FDA检查员指导手册
FDA检查员指导手册——药品生产检查程序
FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求……………………………………………………3 5第一部分背景……………………………………………………………………36第二部分执行…………………………………………………………………362.1.目的……………………………………………………………………362.2.策略……………………………………………………………………362.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等）…362.2.2.系统性检查……………………………………………………………372.2.3.对原料药及制剂生产的系统性检查计划……………………………382.2.3.1.质量系统………………………………………………………………382.2.3.2.厂房设施与设备系统…………………………………………………382.2.3.3.物料系统………………………………………………………………382.2.3.4.生产系统………………………………………………………………382.2.3.5.包装和贴签系统………………………………………………………382.2.3.6.实验室控制系统………………………………………………………392.3.程序管理指3………………2.3.1.定义……………………………………………………………………392.3.1.1.监督性检查……………………………………………………………392.3.1.2.达标检查………………………………………………………………42.3.1.3.受控状态………………………………………………………………42.3.1.4.药品工艺………………………………………………………………42.3.1.5.药品生产检查…………………………………………………………41第三部分检查……………………………………………………………………413.1.检查活动………………………………………………………………413.1.1.总则……………………………………………………………………413.1.2.检查方法………………………………………………………………423.1.2.1.全面性检查的选择……………………………………………………433.1.2.2.简略性检查的选择……………………………………………………433.1.2.3.综合性检查范围………………………………………………………433.1.3.系统性检查范围………………………………………………………433.1.3.1.质量系4……………………3.1.3.2. 厂房设施与设备系统…………………………………………………443.1.3.3.物料系统………………………………………………………………453.1.3.4.生产系统………………………………………………………………463.1.3.5.包装和贴签系统………………………………………………………473.1.3.6.实验室控制系统………………………………………………………483.1.4.取样……………………………………………………………………493.1.5.检查组组成……………………………………………………………493.1.6.报告……………………………………………………………………49第四部分分析……………………………………………………………………5第五部分法律性/行政性策略…………………………………………………55.1.质量系统………………………………………………………………515.2.厂房设施和设备………………………………………………………515.3.物料系统………………………………………………………………515.4.生产系统………………………………………………………………525.5.包装和贴签系5……………5.6.实验室控制系统………………………………………………………52对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。
CP7356.002FDA检查员指导手册范本
FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求 (35)第一部分背景 (36)第二部分执行 (36)2.1.目的 (36)2.2.策略 (36)2.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等） (36)2.2.2.系统性检查 (37)2.2.3.对原料药及制剂生产的系统性检查计划 (38)2.2.3.1.质量系统 (38)2.2.3.2.厂房设施与设备系统 (38)2.2.3.3.物料系统 (38)2.2.3.4.生产系统 (38)2.2.3.5.包装和贴签系统 (38)2.2.3.6.实验室控制系统 (39)2.3.程序管理指导 (39)2.3.1.定义 (39)2.3.1.1.监督性检查 (39)2.3.1.2.达标检查 (40)2.3.1.3.受控状态 (40)2.3.1.4.药品工艺 (40)2.3.1.5.药品生产检查 (41)第三部分检查 (41)3.1.检查活动 (41)3.1.1.总则 (41)3.1.2.检查方法 (42)3.1.2.1.全面性检查的选择 (43)3.1.2.2. 简略性检查的选择 (43)3.1.2.3.综合性检查围 (43)3.1.3.系统性检查围 (43)3.1.3.1.质量系统 (44)3.1.3.2. 厂房设施与设备系统 (44)3.1.3.3.物料系统 (45)3.1.3.4.生产系统 (46)3.1.3.5.包装和贴签系统 (47)3.1.3.6.实验室控制系统 (48)3.1.4.取样 (49)3.1.5.检查组组成 (49)3.1.6.报告 (49)第四部分分析 (50)第五部分法律性/行政性策略 (50)5.1.质量系统 (51)5.2.厂房设施和设备 (51)5.3.物料系统 (51)5.4.生产系统 (52)5.5.包装和贴签系统 (52)5.6.实验室控制系统 (52)对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。
fda检查员指导手册--药品生产检查程序(doc75页)(1)
FDA检查员指导手册CP 7356.002:药品生产检查程序对现场报告的要求 (35)第一部分背景 (36)第二部分执行 (36)2.1. 目的 (36)22 策略 (36)221. 对生产企业两年一度的检查（包括重新包装商、合同实验室等） (36)2.2.2. 系统性检查 (37)2.2.3. 对原料药及制剂生产的系统性检查计划 (38)2.2.3.1. 质量系统 (38)2.2.32 厂房设施与设备系统 (38)2.2.33 物料系统 (38)2.2.34 生产系统 (38)2.2.3.5. 包装和贴签系统 (38)2.2.3.6. 实验室控制系统 (39)2.3. 程序管理指导 (39)2.3.1. 定义 (39)2.3.1.1. 监督性检查 (39)2.3.1.2. 达标检查 (40)2.3.1.3. 受控状态 (40)2.3.1.4. 药品工艺 (40)2.3.1.5. 药品生产检查 (41)第三部分检查 (41)3.1. 检查活动 (41)3.1.1. 总则 (41)3.1.2. 检查方法 (42)3.1.2.1. 全面性检查的选择 (43)3.1.2.2. 简略性检查的选择 (43)3.1.2.3. 综合性检查范围 (43)3.1.3. 系统性检查范围 (43)3.131. 质量系统 (44)3.1.32厂房设施与设备系统 (44)3.1.3.3. 物料系统 (45)3.1.3.4. 生产系统 (46)3.1.3.5. 包装和贴签系统 (47)3.1.3.6. 实验室控制系统 (48)3.1.4. 取样 (49)3.1.5. 检查组组成 (49)3.1.6. 报告 (49)第四部分分析 (50)第五部分法律性/行政性策略 (50)5.1. 质量系统 (51)5.2. 厂房设施和设备 (51)5.3. 物料系统 (51)5.4. 生产系统 (52)5.5. 包装和贴签系统 (52)5.6. 实验室控制系统 (52)对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR) 。
FDA检查员指导手册
原料药生产检查（药物质量保证）目录现场检查汇报规定 (55)第I部分背景 (56)第II部分实行 (57)第III部分检查 (58)第IV部分分析 (63)第V部分法规/行政方略 (65)第VI部分参照资料，附件和联络接触方式 (68)第VII部分中心旳职责 (69)附件A (69)附件B (72)现场检查汇报规定工艺专论汇报在API检查时，要使用下列旳分类进行汇报所检查旳工艺状况1．Non Sterile API by Chemical Synthesis CSN化学合成非无菌原料CSN2．Sterile API by Chemical Synthesis CSS化学合成无菌原料药CSS3．Non Sterile API by Fermentation CFN发酵生产旳非无菌原料CFN4．Sterile API by Fermentation CFS发酵生产旳无菌原料CFS5．Plant/Animal Extraction API CEX植物/动物提取原料药CEX6．Biotechnology API CBI生物技术生产旳原料药CBI第I部分――背景至八十年代后期以来，美国食品与药物管理局以强化了其对原料药(API)生产企业旳检查内容。
从部分方面来说，这归咎于对原料药质量在制剂旳质量、效力、和安全面所起旳重要作用认识旳提高。
例如，在配制成固体口服制剂，混悬剂和局部用药时原料药旳化学特性会对制剂旳溶出度/生物运用度产生不利影响。
此外，原料中旳少许没有鉴别出旳杂质或其特性未知旳杂质会给病人导致旳严重不良反应。
FDA长期以来一直认为，收载在制剂药物生产质量管理规范规定(21 CFR 210 and 211)中旳CGMP概念对原料药生产工艺同样有效。
这些概念包括，与其他一起，产品质量是生产出来旳，雇佣可以胜任和通过培训旳员工，建立合适旳书面程序和管理规定，建立一套在线测试和产品测试系统，工艺验证，和保证原料药在预期旳有效期内质量稳定。
FDA检查员指导手册： 7356.002F中文版
Food and Drug AdministrationCompliance Program Guidance ManualFDA检查员指导手册：7356.002F56002F- Active Pharmaceutical Ingredient Process Inspections (Drug QualityAssurance)56002F-原料药生产检查（药品质量保证）目录现场检查报告要求 (55)第I部分背景 (56)第II部分实施 (57)第III部分检查 (58)第IV部分分析 (63)第V部分法规/行政策略 (65)第VI部分参考资料，附件和联系接触方式 (68)第VII部分中心的职责 (69)附件A (69)附件B (72)现场检查报告要求工艺专论报告在API检查时，要使用下列的分类进行报告所检查的工艺情况1．Non Sterile API by Chemical Synthesis CSN化学合成非无菌原料CSN2．Sterile API by Chemical Synthesis CSS化学合成无菌原料药CSS3．Non Sterile API by Fermentation CFN发酵生产的非无菌原料CFN4．Sterile API by Fermentation CFS发酵生产的无菌原料CFS5．Plant/Animal Extraction API CEX植物/动物提取原料药CEX6．Biotechnology API CBI生物技术生产的原料药CBI第I部分――背景至八十年代后期以来，美国食品与药品管理局以强化了其对原料药(API)生产企业的检查内容。
从部分方面来说，这归咎于对原料药质量在制剂的质量、效力、和安全方面所起的重要作用认识的提高。
例如，在配制成固体口服制剂，混悬剂和局部用药时原料药的化学特性会对制剂的溶出度/生物利用度产生不利影响。
另外，原料中的少量没有鉴别出的杂质或其特性未知的杂质会给病人造成的严重不良反应。
FDA检查员指导手册CP药品生产检查程序
F D A检查员指导手册C P药品生产检查程序Document serial number【NL89WT-NY98YT-NC8CB-NNUUT-NUT108】FDA检查员指导手册CP ：药品生产检查程序目录对现场报告的要求………………………………第一部分背景………………………………第二部分执行…………………………….目的……………………………….策略……………………………………………………………………36对生产企业两年一度的检查（包等）…系统性检查………………………………对原料药及制剂生产的系统性检划…………………………….质量系统……………………………….厂房设施与设备系统……………………………….物料系统……………………………….生产系统……………………………….包装和贴签系统……………………………….实验室控制系统……………………………….程序管理指导………………………………定义……………………………….监督性检查……………………………….达标检查……………………………….受控状态……………………………….药品工艺……………………………….药品生产检查………………………………第三部分检查……………………………….检查活动………………………………总则………………………………检查方法……………………………….全面性检查的选择……………………………….简略性检查的选择……………………………….综合性检查范围………………………………系统性检查范围……………………………….质量系统……………………………….厂房设施与设备系统……………………………….物料系统……………………………….生产系统……………………………….包装和贴签系统……………………………….实验室控制系统………………………………取样………………………………检查组组成………………………………报告………………………………第四部分分析………………………………第五部分法律性/行政性策略……………………………….质量系统……………………………….厂房设施和设备……………………………….物料系统……………………………….生产系统……………………………….包装和贴签系统……………………………….实验室控制系统………………………………对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。
FDA检查员手册
FDA检查员指导手册7356.002F原料药生产检查（药品质量保证）第一部分背景总则法案的501(a)(2)(B)条款要求所有药品的生产都必须遵守现行GMP的要求，而原料药也不例外。
