医疗器械可沥滤物安全性研究（Ⅱ）：残留量检测

医疗器械可沥滤物的安全性是医疗器械安全性的重要保证,也是近年来医疗器械审评过程中关注的重点。本文结合现有产品的审评,简述了高分子医疗器械可沥滤物安全性研究中残留量检测常见问题,并对其产生原因进行了解析,供相关机构及研发人员参考使用。     

医疗器械可沥滤物安全性研究(Ⅰ):常见可沥滤物

医疗器械可沥滤物的安全性是医疗器械安全性的重要保证,也是近年来医疗器械审评过程中关注的重点。结合现有产品的审评,简述了常见医疗器械可沥滤物种类及相关示例,并对其常见毒性进行了解析,供相关机构及研发人员参考使用。     

ISO与国内医疗器械标准化机构设置比较研究

目的比较研究ISO与国际医疗器械标准化机构的设置,为完善我国医疗器械标准化工作提供参考。方法介绍ISO与国内医疗器械标准化机构的机构设置、技委会建设情况,并通过分析比较,梳理我国医疗器械标准体系,分析标准化工作中存在的问题,提出完善我国医疗器械标准化工作的意见和建议。结果与结论医疗器械作为现代医学领域中的重要产品,其安全性与有效性直接关系到人体健康和生命安全。医疗器械标准是保障产品安全性与有效性的重要技术法规,是行政管理机构监督管理的重要技术依据,也是国际技术贸易壁垒的重要组成部分。     

金华市医疗器械产品注册现状及监管对策

为确保医疗器械产品的安全性、有效性,根据国家局、省局的统一部署,我们对金华市85个第一类医疗器械产品、111个第二类医疗器械产品以及在审的5个第三类医疗器械产品进行了注册工作核查,涉及医疗器械生产企业70家。     

喉形态聚羟基烷酸酯类多孔生物材料制备及其与软骨细胞复合培养观察

为探索新型聚羟基烷酸酯类组织工程多孔生物材料制备及其喉支架形态塑形技术,体外观察其与软骨细胞相容性,为进一步探寻适宜喉支架形态软骨组织工程生物材料提供实验依据,以聚羟基烷酸酯类生物材料聚羟基丁酸酯与聚羟基己酸酯共聚物(PHBHH)为原料,氯化钠盐粒为致孔剂,采用溶剂浇铸、模压成形和颗粒滤沥技术制备喉支架形态多孔PHBHH塑形物,以乙醇置换法测定其孔隙率,负载软骨细胞后体外共同培养。通过大体形态、扫描电镜观察材料模压成形效果、材料孔隙连续性及其与软骨细胞粘附、分布和生长情况。结果表明,模压成形的喉形态材料塑形物类似喉支架形态,滤沥除盐后整体结构呈多孔海绵状,具有良好的支撑性,孔隙率达92±2%,孔隙彼此间连续性好,软骨细胞与材料粘附、生长及孔隙内分布状况良好,基质分泌旺盛。结论:以溶剂浇铸、模压成形和颗粒滤沥技术可制备出支撑度和孔隙率适宜的喉支架形态PHBHH组织工程多孔材料,材料与软骨细胞体外培养相容性良好。     

天然胶乳橡胶避孕套的安全性评价

目的：对天然胶乳橡胶避孕套进行安全性评价。方法：参考GB／T16886．0—2005《医疗器械生物学评价》,结合实际临床用途,进行迟发型超敏反应试验。结果：该产品对豚鼠皮肤无致敏反应。结论：本试验研究方法切实可行,可适用于避孕套类产品的安全性评价。     

省级监测中心接收分析医疗器械不良事件报告规范

国家食品药品监督管理局在对1998年后出现的角膜塑形镜(OK镜)不良事件、聚丙烯酰胺水凝胶不良事件相继采取监管措施后,提出在我国建立医疗器械不良事件监测制度,并以此作为医疗器械上市后监管的重要手段,及时发现上市后产品的安全性问题、有效性问题,提供上市后医疗器械的再评价依据.     

