Health Products and Food Branch Inspectorate
食品与健康类产品检查员
Guide-0023 指南-0023
Risk Classification of GMP Observations,
2003 edition
GMP检查发觉的风险分级，
2003版
Supersedes:
June 1st, 2000 edition Date issued: April 4th , 2003
Date of implementation:
June 1st, 2003
Ce document est aussi disponible en français.
本文可提供法语版
TABLE OF CONTENTS
名目
1.0 2.0 3.0 4.0 5.0
PURPOSE目的 ......................................................................................................................................... 3 BACKGROUND背景 .............................................................................................................................. 3 SCOPE范畴 .............................................................................................................................................. 3 DEFINITIONS定义: ................................................................................................................................ 4 GUIDE指南正文 ...................................................................................................................................... 6 5.1 Assignment of the risk to an observation针对缺陷界定风险 .............................................................. 6 5.2 Assignment of the inspection rating检查评定 ...................................................................................... 7
5.2.1 Risk 1 observation:1类风险缺陷.............................................................................................. 7 5.2.2 Risk 2 observation:2类风险缺陷.............................................................................................. 7 5.2.3 Risk 3 observations:3类风险缺陷 ............................................................................................ 8 5.3 Additional guidance补充 ......................................................................................................................... 8 Appendix 1附录1...................................................................................................................................................... 9 Appendix 2 附录2 .................................................................................................................................................. 12 Appendix 3附录3.................................................................................................................................................... 20
1.0 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觉进行分级。
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纳统一的标准。
To inform the industry of the situations that the Inspectorate considers unacceptable and that will generate a Non Compliant (NC) rating following an inspection.
将各种不被检察员同意进而导致认证失败的情形明确告知企业。
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，检查人员将做出判定并对是否应该授予或连续企业许可证〔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峻的后果，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范畴
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，而风险评估需要依照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。然而，大多数导致认证失败的发觉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觉相应的风险级别。请注意附录中并未完全列举所有的检查发觉，需要之处能够补充。
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。缺陷分为严峻，要紧和一样，分别用1〔代表严峻〕，2〔代表要紧〕，3〔代表一样〕表示其风险级别。
Critical observation 严峻缺陷:
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. 严峻缺陷包括可能导致产品不合格的缺陷，可能对健康造成赶忙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类风险的严峻缺陷。
Major observation要紧缺陷:
Observation that may result in the production of a drug not consistently meeting its marketing authorization.
要紧缺陷是指导致产品不能连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 Certain Risk 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类风险的要紧缺陷。一部分能够上升为1类风险的2类风险已用箭头标明。
Other observation一样缺陷:
Observation that is neither critical nor major but is a departure from the GMP. 一样缺陷指不属于严峻或要紧缺陷但偏离GMP要求的缺陷。
〝Other〞 observations are not listed as such (Observations that are neither critical nor major are
considered as 〝other〞 and will be assigned a Risk 3). Appendix 3 lists Risk 3 observations that may be upgraded to Risk 2. 一样风险没有像1，2类风险一样被全部列举出来〔所有不属于严峻或要紧的缺陷都归于一样缺陷，属3类风险。〕附录3列举了能够上升为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: 以下情形有任何一条成立，那么该产品属于最高风险产品。
narrow therapeutic window具有窄治疗窗的药物 high toxicity剧毒性药物 sterile product无菌产品 biological drug生物药品
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. 工艺参数操纵上一点小的偏差便能引发产品不均一或不合格的情形。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的说明〕尽管制造工艺专门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), natural health 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的说明〕， 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:
Compliant合规 C:
Clean-In-Place在线清洁 CIP:
Certificate of Analysis检验报告 COA:
Establishment Licence企业许可证 EL:
Good Manufacturing Practices药品生产质量治理规范 GMP:
Heat, Ventilation, Air Conditioning 空调系统 HVAC:
Inspection Reporting System检查报告 IRS:
MRA: Mutual Recognition Agreement互认协议
Non-compliant 不合规 NC:
Over-The-Counter 非处方药 OTC:
Packaging Material 包材 PM:
Purified Water 纯化水 PW:
Quality Control 质量治理部门 (QA+QC) QC:
Raw Material 原料 RM:
Water For Injection 注射用水 WFI:
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形都排列出来，因此在界定风险时请考虑以下准那么：
-
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.
