living standards, poor farmers in less than complete elimination of 4600 Yuan, 8949, 19008. \e\2.169 billion yuan, similar counties line the city's first complete the 42 km of sewage pipe network construction, completion rate ranked first in the city, won the provincial rural sewage treatment work better; key pollution sources such as electroplating, papermaking, chemical industry management through verification and acceptance of the municipal government, the County removed Black and odorous River, River waste, beginning of river ecological restoration effects. \s: County total demolition illegal area up 2.759 million square meters, completed City issued annual task of 153%, split against area ranking city second; completed \on square meters, completed City issued annual task of 403%, ranking city third, which village in the a target completed total city ranking first; County Government was named city level \split\dvanced. These achievements are hard won and should be appreciated. However, we are fully aware, the new period, and work in the countryside and the environment facing higher standards and requirements, provincial party Committee offered to high level build a comprehensive well-off society goal requires \dirty environment illegal buildings, into a well-off\pal party Committee also proposes to build into the well-off benchmark goals of the city. Compared with the superior claim, \Gate of XX beautiful\nd environment there are a number of weaknesses and gaps, highlighted in the following five aspects: first, agriculture remained \low\n. \n the quality and low; short, value added of the industry chain is low; 123 fusion yield low employee age, low quality. \smaller, specialized cooperatives throughout the County there were 3,396, but on the scale of too little. \cted in production, management, services, decentralized, centralized, standardized, brand, information and organizational level is not high. Second, the countryside is still in \se. \on has not changed. \illage in rural housing construction planning, construction of disorder, no drawings, no construction, no vetting \no\heap lying there. \Bad\overnance is poor. Thirdly, farmers continued to be \stent\ng, rural labor force accounted for 70% over the age of 50. \he reform measures ground resistance, such as the transactions of property rights, land replacement; public service supply gap, rural education, health care, pensions and other services can not meet the demand still difficult for poverty alleviation, with emphasis on poverty alleviation and 191. \d\nts, peasants. Four water effects still lackFDA人用药品和生物制品包装用容器密封系统指导原则
目 录 I．引言 II．背景
A．定义
B．CGMP、CPSC和USP对包装容器的要求 C．其他需要考虑的因素
III．包装组件的合格性确认和质量控制
A．引言 B．一般要求
C．为支持任何药品的原始申请而应提供交的资料 D．吸入制剂
E．注射剂和眼用制剂
F．口服液体制剂、局部用制剂及其局部用给药系统 G．口服固体制剂和复溶用粉末 H．其他剂型
Ⅳ．批准后的包装变更 Ⅴ．Ⅲ类DMF文件
A．总体说明
B．Ⅲ类DMF中包括的信息 Ⅵ．大包装容器
A．散装原料药用容器 B．散装制剂用容器 附件A
法规要求 附件B
与包装有关的政策指南 附件C
提取物研究 附件D
缩略语 附件E
参考文献
compelling.\h the \ork very hard, but the flood of scientific enough, before the treatment and water quality improvement after the treatment effect is not obvious, county-wide focus on river still largely inferior five water, swimming the River could not be found. Five is \e to split\ahead. Notice of stock there, new construction did not receive timely treatment every year (such as ancestral hall as unauthorised repeated), contrary to the created work is very different from the provincial and municipal standards. Meanwhile, when implementation is not in place, generally only focus on illegal construction demolished, failing that split that is clear, combined demolition, insufficient attention to reconstruction of old residential areas, urban villages, shanty towns and promote poor. o solve these problems, we must enhance the sense of responsibility and urgency, insist on problem-oriented, to take strong measures, efforts to make up the%ure\split a\Board, construction of comprehensive safeguards, \Gate of XX beautiful\ng. II, and precision Shi policy, and manpower playing good \e agricultural\protracted \cultural\ork