医疗器械生产企业工艺用水现状调查

医疗器械行业工艺用水涉及无菌医疗器械、植入性医疗器械以及体外诊断试剂产品生产企业中产品清洗、配制、洁净服清洗、工位器具清洗以及环境清洗等方面。工艺用水未经处理会对医疗器械造成化学、微生物污染，影响产品安全性；用不符合标准的工艺用水配制诊断试剂会导致产品无效，从而影响检验的准确性。     

医疗器械不良事件监测对医疗器械重新注册的必要性

医疗器械不良事件监测与医疗器械重新注册是其上市前后不可分割的两个监管阶段,两者相互作用是其全寿命风险管理的内在要求。医疗器械不良事件监测是其重新注册的必要条件,其目的是发现上市后产品的隐患,补充上次注册未尽的风险材料。医疗器械重新注册时,申报其不良事件的评价内容,有利于加强医疗器械不良事件第一责任人——生产企业的责任意识,有利于提高重新注册后产品的安全性,有利于进一步明确各级医疗器械监管部门的职责,它既是对不良事件监测工作的促进,也是重新注册自身的需要。两者的中心目标均是提高产品的安全性。     

江西省2005年医疗器械不良事件的统计分析

医疗器械和药品一样具有两重性，在预防、治疗疾病的同时也可能给人体带来危害和不良影响。任何被批准上市的医疗器械只是一个风险可接受的产品，只有通过持续开展对医疗器械不良事件的监测。才可以及时发现上市后产品的安全性问题、有效性问题。提供上市后医疗器械的再评价。医疗器械不良事件监测是指对可疑医疗器械不良事件的发现、报告评价和控制的过程．旨在保障公众用械安全．且提供技术服务。这是国内一项全新的工作．需要不断地探索。     

A Holistic Approach of Extractables and Leachables Assessment of Rubber Stoppered Glass Vial Systems for Biotechnology Products

Rubber stoppered glass vial systems are widely used as primary containers for storing and delivering therapeutic protein products to patients. Addressing concerns and regulatory expectations related to the risk to biologic drug product quality and patient safety from rubber stoppered glass vial systems requires implementation of an extractable and leachable evaluation program based on material understanding, risk assessment, literature review, and a comprehensive scientifically sound analytical testing methodology. The extractable and leachable study design consisted of twelve drug products filled in twelve different size glass vials capped with laminated and nonlaminated rubber stoppers made from three different rubber formulations. Design of the model solvents was successful as they had little to no analytical interference and mimicked the formulation conditions and generated representative extractables capable of predicting leachables. The extraction conditions of time and temperature were appropriate as not to degrade the test materials or the extractable compounds, and yet generated significant quantities for identification of the extractable compounds with confidence. The extractables testing results were capable of predicting the leachable profiles of the twelve drug products. In each case, the leachable profile was a subset of the extractable profile. The organic and elemental impurities of the leachable profiles of drug products were the end-to-end verification of the quality of the glass vials, rubber stoppers and drug product lifecycles. Overall, the holistic approach was fully successful in the qualification of different vial systems as primary containers and delivery systems for different biotherapeutic products to ensure product quality and patient safety.     

Perspectives on trace chemical safety and chemophobia: risk communication and risk management

Safety issues regarding consumer products contaminated with trace amounts of chemicals are of great concern to consumers, with the degree of concern occasionally escalating to the psychological syndrome, chemophobia, i.e., the fear of chemicals. Hazardous substances frequently implicated in safety concerns include heavy metals (arsenic, mercury, cadmium, and lead), volatile organic compounds (VOC) such as benzene and o-toluidine, pesticides, carcinogens, radioactive substances, and endocrine disrupting chemicals (EDC) such as bisphenol A and phthalates. To improve communication of risk to society, members of academia, government, consumer organizations, and industry participated in this workshop to discuss and exchange perspectives on trace chemical safety. From the perspective of academia, integrated risk assessments need to be implemented to encompass various exposure sources and routes. The identification and investigation of new exposure-related biomarkers are also recommended to verify direct causal relationships between specific chemical exposure and effects on human health. As for regulation, governments need to establish and maintain acceptable limits for trace chemicals in products. In addition, harmonized efforts need to be undertaken among government agencies to share regulatory limits and effectively control trace chemicals in consumer products. Manufacturers need to faithfully abide by Good Manufacturing Practice (GMP) guidelines, monitor sources of contamination, and minimize these for consumer safety. To effectively resolve safety issues arising from trace chemicals exposure, collaborative efforts are needed involving academia, government, consumer organizations, and industry. Further, scientific evidence-based risk assessment is a critical approach to effectively manage trace chemical safety issues.     