一样而言，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，除非极端情形发生，如：虚假，大范畴交叉污染，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 company’s officials, proper explanation will be provided to the establishment and this explanation should be captured in the 〝Inspector’s Comments〞 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〕，应赶忙告知企业的治理层并进行合理的说明，说明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. 一样而言，显现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 company’s officials. The Inspectorate management is to be notified in a timely manner.
这类情形应被赶忙告知企业治理层并及时报告给检查机构治理层。
Where in the opinion of the inspector the resulting products present a significant health hazard, appropriate enforcement actions may be initiated.
假如检察员认为相关产品存在对健康的严峻威逼，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, a NC rating may be assigned in the following situations:
一样而言，显现2类风险缺陷，企业仍将被评定为合规，但在以下情形显现时，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操纵时。
Repetition of many Risk 2 observations noted during previous inspections indicating that the company did not:
当许多前次检查发觉的2类风险缺陷重复显现，显示出企业没有能够 - implement the corrective actions submitted following the previous inspection or
按照递交的打算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. 假如仅发觉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，检查员将在检查终止的总结会上递交检查通告草稿。在最终报告发至企业之前，草稿能够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 with a C rating if, during the inspection:
当显现导致企业被评定为不合规的缺陷时，假如企业能够在检查其间完成以下工作，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,
企业赶忙采取必要措施根除导致缺陷发生的缘故同时 - 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. 这种情形下，原先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.
假如企业期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1
Risk 1 (Critical) Observations 1类风险〔严峻〕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排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.
大范畴交叉污染的事实说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.
治理最高风险，高风险产品质量治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体会。
Sanitation C.02.007 C.02.008 卫生
- Evidence of widespread accumulation of residues / extraneous matter indicative of inadequate cleaning.
清洁的不够充分，存在大范畴残留/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 生产操纵
- 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峻的运算错误。
- 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治理负责人
- 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.
质量治理部门不是独立的机构，缺乏真正的决定权，有证据说明质量治理部门的决定常被生产或治理层否定。
Finished Products Testing C.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 稳固性
- 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. 稳固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/内毒素超标的情形。
- 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连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2
Risk 2 (Major) Observations 2类风险〔要紧〕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. (↑ )
没有做爱护/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.
与产品暴露区域直截了当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通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. (↑ )
未经授权的人员能够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.02.005设备
- Equipment does not operate within its specifications. (↑ ) 不在其额定范畴内操作设备。
- Equipment used for complex manufacturing operations not qualified. (↑ )
- - - -
- - -
- -
-
用于复杂生产的设备不合要求。
Clean in Place (CIP) equipment not validated. 在线清洁设备没有验证。
Tanks for manufacturing of liquids and ointments not equipped with sanitary clamps. 液体制剂或油膏剂的生产罐没有采纳清洁卡箍。 Stored equipment not protected from contamination.(↑ ) 设备存放时未作爱护以防止污染。
Inappropriate equipment for production: surfaces porous and non-cleanable / material to shed particles.(↑ )
设备不适于生产：表面多孔无法清洁/材料自身易产生颗粒。
Evidence of contamination of products by foreign materials such as grease, oil, rust and particles from the equipment.(↑ )
产品被设备上的物质污染如油脂，锈迹和颗粒。
No covers for tanks, hoppers or similar manufacturing equipment. 罐体，料斗或类似的生产设备没有盖子。
No / inadequate precautions taken when equipment such as oven or autoclave contains more than one product (possibility of cross-contamination or mix-ups).(↑ )
同时存放有多个产品的生产设备如烘箱或灭菌柜没有预防交叉污染或混淆的措施或措施不充分。
Equipment location does not prevent cross-contamination or possible mix-ups for operations performed in common area.(↑ )
共用区域内设备的摆放位置不能防止交叉污染或混淆。
PW system not maintained or operated to provide water of adequate quality. (↑ ) 纯化水系统未专门好地爱护与操作，导致不能提供合格的水。 Leaking gaskets. 垫圈破漏
- No calibration program for automatic, mechanical, electronic or measuring equipment / no records maintained.