is do economic social development the work of based, county levels the sector to according to \d agricultural, and and manpower rural, and development farmers\nts, insisted agricultural rural based status not shake, insisted huinong kulak policy not weakened, insisted reform innovation test not stop, efforts created new era \agricultural%uation. (A) to make agriculture more. o establish the concept of agriculture around the people demand, and comprehensively promote the supply side of agriculture structural reform, strive to enhance the quality and efficiency of agriculture and competitiveness. Focus is on doing the four articles. One is the steady increase ofgrain article. Always tighten the string for food security, \ce bag\ch in hand, to hold land in the adjustment of agricultural planting structure in the \ne.\ccelerating the construction of grain ribbons, improving agricultural infrastructure, enhance food production capacity, improve the quality of agricultural products, effectively \ncrease of grain\ntain %ue.\cond, industry convergence article. Enhance the level of concentration, intensification of agriculture, creating production, processing, distribution, sales and service in one of the agricultural industrial chain, to break down the value chain, improve added value. Pushing forward \Internet + agricultural\ove agricultural production, management, and service level, innovating the mode of e-commerce marketing of agricultural products, solve the difficult problem of sales of agricultural products. Agriculture and tourism, education, culture, health, pension and other deep integration, develop leisure, travelliving standards, poor farmers in less than complete elimination of 4600 Yuan, 8949, 19008. \e\2.169 billion yuan, similar counties line the city's first complete the 42 km of sewage pipe network construction, completion rate ranked first in the city, won the provincial rural sewage treatment work better; key pollution sources such as electroplating, papermaking, chemical industry management through verification and acceptance of the municipal government, the County removed Black and odorous River, River waste, beginning of river ecological restoration effects. \s: County total demolition illegal area up 2.759 million square meters, completed City issued annual task of 153%, split against area ranking city second; completed \on square meters, completed City issued annual task of 403%, ranking city third, which village in the a target completed total city ranking first; County Government was named city level \split\dvanced. These achievements are hard won and should be appreciated. However, we are fully aware, the new period, and work in the countryside and the environment facing higher standards and requirements, provincial party Committee offered to high level build a comprehensive well-off society goal requires \dirty environment illegal buildings, into a well-off\pal party Committee also proposes to build into the well-off benchmark goals of the city. Compared with the superior claim, \Gate of XX beautiful\nd environment there are a number of weaknesses and gaps, highlighted in the following five aspects: first, agriculture remained \n. \n the quality and low; short, value added of the industry chain is low; 123 fusion yield low employee age, low quality. \smaller, specialized cooperatives throughout the County there were 3,396, but on the scale of too little. \cted in production, management, services, decentralized, centralized, standardized, brand, information and organizational level is not high. Second, the countryside is still in \se. \on has not changed. \illage in rural housing construction planning, construction of disorder, no drawings, no construction, no vetting \no\heap lying there. \Bad\overnance is poor. Thirdly, farmers continued to be \stent\ng, rural labor force accounted for 70% over the age of 50. \he reform measures ground resistance, such as the transactions of property rights, land replacement; public service supply gap, rural education, health care, pensions and other services can not meet the demand still difficult for poverty alleviation, with emphasis on poverty alleviation and 191. \d\nts, peasants. Four water effects still lacks 行业指南1
