化学药品注射剂与药用玻璃包装容器相容性研究技术指导原则(网站征求意见稿)

化学药品注射剂与药用玻璃包装容器相容性研究技术指导原则(网站征求意见稿) 化学药品注射剂与药用玻璃包装容器相容 性研究技术指导原则(征求意见稿) 目 录 一、概述 二、相容性研究的考虑要点 三、相容性研究的主要内容与分析方法 四、试验结果分析与安全性评估 五、名词解释 六、附件 七、参考文献 一、概述 本指导原则主要针对注射剂与玻璃包装容器的相容性研究进行阐述，旨在指导药品研发及生产企业系统、规范地进行药品与玻璃包装容器的相容性研究，在药品研发初期对药用玻璃(以下简称玻璃)包装容器进行选择，并在整个研发过程中对化学药品注射剂包装系统的适用性进行确认，最终选择和使用与药品具有良好相容性的玻璃包装容器，避免因药用包装容器可能导致的安全性风险。 本指导原则是在现行法规和 标准 excel标准偏差excel标准偏差函数exl标准差函数国标检验抽样标准表免费下载红头文件格式标准下载 体系以及当前认知水平下制定的，遵循了国家食品药品监督管理局发布的《直接接触药品的包装材料和容器管理办法》(局令第13号)，沿用/参考了国家食品药品监督管理局发布的《化学药品注射剂与塑料包装材料相容性研究技术指导原则(试行)》的思路，，借鉴了国内外相关的指导原则及有关专著，重点突出了注射剂与玻璃包装容器相关的相容性研究内容。随着相关法规的不断完善以及药物研究技术要求的提高，本指导原则将不断the neighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse channels. Taking into account the needs of e-commerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wired TV distribution statistics following table: Wired TV information points distribution schedule-medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer underground a layer underground two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floor-East floor 16 16 16 3 51 1th, floor-in the floor 21 15 12 5 53 1th, Floor-West floor 20 15 18 3 56 total 529 (3) information guide and the released system system used concentrated control, and unified management of way will sound video signal, and pictures and scroll subtitles, multimedia information through network transmission to the displayed Terminal, real-time to released visits information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, information. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hospital handle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to the streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and other equipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats such as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( ppt 关于艾滋病ppt课件精益管理ppt下载地图下载ppt可编辑假如ppt教学课件下载triz基础知识ppt ). Hours second time Kok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology to the enemy 修订并完善。 本指导原则主要阐述了注射剂与玻璃包装容器的相容性研究，其它剂型与玻璃包装容器的相容性研究不在本指导原则中详述，另外，玻璃包装容器常与胶塞等组件配合使用，药品研发及生产企业可参照相关指导原则的基本思路，开展其它剂型与玻璃包装容器及其组件(包括胶塞)的相容性研究。 本指导原则是基于目前认知的考虑，其他方法如经证明合理也可采用。 二、相容性研究的考虑要点 2.1 玻璃的分类 中国参照ISO 12775:1997(E)分类方法，根据三氧化二硼(BO)含量和23线热膨胀系数(Coefficecent of Expansion，简称COE)的不同将玻璃分为两类:即硼硅玻璃和钠钙玻璃，其中将硼硅玻璃又分为高硼硅玻璃、中性硼硅玻璃、低硼硅玻璃，如附件一所示。 美国药典、欧洲药典、日本药典以及美国试验与材料协会(ASTM)等对玻璃的分类与我国不同，如附件二所示。 2.2 注射剂与玻璃包装容器可能发生的相容性问 题 快递公司问题件快递公司问题件货款处理关于圆的周长面积重点题型关于解方程组的题及答案关于南海问题 2.2.1 玻璃容器的化学成分与生产工艺 玻璃通常包含二氧化硅、三氧化二硼、三氧化二铝、氧化钠、氧化钾、氧化钙、氧化镁等化学成分。每种化学成分并不恒定，在一定范围内波动。不同玻璃生产企业的玻璃化学组成会有所不同。 为了改善药用玻璃的性能，通常会在玻璃中添加不同的氧化物，如加入氧化钠、氧化钾、氧化钙、氧化钡、氧化锌、三氧化二硼和氟化物可降低玻璃的熔化温度;加入三氧化二铝可以改进玻璃的力学性能;加入铁、锰、钛、钴等过渡金属氧化物形成着色玻璃以产生遮光效果;加入氧化砷、氧化锑、氧化铈等促进玻璃澄清。 上述玻璃中的金属离子或阳离子团均有可能从玻璃中迁移出来。 玻璃包装容器通常采用模制和管制工艺生产。不同生产工艺对玻璃制品质量的影响不同，特别是对玻璃内 表 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf 面的耐水性影响较大。模制玻璃容器内表面耐水性基本相同。对管制玻璃瓶和安瓿瓶，在容器颈部、特别是底部成形过程中，由于局部受热引起的碱金属和硼酸盐的蒸发及分相等原因，使上述热加工部位内表面的化学耐受性低于玻璃容器中未受热的部位;另外，不同厂家可能选择不同的 spitalformation. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hos information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, intime to released visit-es and scroll subtitles, multimedia information through network transmission to the displayed Terminal, reale and the released system system used concentrated control, and unified management of way will sound video signal, and picturWest floor 20 15 18 3 56 total 529 (3) information guid-in the floor 21 15 12 5 53 1th, Floor-East floor 16 16 16 3 51 1th, floor-two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floorunderground a layer underground medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer-red TV distribution statistics following table: Wired TV information points distribution schedulecommerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wi-s. Taking into account the needs of eeighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse channelthe nto the enemyKok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology d timesuch as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours seconequipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats ther he streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and ohandle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to t 2 管制成形工艺，如底部和颈部火焰加工温度及形成玻璃容器后的退火温度等不同，因此即使采用相同生产商提供的玻璃管，也可能存在管制玻璃容器质量的差异。 为了提高玻璃容器内表面耐水性等性能，通常会对玻璃容器的内表面进行处理，常见的方式为硫化，硫化处理虽然可以提高玻璃的耐水能力，但会降低玻璃的化学耐受性;另外，也有少量玻璃容器采用内表面镀膜处理的方式，在药品长期贮藏条件下，膜层材料组分可能迁移进入药液中。 2.2.2 注射剂与玻璃包装容器的相互作用 在注射剂中，玻璃可与药液发生化学反应和/或物理作用。常见的反应有:某些药物对酸、碱、金属离子等敏感，如果玻璃中的金属离子和/或镀膜成分迁移进入药液，可催化药物发生某些降解反应，导致溶液颜色加深、产生沉淀、出现可见异物，药物降解速度加快等现象;某些毒性较大的金属离子或阳离子团迁移进入药液也会产生潜在的安全性风险。 对于某些微量、治疗窗窄、结构上存在易与玻璃发生吸附官能团的药物，或是处方中含有微量的功能性辅料(如抗氧剂，络合剂)等，玻璃容器表面可能会 辅料含量降低。 产生吸附作用，使药物剂量或 注射剂也可能对玻璃内表面耐水性产生影响，降低玻璃容器的保护作用和功能性，甚至导致玻璃网状结构破坏致使其中的成分大量溶出并产生玻璃屑或脱片，引发安全性问题。影响玻璃内表面耐水性的因素包括玻璃容器的化学组成、生产工艺、成形后的处理方式，以及药物制剂的处方(组成成分、离子强度、络合剂、pH值)、灭菌方式等。模制玻璃容器内表面耐水性基本相同，管制玻璃容器颈部和底部内表面的化学耐受性低于其他部位，耐水性受不同药物制剂的影响较大。内表面经过处理(例如用硫酸铵处理)的玻璃可能导致表面层富硅，会造成玻璃结构脆弱。影响玻璃内表面耐水性的因素可参见附件三。 2.2.3 为注射剂选择适宜的玻璃包装容器 本指导原则所指的玻璃包装容器涵盖了模制输液瓶和注射剂瓶，以及管制注射剂瓶、安瓿瓶、卡式瓶、笔式注射器用玻璃套筒和预灌封注射器用玻璃针管等。通常，药用玻璃具有较好的物理、化学稳定性，生物安全性相对较高。 在为注射剂选择玻璃包装容器时，需要关注玻璃容器的保护作用、相容性、安全性与工艺的适用性等。 the neighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse chan3 nels. Taking into account the needs of e-commerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wired TV distribution statistics following table: Wired TV information points distribution schedule-medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer underground a layer underground two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floor-East floor 16 16 16 3 51 1th, floor-in the floor 21 15 12 5 53 1th, Floor-West floor 20 15 18 3 56 total 529 (3) information guide and the released system system used concentrated control, and unified management of way will sound video signal, and pictures and scroll subtitles, multimedia information through network transmission to the displayed Terminal, real-time to released visits information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, information. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hospital handle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to the streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and other equipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats such as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours second time Kok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology to the enemy 在相容性方面，需考察制剂对玻璃容器性能的影响，以及玻璃容器对制剂质量和安全性的影响，可关注以下方面内容:玻璃的类型、玻璃的组成、玻璃容器的生产工艺、规格大小、玻璃成形后的处理方式;药品和处方的性质，如药液的pH值、离子强度等;以及制剂生产过程中的热处理工艺对玻璃容器的影响，如洗瓶阶段的干热灭菌工艺、制剂冷冻干燥工艺、终端灭菌工艺等。 通常，管制玻璃容器多适用于安瓿瓶、卡式瓶和预灌封注射器等，用于包装小容量注射液以及粉末;模制玻璃容器多适用于大容量注射剂、小容量注射液和粉末(模制注射剂瓶)的包装。 