P1.综合研究情况与法规要求 Study summary and certificate requirement |
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P1.1 基本情况 General information |
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P1.1.1产品名称 Product Name |
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P1.1.2 规格 Dosage form |
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P1.2 证明性文件Government Certificate |
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以下三种证明文件的任何一种均可接受:Any set of certificates are accepted: 文件一 Certificates set 1 □GMP □提供 Provided □未提供 Not provided★ □生产许可证Production License □提供 Provided □未提供 Not provided△ □授权书Letter of Authorization □提供 Provided □未提供 Not provided★ □专利无侵权证明 Patent non-infringement □提供 Provided □未提供 Not provided★ □自由销售证明Free Sale Certificate □提供 Provided □未提供 Not provided★
文件二 Certificates set 2 □COPP □提供 Provided □未提供 Not provided★ □授权书Letter of Authorization □提供 Provided □未提供 Not provided★ □专利无侵权证明 Patent non-infringement □提供 Provided □未提供 Not provided★
Certificates set 3 □欧洲药典适用性证书CEP □提供 Provided □未提供 Not provided★ □授权书Letter of Authorization □提供 Provided □未提供 Not provided★ □专利无侵权证明 Patent non-infringement □提供 Provided □未提供 Not provided★ |
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P1.3 原研药物基本情况Originator Information |
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□提供Provide 上市国家Launch countries □上市Launch/□国内首次进口时间First import date to China 生产企业名称Manufacturer □未提供Not provided△ |
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P1.4参比品Reference standards |
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P1.4.1是否与参比品进行对比研究 P1.4.1 Comparison with references standards |
□是Yes □否No★ |
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P1.4.2是否与已进口的原研/原研本地化产品进行了比较 P1.4.2Comparison with imported originator product or localized manufactured originator product
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□是Yes □否(如有)No (If this product available)★ □不适用(如无) N/A (If this product not available) |
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P1.4.3参比品为 □原研产品 /原研本地化生产产品 □ ICH成员国仿制产品 □其他企业产品 P1.4.3Reference standards are □Originator product / localized originator product □ Generic products from ICH members □Products from other company |
标签/样品照片/说明书 Label/Images/Insert □提供 provided □未提供Not provided△ |
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P2.工艺研究 Manufacturing |
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P2.1是否提供了所有辅料的: Provide below excipients information: ① 来源Supplier ② 质量报告COA ③ 质量标准Specification |
□全部提供All provided □部分提供/未提供Partially/Not provided△ □全部提供All provided □部分提供/未提供Partially/Not provided△ □全部提供All provided □部分提供/未提供Partially/Not provided△ |
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P2.2是否结合制剂特点制订了辅料的内控标准 P2.2 Establish the specification for all excipients based on the feature of the finished dosage |
□是Yes □否No△ □ 不适用N/A |
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P2.3是否结合制剂特点制订了原料药内控标准 P2.3 Establish in-house specification for API based on the feature of the finished dosage |
□是Yes □否No△ □ 不适用N/A |
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P2.4是否进行了与制剂性能相关的原料药关键理化性质的研究 P2.4 Studies on API physical-chemical attributes affecting the dosage features |
P2.4.1溶解度与pKa Solubiilty & pKa P2.4.2晶型Crytal Form P2.4.3粒度Particle size P2.4.4 溶解度Stability P2.4.5其他Others |
□是Yes □否No△
□是Yes □否No△ □不适用N/A □是Yes □否No△ □不适用N/A □是Yes □否No△ □是Yes □否No△ |
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P2.5 是否进行了处方筛选研究 Formulation selection and development |
□是Yes □否No★ |
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P2.6是否进行了原辅料相容性研究 Excipient compatibility study |
□是Yes □否No☆ |
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P2.7是否进行了工艺研究 Manufacturing process development |
□是Yes □否No★ |
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P2.8是否有过量投料Overage |
□是Yes □提供说明Supportive research □未提供说明No supportive research△ □否No |
