浅析GMP检查发现的风险分级.doc

Health Products and Food Branch Inspectorate食品与健康类产品检查员Guide-0023指南-0023Risk Classification of GMP Observations,2003 editionGMP检查发现的风险分级，2003版Supersedes:June 1st, 2000 editionDate issued: April 4th , 2003Date of implementation: June 1st, 2003Ce document est aussi disponible en franais.本文可提供法语版24 / 24TABLE OF CONTENTS目录1.0PURPOSE目的32.0BACKGROUND背景33.0SCOPE范围34.0DEFINITIONS定义:45.0GUIDE指南正文65.1Assignment of the risk to an observation针对缺陷界定风险65.2Assignment of the inspection rating检查评定75.2.1Risk 1 observation:1类风险缺陷75.2.2Risk 2 observation:2类风险缺陷75.2.3Risk 3 observations:3类风险缺陷85.3Additional guidance补充8Appendix 1附录19Appendix 2 附录212Appendix 3附录3211.0 PURPOSE目的To classify the observations noted during establishment inspections according to their risk.依据风险的程度对企业检查中的发现进行分级。To ensure uniformity among the inspectors of the Health Products and Food Branch Inspectorate (the Inspectorate) in the attribution of the rating following establishment inspections.确保食品与健康产品检查员（检查员）在对企业进行评估时采用统一的标准。To inform the industry of the situations that the Inspectorate considers unacceptable and that will generate a Non Compliant (NC) rating following an inspection.将各种不被检察员接受进而导致认证失败的情况明确告知企业。2.0 BACKGROUND背景During an establishment inspection, deviations from the Food and Drug Regulations and the current edition of the Good Manufacturing Practices (GMP) guidelines are noted by the inspector and these deviations appear as observations in the inspection exit notice. A judgement based on these observations is then made by the inspector and an overall recommendation for the continuation or issuance of the establishment licence (rating of Compliance) or not to continue or issue the licence (rating of Non-Compliance) is given. Attribution of a NC rating may have serious consequences for a company, ranging from the implementation of important corrective measures to the temporary suspension or termination of the Establishment Licence (EL). Therefore, these situations of non- conformity have to be well defined, unambiguous and directly supported by the applicable regulations. 在工厂检查时，凡违反食品药品法和现行GMP的行为都将被检察员记录下来作为离开时检查通告中的检查缺陷。 基于这些缺陷，检查人员将做出判断并对是否应该授予或延续企业许可证（合规评定）或不授予或取消企业许可证（不合规评定）给出综合性意见。得到不合规评定有可能给企业带来严重的后果，包括停业整顿或吊销执照。因此，所有不合规的界定应有清晰明确的定义并有章可循。 3.0 SCOPE范围The definition of a drug in Canada covers a wide variety of products ranging from pharmaceuticals and biologics to natural health products such as homeopathics and herbal preparations. This guidance document covers all such products to which Division 2 of Part C of the Food and Drug Regulations applies and is based on the current edition of the GMP Guidelines. It is recognised that the evaluation of the conformity to the GMP should be commensurate with the risk involved taking into account the nature and extent of the deviation in relation with the category of products evaluated. Nonetheless, most of the situations involving fraud, misrepresentation or falsification of products or data will generate a NC rating, irrespective of the category of products involved. 在加拿大，药品定义广泛，从生化药物到自然的健康产品如顺势疗法和草药都属于此范畴。本文依照现行GMP制定，适用于所有食品药品法C部第2章节所规定的产品。GMP合规评估和风险评估是同时进行的，而风险评估需要根据缺陷的性质与程度同时与评估产品的类别联系起来，这些都已得到业界的认同。但是，大多数导致认证失败的发现如产品或数据存在虚假，歪曲或蓄意伪造都没有考虑产品的类别。The appendices attached to the present document describe the observations related to each category of risk. Please note that the list of observations in each appendix is not exhaustive and that additional observations may be added where appropriate.