自动化设备，机械设备，电子设备或测量设备没有校验打算/没有校验记录。 - No equipment usage logs. 没有设备使用记录。
Personnel C.02.006人员
- Individual in charge of QC or Production for a fabricator, packager/labeller or tester does not hold a university degree in a science related to the work being conducted or does not have sufficient practical experience in their responsibility area.
负责生产，包装/贴签或测试的质量治理或生产人员没有相关领域的大学文凭同时缺少足够的实践体会。
- Individual in charge of QC for a distributor, importer or wholesaler is not qualified by academic training and experience.
负责分销商，进口商或批发商的质量治理人员没有达到应有的教育与工作体会要求。 - Delegation of responsibilities for QC or Production to insufficiently qualified persons. 质量治理与生产没有足够的合格人员以履行其职责。
- Insufficient personnel for QC or Production operations resulting in a high probability of error. 质量治理与生产人手不足导致错误率专门高。
- Insufficient training for personnel involved in production and QC resulting in related GMP deviations. 生产与质量治理人员培训不足导致了相应的GMP偏差发生。
Sanitation C.02.007 C.02.00↑清洁
- Sanitation program not in writing but premises in acceptable state of cleanliness. 厂房尽管洁净但缺少书面的清洁打算。
- No Standard Operating Procedure (SOP) for microbial / environmental monitoring, no action limits for areas where susceptible non-sterile products are manufactured.
没有微生物/环境监控的标准操作流程，在易受污染的非无菌产品生产区域没有设立监控措施限。
- Cleaning procedure for production equipment not validated (including analytical methods). 生产设备清洁方法没做验证〔包括分析方法〕
- Cleaning procedure for production equipment not validated when non-dedicated equipment is used for high risk products (↑ ).
在非专用设备用于高风险类产品生产的情形下，设备清洁方法没做验证。 - Incomplete health requirements. 不完整的健康要求。
Raw Material Testing C.02.009 C.02.010原料检验
- Reduce testing program in place without adequate certification of the vendors / suppliers. 在未对销售商/供应商进行足够资质认证的情形下减少测试项目。 - Water used in the formulation is not of acceptable quality. 配方用水质量达不到要求。
- No identity test performed by the manufacturer after receipt on it’s premises / Testing for identity not done on each container for APIs or after manipulation or repackaging by third party.
收料后没做鉴别/未对每桶原料做鉴别/经第三方处理或重包装后未做鉴别。 - COA showing incomplete testing. 检验报告上的测试不完全。 - Incomplete specifications. 标准不全。
- Specifications not approved by QC. 标准未被质量治理部门批准。 - Test methods not validated. 检验方法没有验证。
- Use of API after the retest date without proper retesting. 过再验期的活性成分原料没做再检验而直截了当使用。
- Use of inactive RM after the expiration date without proper retesting. 未做检验而使用过期的非主成分原料。
- Multiple lots comprising one reception not considered as separate for sampling, testing and release.
将多批物料做为一次收料而未分开采样，测试与放行。 - No SOP for conditions of transportation and storage. 没有规定运输储藏条件的SOP。
- Certification of brokers or wholesalers allowed without proper documentation. 对所许可的中间商或批发商缺少书面的的授权。
Manufacturing Controls C.02.011 C.02.012生产操纵
- Master Formulae prepared / verified by unqualified personnel. 主处方由无资质人员编写/核对。
- Complex production processes not validated. (↑ ) 复杂生产工艺没有验证。
- Incomplete validation studies / reports for complex manufacturing process (lack of evaluation / approval).
复杂生产工艺的验证研究/报告不完整〔缺少评估/批准〕
- Changeover procedures for manufacturing of medicinal / non-medicinal products are not validated or not available.
药品/非药品生产的改换规程没有验证/缺失。
- Unapproved / undocumented major changes compared to Master Production Documents. (↑ ) 生产工艺上的重大改变没有通过批准/没有书面记录。
- Deviations from instructions during production not documented and not approved by QC. 对生产指令的偏差未做书面记录同时未经质量治理部门认可。
- Discrepancies in yield or reconciliation following production not investigated. 对生产收率或物料平稳的差异未作调查。
- Line clearance between production of different products not covered by SOP and not documented. 没有不同产品之间清场的SOP同时没有书面记录。 - No regular checks for measuring devices / no records. 测量仪器没有定期检查/没有记录。
- Lack of proper identification of in-process materials and production rooms resulting in a high probability of mix-ups.