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P2.9是否提供了中试以上规模的生产工艺,包括操作流程、工艺参数和范围 P2.9 Provide scale-up manufacturing process, including flow chart, description, process parameters and range P2.10是否提供了主要的生产设备型号、技术参数等 P2.10 Provide manufacturing equipment Mould NO. and technique parameters |
□是Yes □否No☆
□是Yes □否No△ |
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P2.11是否明确了关键工艺步骤和关键工艺参数 P.2.11 Establishment of critical process steps and critical process parameters |
□是Yes □否No☆ |
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P2.12关键工艺步骤和关键工艺参数是否有依据 P.2.12 Justification of critical process steps and critical process parameters |
□是Yes □否No☆ |
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P2.13是否制定了所有中间体/半成品的控制标准 P.2.13 Define specification for all intermediates/crudes |
□全部All done □Partially done☆ |
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P2.14试制规模 □未提供△ Pilot batch size □Not provided△ |
P2.15商业批量 □未提供△ Commercial batch size □Not provided△ |
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P2.16工艺验证方案 Process validation protocol |
□提供Provided 批量Batch size △ □未提供Not provided△ |
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P2.17□无菌制剂 Sterile formulation |
灭菌/无菌工艺验证报告 Sterilized/ aseptic validation report |
□提供Provided 批量Batch size △ □未提供Not provided★ |
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P2.18□特殊工艺的制剂 Formulation by special process |
工艺验证报告 Process validation report |
□提供Provided 批量Batch size △ □未提供Not provided☆ |
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P2.19□其他制剂 Other formulations |
工艺验证报告/空白的批记录 Process validation report & blank BMR |
□提供Provided 批量Batch size △ □未提供Not provided☆ |
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P2.20□注射剂 P2.20 □Injection |
P2.20.1无菌保证条件 Sterility Assurance level |
P2.20.1.1□湿热灭菌 Moist heat sterilization |
□F0<8★ □8<F0<12 □F0>12 |
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P2.20.1.2 □无菌生产工艺Aseptic process |
微孔滤膜孔径Pore size of Millipore filter □ ≤ 0.22μm □ > 0.22μm★ |
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P2.20.1.3□其他Others |
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P2.20.2灭菌工艺验证资料 P2.20.2Sterilization process validation |
P2.20.2.1灭菌前微生物控制(残存概率法) □是Yes □否No△ Bio-burden test process P2.20.2.2装载热分布 Heat Load distribution □是Yes □否No△ P2.20.2.3热穿透 Heat penetration test □是Yes □否No△ P2.20.2.4生物指示剂挑战Biological indicator challenge □是Yes □否No△ |
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P2.20.3无菌生产工艺验证资料 P2.20.3Aseptic process validation |
P2.20.3.1除菌过滤系统验证 □是YES □否No△ □不适用N/A P2.20.3.1 Aseptic filtration system validation P2.20.3.2培养基模拟灌装试验 □是YES □否NO△ P2.20.3.2 Medium filling test |
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P2.20.4包材相容性研究资料 P.2.20.4 Compatibility study of container closure system |
□提供Provided □未提供Not provided△ Plastic materials□未提供 Not provided★ □不适用N/A |
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P2.20.5是否提供了容器密封性研究资料 Leakage study on container closure system |
□是Yes □否No☆ □不适用 N/A |
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P3.质量研究与质量标准 Quality study and specification |
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P3.1已收载标准情况 P3.1 Specifications adoption |
□中国药典 ChP □国家药品标准 State-specification □进口药品注册标准 IDL specification □USP □BP □EP □JP □其他Others |
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P3.2有关 物质与 杂质谱分析
P3.2 Related substance and impurity profile analysis
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P3.2.1活性成分来源杂质研究分析资料: P3.2.1 Study on impurities from active substance: □是YES □物料Starting materials □中间体Intermediates □副产物by-products 其它Others □否NO★ |
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P3.2.2辅料来源杂质研究分析资料: P3.2.2 Study on impurities from excipients: □是YES □辅料引入杂质 Impurities from excipients □辅料与API相容性杂质 Impurities from incompatibility of excipients with API □其它杂质 Others □否NO△ |