本文附录描述了检查发现相应的风险级别。请注意附录中并未完全列举所有的检查发现，需要之处可以补充。The numbering system assigned to each section in the appendices is a reference to the applicable regulations in the current edition of the GMP guidelines.附件各章节中的数字代表现行GMP法规中相关章节，以备参考。4.0 DEFINITIONS定义:The following definitions are provided to complement those already available under the glossary of terms in the current edition of the GMP Guidelines or other related documents referenced in the GMP Guidelines.以下定义是对现行GMP法规或其相关文件释义部分的补充Observation 缺陷:A deviation or deficiency to GMP noted by an inspector during the inspection of a drug establishment that is confirmed in writing to the company in the exit notice. The observations are classified as “Critical”, “Major” and “Other” and are assigned a risk classification, ranging from 1 for “critical” to 2 for “major” to 3 for “other”. 药品企业检查过程中，所有被检查人员写入报告的偏差或不足。缺陷分为严重，主要和一般，分别用1（代表严重），2（代表主要），3（代表一般）表示其风险级别。Critical observation 严重缺陷:Observation describing a situation that is likely to result in a non-compliant product or a situation that may result in an immediate or latent health risk and any observation that involves fraud, misrepresentation or falsification of products or data. 严重缺陷包括可能导致产品不合格的缺陷，可能对健康造成立即的或延后的危害的缺陷以及涉及产品或数据存在虚假，歪曲或蓄意伪造的缺陷。Appendix I lists observations that the Inspectorate considers critical which will be assigned a Risk 1.附录1列出了检察员认为属于1类风险的严重缺陷。Major observation主要缺陷:Observation that may result in the production of a drug not consistently meeting its marketing authorization.主要缺陷是指导致产品不能持续达到既定标准的缺陷。 Appendix 2 lists observations that are considered major and which will be assigned a Risk 2 CertainRisk 2 observations may be upgraded to Risk 1. They are indicated with an arrow ( ). 附录2列出了检察员认为属于2类风险的主要缺陷。一部分可以上升为1类风险的2类风险已用箭头标明。Other observation一般缺陷:Observation that is neither critical nor major but is a departure from the GMP.一般缺陷指不属于严重或主要缺陷但偏离GMP要求的缺陷。“Other” observations are not listed as such (Observations that are neither critical nor major areconsidered as “other” and will be assigned a Risk 3). Appendix 3 lists Risk 3 observations that may be upgraded to Risk 2. 一般风险没有像1，2类风险一样被全部列举出来（所有不属于严重或主要的缺陷都归于一般缺陷，属3类风险。）附录3列举了可以上升为2类风险的3类风险。Critical product最高风险产品:A critical product is one for which any of the following criteria may apply:下列情况有任何一条成立，则该产品属于最高风险产品。Snarrow therapeutic window具有窄治疗窗的药物Shigh toxicity剧毒性药物Ssterile product无菌产品Sbiological drug生物药品S complex manufacturing process:生产工艺复杂的产品Process for which slight deviations in the control of parameters could result in a non-uniform product or a product not meeting its specifications. As example, powder mixing or granulation for low dosage solid forms, long acting / delayed action products, sterile products. 工艺参数控制上一点小的偏差便能引发产品不均一或不合格的情况。如小剂量固体制剂中的混合与制粒，长效或缓释药品，无菌药品。 Note注意:OTC low dosage vitamins and minerals preparations and Category 4 products (as listed in Interpretation 2.3 under section C.02.028) should not be considered as critical products even when the manufacturing processes involved are complex. 非处方低剂量药物如维生素，微量元素类制剂以及4类产品（参见C.02.028章节下2.3的解释）尽管制造工艺非常复杂但仍不被认作为最高风险产品。 High risk product高风险产品:Any product that may trigger a health risk even at low levels, following cross-contamination. Those include but are not limited to penicillins, certain cytotoxic and biological products.任何只需小剂量便能危害健康，引起交叉污染的产品，包括但不仅限于：盘尼西林，部分细胞毒素和生物制品。