生产区域和中间物料没有适当的标识专门容易造成混淆。
- Inadequate labelling / storage of rejected materials and products that could generate mix-ups. 报废物料没有标识不清，储藏空间不够，易引起混淆。
- Upon receipt, bulk and in-process drugs, RM and PM not held in quarantine until released by QC. 收料后，在由质量治理部门放行之前，粗制品，中间体，原料和包材没有放置到待检区域。 - Production personnel using bulk and in-process drugs, RM and PM without prior authorization by QC. (↑ )
未经质量治理部门的授权，生产人员使用粗制品，中间体，原料和包材。 - Inadequate / inaccurate labelling of bulk / in-process drugs, RM and PM. 粗制品，中间体，原料和包材标识不清/不正确
- RM dispensing not done by qualified persons, according to an SOP. 没有按照SOP，由有资质的人员完成配料。
- Master Formulae incomplete or showing inaccuracies in the processing operations. 主处方不完整或在生产过程中显示出不够准确。
- Changes in batch size not prepared / verified by qualified personnel. 产品规格更换没有由有资质的人员完成/审核。
- Inaccurate / incomplete information in manufacturing / packaging batch documents. 生产包装批文件信息不准确/不完整。
- Although documented, combination of batches done without QC approval / not covered by SOP.
- - -
-
-
-
尽管有文件记录，但未经质量治理部门批准合并批号/没有SOP涵盖此内容。 No written procedures for packaging operations. 包装操作没有书面规程规定。
Non-standard occurrences during packaging not investigated by qualified personnel. 有资质的人员未对包装过程中显现的非正常情形进行调查。
Inadequate control of coded and non-coded printed PM (including storage, dispensing, printing, disposal).
编码，未编码打印的包装材料〔储藏， 发放，打印和销毁〕操纵不严。
No or inadequate self-inspection program / Program does not address all applicable sections of GMPs / Records incomplete or not maintained.
自检打算缺少或不完全/自检打算没能涵盖所应涉及的GMP领域/自检记录不完整或没有储存。 Products imported from foreign sites that are not listed on the Foreign Site Annex of the Establishment Licence (↑ )
产品由海外工厂进口，但海外工厂没有在企业许可证附件-海外工厂中列出。 Recall: 召回： - Absence of recall procedure combined with distribution practices that would not permit an
adequate recall (distribution records unavailable or not kept).
缺少召回程序同时发货操作的方式导致不可能完全召回〔发货记录缺失或未留记录〕 - Improper quarantine and disposal practices that would allow recalled / rejected units to be
returned for sale.
隔离和销毁操作不当，可能导致召回产品，退货重新被销售。
Quality Control Department C.02.013 C.02.014 C.02.015 质量治理部门
- Inadequate facilities, personnel and testing equipment. 设施，人员和测试仪器不足
- No authority to enter production areas.(↑ ) 无权进入生产区域
- No SOPs approved and available for sampling, inspection and testing of materials. 物料抽样，检查和测试的SOP未被批准或无法获得。
- Products made available for sale without approval of QC department. (↑ ) 产品未经质量治理部门批准便能够销售。
- Products released for sale by QC without proper verification of manufacturing and packaging documentation.
质量治理部门未核对生产与包装的文件，便批准销售产品。
- Deviations and borderline conformances not properly investigated and documented, according to a SOP.
偏差和紧扣质量底线的合格情形没能按照SOP进行完全的调查并做书面记录。 - RM / PM used in production without prior approval of QC. 原料与包材未经质量治理部门批准便已用于生产。
- Reprocessing / Reworking done without prior approval of QC department. (↑ ) 未经质量治理部门批准而进行再制/返工操作。 - No system for complaint handling and returned goods. 没有投诉与退处理货的系统。
- SOPs covering operations that can affect the quality of a product such as transportation, storage, etc. not approved by QC department / not implemented.