人用药品和生物制品包装用容器封闭系统指导原则
化学，生产和质控文件
I．引言
本指导原则为提交人用药品与生物制品2所用包装材料信息提供一般原则的指导3。本文件替代FDA于1987年2月发布的关于提交人用药品和生物制品包装资料的指导原则和仿制药办公室于1995年6月30日向行业发布的包装政策声明4。本指导原则并非是阐述制剂生产有关的包装操作应提供的信息。
可以采用与本指导原则不同的研究方法，但建议申请人提前就重大的差异，和CDER化学审评员或CBER审评员进行讨论。这是为了避免申请人花费不必要的时间和精力去准备资料，而这种资料可能不被FDA接受。 II．背景
《联邦食品、药和化妆品法》（以下简称“法案”）要求必须提供包装材料的充分信息。法案第501（a）（3）部分规定，“如果某个药品的容器整体或部分含有毒或有害物质，可能导致药品对健康有害的...”，则该药为劣药。此外，法案第502部分规定，如果某药品的包装存在过失，则被认为错标药品。另外，法案第505部分要求详细描述包装药品所使用的方法，用于包装的设施设备及控制措施（见附录A）。
法案第505（b）（1）（D）部分规定，申请人应完整描述药品的生产、加工和包装过程中所采用的方法。其中包括包装药品所使用的设备和控制措施。
A．定义5
组成材料6指的是用来生产包装组件的物质（例如玻璃、高密度聚乙烯（HDPE）树脂、金属）。
包装组件指容器密封系统的任何一个组成部件。典型的组件有容器（例如安瓿、西林瓶、瓶子）、容器衬垫（例如管衬）、密封件（螺旋盖、胶塞）、密封件垫片、胶塞顶封、容器内封、输液口（例如大容量注射剂（LVP））、外包装、给药附件和容器标签。主包装组件指的是与药物直接接触或可能直接接触的包装组件。次级包装组件指的是不与药物直接接触的包装组件。
compelling.\h the \ork very hard, but the flood of scientific enough, before the treatment and water quality improvement after the treatment effect is not obvious, county-wide focus on river still largely inferior five water, swimming the River could not be found. Five is \e to split\ahead. Notice of stock there, new construction did not receive timely treatment every year (such as ancestral hall as unauthorised repeated), contrary to the created work is very different from the provincial and municipal standards. Meanwhile, when implementation is not in place, generally only focus on illegal construction demolished, failing that split that is clear, combined demolition, insufficient attention to reconstruction of old residential areas, urban villages, shanty towns and promote poor. o solve these problems, we must enhance the sense of responsibility and urgency, insist on problem-oriented, to take strong measures, efforts to make up the%ure\split a\Board, construction of comprehensive safeguards, \Gate of XX beautiful\ng. II, and precision Shi policy, and manpower playing good \e agricultural\protracted \cultural\ork is do economic social development the work of based, county levels the sector to according to \d agricultural, and and manpower rural, and development farmers\nts, insisted agricultural rural based status not shake, insisted huinong kulak policy not weakened, insisted reform innovation test not stop, efforts created new era \agricultural%uation. (A) to make agriculture more. o establish the concept of agriculture around the people demand, and comprehensively promote the supply side of agriculture structural reform, strive to enhance the quality and efficiency of agriculture and competitiveness. Focus is on doing the four articles. One is the steady increase ofgrain article. Always tighten the string for food security, \ce bag\ch in hand, to hold land in the adjustment of agricultural planting structure in the \ne.\ccelerating the construction of grain ribbons, improving agricultural infrastructure, enhance food production capacity, improve the quality of agricultural products, effectively \ncrease of grain\ntain %ue.\cond, industry convergence article. Enhance the level of concentration, intensification of agriculture, creating production, processing, distribution, sales and service in one of the agricultural industrial chain, to break down the value chain, improve added value. Pushing forward \Internet + agricultural\ove agricultural production, management, and service level, innovating the mode of e-commerce marketing of agricultural products, solve the difficult problem of sales of agricultural products. Agriculture and tourism, education, culture, health, pension and other deep integration, develop leisure, travelliving standards, poor farmers in less than complete elimination of 4600 Yuan, 8949, 19008. \e\2.169 billion yuan, similar counties line the city's first complete the 42 km of sewage pipe network construction, completion rate ranked first in the city, won the provincial rural sewage treatment work better; key pollution