Low Risk product低风险产品:Products such as Category 4 product (as listed in Interpretation 2.3 under section C.02.028), naturalhealth products including vitamins and minerals preparations that are not a schedule drug or a sterile drug, and certain topical non prescription veterinary formulations registered as “old drugs”. 4类产品（参见C.02.028章节下2.3的解释）， 自然健康产品包括维生素，微量元素类非周期性，非无菌性制剂，还有部分注册为“老药”的非处方类兽药。 Acronyms缩写:C:Compliant合规CIP:Clean-In-Place在线清洁COA:Certificate of Analysis检验报告EL:Establishment Licence企业许可证GMP:Good Manufacturing Practices药品生产质量管理规范 HVAC:Heat, Ventilation, Air Conditioning 空调系统IRS:Inspection Reporting System检查报告MRA: Mutual Recognition Agreement互认协议NC:Non-compliant 不合规OTC:Over-The-Counter 非处方药PM:Packaging Material 包材PW:Purified Water 纯化水QC:Quality Control 质量管理部门 (QA+QC)RM:Raw Material 原料WFI:Water For Injection 注射用水5.0 GUIDE指南正文5.1 Assignment of the risk to an observation针对缺陷界定风险Whereas it is recognized that it is impossible to encompass every situation that may generate a risk, the following principles should be considered: 鉴于我们都认识到不可能将所有可能导致危险的情况都罗列出来，因此在界定风险时请考虑以下准则：-The risk assigned will be in relation to the nature of the deviation as well as the number of occurrences. 风险的界定应与缺陷的性质与发生次数关联起来。 -Generally, when only low risk products are involved, a risk 1 will not be assigned to observations described in Appendix 1, except for extreme situations such as fraud or widespread cross-contamination, infestation or unsanitary conditions. 一般而言，当涉及的产品为低风险产品时，附录1中所描述的缺陷不应被界定为1类风险，除非极端情况发生，如：虚假，大范围交叉污染，感染或不卫生情形。-Where a risk 2 observation is re-evaluated as a risk 1 (risk 2 observation with an arrow), this situation is immediately brought to the attention of the companys officials, proper explanationwill be provided to the establishment and this explanation should be captured in the “InspectorsComments” field of the “Inspection Summary” in the IRS. 当2类风险被重新评估为一类风险时（2类风险中标有箭头的缺陷），应立即告知企业的管理层并进行合理的解释，解释内容应记录在检查报告总结部分的检察员意见栏中。5.2 Assignment of the inspection rating检查评定The overall inspection rating assigned is based on the risk involved taking into account the nature and extent of the deviations with the category of products evaluated. 综合评定基于存在的风险，缺陷的性质与程度以及评估产品的类别。5.2.1 Risk 1 observation:1类风险缺陷Generally, a NC rating is assigned when a Risk 1observation is noted during an inspection. 一般而言，出现1类风险缺陷，企业将被评定为不合规。Such situation is immediately brought to the attention of the companys officials. The Inspectorate management is to be notified in a timely manner. 这类情况应被立即告知企业管理层并及时报告给检查机构管理层。Where in the opinion of the inspector the resulting products present a significant health hazard, appropriate enforcement actions may be initiated.如果检察员认为相关产品存在对健康的严重威胁，将会对其启动适当的强制手段。5.2.2 Risk 2 observation:2类风险缺陷Generally, a C rating is assigned when Risk 2 observations are noted during an inspection. However, aNC rating may be assigned in the following situations: 一般而言，出现2类风险缺陷，企业仍将被评定为合规，但在以下情况出现时，企业将被评定为不合规：-When numerous Risk 2 observations are noted during an inspection indicating that the company does not control its processes and operations sufficiently. 当2类风险缺陷显示出企业在工艺和运作方面没能加以足够的控制时。-Repetition of many Risk 2 observations noted during previous inspections indicating that the company did not: 当许多前次检查发现的2类风险缺陷重复出现，显示出企业没有能够-implement the corrective actions submitted following the previous inspection or按照递交的计划执行前一次检查缺陷的纠正工作或-did not put in place adequate preventive actions in a timely manner to avoid recurrence of such deviations.