对于原料药和制剂这两者的要求，法案并没有区别对待，而任何原料药或制剂方面的GMP缺陷都构成了对法案的偏离。
对于原料药或药物成分来说，FDA并没有为此而专门发布cGMP法规文件（就像我们现在有的制剂cGMP法规一样）。
因此，本文提到的“cGMP”指的是法案要求，而并非美国联邦法规（CFR）第21部分210和211条款中关于制剂的要求。
其实，FDA早就意识到cGMP对制剂的要求（美国联邦法规第21部分210、211条款）在理念上对于原料药生产来说同样适用且有效。
这些理念包括使用合适的设备；聘用经过培训且通过资质确认的人员；建立充分合理的书面程序和控制，确保生产工艺和控制的有效性，从而保证产品质量；建立一套中间体和最终药品检测方法的体系，确保药品在规定的使用期限内保持质量的稳定性。
2001年，FDA在人用药物注册技术要求国际协调会议（ICH）上与其他政府监管部门共同努力，采用了针对API行业cGMP的国际性指南，也就是ICH Q7A，活性药物成分的药品质量管理的指南。
ICH Q7A正体现了FDA对于原料药现行GMP体系的要求。
因此，遵循该指南要求的API及其相关生产和检验设施是符合法定cGMP要求的。
然而，只要是能符合法案501(a)(2)(B)的要求，并能确保API符合其纯度、均一性和质量特性的方法都可以采用。
在本程序中所使用的术语“活性药物成分”（原料药）的含义与ICH Q7A 中的定义一致。
在ICH Q7A中活性药物成分被定义为“旨在用于药品生产的任何物质或混合物，当用于药品生产时，这些物质即成为药品中的活性成分。
这种物质被用来提供药学活性或在诊断、治疗、止痛、缓解、处理或疾病预防中起着直接作用或用于影响机体结构和功能。
FDA检查员指导手册——药品生产检查程序
FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求……………………………………………………3 5第一部分背景……………………………………………………………………36第二部分执行…………………………………………………………………362.1.目的……………………………………………………………………362.2.策略……………………………………………………………………362.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等）…362.2.2.系统性检查……………………………………………………………372.2.3.对原料药及制剂生产的系统性检查计划……………………………382.2.3.1.质量系统………………………………………………………………382.2.3.2.厂房设施与设备系统…………………………………………………382.2.3.3.物料系统………………………………………………………………382.2.3.4.生产系统………………………………………………………………382.2.3.5.包装和贴签系统………………………………………………………382.2.3.6.实验室控制系统………………………………………………………392.3.程序管理指3导…………………………………………………………92.3.1.定义……………………………………………………………………392.3.1.1.监督性检查……………………………………………………………392.3.1.2.达标检查………………………………………………………………42.3.1.3.受控状态………………………………………………………………42.3.1.4.药品工艺………………………………………………………………42.3.1.5.药品生产检查…………………………………………………………41第三部分检查……………………………………………………………………413.1.检查活动………………………………………………………………413.1.1.总则……………………………………………………………………413.1.2.检查方法………………………………………………………………423.1.2.1.全面性检查的选择……………………………………………………433.1.2.2. 简略性检查的选择……………………………………………………433.1.2.3.综合性检查围………………………………………………………433.1.3.系统性检查围………………………………………………………433.1.3.1.质量系统………………………………………44………………………3.1.3.2. 厂房设施与设备系统…………………………………………………443.1.3.3.物料系统………………………………………………………………453.1.3.4.生产系统………………………………………………………………463.1.3.5.包装和贴签系统………………………………………………………473.1.3.6.实验室控制系统………………………………………………………483.1.4.取样……………………………………………………………………493.1.5.检查组组成……………………………………………………………493.1.6.报告……………………………………………………………………49第四部分分析……………………………………………………………………5第五部分法律性/行政性策略…………………………………………………55.1.质量系统………………………………………………………………515.2.厂房设施和设备………………………………………………………515.3.物料系统………………………………………………………………515.4.生产系统………………………………………………………………525.5.包装和贴签系统………………………………………………………525.6.实验室控制系统………………………………………………………52对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。
CP7356.002FDA检查员指导手册范本
FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求 (35)第一部分背景 (36)第二部分执行 (36)2.1.目的 (36)2.2.策略 (36)2.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等） (36)2.2.2.系统性检查 (37)2.2.3.对原料药与制剂生产的系统性检查计划 (38)2.2.3.1.质量系统 (38)2.2.3.2.厂房设施与设备系统 (38)2.2.3.3.物料系统 (38)2.2.3.4.生产系统 (38)2.2.3.5.包装和贴签系统 (38)2.2.3.6.实验室控制系统 (39)2.3.程序管理指导 (39)2.3.1.定义 (39)2.3.1.1.监督性检查 (39)2.3.1.2.达标检查 (40)2.3.1.3.受控状态 (40)2.3.1.4.药品工艺 (40)2.3.1.5.药品生产检查 (41)第三部分检查 (41)3.1.检查活动 (41)3.1.1.总则 (41)3.1.2.检查方法 (42)3.1.2.1.全面性检查的选择 (43)3.1.2.2. 简略性检查的选择 (43)3.1.2.3.综合性检查围 (43)3.1.3.系统性检查围 (43)3.1.3.1.质量系统 (44)3.1.3.2. 厂房设施与设备系统 (44)3.1.3.3.物料系统 (45)3.1.3.4.生产系统 (46)3.1.3.5.包装和贴签系统 (47)3.1.3.6.实验室控制系统 (48)3.1.4.取样 (49)3.1.5.检查组组成 (49)3.1.6.报告 (49)第四部分分析 (50)第五部分法律性/行政性策略 (50)5.1.质量系统 (51)5.2.厂房设施和设备 (51)5.3.物料系统 (51)5.4.生产系统 (52)5.5.包装和贴签系统 (52)5.6.实验室控制系统 (52)对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。
FDA检查员指导手册(doc 33页)
FDA检查员指导手册(doc 33页)FDA检查员指导手册7356.002F原料药生产检查（药品质量保证）第一部分背景总则法案的501(a)(2)(B)条款要求所有药品的生产都必须遵守现行GMP的要求，而原料药也不例外。
对于原料药和制剂这两者的要求，法案并没有区别对待，而任何原料药或制剂方面的GMP缺陷都构成了对法案的偏离。
对于原料药或药物成分来说，FDA并没有为此而专门发布cGMP法规文件（就像我们现在有的制剂cGMP法规一样）。
因此，本文提到的“cGMP”指的是法案要求，而并非美国联邦法规（CFR）第21部分210和211条款中关于制剂的要求。
其实，FDA早就意识到cGMP对制剂的要求（美国联邦法规第21部分210、211条款）在理念上对于原料药生产来说同样适用且有效。
这些理念包括使用合适的设备；聘用经过培训且通过资质确认的人员；建立充分合理的书面程序和控制，确保生产工艺和控制的有效性，从而保证产品质量；建立一套中间体和最终药品检测方法的体系，确保药品在规定的使用期限内保持质量的稳定性。
2001年，FDA在人用药物注册技术要求国际协调会议（ICH）上与其他政府监管部门共同努力，采用了针对API行业cGMP的国际性指南，也就是ICH Q7A，活性药物成分的药品质量管理的指南。
ICH Q7A正体现了FDA对于原料药现行GMP体系的要求。
因此，遵循该指南要求的API及其相关生产和检验设施是符合法定cGMP要求的。
然而，只要是能符合法案501(a)(2)(B)的要求，并能确保API符合其纯度、均一性和质量特性的方法都可以采用。
在本程序中所使用的术语“活性药物成分”（原料药）的含义与ICH Q7A 中的定义一致。
在ICH Q7A中活性药物成分被定义为“旨在用于药品生产的任何物质或混合物，当用于药品生产时，这些物质即成为药品中的活性成分。
这种物质被用来提供药学活性或在诊断、治疗、止痛、缓解、处理或疾病预防中起着直接作用或用于影响机体结构和功能。
FDA检查员指导手册CP：药品生产检查程序
F D A检查员指导手册C P：药品生产检查程序LEKIBM standardization office【IBM5AB- LEKIBMK08- LEKIBM2C】FDA检查员指导手册CP ：药品生产检查程序目录对现场报告的要求……………………………………………………35第一部分背景……………………………………………………………………36第二部分执行…………………………………………………………………36.目的……………………………………………………………………36.策略……………………………………………………………………36对生产企业两年一度的检查（包括重新包装商、合同实验室等）…36系统性检查……………………………………………………………37对原料药及制剂生产的系统性检查计划……………………………38质量系统………………………………………………………………38厂房设施与设备系统…………………………………………………38物料系统………………………………………………………………38生产系统………………………………………………………………38包装和贴签系统………………………………………………………38实验室控制系统………………………………………………………39.程序管理指导…………………………………………………………39 定义……………………………………………………………………39 监督性检查……………………………………………………………39 达标检查………………………………………………………………40 受控状态………………………………………………………………40 药品工艺………………………………………………………………40药品生产检查…………………………………………………………41第三部分检查……………………………………………………………………41.检查活动………………………………………………………………41 总则……………………………………………………………………41 检查方法………………………………………………………………42 全面性检查的选择……………………………………………………43 简略性检查的选择……………………………………………………43 综合性检查范围………………………………………………………43 系统性检查范围………………………………………………………43 质量系统………………………………………………………………44 厂房设施与设备系统…………………………………………………44 物料系统………………………………………………………………45 生产系统………………………………………………………………46 包装和贴签系统………………………………………………………47 实验室控制系统………………………………………………………48 取样……………………………………………………………………49 检查组组成……………………………………………………………49 报告……………………………………………………………………49第四部分分析……………………………………………………………………50第五部分法律性/行政性策略…………………………………………………50.质量系统………………………………………………………………51.厂房设施和设51备……………………………………………………….物料系统………………………………………………………………51.生产系统………………………………………………………………52.包装和贴签系统………………………………………………………52.实验室控制系统………………………………………………………52对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。
FDA 483 指导手册说明书