2.3 相容性研究的步骤 相容性是药品包装必须具备的特性之一，研究内容应包括包装材料对药品的影响以及药品对包装材料的影响，主要分为如下六个步骤:1)确定直接接触药品的包装组件;2)了解或分析包装组件材料的组成、包装组件与药品的接触方式与接触条件、生产工艺过程，如:玻璃容器的生产工艺(模制或管制)、玻璃类型、玻璃成型后的处理方法等，并根据注射剂的理化性质对拟选择的玻璃容器进行初步评估;3)对玻璃包装进行模拟试验，预测玻璃容器是否会产生脱片以及其他问题;4)进行制剂与包装容器系统的相互作用研究，主要考察玻璃容器对药品的影响以及药品对玻璃容器的影响，应进行药品常规检查项目检查、迁移试验、吸附试验，同时对玻璃内表面的侵蚀性进行考察;5)对试验结果进行分析与安全性评估和/或研究;6)对药品与所用包装材料的相容性进行总结，得出包装系统是否适用于药品的结论。玻璃容器相容性研究决策树可参见附件四。 三、相容性研究的主要内容与分析方法 在进行注射剂与玻璃容器的相容性研究前，需要了解玻璃的组成成分、生产工艺，内表面处理方式等信息，以及必要的提取试验研究等数据，然后在此基础之上进行后续的相容性研究。 这里的相容性研究包括模拟试验和相互作用研究。 3.1 模拟试验 模拟试验的主要目的是预测玻璃容器发生脱片的可能性，通常采用模拟药品的溶剂，在较剧烈的条件下，对玻璃包装进行的试验研究。 试验研究容器宜首选比表面积最大或包装规格最小的玻璃容器。 模拟溶剂:首选含目标药物的注射剂，如果药物对分析方法产生干扰，可选 formation. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hos information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, intime to released visit-es and scroll subtitles, multimedia information through network transmission to the displayed Terminal, reale and the released system system used concentrated control, and unified management of way will sound video signal, and picturWest floor 20 15 18 3 56 total 529 (3) information guid-in the floor 21 15 12 5 53 1th, Floor-East floor 16 16 16 3 51 1th, floor-two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floorunderground a layer underground medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer-red TV distribution statistics following table: Wired TV information points distribution schedulecommerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wi-s. Taking into account the needs of eeighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse channelthe nto the enemyKok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology d timesuch as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours seconequipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats ther he streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and ohandle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to t spital4 择与制剂具有相同或相似理化性质的模拟溶剂，重点考虑溶液的pH、极性及离子强度、离子种类等，如不含药物的空白制剂。 模拟条件:模拟试验需在较剧烈的条件下进行。应结合药品在生产、贮存、运输及使用过程中的最极端条件，并选择更强烈的试验条件，如加热、回流或超声等。 除了选择以上模拟溶剂和模拟条件以外，也可参考美国药典<1660>玻璃内表面耐受性评估指南中加速脱片试验方法(如附件五所示)，并结合药品的pH值、离子强度等因素，选择模拟溶剂和模拟条件。 应对玻璃容器内表面进行检查，并对侵蚀后的模拟溶液进行检测分析，以预测玻璃内表面脱片的倾向，测定指标包括玻璃表面麻点、裂痕，试验液中SiO2浓度增加量、SiO/BO或Si/Al比值、可见和不可见微粒数，以及pH值下降程度223 等。 如果在包材注册时已经完成了该项研究，且模拟溶剂的pH值、离子强度等与目标注射剂相似，可以借鉴相关研究信息。 3.2 相互作用研究 进行注射剂与玻璃容器相互作用研究时，应采用拟上市的处方工艺和包装容器生产的制剂，并将玻璃容器以及注射剂均作为试验样品，应采用至少3批制剂与1批包装容器进行研究。 考察条件需充分考虑药品在贮存、运输及使用过程中可能面临的最极端条件。考察时间点的设置应基于对玻璃包装容器性质的认识，包装容器与药品相互影响的趋势而设置。一般应选择按正常条件生产、包装、放置的注射剂的包装容器(而不是各包装组件)进行相互作用研究，可参考加速稳定性试验以及长期稳定性试验的试验条件(温度和时间)，至少应包括起点和终点，中间点可适当调整，例如，在考察离子浓度的变化情况时，为了使离子浓度-时间曲线的斜率变化结果更具可评价性，可适当增加中间取样点。 在对不同浓度的注射剂进行研究时，也可采用ICH稳定性指导原则中推荐的括号法或矩阵法进行试验。 3.2.1 玻璃容器对药品质量的影响 3.2.1.1 药品常规检查项目 在不同的考察条件和时间点对药品进行检查时，应重点关注玻璃容器及其添 the neighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse chan5 nels. Taking into account the needs of e-commerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wired TV distribution statistics following table: Wired TV information points distribution schedule-medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer underground a layer underground two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floor-East floor 16 16 16 3 51 1th, floor-in the floor 21 15 12 5 53 1th, Floor-West floor 20 15 18 3 56 total 529 (3) information guide and the released system system used concentrated control, and unified management of way will sound video signal, and pictures and scroll subtitles, multimedia information through network transmission to the displayed Terminal, real-time to released visits information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, information. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hospital handle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to the streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and other equipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats such as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours second time Kok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology to the enemy 加物质对药物稳定性的影响，如对药品pH值、溶液澄清度与颜色、可见异物、不溶性微粒、重金属、有关物质和含量等的影响，可参考药品标准进行检验。对pH值较敏感的药品，应重点关注从玻璃中浸出的碱金属离子等成分对药品稳定性的影响，如药品pH值、药液颜色的变化情况、可见异物的出现等。 3.2.1.2 迁移试验 玻璃包装容器中组分多为无机盐。迁移入注射剂药液的常见离子包括Si、Na、K、Li、Al、Ba、Ca、Mg、B、Fe、Zn、Mn、Cd、Ti、Co、Cr、Pb、As、Sb等。应结合特定玻璃容器的组分以及添加物质的信息，对所含有的离子进行检查并进行安全性评估;另外，还需对SiO、BO、Al等可预示玻璃脱片的成分进行检查。 223 对于内表面镀膜的玻璃容器，应对膜层材料的组分及其降解物的迁移进行考察。 3.2.1.3 吸附试验 吸附试验主要针对微量、治疗窗窄、结构上存在易与玻璃发生吸附的官能团的药物，以及处方中含有微量的功能性辅料进行。推荐选择该药品加速试验以及长期留样试验条件(温度和时间)进行，通常可选择加速试验以及长期留样试验的考察时间点，按照药品标准进行检验，并根据考察对象(如功能性辅料)等适当增加检验项目，主要对药品以及拟考察辅料的含量等项目进行检查。 3.2.2 药品对玻璃容器内表面的影响 对于含有机酸、络合剂、偏碱、高离子强度的注射剂，应重点关注玻璃容器被侵蚀后出现脱片、微粒(玻屑)的可能性。可在模拟试验和迁移试验的同时，对玻璃容器内表面脱片的趋势和程度进行考察。应该注意，药品对玻璃容器成形处的侵蚀程度与药品对玻璃壁的侵蚀程度不同，对玻璃容器与药品接触处与非接触处的侵蚀程度也不同(如冻干制剂)，在考察药品对玻璃容器内表面的影响时，需注意对玻璃容器不同部位进行考察。 可通过对玻璃容器内表面及/或注射液进行检测分析，评估药品对玻璃容器内表面的影响。常见的方法包括肉眼观察玻璃表面麻点、裂痕，以及注射液中的可见异物;采用表面分析技术对玻璃内表面的化学侵蚀进行检测;测定注射液中的不溶性微粒、以及试验液中SiO浓度增加量、SiO/BO或Si/Al比值及其变化2223 趋势等进行考察，上述数值如发生显著变化，则预示玻璃容器受侵蚀产生脱片和微粒(玻屑)或风险增加。 e and the released system system used concentrated control, and unified management of way will sound video signal, and picturWest floor 20 15 18 3 56 total 529 (3) information guid-in the floor 21 15 12 5 53 1th, Floor-East floor 16 16 16 3 51 1th, floor-two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floorunderground a layer underground medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer-red TV distribution statistics following table: Wired TV information points distribution schedulecommerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wi-s. Taking into account the needs of eeighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse channelthe nto the enemyKok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology d timesuch as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours seconequipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats ther he streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and ohandle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to t spitalformation. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hos information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, intime to released visit-es and scroll subtitles, multimedia information through network transmission to the displayed Terminal, real6 在进行不溶性微粒考察时，常规方法是取一定体积的溶液进行测定，因玻璃微粒比溶剂重，微粒易积聚在容器底部，为了得到准确数据，应对溶液进行充分振摇后进行测定。 应该注意，玻璃容器产生脱片的倾向与盛装注射液的时间长短直接相关，通常在盛装注射液3,6个月以后或者更长时间才可观察到明显的脱片现象，为明确药品对玻璃内表面的影响，可适当延长考察的时间，如在药品加速试验下进行9,12个月试验，并在长期留样试验过程中进行考察。 对于可见及不可见微粒检查均符合要求但注射液中离子浓度突然发生变化的情况，可采用适宜方法，对不溶性微粒检查方法难以检出的粒径更小的微粒进行考察，对玻璃容器受侵蚀产生脱片和微粒(玻屑)的风险和趋势进行分析和评估。 3.3 空白干扰试验 必要时需进行空白干扰试验,试验过程中所采用的试验器具，以及进行参比试验时，原则上应尽量避免使用玻璃容器。另外玻璃包材多与胶塞配合使用，在进行相容性试验时，应考虑避免胶塞对试验结果的影响。 例如:在对玻璃包装容器进行相关试验时，空白试验不宜选择橡胶塞作为密封件，可选择聚四氟乙烯瓶，以及聚四氟乙烯或聚丙烯塞，或其它惰性容器进行平行对照。 3.4 分析方法与方法学验证 模拟试验和迁移试验应采用专属性强、准确、精密、灵敏的分析方法，以保证试验结果的可靠性;并应针对不同的待测项目选择适宜的分析方法。