sources such as electroplating, papermaking, chemical industry management through verification and acceptance of the municipal government, the County removed Black and odorous River, River waste, beginning of river ecological restoration effects. \s: County total demolition illegal area up 2.759 million square meters, completed City issued annual task of 153%, split against area ranking city second; completed \on square meters, completed City issued annual task of 403%, ranking city third, which village in the a target completed total city ranking first; County Government was named city level \split\dvanced. These achievements are hard won and should be appreciated. However, we are fully aware, the new period, and work in the countryside and the environment facing higher standards and requirements, provincial party Committee offered to high level build a comprehensive well-off society goal requires \dirty environment illegal buildings, into a well-off\pal party Committee also proposes to build into the well-off benchmark goals of the city. Compared with the superior claim, \Gate of XX beautiful\nd environment there are a number of weaknesses and gaps, highlighted in the following five aspects: first, agriculture remained \n. \n the quality and low; short, value added of the industry chain is low; 123 fusion yield low employee age, low quality. \smaller, specialized cooperatives throughout the County there were 3,396, but on the scale of too little. \cted in production, management, services, decentralized, centralized, standardized, brand, information and organizational level is not high. Second, the countryside is still in \se. \on has not changed. \illage in rural housing construction planning, construction of disorder, no drawings, no construction, no vetting \no\heap lying there. \Bad\overnance is poor. Thirdly, farmers continued to be \stent\ng, rural labor force accounted for 70% over the age of 50. \hat the reform measures ground resistance, such as the transactions of property rights, land replacement; public service supply gap, rural education, health care, pensions and other services can not meet the demand still difficult for poverty alleviation, with emphasis on poverty alleviation and 191. \d\nts, peasants. Four water effects still lack 容器密封系统指共同盛装和保护制剂的所有包装组件的总和。如果次级包装组件具有为药品提供额外保护的功能，则容器密封系统包括主包装组件和次级包装组件。包装系统等同于容器密封系统。
包装或上市包装7是指容器密封系统和标签、相关配件（例如量杯、滴管、药匙）和外包装（例如纸箱或热缩塑料包装）。上市包装是指提供给药师或零售消费者的包装物件，不包括专门用于运输的包装物件。
质量是指一种药品若被认为具有治疗或诊断用途时，它所具有的物理、化学、微生物、生物、生物利用度和稳定性方面的品质。在本指导原则中，该术语还可理解为安全性、鉴别、规格、质量和纯度等性质（请见21 CFR 211.94（a））。 提取物特性是指从包装组件中提取的物质的分析特征（通常采用色谱方法）。提取物定量特性是指每种检测成分都可以被量化。
B． CGMP、CPSC和USP对包装容器的要求
《药品生产质量管理规范（cGMP）》对药品包装容器的要求在21 CFR第210和211部分。相关部分的列表见附录A。此外，附录B列出了涉及包装问题的政策指南。本指导原则中有关cGMP的参考文献，有助于完整地理解相关要求。更多的信息，请参考FDA关于批准前检查/调查的合规性指导手册(7346.832)，它提供了CDER科学家和地区检查员的具体职责。
FDA关于保险包装的要求列在21 CFR 211.132中，消费品安全委员会（CPSC）关于儿童安全盖的要求列在16 CFR 1700中。这些法规要求以及其他相关法规要求的要点见附录A。
美国药典会已经制定了药物容器相关的要求，在美国药典/国家处方集（USP/NF）收载的药品专论中有所阐述。对于胶囊剂和片剂用包装容器的要求，一般与容器的设计特性有关（例如，牢固、密封良好或避光）。对于注射剂用包装材料，还对包装材料进行了要求（例如，“单剂量或多剂量用容器，优先选择I类玻璃，避光”）。这些要求详见USP“凡例和要求”项下（保存、包装、贮藏和标签）部分。关于包装材料的要求，USP的“通则”中有详细说明（详见附录A）。
C．其他需要考虑的因素
compelling.\h the \ork very hard, but the flood of scientific enough, before the treatment and water quality improvement after the treatment effect is not obvious, county-wide focus on river still largely inferior five water, swimming the River could not be found. Five is \e to split\ahead. Notice of stock there, new construction did not receive timely treatment every year (such as ancestral hall as unauthorised repeated), contrary to the created work is very different from the provincial and municipal standards. Meanwhile, when implementation is not in place, generally only focus on illegal construction demolished, failing that split that is clear, combined demolition, insufficient attention to reconstruction of old residential areas, urban villages, shanty towns and promote poor. o solve these problems, we must enhance the sense of responsibility and urgency, insist on problem-oriented, to