没有及时采取足够的预防措施来防止偏差的再次发生。5.2.3 Risk 3 observations:3类风险缺陷A C rating will be assigned in all situations where only Risk 3 observations are noted. 如果仅发现3类风险缺陷，企业将被评定为合规的。 5.3 Additional guidance补充When a NC rating is assigned, the inspector will issue a draft Inspection Exit Notice during the exit meeting. The draft inspection exit notice will be reviewed for quality assurance purposes before the final report is issued to an establishment. 当企业被评定为不合规时，检查员将在检查结束的总结会上递交检查通告草稿。在最终报告发至企业之前，草稿可以用于质量保证目的的阅读。When observation(s) leading to a NC rating are made, the Inspection Exit Notice could be issued witha C rating if, during the inspection: 当出现导致企业被评定为不合规的缺陷时，如果企业能够在检查其间完成下列工作，检查通告仍会给出企业合规的结论： - the establishment immediately implements all necessary actions to resolve the cause(s) of the observation(s) leading to the NC rating and, 企业立即采取必要措施根除导致缺陷发生的原因并且- sufficient assurance can be provided to prevent a recurrence.采取足够的预防措施防止缺陷再度发生。In such instances, the risk assigned to the observation will remain the same. 这种情况下，原来对缺陷所作的风险评估等级仍保持不变。If the management of the company wishes to dispute the results of the inspection report, the “Dispute resolution and appeals” mechanism described in the GMP and EL Enforcement Policy POL-0004 should be followed.如果企业希望对检查结果进行申辩，GMP与企业强制认证政策POL-0004 中的“争议解决与上诉”机制将被启动。Appendix 1附录1Risk 1 (Critical) Observations 1类风险（严重）缺陷Premises C.02.004 厂房- No air filtration system to eliminate airborne contaminants that are likely to be generated during fabrication or packaging. 没有空气过滤系统以消除生产和包装时可能产生的沉降污染。- Generalized malfunctioning of the ventilation system(s) with evidence of widespread cross-contamination.大范围交叉污染的事实表明通风系统存在故障。- Inadequate segregation of manufacturing or testing areas from other manufacturing areas for high risk products.高风险产品之间的生产区域或测试区域没能有效地隔开。Equipment C.02.005 设备- Equipment used for complex manufacturing operations of critical products not qualified and with evidence of malfunctioning. 用于最高风险产品复杂生产过程的设备不合规定同时也存在故障。Personnel C.02.006 人员- Individual in charge of Quality Control (QC) or production for a fabricator of critical / high risk products does not hold a university degree in a science related to the work being conducted and does not have sufficient practical experience in their responsibility area. 管理最高风险，高风险产品质量管理或生产的人员没有相关领域的大学文凭同时缺乏足够的实践经验。Sanitation C.02.007C.02.008 卫生- Evidence of widespread accumulation of residues / extraneous matter indicative of inadequate cleaning. 清洁的不够充分，存在大范围残留/异物积聚。- Evidence of gross infestation. 明显的虫害或污染Raw Material Testing C.02.009 C.02.010 原料检验- Evidence of falsification or misrepresentation of analytical results.分析结果造假或歪曲- No evidence of testing (COA) available from the supplier / synthetizer and no testing done by the Canadian fabricator. 缺少供应商的检验报告同时企业也没做相关的测试。Manufacturing Control C.02.011 C.02.012 生产控制- No written Master Formula. 没有书面的主处方- Master Formula or manufacturing batch document showing gross deviations or significant calculation errors. 主处方或生产批记录存在明显的偏差或严重的计算错误。- Evidence of falsification or misrepresentation of manufacturing and packaging orders.生产和包装订单的造假或错误Quality Control Department C.02.013 C.02.014 C.02.015 质控部门- No person in charge of QC available on premises in Canada. 加拿大工厂内没有质量管理负责人- QC department not a distinct and independent unit, lacking real decisional power, with evidence that QC decisions are often overruled by production department or management.