可能阻碍产品品质的操作如运输，储备等等的SOP没有经质量治理部门批准/没有被执行。 - Absence of change control system. 缺少更换操纵
- For testing laboratories, (in house or contract) the systems and controls in place for the proper
qualification, operation, calibration and maintenance of equipment, standards, solutions, and records keeping do not assure that the results and conclusions generated are accurate, precise and reliable. (↑ ) 测试实验室〔内部或外部〕的现场治理与监控体系〔包括验证，操作，校验，设备爱护，标准品，各种溶液，记录储存〕无法保证其出具数据的准确，周密和可靠。
Packaging Material Testing C.02.016 C.02.017包材检验
- Reduce testing program in place without adequate certification of vendors / suppliers. 在未对销售商/供应商进行足够资质认证的情形下减少测试项目。 - Absence of testing of PM .缺少包材检验
- Specifications not approved by QC. 质量标准没有被质量治理部门批准。
- No identity test done by the packager / labeller after receipt on its premises. 包装/贴签人员领料后未做鉴别测试。
- Certification of brokers or wholesalers done without proper documentation. 对中间商或批发商所做认证没有正确地书面归档。
Finished Product Testing C.02.01↑ C.02.019成品检验
- Noncompliant products made available for sale without proper justification.(↑ ) 没有充分的说明而销售不合格品。 - Incomplete / inadequate specifications. 不完整/不正确的质量标准
- Finished product specifications not approved by QC. 成品标准未经质量治理部门批准。 - Incomplete testing. 测试不完全。
- No identity testing upon receipt in Canada from non-MRA country and no periodic complete confirmatory testing.
从非互认国家进口到加拿大的产品未做鉴别试验同时没有周期性的全项检验。 - Test methods not validated. 分析方法没有验证。
- No SOP for conditions of transportation and storage. 没有SOP规定储藏运输的条件。
- Use of unique identifier principles not meeting the acceptable options. 使用不被同意的专门鉴别方法
Records C.02.020 to C.02.024记录
- Absence of Master Production Documents. 缺少生产主记录
- Unavailability of documentation from suppliers in a timely manner.
供应商提供文件不及时。
Samples C.02.025 C.02.026样品
- Retained samples not kept for finished products. 成品未做留样。
- Failure to submit retained samples when alternative sample retention granted. 没有递交留样而擅自改变留样打算。
Stability C.02.027 C.02.02↑稳固性
- Insufficient number of lots / insufficient data to establish shelf-life. 用于建立效期的数据和样品数量不够。
- No action taken when data shows that the products do not meet their specifications prior to the expiry date.
对效期未到产品便显现达不到标准的情形未采取措施。 - No continuing stability program. 没有连续的稳固性监测打算
- No stability studies pertaining to changes in manufacturing (formulation) / packaging materials. 生产〔配方〕/包材改变后没做稳固性试验 - Testing methods not validated. 稳固性实验方法未体会证。
Sterile products C.02.029无菌产品
- Aqueous-based products not subject to terminal steam sterilisation without proper justification or approval through the marketing authorization.
缺乏充分的理由或治理部门的批准，对水溶性产品不做最终灭菌处理。 - Inadequate room classification for processing / filling operations. (↑ ) 加工/灌装房间级别不够。
- Aseptic manufacturing suites under negative pressure compared to clean ©-D) areas. Clean ©-D) areas under negative pressure to unclassified areas. (↑ )
无菌生产间对万级车间呈负压，万级车间对无级别间呈负压。
- Insufficient number of samples for room classification / inadequate sampling methods. (↑ ) 测定房间级别时采样数不够/采样方法不正确。
- Insufficient environmental controls / Insufficient monitoring for viable microorganisms during filling for aseptically filled products. (↑ )
无菌灌装时的环境监控/微生物监测不充分。
- Premises and equipment not designed or maintained to minimize contamination / generation of particles. (↑ )
厂房与设备设计上或爱护上没能做到尽量减少污染与颗粒。 - Inadequate maintenance of PW and WFI systems. 纯化水与注射用水的爱护不力。
- Inadequate re-validation of PW and WFI systems after maintenance, upgrading, out-of-specs trends. 纯化水与注射用水系统在爱护，升级和显现超标趋势后没能进行充分的再验证。 - Inadequate training of personnel.