Guide for US FDA-Regulated Organizations “How to Respond to (and Avoid) FDA Form 483s forTemperature, Humidity and other Controlled Environments”By Ken Appel, VP of Regulated MarketsVeriteq, a Vaisala companyNo cGMP manufacturer wants to receive a Form 483 letter (“Notice of Inspectional Observations‖). In such stringently controlled industries as pharma-ceutical/biotechnical development, manufacturing and warehousing, receiving a list of deficiencies can feel like a heavy blow to your quality system. Worse, with the 2009 increase in enforcement staff 1 and the September 2009 change to the response time—now 15 days—the FDA appears to be ramping up its enforcement mandate. 2The following article shows three excerpts from some of the more common “obser vatio ns‖ noted in Form 483 Letters during 2008-2009. (The names have been left out in this article, but are a matter of public record). 3 Each of these deviations involved environmental conditions (temperature, humidity, etc.) in a variety of cGMP settings; they range from failure to properly validate containers for Human Cell & Tissue Products to a lack of temperature records in an aseptic processing area of a drug manufacturing facility. None of the deviations excerpted here are unique, but all are avoidable.1 Parts of this article were sourced, with permission, from two documents 1) “FDA 483 Responses—Compliance Considerations” by Richard Poska and Ballard Graham, as published in the Journal of Validation Technology, Winter 2010 ― available with subscription at:/ivtnews/templates/IVTNews.as px?articleid=1896&zoneid=27and the FDA Presentation 2)“Writing An Effective 483 Response” presented by Anita Richardson, Associate Director for Policy, Office of Compliance & Biologics Quality at the 5th Annual FDA University RI Pharma Conference, January 2009 available at:/downloads/BiologicsBloodVaccines/ NewsEvents/WorkshopsMeetingsConferences/UCM1029 21.pdf2"FDA’s Enforcement Crackdown To Increase Inspections, Delays", Drug GMP Report - Issue No. 210, January 20103From the FDA’s Warning Letter web page: “Inspections, Compliance, Enforcement, and Criminal Investigations”/scripts/warningletters/wlSe archResult.cfm?filter=temperature&sortColumn=&qryStr =21+CFR+Part+11) After the excerpts, we’ll outline some best practices of a 483 response, providing you with a 10-point checklist that should make that 15-day time limit more manageable, and some links for further research. Finally, we’ll look at ways to simplify and automate monitoring, alarming and reporting on FDA regulated environments. Options range from low-tech manual methods, to hybridized systems that combine written and electronic methods of documentation, to fully automated systems.Many opportunities are available to tighten up documentation of controlled environments with modern technology.Sample Deviation #1To a Contract Pharma manufacturer: “Requirements for stability testing of drug products are not being met. For example, you do not have, as part of the storage condition, any documentation that stability samples are maintained at the designated temperature [21 CFR 211.166(a)(2)]; and you do not have appropriate stability data to support the 4 year expiration date for the product. [21 CFR 211.166(b)]”Sample Deviation #2To a blood bank:“Failure to have quality control procedures and follow those procedures for periodic tests of containers to maintain proper temperature...as required by 21 CFR 606.160(b)(5)(iv)...”Guide for US FDA-Regulated Organizations “How to Respond to (and Avoid) FDA Form 483 for Temperature, Humidity & other Controlled Environments”There must be documented evidence at any point in time thatan environment was within its recommended specifications.Sample Deviation #3To a major manufacturer of OTC Pharmaceuticals: “Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70(c). Specifically, temperature conditions within the aseptic processing area are not being documented to ensure such conditions are consistently within established specifications...For example, during the inspection we observed that your firm was recording the relative humidity (RH) in the processing room, but not in the sterilization chamber. We also observed that your firm was not maintaining or reviewing the temperature recorder charts generated during your sterilization process of [product x]...”Controlling environmental conditions is more often about being notified of a problem than the actual failure itself.There is no regulatory requirement to respond to a 483. According to the agency, they are merely “…inspectional observations, and do not represent a final agency determination regarding your compliance.” Sort of like an offer to help you with your compliance concerns. However, not responding quickly and carefully will most likely result in further investigation. In addition, all Warning Letters are posted on the FDA’s site4 in html format and are indexed by search engines. Once you receivea 483, all anyone needs to do is type [Your Company/Lab’s Name] + FDA (or +483) into the search box, and there you are.10 ½ Tips for the Right ResponseYour initial response must do three things: itmust establish credibility, it must demonstrate acknowledgement of the observations and an understanding of the specific requirements referenced, and it must show that your facility is committed to corrective actions, any and all.You can show commitment by working cross-departmentally; include a statement from all relevant department heads that briefly but specifically addresses each observation. Each observation needs to have a corrective action—either planned or accomplished—and it must be feasible and deliverable within a predetermined time-frame. Here are some tips—some simple, some in depth—for responding appropriately to 483 letters:1.Get your response in on time and in writing. Youhave 15 days, so ensure that final proofing andsubstantive editing is done at least by day 10.2.In the first paragraph of the response letter, beexplicit in your understanding of and desire tocomply with FDA regulations.3.Respond individually to each item that wasaddressed in the Warning letter. Be specific.Do not try to solve all issues in one paragraphor your response may be rejected, promptingfurther action from the FDA.4.Respond by importance – that is, respondindividually to items most likely to impactproduct quality.4 See the ORA FOIA Electronic Reading Room at:/ICECI/EnforcementActions/Warning Letters/default.htm5.Be detailed yet concise in each response.Outline how each deficiency will be corrected,and when, rather than how the deficiency cameto be. Provide documentation of a correctiveaction commitment from the person responsiblefor it.e positive statements; avoid language thatimplies fault. Address each item in the form483 as an opportunity to fine-tune the qualityand compliance systems and personnel.7.Include reference to how you will beforwarding evidence to support the correction.For example, <Company X>will use Veriteq'svalidated monitoring and alarming system toprovide reports on temperature recordingstaken at 10 minute intervals month-by-mont h.