;


　　进货物料和辅料记录的保存和辅料留样的时间应符合PIC/S 药品GMP指南，部分II;


　　(l) systems to ensure that any activity contracted out is subject to a written contract;


　　确保所有外包活动均有书面合同的制度;


　　(m) maintenance of an effective system whereby complaints are reviewed and excipients may be recalled;


　　下述有效系统的维护：投诉审查，(可能的)辅料召回;


　　(n) change management and deviation management system;


　　变更管理和偏差管理体系;


　　(o) self-inspection program;


　　自检程序;


　　(p) environmental control and storage conditions.


　　环境控制和仓储条件。


　　5. DETERMINATION OF EXCIPIENT MANUFACTURER’S RISK PROFILE


　　确定辅料生产商的风险预测


　　5.1 After determination of the appropriate GMP, a gap analysis of the required GMP against the activities and capabilities of the excipient manufacturer should be performed.


　　确定了适当的GMP后，应对辅料生产商的活动和能力与所需GMP进行差距分析。


　　5.2 Data/evidence to support the gap analysis should be obtained through audit or from information received from the excipient manufacturer.


　　用以支持差距分析的数据/证据应通过审计获得，或从辅料生产商处收到的信息获得。


　　5.3 Certification of quality systems and/or GMP held by the excipient manufacturer and the standards against which these have been granted should be considered as such certification may fulfil the requirements, subject to national legislation requirements.


　　辅料生产商持有的质量体系和/或GMP证书，和颁发证书所依据的标准应进行考虑，因为此类认证可以满足要求，依照国家法规要求。


　　5.4 Any gaps identified between the required GMP and the activities and capabilities of the excipient manufacturer should be documented. Furthermore, the manufacturing authorisation holder should perform a further risk assessment to determine the risk profile, e.g. low risk, medium risk or high risk, for that excipient manufacturer. PIC/S PE 009 Guide to Good Manufacturing Practice for Medicinal Products Annex 20: Quality Risk Management should be used for that purpose. Quality risk management tools such as those listed there—HACCP etc.—should be used for this.


　　所识别的GMP要求和辅料生产商的活动与能力之间的所有差距应进行记录。此外，生产许可持有方应进行进一步的风险分析，以确定该辅料生产商的风险预测，例如，低风险、中等风险或高风险。《PIC/S PE 009 药品GMP指南 附录20：质量风险管理》应用于此。质量风险管理工具，例如列于其中的那些----HACCP等-----应用于此。


　　5.5 The manufacturing authorisation holder should have a series of strategies ranging from acceptance through control to unacceptable for the different risk profiles and based on these a control strategy, e.g. audit, document retrieval and testing, should be established.


　　生产许可持有方应具备一系列的策略，对不同风险的预测从可接受到控制到不可接受。基于这些，应建立一种控制策略，例如，审计，文件恢复和检测。


　　6. CONFIRMATION OF APPLICATION OF APPROPRIATE GMP


　　采用适当GMP的确认


　　6.1 Once the appropriate GMP for the excipient and the risk profile of the excipient manufacturer have been defined, ongoing risk review should be performed through mechanisms such as:


　　一旦确定了该辅料适用的GMP，以及辅料生产商的风险概况，应通过一定机制进行持续的风险评审，如：


　　(a) number of defects connected to batches of excipient received;


　　与收到的辅料批次相关的缺陷的数量;


　　(b) type/severity of such defects;


　　上述缺陷的类型/严重性;


　　(c) monitoring and trend analysis of excipient quality;


　　辅料质量的监控和趋势分析;


　　(d) loss of relevant quality system and/or GMP certification by excipient manufacturer;


　　相关质量体系和/或辅料生产商GMP证书的缺失;


　　(e) observation of trends in drug product quality attributes; this will depend on the nature and role of excipient;


　　药品质量属性的趋势观察，这将取决于辅料的性质和作用;


　　(f) observed organisational, procedural or technical/process changes at the excipient manufacturer;


　　发现的辅料生产商在组织、规程或技术/工艺方面的变更;


　　(g) audit/re-audit of excipient manufacturer;


　　辅料生产商的审计/再次审计;


　　(h) questionnaires.


　　问卷;


　　Based on the outcome of the risk review, the established control strategy should be reviewed and revised if needed.


　　基于风险评审的结果，应对已建立的控制策略进行审查，需要的话可进行修订。