take strong measures, efforts to make up the%ure\split a\Board, construction of comprehensive safeguards, \Gate of XX beautiful\ng. II, and precision Shi policy, and manpower playing good \e agricultural\protracted \cultural\ork is do economic social development the work of based, county levels the sector to according to \d agricultural, and and manpower rural, and development farmers\nts, insisted agricultural rural based status not shake, insisted huinong kulak policy not weakened, insisted reform innovation test not stop, efforts created new era \agricultural%uation. (A) to make agriculture more. o establish the concept of agriculture around the people demand, and comprehensively promote the supply side of agriculture structural reform, strive to enhance the quality and efficiency of agriculture and competitiveness. Focus is on doing the four articles. One is the steady increase ofgrain article. Always tighten the string for food security, \ce bag\ch in hand, to hold land in the adjustment of agricultural planting structure in the \ne.\ccelerating the construction of grain ribbons, improving agricultural infrastructure, enhance food production capacity, improve the quality of agricultural products, effectively \ncrease of grain\ntain %ue.\cond, industry convergence article. Enhance the level of concentration, intensification of agriculture, creating production, processing, distribution, sales and service in one of the agricultural industrial chain, to break down the value chain, improve added value. Pushing forward \Internet + agricultural\ove agricultural production, management, and service level, innovating the mode of e-commerce marketing of agricultural products, solve the difficult problem of sales of agricultural products. Agriculture and tourism, education, culture, health, pension and other deep integration, develop leisure, travelliving standards, poor farmers in less than complete elimination of 4600 Yuan, 8949, 19008. \e\2.169 billion yuan, similar counties line the city's first complete the 42 km of sewage pipe network construction, completion rate ranked first in the city, won the provincial rural sewage treatment work better; key pollution sources such as electroplating, papermaking, chemical industry management through verification and acceptance of the municipal government, the County removed Black and odorous River, River waste, beginning of river ecological restoration effects. \s: County total demolition illegal area up 2.759 million square meters, completed City issued annual task of 153%, split against area ranking city second; completed \on square meters, completed City issued annual task of 403%, ranking city third, which village in the a target completed total city ranking first; County Government was named city level \split\dvanced. These achievements are hard won and should be appreciated. However, we are fully aware, the new period, and work in the countryside and the environment facing higher standards and requirements, provincial party Committee offered to high level build a comprehensive well-off society goal requires \dirty environment illegal buildings, into a well-off\pal party Committee also proposes to build into the well-off benchmark goals of the city. Compared with the superior claim, \Gate of XX beautiful\nd environment there are a number of weaknesses and gaps, highlighted in the following five aspects: first, agriculture remained \n. \n the quality and low; short, value added of the industry chain is low; 123 fusion yield low employee age, low quality. \smaller, specialized cooperatives throughout the County there were 3,396, but on the scale of too little. \cted in production, management, services, decentralized, centralized, standardized, brand, information and organizational level is not high. Second, the countryside is still in \se. \on has not changed. \illage in rural housing construction planning, construction of disorder, no drawings, no construction, no vetting \no\heap lying there. \Bad\overnance is poor. Thirdly, farmers continued to be \stent\ng, rural labor force accounted for 70% over the age of 50. \he reform measures ground resistance, such as the transactions of property rights, land replacement; public service supply gap, rural education, health care, pensions and other services can not meet the demand still difficult for poverty alleviation, with emphasis on poverty alleviation and 191. \d\nts, peasants. Four water effects still lacks 1．IND的申报资料要求