‖Product specifications and protocols of anynew systems can be provided or offered insupport of the corrective action plan.8.If the inspector noted something that you feelwas an isolated incident, document this factand note it in your response. Be sure your datais complete and accurate. If you find some ofthe observations were in error after receivingthe 483, there is a formal dispute resolutionprocess outlined in the agency's "Guidance forIndustry - Formal Dispute Resolution:Scientific and Technical Issues Related toPharmaceutical CGMP.5"9.Be proactive. Reassess your internalcompliance programs — Why were 483deficiencies not detected internally? Mentionthis in your response letter, noting yourcommitment to QC/QA audit management.The definitive guide to what FDA inspectorsare looking for (at least in theory) is theagency’s “Investigations Operations Manual‖accessible at:/ICECI/Inspections/IOM/default.htm10.If you need clarification, seek it—in writingand from the correct party. Ideally, when theinvestigator gave you the Form 483 after theinspection you asked a lot of questions toclarify each observation. Try to be sure you are5/downloads/Drugs/GuidanceComplian ceRegulatoryInformation/Guidances/UCM070279.pdfclear on each observation before the inspectorleaves your facility and make notes whilehe/she is explaining the observations. If yourquestions involve policy, contact the FDAheadquarters—don’t contact your local FDAbecause policy is set at HQ.10.5 You may need an industry expert. Thereare many companies who specialize in creatingand implementing regulatory strategy, whetherfrom the ground up or from your existingquality and regulatory systems. If it’s worthdoing, it may be worth hiring someone whoknows how to do it really well. As regulatorycompliance issues grow more complex, manycompanies have been created to providesolutions in common compliance areas like:response to agency queries and help withagency meetings, regulatory gap analysis &remediation, internal GLP/GMP auditing andpre-approval inspections.Ways to Avoid 483s with Audit-Ready Environmental MonitoringIdeally, your regulated environments and equipment are always in full compliance with FDA regulations. An automated monitoring and alarming system providing high accuracy data at the point of measurement with back-up recording — can make your QA/QC efficient, optimal and ready for any critical evaluation, internal or external. The continuous records that this type of system should provide could help be part of your detailed response to quality concerns outlined in a Form 483 letter.For example, in the 483 excerpt of the CMO, which noted that “do cumentation that stability samples are maintained at the designated temperature” A validated monitoring and alarming system would provide secure, gap-free temperature data recording. Data loggers with long-life batteries (up to 10 years) can continue to record temperature at the point of measurement, rendering environmental data immune to network or power failures.Monitoring, alarming and reporting are only as goodas the measured data—accurate and continuous.Regarding the blood bank 483 example, the storage units can be validated with the same equipment used to monitor. Self-contained data loggers with internal sensors, memory and battery can be equipped for―pe r iodic testing‖ o r mapping the temperature distribution of the containers.In regard to the observations on the OTC Pharmaceutical manufacturer, the challenge of not having adequately documented temperature conditions would be solved by following the detailed IQ/OQ and SOPs provided with the monitoring, alarming and reporting system.Every monitoring system should have a detailed IQ/OQ change control document make validation a straightforward process. Some organizations compliant with GMP still use chart recorders or manual methods to track temperature and humidity. The issues with these methods are beyond the scope of this article, but as more facilities automate processes within quality assurance and regulatory compliance, relying on older technologies is and will continue to be problematic. The FDA, with its "strong recommendatio ns", cannot insist that organizations upgrade to any given technology. But, a commitment to using industry-best instrumentation and systems in FDA-regulated research, storage and manufacturing processes can stave off misgivings about a facility’s commitment to quality. It will also lower your financial risk of damage to temperature and humidity-sensitive products.For more information on how to avoid Form 483’s, visit /avoid-fda-483s or call800-683-8374, or email***************************.By Ken Appel, VP Regulated MarketsVerite q, a Vaisala company。
FDA 发布药械组合产品检查合规手册
FDA 发布药械组合产品检查合规手册美国 FDA 于 6 月 4 日发布了新的合规项目指南手册（CPGM）7356.0000《检查 CDER 或 CDRH 主管的组合产品》，解释了其对由药品审评与研究中心（CDER）或器械与放射健康中心（CDRH）主管的组合产品制造商的检查方法。
FDA 于 2013 年 1 月颁布组合产品 CGMP 最终规定，2017 年 1 月发布组合产品 CGMP 要求定稿指南，除此之外没有更多有关组合产品 CGMP 的法规和指南澄清。
【FDA发布组合产品CGMP要求定稿指南2017/01/30】（法规和指南中英文内容可登录识林阅览。
）CPGM 是 FDA 指导检查员的工作手册，包含了对 FDA 检查员执行检查的细致考虑和要求，是企业学习的好资料。
这份长达 46 页的文件列出了 FDA 对组合产品合规计划的实施期望；检查执行和报告注意要点；采样和分析检测期望；监管和行政策略；以及对中心职责的解释。
该 CGPM 主要针对具有药物和器械或生物制品和器械组成部分的单体（各组成部分物理上或化学上组合在一起，例如预充针或药物洗脱支架）和组合包装组合产品（例如手术套装或急救箱），不涵盖由 CBER 作为主管中心的组合产品的检查，也不适用于仅生产一种类型的组成部分或产品组件（例如，器械组件或原料药）的设施的检查。
组合产品制造商可以通过以下两种方式证明 CGMP 合规：遵守所有适用的 CGMP 或遵守简化方法。
简化方法允许制造商证明符合药品CGMP 或器械质量体系规范之一，以及除此之外的一些具体 CGMP 规定。
手册在附录中详细给出了具体 CGMP 规定包括哪些条款。
FDA 指出，“由于大多数组合产品制造商使用简化方法，因此该手册侧重于对基本 CGMP 合规性以及 21 CFR Part 4 中规定的具体条款合规性的检查。
”FDA 还解释指出，除手册中提到的“具体产品”合规计划外，组合产品还应遵循主管中心和基本合规计划的要求。
FDA 检查指南说明书