Perspectives on trace chemical safety and chemophobia: risk communication and risk management

Safety issues regarding consumer products contaminated with trace amounts of chemicals are of great concern to consumers, with the degree of concern occasionally escalating to the psychological syndrome, chemophobia (i.e., the fear of chemicals). Hazardous substances frequently implicated in safety concerns include heavy metals (arsenic, mercury, cadmium, and lead), volatile organic compounds (VOC) such as benzene and o-toluidine, pesticides, carcinogens, radioactive substances, and endocrine disrupting chemicals (EDC) such as bisphenol A and phthalates. To improve communication of risk to society, members of academia, government, consumer organizations, and industry participated in this workshop to discuss and exchange perspectives on trace chemical safety. From the perspective of academia, integrated risk assessments need to be implemented to encompass various exposure sources and routes. The identification and investigation of new exposure-related biomarkers are also recommended to verify direct causal relationships between specific chemical exposure and effects on human health. As for regulation, governments need to establish and maintain acceptable limits for trace chemicals in products. In addition, harmonized efforts need to be undertaken among government agencies to share regulatory limits and effectively control trace chemicals in consumer products. Manufacturers need to faithfully abide by Good Manufacturing Practice (GMP) guidelines, monitor sources of contamination, and minimize these for consumer safety. To effectively resolve safety issues arising from trace chemicals exposure, collaborative efforts are needed involving academia, government, consumer organizations, and industry. Further, scientific evidence-based risk assessment is a critical approach to effectively manage trace chemical safety issues.     

可提取物与浸出物的毒理学风险评价策略

生产用一次性组件与容器密闭系统中的可提取物和浸出物（extractable&leachable，E&L）安全性评估是药品上市申报的重要环节之一。E&L的毒理学评价是其安全性评估的重点内容，目前尚未有E&L毒理学评价的系统性指导法规，特别是多个毒理数据来源的合理选择，以及毒理数据缺乏的问题，是E&L安全性评估的难点。基于E&L安全性评估，重点介绍了安全阈值的确定策略，包括每日允许最大暴露量和日摄入量计算、多层次毒理学关注阈值的选择；相关毒理数据的选择和评价，包括毒理学观测指标和试验选择，以及关键毒性效应的选择。并结合实际事例，为解决E&L研究中安全性评估问题提供新思路，为药品研发及生产企业提供借鉴。     

Extractable/leachable substances from plastic materials used as pharmaceutical product containers/devices

A review is provided related to the accumulation of organic and inorganic leachable substances from DEHP-plasticized PVC, polyolefin and various other related pharmaceutical plastic packaging materials. The review considers both the identification of such leachables as well as their reported levels in actual and simulated pharmaceutical products.     

Evaluation of safety and quality impact of extractable and leachable substances in therapeutic biologic protein products: a risk-based perspective

Leachables are chemical entities that migrate spontaneously from the final container closure system, packaging components and/or processing equipment under recommended conditions of product use and storage. Unlike leachables, extractables are generated under exaggerated temperature and time conditions in the presence of an appropriate solvent. Increasing evidence suggests that leachables may pose a safety risk by causing toxicity, carcinogenicity, immunogenicity and/or endocrine dysregulation. These substances may also alter product physico-chemical properties via interaction with the active pharmaceutical ingredient or the excipients in product vehicle, thereby adversely affecting the final product quality. The evaluation of leachable compounds begins with a thorough identification of extractable compounds released from the production and packaging components under exaggerated conditions. The set of observed extractables helps to identify possible targets to be monitored in a subsequent leachables study over extended time periods. Although extractables and leachables also present a challenge for the safe use of device components (e.g., metered dose inhalers, dry powder inhalers, nasal spray devices or various implants), this review focusses on a safety risk assessment for specified therapeutic biological protein products. Regulatory, safety and scientific considerations in evaluating extractables and leachables are discussed, along with strategies for the analytical identification, quantification and monitoring.     

Evaluation of safety and quality impact of extractable and leachable substances in therapeutic biologic protein products: a risk-based perspective

Leachables are chemical entities that migrate spontaneously from the final container closure system, packaging components and/or processing equipment under recommended conditions of product use and storage. Unlike leachables, extractables are generated under exaggerated temperature and time conditions in the presence of an appropriate solvent. Increasing evidence suggests that leachables may pose a safety risk by causing toxicity, carcinogenicity, immunogenicity and/or endocrine dysregulation. These substances may also alter product physico-chemical properties via interaction with the active pharmaceutical ingredient or the excipients in product vehicle, thereby adversely affecting the final product quality. The evaluation of leachable compounds begins with a thorough identification of extractable compounds released from the production and packaging components under exaggerated conditions. The set of observed extractables helps to identify possible targets to be monitored in a subsequent leachables study over extended time periods. Although extractables and leachables also present a challenge for the safe use of device components (e.g., metered dose inhalers, dry powder inhalers, nasal spray devices or various implants), this review focusses on a safety risk assessment for specified therapeutic biological protein products. Regulatory, safety and scientific considerations in evaluating extractables and leachables are discussed, along with strategies for the analytical identification, quantification and monitoring.