IND的化学、生产和质控部分通常应提供临床样品的包装容器信息，包括包装组件、组装后的完整包装系统和所有使用注意事项，以保证原料药及制剂在其临床试验期间得到合适的保护及保存。
关于新药I期临床试验需申报的容器密封系统信息的指导原则，请参考FDA关于新药（包括经充分鉴定的治疗性生物技术制品）I期临床试验（IND）申报资料的内容和格式要求（1995年11月）。
关于新药II期或III期临床试验需申报的容器密封系统信息的指导原则，将发布在FDA关于新药（包括经充分鉴定的治疗性生物技术制品）II期或III期临床试验（IND）申报资料的内容和格式要求最终版（草案于1999年4月21日公布）。
2．由其他公司包装制剂的申报资料要求 a．合同包装商
合同包装商是指受申请人委托，代为包装药品的公司。申请人对制剂运输、储存和包装期间的质量负责。
和申请人自己包装药品相同，合同包装商所使用的容器密封系统的相关信息，须包括在NDA、ANDA或BLA申报资料的CMC部分或引用的DMF文件中。如果需引用DMF文件，申保资料中应提供相应DMF的授权许可证明（详见第V.A部分）。
b．再包装商8
再包装商是指从制剂生产厂或经销商处购买制剂，经重新包装，标签标注新生产厂后，再销售的公司。再包装商对该药品的质量和稳定性负责。重新包装的操作要求须符合cGMP（21 CFR第211部分）的要求。除非再包装商进行稳定性研究外，cGMP（21 CFR第211部分）还对重新包装制剂的有效期有所限制9。如果再包装商使用与原申请中已批准的相同容器密封系统，则不要求提供包装容器的合格性确认信息。
药品生产和加工的所有重要流程（包括制剂包装流程），须包括在NDA、ANDA或BLA申报资料的CMC部分或引用的DMF文件中。唯一例外的情况是固体口服制剂的再包装步骤，因为其注册申请已经被批准10。对于生物制品，认
compelling.\h the \ork very hard, but the flood of scientific enough, before the treatment and water quality improvement after the treatment effect is not obvious, county-wide focus on river still largely inferior five water, swimming the River could not be found. Five is \e to split\ahead. Notice of stock there, new construction did not receive timely treatment every year (such as ancestral hall as unauthorised repeated), contrary to the created work is very different from the provincial and municipal standards. Meanwhile, when implementation is not in place, generally only focus on illegal construction demolished, failing that split that is clear, combined demolition, insufficient attention to reconstruction of old residential areas, urban villages, shanty towns and promote poor. o solve these problems, we must enhance the sense of responsibility and urgency, insist on problem-oriented, to take strong measures, efforts to make up the%ure\split a\Board, construction of comprehensive safeguards, \Gate of XX beautiful\ng. II, and precision Shi policy, and manpower playing good \e agricultural\protracted \cultural\ork is do economic social development the work of based, county levels the sector to according to \d agricultural, and and manpower rural, and development farmers\nts, insisted agricultural rural based status not shake, insisted huinong kulak policy not weakened, insisted reform innovation test not stop, efforts created new era \agricultural%uation. (A) to make agriculture more. o establish the concept of agriculture around the people demand, and comprehensively promote the supply side of agriculture structural reform, strive to enhance the quality and efficiency of agriculture and competitiveness. Focus is on doing the four articles. One is the steady increase ofgrain article. Always tighten the string for food security, \ce bag\ch in hand, to hold land in the adjustment of agricultural planting structure in the \ne.\ccelerating the construction of grain ribbons, improving agricultural infrastructure, enhance food production capacity, improve the quality of agricultural products, effectively \ncrease of grain\ntain %ue.\cond, industry convergence article. Enhance the level of concentration, intensification of agriculture, creating production, processing, distribution, sales and service in one of the agricultural industrial chain, to break down the value chain, improve added value. Pushing forward \Internet + agricultural\ove agricultural production, management, and service level, innovating the mode of e-commerce marketing of agricultural products, solve the difficult problem of sales of agricultural products. Agriculture and tourism, education, culture, health, pension and other deep integration, develop leisure, travel
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