FDA Inspections – Best and Worst Practices Bioresearch Monitoring InspectionsFDA Inspections •Intro•Before FDA arrives•While FDA is on-site•As the inspection closes•Common observations•Following the inspectionBefore FDA Arrives…•Be in compliance!–Have the appropriate staff–Provide training to staff on regulatory requirements, specific protocol requirements, any processes or procedures–Facilitate open communications–Not just the what, but the why compliance matters–Assume all studies conducted will be inspected•Be prepared for an inspection–Have procedures for how to handle an inspection–Mock inspection with staff; use sponsor audits as a toolWhile FDA is on-site•Opening meeting–Scope of inspection–Schedule–Explain roles and responsibilities, study conduct–Explain records, organization, access•Objective is to ensure investigator and site staff have clear communication and expectationsWhile FDA is on-site•During the inspection–Be accessible to answer questions, provide copies–Don’t delay unnecessarily, if time is needed to retrieve records/answer, explain why•Daily wrap up–Questions?–Concerns?–Progress?–Plan for following dayAs the inspection closes•Schedule close out meeting, ensure responsible/knowledgeable parties available•Is there an FDA 483?–Observations clear?–Do you have additional documentation not reviewed during inspection?–Verbal response? Will be included in Establishment Inspection Report –Plan to respond in writing?After the Inspection has Ended•If there was an FDA 483 – should respond in writing –Recap observation–Provide explanation if appropriate–Describe corrective actions considered and when they will beimplemented including any SOP revisions, staff training–Consider impact on any other on-going or future studies•No FDA 483, but discussion items?–Consider any impacts and corrective actions you may need to do –Consider a written response, the items will be reported in theEstablishment Inspection Report and reviewedWritten Responses•Will be reviewed by investigator and center•Will be considered if any regulatory/administrative action is contemplated•Thorough responses help!Common ObservationsWarning Letters and FDA 483s21 CFR 312.60 – General Responsibilities•Failure to Follow the Investigational Plan•Failure to Personally Conduct or Supervise •Failure to Protect Rights, Safety & Welfare of Human Subjects•Failure to Obtain ConsentCommon ObservationsWarning Letters and FDA 483s21 CFR 312.62 - RECORDKEEPINGAND RECORD RETENTION•Inadequate Case Histories•Record Retention•Drug DispositionHow do these Drug findings compare to MedicalDevice Research?•Failure to ensure that an investigation was conducted in accordance with the investigational plan [21 CFR 812.100 & 21 CFR 812.110(b)] was cited in 3 of 3 Warning Letters to Medical Device CIs.•Failure to maintain accurate, complete, and current records of each subject’s case history and exposure to the device [21 CFR 812.140(a)(3)] was included in 2 of 3 Warning Letters issued in 2014 & 2015.Failure to follow the Investigational Plan – WLsspecifically identified•Eligibility Violations - including unacceptable ECG results, a subject previously enrolled in a study and received a treatment that was disqualifying, out of range clinical labs (e.g., liver function, kidney function, hematology), disqualifying medical history, prohibited prior/ConMeds, (+) pregnancy test •Randomization prior to receipt/evaluation of Eligibility DataFailure to follow the Investigational Plan – WLsidentified•Dosing Errors – including overdosing, under-dosing, dispensing wrong drug, wrong sequence of dosing, & failing to follow titration or stopping rules•Missed Efficacy and/or Safety Assessments- blood, urine, and/or stool specimens, ECGs, scans•Out of Window Tests/AssessmentsViolations Can Be Avoided•As I mentioned previously, ensuring staff understand the protocol and regulatory requirements will aid in conducting research in compliance with the regulations•Training–make it effective for your staff–Most sites provide training and yet there are still violations–Not just standard GCP training, but training tailored to the studyrequirementsInvestigator Interaction•Most investigators are well trained professionals…•Each site and study are different, help the investigator understand how your site works and any specific study requirements that may be unique•What to do when there are disagreements between investigator and study staff•Should I fear retaliation?Contacts•FDA 482 will list the geographical district office and phone number•District/Program Division Director, HQ – Deputy Program Director, Program Director•OmbudsmanContacts•Program Director–Chrissy Cochran – Chrissy ***************.gov (301) 796-5663 •Deputy Program Director–David Glasgow –*********************.gov (301) 796-5403 •BIMO East Director–Anne Johnson –********************.gov (215) 717-3003 •BIMO West Director–Eric Pittman –********************.gov (312) 596-4259ORA Ombudsman•Jessica Zeller ********************.gov 240-535-6021•The ORA Ombudsman is dedicated to two primary objectives: –Informally address concerns, complaints, and other issues that arise between ORA and stakeholders outside of the Agency,including industry, governmental organizations (federal, state, territorial, and tribal), and other members of the public; and –Engage in outreach and education for these stakeholders and employees of ORA to enhance communication andtransparency with stakeholders.Questions? •Post Conference Follow-upDavid K. GlasgowDeputy Program Director*********************.gov301-796-5403FDA INSPECTIONSSPONSOR/MONITOR/CROPERSPECTIVE Cassandra KennedyGlobal Head, Regulatory Compliance & Quality AssuranceBest Approaches to InspectionsInspection Preparation begins at the time of study startPosted company policies on photography, internet, guestsCreation of Tried and True Inspection Management Procedures Official Management/Sponsor NotificationsClear Roles and Responsibilities•Inspection Lead•Dedicated Scribe•Document Assembly/Reviewers•Runner•Administrative AssistanceLog of all Document Requested and Provided – Reviewed at least daily Live display of scribe notes to the Prep RoomMaintenance of Duplicate Set of Documents TakenOfficial Daily UpdatesFinal ReportResponse Process including internal/external reviewersResolution and completion of findings (both written and verbal)ConfidentialInspection Lessons LearnedInspection Training – will need to be refreshed often!ReceptionistSecurity GuardsInspection RolesInspection ParticipationSenior Leaders – Not always a good ideaAffiliated representatives (sponsor, CRO, vendor, etc) – Good idea or more to manage??Training opportunity as an observerDon’t lose an inspector within your facility..