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P3.2.3降解杂质研究分析资料: P3.2.3 Study on degradation impurities □提供 Provided □正常贮藏条件降解 degradation under normal storage condition □工艺过程降解 degradation during process □强制降解 forced degradation □未提供★Not provided |
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P3.2.4与原研产品的杂质谱对比研究资料 P3.2.4 Comparison of impurity profile with that of originator products |
□提供Provided □未提供Not provided★ |
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P3.2.5超鉴定限杂质的定性研究及限度控制 P3.2.5 Characterization and limit control on impurities over identification threshold |
□提供 Provided □未提供Not provided★ □无超限杂质No impurities over identification threshold |
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P3.2.6分析方法研究与验证Method development and validaton |
P3.2.6.1标准中分析方法的来源与筛选优化过程Source selection and optimization of analytical procedure listed in specification |
□提供 Provided □未提供Not Provided☆ |
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P3.2.6.2与ICH成员国药典/中国药典标准方法对比 Method comparison with those adopted in ICH members monograph / ChP for the same product |
□提供Provided □未提供Not Provided☆ □未收载Not adopted yet |
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P3.2.6.3分析方法学验证资料 Method validation |
□提供 Provided □基本全面 all-rounded □缺项较多☆Lots of deficiencies □未提供★Not provided |
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P3.2.6.4杂质谱对比用分析方法的研究与验证资料 Method for impurity profile comparison and corresponding validation |
□提供 □Provided □未提供☆ □Not Provided☆ |
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P3.2.7基因毒性杂质研究控制 Study and control on gene toxic impurities |
□研究并列入Studied and adopted □研究未列入Studied but not adopted△ □未研究Not studied★ □不适用N/A |
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P3.2.8标准中杂质的控制 Control of impurities listed in specification |
□控制Controlled □已知杂质 Known impurity □特定未知杂质Specified unknown impurities □非特定杂质 Not specified impurities □总杂质Total impurities □未控制Not controlled □提供依据Justification □未提供依据No Justificaton★ |
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P3.2.9杂质限度与已有最严格标准的对比 Comparison of impurity limits with those strictest ones |
□相当或严格comparable or stricter □宽松less stricter □提供依据Supportive data □未提供依据No supportive data★ □未比较No comparison 已有最严格标准Strictest standard □可以获得Obtainable ☆ □不可获得Not Obtainable |
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P3.3□ 固体口服制剂溶出度 /释放度 Dissolution and release rate for oral solid dosage |
P3.3.1是否与原研产品进行了溶出曲线对比Comparison of dissolution curve with that of the originator products |
□是Yes □否No★ |
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P3.3.2溶出方法的来源与筛选过程 Selection, development and optimization of dissolution method P3.3.3溶出量测定方法的验证 Method validation for dissolution
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□提供 Provided □未提供Not provided△
□提供 Provided □基本全面 All rounded □缺项较多Lots of deficiencies△ □未提供 Not provided☆ |
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P3.4□ β-内酰胺类抗生素聚合物 |
P3.4.1是否进行了聚合物研究 Study on polymer |
□是Yes □否(注射剂和青霉素类制剂) ★ No(API for injection and penicillin group API) |
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P3.4.2方法学研究与验证资料 Method validation |
□提供 Provided □基本全面 all-rounded □缺项较多Lots of deficiencies☆ □未提供★Not provided |
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P3.4.3是否与原研产品进行了聚合物含量水平对比考察 Comparison of polymer assay level with that of originator product |
□是Yes 含量水平Content lever □不高于原研 not higher than that of originator product □高于原研highter than that of originator product△ □否No☆ |
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P3.5□ 残留 溶剂 |
P3.5.1制剂生产过程中使用的有机溶剂 Organic solvents used in the process of finished dosage |
□研究并列入□研究未列入□未研究☆ □Studied & controlled □studied but not controlled△ □Not studied☆ |
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P3.5.2分析方法学验证资料 Method validation |