由于玻璃容器最常见的可提取物为金属离子、不挥发性物质等组分，对可提取物和浸出物的常见分析方法包括:电感耦合等离子体发射光谱(ICP)、原子吸收光谱(AAS)、离子色谱(IC)、高效液相色谱(HPLC)，以及与质谱的联机技术，ICP-MS、HPLC-MS等，方法学研究时重点关注灵敏度(检测限、基线值)、专属性、准确性等。 考察药品对玻璃内表面影响的分析方法较多。可参照药典方法进行不溶性微粒、可见异物检查;可选择粒径分析仪、扫描电子显微镜- X射线能量色散光谱仪(SEM-EDX)对微粒进行检查;也可选择微分干涉差显微镜(DIC显微镜)、电子显微镜(EM)以及次级离子质谱(SIMS)以及原子力显微镜(AFM)、电子探 the neighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse chan7 nels. Taking into account the needs of e-commerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wired TV distribution statistics following table: Wired TV information points distribution schedule-medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer underground a layer underground two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floor-East floor 16 16 16 3 51 1th, floor-in the floor 21 15 12 5 53 1th, Floor-West floor 20 15 18 3 56 total 529 (3) information guide and the released system system used concentrated control, and unified management of way will sound video signal, and pictures and scroll subtitles, multimedia information through network transmission to the displayed Terminal, real-time to released visits information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, information. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hospital handle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to the streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and other equipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats such as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours second time Kok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology to the enemy 针(EPMA)等方法对玻璃表面的侵蚀程度以及功能层的化学组成进行考察。方法学研究时重点关注检测限，基线值。 试验过程中需注意:进行模拟试验和迁移试验时，目标元素的回收率应符合要求。所有测试项目应提交具有统计学意义的数据。 四、试验结果分析与安全性评估 根据模拟试验结果对玻璃容器在盛装实际药液时发生脱片的可能性进行初步预测;通过对药品常规项目检查数据、迁移试验中浸出物的种类及含量、吸附试验以及药品对玻璃内表面的影响进行评估，分析判断包装系统是否与药品具有相容性。 4.1 模拟试验结果评估 如果试验过程中，玻璃内表面出现麻点、裂痕;或者试验液中SiO浓度、2SiO/BO或Si/Al比值、微粒数以及pH值等发生显著变化，则预示玻璃容器发223 生脱片的可能性较大。 需注意的是，模拟试验仅是预测玻璃容器发生脱片的可能性，在盛装实际药物时并不一定会发生脱片，因此，可对模拟试验结果进行评估，并选择继续进行后续相容性试验还是更换包装容器的供应商和/或其他种类的包装容器。 4.2 药品常规项目检查结果评估 如果试验发现出现溶液颜色加深、产生可见异物、pH值变化等现象，应分析原因并对试验结果进行评估。如果上述变化已达到不可接受的程度，且为玻璃容器所致，应考虑采用其它类型玻璃包装容器以及其它形式的包装容器;如果是其他原因所致，应对产品进行优化，如完善制剂的处方工艺等以使产品符合相关质量控制要求。 4.3迁移试验结果评估 根据浸出物的PDE值、每日最大用药剂量计算每单个包装容器中各浸出物的最大允许浓度，并在此基础上经计算得到分析评价阈值(Analytical Evaluation Threshold，AET)，分析测试方法应满足该AET值的测定要求。 在提交注册资料时，应提供浸出物的PDE、AET等数值及其计算过程。 如果浸出物含量低于PDE时，可认为浸出物的量不会改变药品的有效性及安全性，对患者的安全性风险小。 如果浸出物的含量高于PDE，则认为包装容器与药品不具有相容性，建议更 equipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats ther he streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and ohandle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to t spitalformation. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hos information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, intime to released visit-es and scroll subtitles, multimedia information through network transmission to the displayed Terminal, reale and the released system system used concentrated control, and unified management of way will sound video signal, and picturWest floor 20 15 18 3 56 total 529 (3) information guid-in the floor 21 15 12 5 53 1th, Floor-East floor 16 16 16 3 51 1th, floor-two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floorunderground a layer underground medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer-red TV distribution statistics following table: Wired TV information points distribution schedulecommerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wi-s. Taking into account the needs of eeighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse channelthe nto the enemyKok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology d timesuch as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours secon8 换包装材料。 