“Typically”, “Usually”, “I think” – if this is the beginning of your inspection response –STOP The inspection isn’t over until the inspector is gone!ConfidentialFDA Inspections•Philip T. Leese MD•Board Certified in Internal Medicine (1980); I year ER Fellowship. •Investigator for Phase I/II Clinical Research studies (1979-2016) •VP Ph. I for Quintiles’ Phase I CRU in KC (1996-2013)•Retired from Quintiles in Spring of 2016•IRB Board Member for Midlands IRB (MLIRB)- 2016 to present •Consultant for Private Practice Research Initiatives 2016-2018 •Presently consulting with Dept. of Psychiatry Kansas University Medical Center•No Conflicts of Interest to disclose.1572 Investigator Commitments•I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.•I agree to personally conduct or supervise the described investigation(s).•I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.1572 Investigator Commitments•I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64.•I have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the drug.•I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.•I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68.1572Investigator Commitments•I will ensure that an IRB that complies with the requirements of 21 CFR Part 56will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.•I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312.The FDA Inspector wants to ascertain•who performed various aspects of the protocol for the study (e.g., who verified inclusion and exclusion criteria, who obtained informed consent, who collected adverse event data);•whether the IRB approved the protocol, informed consent form, and any amendments to the protocol prior to implementation;•whether the clinical investigator and study staff adhered to the sponsor’s protocol and investigational plan and whether protocol deviations were documented and reported appropriately;•whether informed consent documents were signed by the subject or the subjects’ legally authorized representative prior to entry in the study (i.e., performance of any study related procedures);•whether authority to conduct aspects of the study was delegated, and if so, how the conduct of the study was supervised by the clinical investigator2 ; •where specific aspects of the investigation were performed;The FDA Inspector wants to ascertain •how the study data were obtained and where the study data were recorded;•accountability for the investigational product, including shipping records and disposition of unused investigational product; •whether the clinical investigator disclosed information regarding his financial interests to the sponsor and/or interests of any sub-investigator(s), spouse(s) and dependent children3 ;•the monitor’s communications with the clinical investigator;•the monitor’s evaluations of the progress of the investigation; and •corrective actions in response to previous FDA inspections, if any, regulatory, sponsor and/or monitor correspondence.Common Clinical Investigator Deficiencies*•Failure to follow the investigational plan/agreement &/or regulations. •Protocol deviations.•Inadequate recordkeeping.•Inadequate subject protection – informed consent issues, failure to report Aes.•Inadequate accountability for the investigational product. •Inadequate communication with the IRB.•Investigational product represented as safe/effective.* Clinical Investigator (CP 7348.811) deficiencies identified in FDA Form 483 issued at close of inspections. 2017 BIMO DataPre-study Preparation•Review past Audits/Inspections: Recommendations and lessons learned?•Identify Study Specific tasks which are potential problem areas. •Are there nuances to the I/E criteria, screening, admission, dosing, safety monitoring procedures which could deep six your study? •Review Training files and update for study specific purposes. •Apply Failure Mode Effect Analysis (FMEA) tool to your study. •Use the SIV to clarify questions/issues which surfaced during the above steps.•Implement Checkoff sheets. Have verifiers for critical steps. •Communicate “knowledge” to your study team- not just by e-mail.During Study preparation •Evaluate FMEA risk mitigation action steps.•Document what is working, what is not working.•Make certain your CAPAs are clearly written.•Make certain you document follow-up on your CAPA action steps. •Document if your action steps worked, needed modifications. •Scrutinize amendments for important changes to I/E criteria, dose instructions or procedures, safety monitoring, stopping thresholds. •Communicate, Communicate, Communicate. (esp. Staff turnover). •Study specific sign off sheets for important delegation: PI and partner/s each sign off on a study specific delegation form.Post study Preparation•Have an internal post study “lessons learned session” and do the same with the CRO/Sponsor.•Use a checklist (e.g. UT Southwestern IRB FDA Inspection Preparation Guide) to scrutinize your study TMF and documents for FDA Inspection preparedness.•Go back to your study specific worksheets, your CAPA documents, your CRA memos, etc. to make certain you have documented follow-up on your action items.•Make your corrections and notes to file now, not months or years later when your are preparing for an audit.•Review page 4 of Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors FDA Inspections of Clinical InvestigatorsFDA Inspections•If you have SOPs- periodically review, revise, and update them and then read them and sign off that you have read them.•Have a “sign off” sheet for critical research documents: IB, Protocol, ICF, amendments, revised consents. Use a master checklist to track that Sub Investigators and other team members are updating their knowledge of the investigation. (Keep good team meeting minutes).•Use I/E exclusion checklists.•Dose escalation, Dose titration checklists- use them.•Subject is lost to follow-up- go the extra mile and find out why? •Train, Train, Train.•Communicate, Communicate, Communicate•Problem anticipate and expect errors. Promptly implement plan to address errors or omissions.•Document, Document, Document.FDA Inspection: “Do”•Have a Procedure for handling Audits/Inspections.a. Audit room, War room, scribes, document request process, etc. •Follow that procedure with the help of your team.•Concisely answer only the question asked.•It’s OK to say- I will get back to you.•Be prompt, accurate, honest, and courteous with your responses. •Ask questions to seek clarity around the Inspector’s observations orconcerns.•Update your team daily as to the flow of the “Inspection”.