□提供 Provided □基本全面 all-rounded □缺项较多Lots of deficiencies△ □未提供Not provided△ |
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P3.6含量 测定 |
P3.6.1标准中分析方法的来源与筛选优化 Source/seclection and optimization of analytical procedure |
□提供 □未提供△ □Provided □Not Provided△ |
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P3.6.2与ICH成员国药典/中国药典的对比 Comparison with specification adopted by ICH members monograph |
□提供 □未提供△ □未收载 □Provided □Not Provided△ □Not adopted yet |
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P3.6.3分析方法学验证资料 Method validation |
□提供 Provided □基本全面 all-rounded □缺项较多☆Lots deficiencies □未提供★Not provided |
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P3.6.4与已收载最严格标准的比较 □相当或严格 □宽松 □YES依据 □NO依据☆ □未比较 已收载最严格标准 □可以获得☆ □不可获得 P3.6.4 Comparison with the tightest specification ever adopted □Equivalent or tighter □Looser_________ □Reason provided □Reason not provided★ □No comparison The tightest specification □obtainable □not obtainable★ |
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P3.7 □无菌制剂中关键辅料控制 |
P3.7.1□抗氧剂 Antioxygen P3.7.2□抑菌剂 Bacteriostatic agent P3.7.3□稳定剂 Stabilizer P3.7.4□增溶剂 Solubilizer |
□研究并列入 □研究未列入△ □未研究☆ □Studied & controlled □studied but not controlled△ □Not studied☆ □研究并列入 □研究未列入△ □未研究☆ □Studied & controlled □studied but not controlled△ □Not studied☆ □研究并列入 □研究未列入△ □未研究☆ □Studied & controlled □studied but not controlled△ □Not studied☆ □研究并列入 □研究未列入△ □未研究☆ □Studied & controlled □studied but not controlled△ □Not studied☆ |
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P3.8其他控制项目 P3.8Other control parameters |
P3.8.1□无菌 Sterilization P3.8.2□细菌内毒素 Bacterial endotoxin P3.8.3□微生物限度 Microbial limit P3.8.4□其他 Others |
□研究并列入 □研究未列入△ □未研究☆ □Studied & controlled □studied but not controlled△ □Not studied☆ □研究并列入 □研究未列入△ □未研究☆ □Studied & controlled □studied but not controlled△ □Not studied☆ □研究并列入 □研究未列入△ □未研究☆ □Studied & controlled □studied but not controlled△ □Not studied☆ □研究并列入 □研究未列入△ □未研究☆ □Studied & controlled □studied but not controlled△ □Not studied☆ |
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P3.8.5方法学验证资料 Method validation |
□提供Provided □未提供Not provided☆(无菌、细菌内毒素sterilization and bacterial endotoxin) |
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P3.9质量 标准 |
是否与已收载最严格标准进行了对比 Comparison with tightest specification ever adopted |
□提供Provided □未提供Not provided△ |
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P3.10 标准物质 P3.10 Reference standards |
P3.10.1法定对照品 Monograph standards |
P3.10.1.1标签/样品照片/说明书 □提供 □未提供△ Label, picture, purchasing invoice, insert □provided □Not provided△ |
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P3.10.2□试剂公司商品 公司名称 □Purchased standard: Manufacturer |
P3.10.2.1 结构确证资料□提供 □未提供△ P3.10.2.1标定赋值资料□提供 □未提供△ □不适用 P3.10.2.1Structure characterization □Provided □Not provided△ P3.10.2.1 Calibration & standardization □Provided □Not provided△ □N.A. |
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P3.10.3□自行或委托制备 Self-developed or authorized-prepared reference standard |
P3.10.3.1制备工艺资料 □提供 □未提供△ P3.10.3.Manufacturing process □Provided □Not provided△
P3.10.3.2结构确证资料 □提供 □未提供△ P3.10.3.2 Structure characterization □Provided □Not provided△
P3.10.3.3标定赋值资料 □提供 □未提供△ □不适用 P3.10.3.3 Calibration & standardization □Provided □Not provided△ □N.A. |
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P4.稳定性研究 Stability |
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P4.1影响因素试验 Influencing-factor test: 批量Batch Size: □未提供Not provided△ |
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P4.2注射剂的配伍稳定性研究 Compatibility stability of injection |
□提供 Provided □Not provided☆ □不适用N/A |
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P4.3多剂量制剂使用中的稳定性研究 Stability during in use of multi-dose formulation |
□提供 Provided □Not provided☆ □不适用N/A |
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P4.4加速试验与长期试验 Accelerated and long-term stability test |