玻璃容器中常用金属元素(注射途径)的每日允许摄入量(PDE)请参见附件六。 4.4 吸附试验结果评估 如果吸附试验结果显示包装容器对药品或辅料存在较强吸附，并对药品质量产生了显著影响，建议更换包装容器。 4.5 药品对玻璃内表面的影响结果评估 在模拟试验和迁移试验过程中，如果肉眼观察玻璃表面出现麻点、裂痕;或者出现玻屑或者脱片，或者肉眼可见以及不可见微粒的数量超出药典控制要求，则提示药品质量已经产生了显著影响，建议更换包装容器。 如果可见及不可见微粒检查均符合要求但溶液中SiO浓度、SiO/BO或2223Si/Al比值发生显著变化，提示玻璃容器产生脱片和微粒(玻屑)的风险及趋势在增大，需继续开展相关研究，并持续监测玻璃容器内表面的变化，或者更换包装容器。 五、名词解释 药用玻璃:具有良好化学稳定性和光谱特性，且能稳定贮存医药产品的玻璃材料或制品。 管制玻璃容器、模制玻璃容器:是按玻璃成型方法对玻璃容器的分类方法，模制瓶是借助各种不同形状的模具成型的产品，管制玻璃容器是用已拉制成型的各类玻璃管二次加工成型的产品。 玻璃内表面耐水性:是一种表面试验法，是用规定的水注入被测容器到规定的容量，并在规定温度、时间下进行处理后，通过滴定浸提液来测量水对容器内表面的侵蚀程度。 线热膨胀系数:(Coefficecent of Expansion，简称COE):线热膨胀系数是玻璃重要的热学性质，是指温度升高1?，单位长度上的伸长量。 表面处理:为提高玻璃表面的某些性能对玻璃容器表面进行处理的工艺，包括为减少制品碱金属离子的中性化处理、为提高制品表面憎水性的硅化镀膜等。 镀膜玻璃:为改变玻璃表面的某些性能，在玻璃容器的内表面喷涂某些组分，并 the neighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse chan9 nels. Taking into account the needs of e-commerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wired TV distribution statistics following table: Wired TV information points distribution schedule-medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer underground a layer underground two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floor-East floor 16 16 16 3 51 1th, floor-in the floor 21 15 12 5 53 1th, Floor-West floor 20 15 18 3 56 total 529 (3) information guide and the released system system used concentrated control, and unified management of way will sound video signal, and pictures and scroll subtitles, multimedia information through network transmission to the displayed Terminal, real-time to released visits information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, information. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hospital handle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to the streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and other equipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats such as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours second time Kok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology to the enemy 经过一定的工艺使其与玻璃制品烧结一体。根据膜层的成分不同分为有机硅镀膜玻璃和无机硅镀膜玻璃。 脱片:玻璃表面的碱金属离子被溶液浸出后，在玻璃表面形成一层高硅氧层，同时由于溶液碱性增强。这层高硅氧层在较强的碱性溶液作用下损坏加快。又由于高硅氧层与其内部的未变质玻璃膨胀系数不同，在温度变化时两者之间会产生应力。在这两种作用下，高硅氧层就会从主体玻璃上脱落到溶液中形成脱片。 人每日允许暴露量(permitted daily exposure, PDE):指某一物质被允许摄入而不产生毒性的日平均最大剂量，某一具体物质的PDE值是由不产生反应量、体重调整系数、种属之间差异的系数、个体差异、短期接触急性毒性研究的可变系数等推算出的。 分析评价阈值(Analytical Evaluation Threshold AET):根据人每日允许最大暴露量或安全性阈值/限定阈值、用药剂量以及制剂包装特点等计算每单个包装容器中特定的可提取物和/或浸出物含量，当一个特定的可提取物和/或浸出物水平达到或超过这个量值时，需要开始对这个可提取物/浸出物进行分析，并需要报告给相关部门以便开始进行安全性评估。 六、附件 附件一:中国以及ISO对玻璃的分类:(将随中检院发布的YBB标准进行修订) 硼硅玻璃 材质分类 钠钙玻璃 化学组成 高硼硅玻璃 中性硼硅玻璃 低硼硅玻璃 颗粒法耐水性 1级 1级 1级 2级 线热膨胀系数(50,3.2,3.4 3.5,6.1 6.2,7.5 7.6,9.0 -6o300?, ×10/C HC1级或HC2级或内表面耐水性 HC1级 HC1级 HCB级 HC3级 耐酸性 1级 1级 1级 1-2级 耐碱性 2级 2级 2级 2级 formation. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hos information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, intime to released visit-es and scroll subtitles, multimedia information through network transmission to the displayed Terminal, reale and the released system system used concentrated control, and unified management of way will sound video signal, and picturWest floor 20 15 18 3 56 total 529 (3) information guid-in the floor 21 15 12 5 53 1th, Floor-East floor 16 16 16 3 51 1th, floor-two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floorunderground a layer underground medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer-red TV distribution statistics following table: Wired TV information points distribution schedulecommerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wi-s. Taking into account the needs of eeighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse channelthe nto the enemyKok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology d timesuch as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours seconequipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats ther he streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and ohandle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to t spital10 附件二:美国、欧洲以及日本对玻璃的分类: ASTM-E438 I Class A I Class B II Class III Class USP 1 1 2 2 EP I I II III 1 1 2 2 日本 1 1 2 3 内表面耐水性 用 途 注射及冻干 注射 口服及试剂 干粉及油剂 附件三:影响玻璃内表面耐水性的因素 玻璃容器的组成玻璃容器成型后的药物 成分、生产工艺 处理工艺以及储存 条件 ?玻璃组成 ?成型后的处理: ?原料药 ?模制或者管制 -硫酸铵 ?制剂处方: 制备工艺 ?储存条件: -醋酸盐、柠檬酸盐、磷酸盐缓冲液 ?生产过程: -高湿 -有机酸的钠盐，如葡萄糖酸盐、马来酸 -成型速度 盐、琥珀酸盐、酒石酸盐 -成型温度 -高离子强度，如>0.1M的碱金属盐 -配位试剂，例如EDTA -高pH值(> 8.0) ?终端灭菌 ?标示的储存条件(冷藏或可控室温) ?保质期限 the neighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse chan11 nels. Taking into account the needs of e-commerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wired TV distribution statistics following table: Wired TV information points distribution schedule-medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer underground a layer underground two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floor-East floor 16 16 16 3 51 1th, floor-in the floor 21 15 12 5 53 1th, Floor-West floor 20 15 18 3 56 total 529 (3) information guide and the released system system used concentrated control, and unified management of way will sound video signal, and pictures and scroll subtitles, multimedia information through network transmission to the displayed Terminal, real-time to released visits information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, information. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hospital handle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to the streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and other equipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats such as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours second time Kok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology to the enemy 附件四:玻璃容器相容性研究决策树 采用玻璃包装容器的制剂固体制剂 风险低非固体制剂提供相关证明文件 否 提供相关证明文件并按照是否为注射液和冻干粉针要求进行相关研究 是 提供包材上市时进行的相关 试验资料并进行模拟试验 对试验结果进行初步的评估，预测脱更换包装材料片情况 相互作用研究 容器对药品质量的影响符合要求药品对容器的影响 吸附试验药品常规检查项目迁移试验对玻璃耐水性的影响 迁移物 超出颜色、可见异物，PDE值吸附性杂质等发生较大变脱片，玻屑太强化，且与容器相关 更换包装材料提供相关证明文件更换包装材料 附件五:加速脱片的介质和条件(美国药典<1660>玻璃内表面耐受性评估指南) 介质 0.9%KCl溶液 3%枸橼酸钠溶液 20mM甘氨酸溶液 pH8.0 pH8.0 pH10.0 条件 121?，2hr 80?，24hr 50?，24hr equipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats ther he streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and ohandle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to t spitalformation. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hos information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, intime to released visit-es and scroll subtitles, multimedia information through network transmission to the displayed Terminal, reale and the released system system used concentrated control, and unified management of way will sound video signal, and picturWest floor 20 15 18 3 56 total 529 (3) information guid-in the floor 21 15 12 5 53 1th, Floor-East floor 16 16 16 3 51 1th, floor-two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floorunderground a layer underground medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer-red TV distribution statistics following table: Wired TV information points distribution schedulecommerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wi-s. Taking into account the needs of eeighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse channelthe nto the enemyKok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology d timesuch as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours secon12 附件六:玻璃容器中常用金属元素的每日允许摄入量(注射途径) PDE 金属元素 Pb 5.0μg/day Co 5.0μg/day Cd 6μg/day As 15μg/day Li 390μg/day Sb 600μg/day Ba 1300μg/day Fe 1300μg/day Zn 1300μg/day Cr 1100μg/day 七、参考文献 1、《中华人民共和国药品管理法》(中华人民共和国主席令第45号) 2、《药品管理法实施条例》(中华人民共和国国务院令第360号) 3、《直接接触药品的包装材料和容器管理办法》(国家食品药品监督管理局令第13号) 4、玻璃包装材料和容器审评技术指导原则(征求意见稿) 5、美国药典<1660>玻璃内表面耐受性评估指南(征求意见稿) 6、化学药品注射剂与塑料包装材料相容性研究技术指导原则(试行)(国食药监注[2012]267号) 7、ICH Q3D GUIDELINE FOR ELEMENTAL IMPURITIES. the neighbouring frequency transmission planning, the system can accommodate more than more than 80 TV channels, 2 reverse chan13 nels. Taking into account the needs of e-commerce in the future, this system increase in backhaul bandwidth, take up to 4 channels. Wired TV distribution statistics following table: Wired TV information points distribution schedule-medical floor, rehabilitation floor, 1th, floor, 2nd, floor serial number a layer two layer three layer four layer five layer underground a layer underground two layer total medical floor 53 54 52 71 54 7 5 296 rehabilitation floor 7 5 5 4 4 2 27 2nd, floor 18 18 10 46 1th, floor-East floor 16 16 16 3 51 1th, floor-in the floor 21 15 12 5 53 1th, Floor-West floor 20 15 18 3 56 total 529 (3) information guide and the released system system used concentrated control, and unified management of way will sound video signal, and pictures and scroll subtitles, multimedia information through network transmission to the displayed Terminal, real-time to released visits information, and rehabilitation center image advertising, and medical common sense, and experts introduced, health life, information. and can at any time spots pictures, news, emergency notification, content, main distribution in Center of Hall, hospital handle district, Elevator Hall, public. Systems Management Server security management on the medical floor room, connect to the streaming media over a network control terminals, control terminals and display devices such as LCD TVs, LED screens and other equipment connected, the output information, system support MPEG1/2/4,WMV,AVI and other video format, supports image formats such as JPG,PNG,GIF, support DTS/AC3, MP3 MPEG1/MPEG2 MP3,WMA audio format support slide presentations ( PPT). Hours second time Kok's public security system ... Information for safe, reliable, and mature application of equipment and advanced technology to the enemy