•Ask for recommendations on how to improve: “What have you seen at other sites that you would recommend for us”.FDA Inspection: “Do Not”•Don’t state you will do something and then fail to follow through.•Don’t try to recreate source documents.•Don’t Back date. Use Note to File.•Avoid saying “We usually do this procedure this way or most of the time”.•Don’t blame others for errors, omissions, protocol deviations.•Don’t fail to implement recommendations from an earlier inspection-esp. from the same inspector•Don’t treat the Inspector as an AdversarySome Relevant References•Howard Lee, Heechan Lee. Failure mode and effects analysis drastically reduced potential risks in clinical trial conduct. Drug Design, Development and Therapy 2017:11 3035-3043.•Robert J. Cody, M.D., M.B.A. Anticipating Risk for Human Subjects Participating in Clinical Research: Application of Failure Mode and Effects Analysis. Cancer Investigation, 24:209–214, 2006•/research/research-administration/irb/•1 U.S. FDA, Inspections, Compliance, Enforcement, and Criminal Investigations,/ICECI/EnforcementActions/Warninglett ers/defauIt.htm•Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors FDA Inspections of Clinical Investigators•/downloads/RegulatoryInformation/Guidances/UCM12 6553.pdfFDA Inspections •Questions?Reasons for Routine PI Federal Inspections•Top Recruiter•PI Reputation (Good or Bad)•Data are inconsistent with data from other sites•Importance of a particular study•Impact of site’s data•Just a chance occurrence•Scheduled pre-planned inspectionReasons for Directed (for cause) Inspection•Suspect false or fraudulent data; outlier data•PI appears to be “outside” his/her specialty•Sponsor appears to have rejected data from the site•Appearance of delay in reporting/submitting safety data (SAE and SUSAR reports are delayed)•Questionable sponsor or PI-sponsor monitoring•Questionable informed consent procedures•Questionable IRB approvals•Study carries significant influence on IP approval•Questionable compliance from the site’s IRBReasons for Direct (for cause) Inspection •Complaint filed by• a subject/patient/family member,• Research team staff, Institution, or• Sponsor•IRB•Concern for conflict of interest (COI) among the research team at the siteFDA Inspections from the IRB PerspectiveDavid BoraskyVice President, IRB ComplianceScope of IRB InspectionsFDA Regs21 CFR 11, 50, and 56Published guidance (not typically held to it)DocumentationIRB recordsRoster and related membership informationWritten procedures i.e., SOPs and controlled documentsProtocol-level documents, correspondence, etc.Inspection guided by BIMO manual Manual should guide the inspectionsCovers all areas of IRB work that fall under FDA regulationCan also be used to self-inspect an IRB or to audit vendorsTypical IRB Experience with BIMO InspectionAnnounced 1 to 3 business days in advance21 CFR 50 and 5621 CFR 11 has not been part of audits even when IRB is on Part 11 system Follow the manualRosters, SOPs, etc1 FDA person on site for2 –3 days2 –3 studies and a sample of approved sitesSite level records including ICFs, approval documentation, correspondenceQuestions for the Panel。
FDA药品质量控制实验室检查指南2008.11.21培训
5.不合格（OOS）结果
（4/4）
国外OOS调查程序范例：
OOS结果产生
YES
生产
B
调查
A
实验室
OOS结果 NO
再测验
NO
清拒收）
不同的样品/不同的分析者
IF OOS结果
NO
无效的结果 （不保留结果）
保留/报告 结果
YES
不可信的结果 THEN
产品处理
➢ 是否有实验室不合格（OOS）检验结果调查的体系，查看几批不符合标准 的测试结果。审查几批被复检、报废或返工的产品的分析数据。对于某些批 次的产品，当实验室结果表明该产品不能满足标准而被发放时，应当评价该 发放决定并查明该发放决定由谁决定发放了这些批次的产品。
6
4.检查方法
（2/2）
B.审批前检查
如果药厂的样品不是取自混合器，则应通过验证证明其取样技术能反 映混料各个部分和总体的特征。也就是说，这些样品必须能够代表生产 中可能发生问题的位点，如混料中的薄弱点或过热点。
16
11.微生物方面
应审查的数据包括防腐剂的有效性测试、生物负荷数据以及特定 产品的微生物检验及其方法。
从细菌内毒素与无菌性两方面审查过滤前和(或)灭菌前产品的生 物负荷状况。对于原料药检验实验室，要评价其方法验证以及无 菌性和细菌内毒素检验、环境监测、滤器及过滤方法验证的原始 数据。此外，还要评价实验室检验及确定生物负荷量所采用的方 法。
所致，或复检结果符合规定，并不表示产品合格。
OOS结果可分为三类：
➢ 实验室误差；
➢ 非生产工艺性误差或者成为操作者误差；
➢ 和生产工艺有关的误差或者称生产工艺误差。
A.实验室误差
实验室误差产生于下列情况：化验员未能正确地按分析方法操作；使用不正确的标 准和（或）简单地算错了数据。（检验设备、标准品、标准、取样等）
FDA检察员指导手册
FDA检查员指导手册CP 7356.002A：无菌药品工艺检查目录第一部分背景 (4)第二部分实施 (4)2.1 目的 (4)2.2 程序实施指南 (4)第三部分检查 (5)3.1. 审核和评估 (5)3.2. 简略性检查 (5)3.3. 全面性检查 (6)3.4. 附录A (7)3.5 样品采集 (7)3.6 样本大小 (8)3.7 报告 (8)第四部分分析 (8)4.1 分析内容 (8)4.2 分析 (8)第五部分法律/行政策略 (9)第六部分中心的职责 (10)无菌工艺检查的评估指南 (10)A. 组分的储存和准备 (10)B. 评估系统 (11)C. 主要系统和工艺 (12)a. 环境监测 (12)b. 设备清洁/消毒 (13)D. 生产设施 (13)a. 更衣 (13)b. 冻干 (13)c. 冻干验证 (14)E. 辅助系统 (15)F. 除热原 (15)G. 容器和封口材料的完整性 (16)H. 灭菌系统 (17)a. 总则 (17)b. 蒸气灭菌 (17)c. 蒸汽灭菌验证 (18)d. 干热灭菌（不包括除热原） (19)e. 化学灭菌/消毒/ (21)f. 化学灭菌验证 (21)g. 环氧乙烷气体灭菌 (21)h. 环氧乙烷验证 (23)i. 辐射灭菌 (24)j. 辐射灭菌验证 (25)k. 无菌除菌系统 (26)l. 无菌灌装验证 (28)I. 实验室 (29)a. 稳定性和有效期 (29)b. 无菌测试 (29)c. 热源检测 (30)d. 环境 (30)e. 校正 (30)I. 计算机 (30)J. 生物指示剂的用法 (30)该程序适用于所有无菌药品的生产，包括无菌原料药，眼科用药，小容量注射剂(SVP)，大容量注射剂（LVP）以及其它无菌制剂。
生物产品，兽药和生物分析药品不在本程序管辖范围内。
第二部分实施2.1目的为确定某无菌原料药，无菌制剂生产者符合食品、药品和化妆品法案和药品生产质量管理规范的规定(cGMPs)，提供进行检查的指南。
FDA检查员指导手册
FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求……………………………………………………3 5第一部分背景……………………………………………………………………36第二部分执行…………………………………………………………………362.1.目的……………………………………………………………………362.2.策略……………………………………………………………………362.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等）…362.2.2.系统性检查……………………………………………………………372.2.3.对原料药及制剂生产的系统性检查计划……………………………382.2.3.1.质量系统………………………………………………………………382.2.3.2.厂房设施与设备系统…………………………………………………382.2.3.3.物料系统………………………………………………………………382.2.3.4.生产系统………………………………………………………………382.2.3.5.包装和贴签系统………………………………………………………382.2.3.6.实验室控制系统……………………………………39…………………2.3.程序管理指导…………………………………………………………392.3.1.定义……………………………………………………………………392.3.1.1.监督性检查……………………………………………………………392.3.1.2.达标检查………………………………………………………………42.3.1.3.受控状态………………………………………………………………42.3.1.4.药品工艺………………………………………………………………42.3.1.5.药品生产检查…………………………………………………………41第三部分检查……………………………………………………………………413.1.检查活动………………………………………………………………413.1.1.总则……………………………………………………………………413.1.2.检查方法………………………………………………………………423.1.2.1.全面性检查的选择……………………………………………………433.1.2.2.简略性检查的选择……………………………………………………433.1.2.3.综合性检查范围………………………………………………………433.1.3.系统性检查范围………………………………………………………433.1.3.1.质量系统………………………………………………………………443.1.3.2. 厂房设施与设备系统…………………………………………………443.1.3.3.物料系统………………………………………………………………453.1.3.4.生产系统………………………………………………………………463.1.3.5.包装和贴签系统………………………………………………………473.1.3.6.实验室控制系统………………………………………………………483.1.4.取样……………………………………………………………………493.1.5.检查组组成……………………………………………………………493.1.6.报告……………………………………………………………………49第四部分分析……………………………………………………………………5第五部分法律性/行政性策略…………………………………………………55.1.质量系统………………………………………………………………515.2.厂房设施和设备………………………………………………………515.3.物料系统……………………………………51…………………………5.4.生产系统………………………………………………………………525.5.包装和贴签系统………………………………………………………525.6.实验室控制系统………………………………………………………52对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。