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P4.4.1是否市售包装Commercial package:□是Yes □否No★ □未提供Not provided☆ 批次: 批Batches 批量Batch Size:1. 2. 3. □未提供Not provided△ □批量过小 too small size★ |
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P4.4.2加速试验条件:Accelerated test conditions:□ 40℃±2℃/RH 75%±5% □其他 ℃/RH % 是否提供依据 □是 □否☆ □Other ℃/RH % Justification of the condition □Yes □No☆ 稳定性考察时间:□<6月★ □6月 □其他 Time interval: □<6M★ □6M □Others |
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P4.4.3中间试验Intermediate test (30℃±2℃/RH65%±5%) □提供Provided 稳定性考察时间:□<6月★ □6月 □12月 □其他 Duration:□<6M★ □12M □Others □不适用 N.A. |
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P4.4.4长期试验条件: □ 25℃±2℃/RH 60%±10% □其他 ℃/RH % 是否YES依据 □是 □否☆ 稳定性考察时间:□<6月★ □6月 □9月 □12月 □18月 □24月 □其他 P4.4.4 Long-term stability test:□25℃ ±2℃/RH 60 ±10% □Others ℃/RH % Justification □Yes □No☆ Duration: □<6M★ □6M □9M □12M □18M □24M □Others |
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P4.4.5是否缺乏重要质量考察指标 P4.4.5 Lack of key quality-indicating parameters |
□是Yes★ 未考察项目parameters not tested □否No |
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P4.4.6长期试验在拟定效期内考察指标是否出现显著变化 Significant change observed on stability parameters during long-term stability test |
□是Yes★ □否No |
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P4.4.7长期试验是否出现超鉴定限杂质Occurrence of over-identification limit among impurities during long-term stability |
□是Yes □进行定性研究 Qualitative research □未进行定性研究No qualitative research★ □否No |
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P4.5是否缺乏重要质量考察指标 Chromatograms for related substance |
□提供All provided □部分提供Partially provided△ □未提供Not provided★ |
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P4.6 含量测定相关图谱 Chromatograms for Assay |
□提供或部分提供All provided or partially provided □未提供Not provided △ □不适用N/A |
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P5.其他Others |
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P5.1研究数据及图谱真实性 □未发现问题 □有★发现的问题 : S5.1 Authenticity of Raw data and chromatograms □No problems □With problems★, namely |
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P5.2包材是否与原研品一致 P.5.2 Consistence of packing materials with those of originator products |
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□是Yes □否No □有数据支持 data-supporting □无数据支持且无分析论证No data-supporting and without explanation △ |
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P5.3储藏条件是否与原研品一致 P.5.3 Consistence of storage conditions with those of originator products |
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□是Yes □否No □比原研品(参比品)宽松且数据支持不足 Loose conditions but without enough supporting data □无数据支持且无分析论证No data-supporting and without explanation △ |
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审查结论 Overview conclusion |
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(标记★涂红色背景的项目为重大缺陷项,标记☆涂蓝色背景的项目为较大缺陷项, 标记△涂黄色背景的项目为一般缺陷项) Note: ★ significant deficiency, ☆:general deficiency△: minor deficiency) 存在的问题: Deficiencies detected: 重大缺陷项X项: Significant deficiency_____items 1、 2、 较大缺陷项(加权计算为2个一般缺陷项)和一般缺陷项共X项: general deficiency(calculated as two minor deficiencies) and mino deficiency _____items 一、综合研究情况与法规要求 Study summary and certificate requirement 1、 2、 二、处方工艺研究 Manufacturing 1、 2、 三、质量研究与质量标准Quality study and specification 1、 2、 四、稳定性研究 Stability 1、 2、 五、其他 Others 1、 2、 |
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评判标准 Acceptance criteria
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申报资料存在“重大缺陷项”,结论为“不通过”;无“重大缺陷项”的申报资料,但有10个及以上“折算一般缺陷项”,结果亦为“不通过”。 CTD with any significant deficiency, rejected. CTD without any significant deficiency but minor deficiencies>10, rejected. Accepted only when no significant deficiency and ≤10 monor deficiencies are detected. (Note: Calculate 1 general deficiency as 2 minor ones.) |
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审查结论Conclusion |
□通过 □Accepted □未通过 □Rejected |