- - - -
-
人员培训不足。
Inadequate gowning practices for clean and aseptic areas. 清洁区，无菌区着装规程不充分
Inadequate sanitation /disinfection program. 清洁与消毒打算不够完备
Inadequate practices / precautions to minimize contamination or prevent mix-ups. 减少污染或防止混批方面缺少足够的操作程序/预防措施
Non-validated time lapse between cleaning, sterilization, use of components, containers and equipment.
没有对清洁，灭菌，部件，容器和设备使用的有效时限进行验证。 No consideration given to bioburden prior to sterilization. 没有考虑灭菌前的生物负载。
- Non-validated time lapse between start of manufacturing and sterilization or filtration. 生产开始到灭菌或过滤之间的时限未体会证。 - Inadequate procedures for media-fills. 培养基灌装的规程不充分。
- Insufficient number of units filled during media-fills. 培养基灌装数量不足。
- Medial fills do not simulate actual operations. 培养基灌装未能模拟实际的生产情形。
- Capability of media to grow a wide spectrum of microorganisms not demonstrated. 培养基的有效性未经测试。
- Misinterpretation of results for media-fills. 培养基灌装结果的歪曲。
- Absence of leak test for ampules. 没做安瓿瓶测漏。
- Samples for sterility testing insufficient in number or not representative of the entire production run. 无菌检验样品数量不足或不具代表性。
- Each sterilizer load not considered as a separate lot for sterility testing. 未将每一个灭菌装载单独做为一批产品进行无菌检验
- PW is not used as the feed water for the WFI system and the clean steam generator. 注射用水系统和纯蒸气发生器没有使用纯化水作为其源水。
- The WFI used in the preparation of parenterals is not tested for endotoxins. 制备大输液的注射用水未测内毒素。
- The WFI used for the final rinsing of containers and components used for parenteral drugs is not tested for endotoxins when those containers and components are not depyrogenated subsequently.
用于淋洗大输液瓶和部件的注射用水没有测试内毒素，而输液瓶和部件此后也未做除热原处理。
Appendix 3附录3
Risk 3 (Other) Observations3类风险缺陷
Premises C.02.004厂房
- Doors giving direct access to exterior from manufacturing and packaging areas used by personnel.
人员通过直达室外的门进出生产与包装区域。 - Un-screened / Un-trapped floor drains. 地漏敞口。
- Outlets for liquids and gases not identified. 液体气体的出口没有标明。
- Damages to surfaces not directly adjacent or above exposed products.
非直截了当与暴露产品相邻或非直截了当位于暴露产品上方的表面存在损坏。 - Non-production activities performed in production areas. 生产区内从事与生产无关的活动。
- Inadequate rest, change, wash-up and toilet facilities. 没有足够的休息，更衣，清洁和盥洗设施。
Equipment C.02.005设备
- Insufficient distance between equipments and walls to permit cleaning. 设备与墙体之间距离太小而无法进行清洁。
- Base of immovable equipment not adequately sealed at points of contact. 固定设备基座与接触面的连接处没有被完全密封。 - Use of temporary means or devices for repair. 使用临时性的方法和设备进行修理。
- Defective or unused equipment not removed or appropriately labelled. 损坏或不使用的设备未被移除或贴上状态标记。
- Minor equipment used for non critical products not qualified. 用于非最高风险产品的小型设备不符合要求。
Sanitation C.02.007 C.02.00↑清洁
- Incomplete written sanitation program but premises in acceptable state of cleanliness. 书面清洁规程不完整但厂房清洁度仍可同意。
- Sanitation or Health and hygiene programs not properly implemented or followed by employees.