质量管理部门不是独立的机构，缺乏真正的决定权，有证据表明质量管理部门的决定常被生产或管理层否定。Finished Products TestingC.02.018 C.02.019 成品检验- Finished product not tested for compliance with applicable specifications by the importer / distributor before release for sale and no evidence is available that the products have been tested by the fabricator.销售前，进口商/分销商没有按照合适的标准对成品进行检验同时没有证据显示生产商做过相关测试。- Evidence of falsification or misrepresentation of testing results / forgery of COA.检验结果造假或歪曲/伪造检验报告Records C.02.020 to C.02.024 记录- Evidence of falsification or misrepresentation of records. 记录造假或歪曲事实Stability C.02.027 C.02.028 稳定性- No data available to establish the shelf-life of products. 缺少建立产品效期的数据- Evidence of falsification or misrepresentation of stability data / forgery of COA.稳定性数据的造假或歪曲/伪造检验报告Sterile Products C.02.029 无菌产品- Critical sterilization cycles based on Probability of Survival not validated.关键灭菌过程没有基于细菌存活率的进行验证。- Water for Injection (WFI) systems not validated with evidence of problems such as microbial /endotoxin counts not within specifications.注射用水系统未作验证，存在微生物/内毒素超标的情况。- No media fills performed to demonstrate the validity of aseptic filling operations.无菌灌装工艺未做培养基灌装验证。- No environmental controls / No monitoring for viable microorganisms during filling for aseptically filled products. 无菌灌装产品在灌装期间缺少环境监控/微生物监控。- Aseptic filling operations maintained following unsatisfactory results obtained for media fills.培养基灌装验证失败后仍继续进行无菌灌装生产。- Batches failing initial sterility test released for sale on the basis of a second test without proper investigation.产品基于第二次无菌检测结果放行，而对首次的菌检失败未作调查。Appendix 2 附录2Risk 2 (Major) Observations 2类风险（主要）缺陷Premises C.02.004厂房- Malfunctioning of the ventilation system that could result in possible localized or occasional cross-contamination.通风系统的故障导致固定的或间歇性的交叉污染。- Maintenance / periodic verification such as air filter replacement, monitoring of pressure differentials not performed. ( )没有做维护/周期性的性能确认如：空气过滤器的更换，检测压差。- Accessory supplies (steam, air, nitrogen, dust collection, etc.) not qualified.辅助系统（蒸气，空气，氮气，灰尘收集）不符合要求- Heat Ventilation Air Conditioning (HVAC) and purified water (PW) system not qualified.空调系统和纯化水系统不符合要求- Temperature and humidity not controlled or monitored when necessary (e. g. storage not in accordance with labelling requirements).在需要监控温湿度的环节没能监控温湿度（如未按温湿度要求存放标签）- Damages (holes, cracks or peeling paint) to walls / ceilings immediately adjacent or above manufacturing areas or equipment where the product is exposed.与产品暴露区域直接相邻或在其上方的墙面，天花板损坏（破洞，裂缝或油漆剥落）- Un-cleanable surfaces created by pipes, fixtures or ducts directly above products or manufacturing equipment. 无法进行表面清洁的管道经过产品或生产设备的上方。- Surfaces finish (floors, walls and ceilings) that do not permit effective cleaning. 地板，墙体和天花板表面的外层涂料或覆盖无法有效清洁。 - Unsealed porous finish in manufacturing areas with evidence of contamination (mildew, mould, powder from previous productions, etc.) ( )生产区域未封闭的孔状表面内在污染（霉菌，前批生产的药粉等等）- Insufficient manufacturing space that could lead to mix-ups. ( )生产区域空间太小易造成差错- Physical and electronic quarantine accessible to unauthorized personnel / Physical quarantine area not well marked and /or not respected when used. ( )未经授权的人员可以通过机械和电子门禁/机械隔离的区域缺少标示而且/或没有按规程使用。- No separate area / Insufficient precautions to prevent contamination or cross-contamination during RM sampling.原料抽样缺少独立区域/没有足够的预防措施来防止污染或交叉污染。 Equipment C.