FDA检查员指导手册 中文译
FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求 (35)第一部分背景 (36)第二部分执行 (36)2.1.目的 (36)2.2.策略 (36)2.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等） (36)2.2.2.系统性检查 (37)2.2.3.对原料药及制剂生产的系统性检查计划 (38)2.2.3.1.质量系统 (38)2.2.3.2.厂房设施与设备系统 (38)2.2.3.3.物料系统 (38)2.2.3.4.生产系统 (38)2.2.3.5.包装和贴签系统 (38)2.2.3.6.实验室控制系统 (39)2.3.程序管理指导 (39)2.3.1.定义 (39)2.3.1.1.监督性检查 (39)2.3.1.2.达标检查 (40)2.3.1.3.受控状态 (40)2.3.1.4.药品工艺 (40)2.3.1.5.药品生产检查 (41)第三部分检查 (41)3.1.检查活动 (41)3.1.1.总则 (41)3.1.2.检查方法 (42)3.1.2.1.全面性检查的选择 (43)3.1.2.2.简略性检查的选择 (43)3.1.2.3.综合性检查范围 (43)3.1.3.系统性检查范围 (43)3.1.3.1.质量系统 (44)3.1.3.2. 厂房设施与设备系统 (44)3.1.3.3.物料系统 (45)3.1.3.4.生产系统 (46)3.1.3.5.包装和贴签系统 (47)3.1.3.6.实验室控制系统 (48)3.1.4.取样 (49)3.1.5.检查组组成 (49)3.1.6.报告 (49)第四部分分析 (50)第五部分法律性/行政性策略 (50)5.1.质量系统 (51)5.2.厂房设施和设备 (51)5.3.物料系统 (51)5.4.生产系统 (52)5.5.包装和贴签系统 (52)5.6.实验室控制系统 (52)对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。
无菌药品FDA检查员指导手册
无菌药品FDA检查员指导手册FDA检查员指导手册无菌药品工艺检查目录第一部分背景 (4)第二部分实施 (4)2.1 目的 (4)2.2 程序实施指南 (4)第三部分检查 (5)3.1. 审核和评估 (5)3.2. 简略性检查 (5)3.3. 全面性检查 (6)3.4. 附录A (7)3.5 样品采集 (7)3.6 样本大小 (8)3.7 报告 (8)第四部分分析 (8)4.1 分析内容 (8)4.2 分析 (8)第五部分法律/行政策略 (9)第六部分中心的职责 (10)无菌工艺检查的评估指南 (10)A. 组分的储存和准备 (10)B. 评估系统 (11)C. 主要系统和工艺 (12)a. 环境监测 (12)b. 设备清洁/消毒 (13)D. 生产设施 (13)a. 更衣 (13)b. 冻干 (13)c. 冻干验证 (14)E. 辅助系统 (15)F. 除热原 (15)G. 容器和封口材料的完整性 (16)H. 灭菌系统 (17)a. 总则 (17)b. 蒸气灭菌 (17)c. 蒸汽灭菌验证 (18)d. 干热灭菌（不包括除热原） (19)e. 化学灭菌/消毒/ (21)f. 化学灭菌验证 (21)g. 环氧乙烷气体灭菌 (21)h. 环氧乙烷验证 (23)i. 辐射灭菌 (24)j. 辐射灭菌验证 (25)k. 无菌除菌系统 (26)l. 无菌灌装验证 (28)I. 实验室 (29)a. 稳定性和有效期 (29)b. 无菌测试 (29)c. 热源检测 (30)d. 环境 (30)e. 校正 (30)I. 计算机 (30)J. 生物指示剂的用法 (30)。
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求 (35)第一部分背景 (36)第二部分执行 (36)2.1.目的 (36)2.2.策略 (36)2.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等） (36)2.2.2.系统性检查 (37)2.2.3.对原料药及制剂生产的系统性检查计划 (38)2.2.3.1.质量系统 (38)2.2.3.2.厂房设施与设备系统 (38)2.2.3.3.物料系统 (38)2.2.3.4.生产系统 (38)2.2.3.5.包装和贴签系统 (38)2.2.3.6.实验室控制系统 (39)2.3.程序管理指导 (39)2.3.1.定义 (39)2.3.1.1.监督性检查 (39)2.3.1.2.达标检查 (40)2.3.1.3.受控状态 (40)2.3.1.4.药品工艺 (40)2.3.1.5.药品生产检查 (41)第三部分检查 (41)3.1.检查活动 (41)3.1.1.总则 (41)3.1.2.检查方法 (42)3.1.2.1.全面性检查的选择 (43)3.1.2.2.简略性检查的选择 (43)3.1.2.3.综合性检查范围 (43)3.1.3.系统性检查范围 (43)3.1.3.1.质量系统 (44)3.1.3.2. 厂房设施与设备系统 (44)3.1.3.3.物料系统 (45)3.1.3.4.生产系统 (46)3.1.3.5.包装和贴签系统 (47)3.1.3.6.实验室控制系统 (48)3.1.4.取样 (49)3.1.5.检查组组成 (49)3.1.6.报告 (49)第四部分分析 (50)第五部分法律性/行政性策略 (50)5.1.质量系统 (51)5.2.厂房设施和设备 (51)5.3.物料系统 (51)5.4.生产系统 (52)5.5.包装和贴签系统 (52)5.6.实验室控制系统 (52)对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。
对所有已签发了警告信的检查，要向生产和产品质量处，案件管理和指导组(HFD-325)交一份该信的电子版。
本程序提供了评估符合CGMP要求程度的指南。
一旦地区分局意识到该程序所产生的检查、分析或其它信息会影响到FDA对相关企业新药的批准，地区分局应立即参照现行的FACTS程序报告这些信息。
包括编写OAI通告和撤销该通告。
要求各地区分局按照这份修订后的检查程序进行所有的GMP检查。
第一部分背景FDA的主要任务就是对原料药及制剂生产、销售的所有方面进行相应的法律监管以确保这些产品符合联邦食品药品化妆品法案501(a)(2)(B)的要求。
FDA已开发出了两项基本策略：1）通过对企业的检查，包括采集和分析相关样品，来进行评估原料药和制剂生产、包装、检测和储存的条件和方法，2) 通过一系列监督活动如从销售渠道抽取和分析样品来监督原料和制剂的质量。
制定本监督程序是为了给实施第一项策略提供指导。
如果企业的操作一直处于受控状态的话本程序所覆盖的从生产到销售企业的所有产品的质量就会持续稳定。
制剂监督程序(CP 7356.008)为后一个策略提供指导。
因为认识到两年一度的检查中不能对所有企业的所有系统和所有过程进行全面检查，制定本程序中的检查指南是为了使常规监督能充分利用现有的资源。
它也为随后监督提供所需的指导。
第二部分执行2.1目的本程序所涉及的活动的目的是为了将消费者接触劣药的机会降至最低。
在本程序下，所进行的检查、样品抽取与分析，和随后采取的法律或行政措施都是为了：1）判定被检查的企业是否按照相应的cGMP要求运行；为采取行动防止劣药进入市场以及将劣药从市场中去除，并对责任人采取相应的措施提供证据。
2) 为决定是否批准某企业的新药申请提供cGMP评估意见。
3) 为接受检查中的企业提供法规达标水平的信息输入。
4) 延伸FDA在判定药品生产符合cGMP方面的专业化水平，也是FDA cGMP政策和指导性文件的继续。
2.2策略2.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等）药品是通过许多种物理性的操作将各成分和容器，封口材料等组成的一种可以销售的产品。
药品生产企业内的各种活动可以组成一系列相互关联的系统化的操作和活动。
控制所有这些系统就能有助于确保企业生产出安全、有效，符合应有的质量和纯度特征的药品。
每两年一度的检查要按照下列程序来进行：1）减少劣药进入市场的危险；2）增强企业与FDA之间的沟通；3) 对企业内部的生产操作提供及时的评估；4)为FDA与企业之间就企业符合GMP要求的持续情况提供有序的反馈渠道。
该程序适用于所有的药品生产运作。
目前，FDA没有足够的资源在每一次对每个生产企业的检查中，对cGMP的各个方面进行审核。
产品分类检查法覆盖范围可以从对数量少的特殊产品检查到对那一类中所有产品的检查。
本程序建立了一套系统性的方法来进一步将对产品的检查延伸到对该企业的全面评估。
在两年一度的检查中，按照FACTS中所规定的对每一类产品检查所作的报告提供了最广泛的资源利用方法。
两年一度的产品档案的更新是不能说明企业符合cGMP的。
这样做可加快评估的进程，缩短申批时间，并响应了1997年颁布的FDA现代化法案(FDAMA)。
这将使得批准前检查/检查性检查和批准后的审计性检查能专注处理相关事宜。
该检查是一种对2个或多个系统进行的审计性检查，质量系统是强制性的检查内容。
检查中对要检查系统数量的选择取决于检查的目的。
由各地区分局决定的是检查最少量的系统还是数量更多的系统，而这应能为全面判定是否符合CGMP要求提供相应依据。
2.2.2. 系统性检查对药品生产企业的检查及对结果的报告应按照本监督程序中的系统性方法来进行。
按系统进行检查，而不是按产品检查，能够提高检查的效率，因为系统通常包含多种产品。
每两年一度的检查都将能判定所有的产品是否符合/不符合要求。
检查范围应能代表该企业所生产的所有的产品。
因为对企业所进行的多次检查不必覆盖所有的产品，这样就能实现高效率。
由于能随时得到更新了的所有产品的信息就能避免对申请批准的拖延。
通过选择特定的范例，每个系统所包含的范围会非常详细，这样系统性检查的结果就能够反映出系统内每种产品的受控状态。
如果系统是适当的，则该企业内所有产品也就是合格的。
例如，一个企业处理物料的方式（即，接收、取样、测试、接受，等）对所有产品的都是一样的。
检查员没有必要去检查所有产品的物料系统。
对生产系统也一样，对诸如SOP的使用，组分的管理，设备的标识，过程取样和测试有一个通用的要求，这些可以通过从不同产品中抽取产品样本来进行评估。
在每个系统下，每一种产品可能会有特殊的地方，如：在物料系统中，生产中用到的符合USP要求的注射用水的生产。
选择某一系统中具体的方面由带队检查员决定。
任何检查都没有必要覆盖所有的系统。
见第三部分。
完成对一个系统的所有检查可能需要进一步探究另一个/其它系统内活动的内容以充分证明所得出的发现。
然而，这并不是说要对其它所有的系统进行全面检查。
2.2.3. 对原料药及制剂生产的系统性检查计划对原料药及制剂生产审计的系统性计划由以下方面构成：2.2.3.1.质量系统该系统是为了保证全面符合cGMP和内部程序及规格标准的要求。
该系统包括质量控制和其所有的评审和批准职责（如，变更控制，返工，批放行，年度评审报告，验证方案和报告等）。
它包括对所有产品失败的评估和对退回和回收制剂的评估。
见CGMP规定，21 CFR 211分录B, E, F, G, I, J, 和 K。
2.2.3.2.厂房设施与设备系统该系统包括为药品生产提供适宜的环境和资源。
它包括：a)厂房设施及其维护b)设备确认（安装和运行）；设备校正和预防性维护；清洁和清洁方法的验证。
性能确认是工艺验证检查的一部分，它评估工艺是在该系统范围内进行；c)空调系统，压缩空气，蒸气和水系统等公用设施。
见CGMP规定，21 CFR 211分录B, C,D和J。
2.2.3.3.物料系统该系统包括对产品，组分(包括水和气体)、容器和封口材料进行控制的措施和活动。
它包括对计算机化的存货清单控制程序的验证，药品储存，销售管理和记录。
见CGMP 规定，21 CFR 211分录B, E,H和J。
2.2.3.4.生产系统该系统包括对药品的生产、加工、配制、过程取样和测试、工艺验证等进行控制的措施和活动。
它还包括建立所批准的生产程序，和记录生产程序的执行过程。
见CGMP 规定，21 CFR 211分录B,F和J。
2.2.3.5.包装和贴签系统该系统包括对药品包装和贴签进行控制的措施和活动。
它包括书面程序，标签的检测和使用，标签的储存和发放，对包装和贴签操作的控制，对这些操作的验证。
见CGMP 规定，21 CFR 211分录B,G和J。
2.2.3.6.实验室控制系统该系统包括对实验室操作、检测、分析方法的研发和验证或确认、稳定性计划等相关的措施和活动。
见CGMP规定，21 CFR 211分录B,I,J和K。
这些系统都属于CGMP法规的各章节的范围。
这样做是为了按照药品生产六大系统的原理将CGMP各章节组合起来。
在上述某个系统中涉及到的组织和人员，包括适当的确认和培训，都将作为该系统运作的一部分进行评估。
在对上面各系统的审计中应包括对按照CGMP要求保持的生产，控制和销售记录的检查。
对合同厂商的检查也应纳入其产品或服务所涉及的系统内一并审核，包括对其质量系统的审核。
在本程序得到执行之后，应对所获得的经验进行评审以根据需要对系统的定义或组织结构进行调整。
2.3程序管理指导2.3.1. 定义2.3.1.1监督性检查2.3.1.1.1全面检查全面检查是一种监督性检查或达标检查，其目的是对该企业执行CGMP的情况提供一次广泛而深层次的评估。
在没有某企业执行CGMP的情况资料或资料很少的情况下采取这种方法（如，对新企业）；或在对某一企业执行CGMP的情况有怀疑时（如，某个企业历史记录显示其只在短时间内执行CGMP和有反复）。
根据在一个或多个系统中存在下述第五部分所列的情况（至少必须检查了两个系统）时，可根据地区分局的意见，可将全面检查转为简略检查。
见第三部分，B.1小节。
在全面检查的过程中，质量系统的检查确认可以适当地覆盖其他系统。
全面检查通常包括至少四个系统的检查，其中一个必须是质量系统（该系统包括年度产品评审的职责）。
2.3.1.1.2简略性检查简略性检查是一种监督性或达标检查，其目的是对某企业执行CGMP情况的高效评估。
简略性检查会提供一个企业持续执行CGMP情况的相关记录。
简略性检查通常用于某企业有执行CGMP的良好记录，没有重大的产品召回，或产品失败或警告事件，或在最近两年内该企业药品生产方面仅有很少的变动情况。