清洁或健康卫生规程没能有效贯彻或被职员遵守。
Raw Material Testing C.02.009 C.02.010原料测试
- Lots identified for confirmatory testing used in production without QC approval. 指定用于验证试验的批号被用于生产，但未经质量治理部门批准。 - Incomplete validation of test methods. 测试方法验证不完整。
Manufacturing Control C.02.011 C.02.012生产操纵
- Incomplete SOPs for handling of materials and products. 原料与产品处理方面的SOP不完整。
- Access to production areas not restricted to authorized personnel. 生产区域没有严格限于通过授权的人员进入。 - Inadequate checks for incoming materials. 来料检查不够
- Written procedures incomplete for packaging operations. 书面的包装规程不完整 - Incomplete recall procedure. 召回规程不完整
Packaging Material Testing C.02.016 C.02.017包材测试
- Inadequate procedures of transportation and storage. 运输储藏规程不完整
- Inadequate handling of outdated / obsolete PM. 过期/作废的包材处理规程不充分 - Incomplete testing. 测试不完整
- Inadequate specifications. 标准不全
- Multiple lots comprising one reception not considered as separate for sampling, testing and release.
收料时多批合并为一批，没有考虑到需要分批取样，测试和放行。
Finished Product Testing C.02.01↑ - C.02.019成品检验
- Incomplete testing of physical parameters. 理性指标测试不完整。
Records C.02.020 to C.02.024记录
- Incomplete records / documentation for a product. 产品记录/文件不完整。
- Incomplete plans and specifications for the manufacturing buildings. 生产建筑平面图和标准不完整。
- Incomplete documentation pertaining to supervisory personnel. 车间治理人员的材料不完整。
- Insufficient retention time for evidence and records to be maintained. 记录和证据的保留时刻不够。 - No organization charts. 无组织机构图
- Incomplete records for the sanitation program. 清洁记录不完整。
Samples C.02.025 C.02.026样品
- Samples of RM not available. 无法得到原料样品
- Insufficient quantity for finished products or active pharmaceutical ingredient. 成品或主成分原料数量不足 - Improper storage conditions. 储备条件不合适
Stability C.02.027 C.02.02↑
- Insufficient number of lots in continuing stability program. 进行连续稳固性试验的样品数量不足。 - Incomplete testing of parameters. 测试参数不完整。
- Insufficient quantities for complete testing. 完成测试的样品数量不足。
Sterile Products C.02.029无菌产品
- Steam used for sterilization not monitored to assure suitable quality and absence of additives. 没有对灭菌用蒸气进行监测，以保证它有适合的品质并不含添加剂。
- Inadequate control on the maximum number of personnel present in clean and aseptic areas. 对清洁和无菌区域所承诺容纳的最大人数没有操纵。
- Gases used to purge solutions or blanket products not passed through a sterilizing filter. 用于清除溶液和隔离产品的空气没有通过除菌过滤器。 Inadequate inspection for particles and defects. -
颗粒与瑕疵的检查不充分。
人名不翻了
GMP Committee Members
Name Alicja Kasina France Dansereau, (Chair) Title / Office / Bureau Good Clinical Practices Specialist,, Atlantic Operation Centre, HPFBI* Manager, Inspection Unit, National Coordination Centre, HPFBI MRA Officer, HPFBI Compliance Specialist, Ontario Operation Centre, HPFBI Acting Manager, Division of Pharmaceutical Quality, BPA*** Scientific Assessment Advisor, Manufacturing and Chemical Evaluation Division, VDD**** Location Halifax, NS Ottawa, ON Longueuil, QC Scarborough, ON Richard Ferland Francisco Fernandes Taraz Gedz Denis Girard Raymond Giroux Daryl Krepps Stephen McCaul Ottawa, ON Ottawa, ON Longueuil, QC Ottawa, ON Scarborough, ON GMP Specialist, Quebec Operation Centre, HPFBI Senior Regulatory Advisor, BGTD***** MRA Officer, HPFBI Compliance Officer, National Coordination Centre, HPFBI Médic Ndayishimiye (Secretary) Ottawa, ON Winnipeg, MB Ottawa, ON Burnaby, BC Paul Gustafson Stéphane Taillefer Sheila Welock Compliance Officer, Manitoba and Saskatchewan Operation Centre, HPFBI Compliance Specialist, National Coordination Centre, HPFBI Drug Specialist, Western Operation Centre, HPFBI
* ** *** **** ***** Health Products and Food Branch Inspectorate
Bureau of Policy and Coordination, Therapeutic Products Directorate Bureau of Pharmaceutical Assessment, Therapeutic Products Directorate Veterinary Drugs Directorate
Biologics and Genetic Therapies Directorate
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