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S1. 综合研究情况与法规要求 General information and Regulatory rules

S1.1 基本情况 General information

 

S1.1.1产品名称

Drug Name

 

S1.1.2 规格

Dosage form

 

 

S1.2 证明性文件Government Certificate

 

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                        

生产许可证Production License  

授权书Letter of Authorization   

专利无侵权证明 Patent non-infringement   

自由销售证明Free Sale Certificate       

 

文件二 Certificates set 2

□COPP or CEP                         

授权书Letter of Authorization           

专利无侵权证明 Patent non-infringement  

 

 

提供 Provided    未提供 Not provided

提供 Provided    未提供 Not provided

提供 Provided    未提供 Not provided

提供 Provided    未提供 Not provided

提供 Provided    未提供 Not provided

 

 

提供 Provided    未提供 Not provided

提供 Provided    未提供 Not provided

提供 Provided    未提供 Not provided

 

S1.3 原研药物基本情况Originator Information

 

提供Provide                                                 

      上市国家Marketing countries                                  

      □上市On market /□国内首次进口时间First time import to China                         

      生产企业名称Manufacturer                                       

未提供Not provided

 

S1.4参比品(原料药或制剂)RLD (API or dosage)

With reference to Appendix A.

S1.4.1是否与参比品进行对比研究

S1.4.1 Is comparative study with RLD conducted?

Yes   No

S1.4.2是否与已进口的原研/原研本地化产品进行了比较

S1.4.2 Ever compared with imported originator product or localized manufactured originator product ?

Yes

(如有)No (If this product available)

不适用(如无)  N/A (If this product not available)

S1.4.3参比品为 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                      

S1.4.3RLD is

 □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

S1.7.1 直接接触药品的包装材料和容器执行标准和检验报告

S.1.7.1 Specification and COAs for immediate packing materials

提供 provided    

未提供Not provided

 

S2.工艺研究 Manufacturing Process

 

S2.1是否为粗品精制制备原料药

S2.1 Is this API directly obtained from purifying the crude products?

 □Yes     

   □No

S2.2是否采用游离酸/碱经一步成盐精制制备原料药

S2.2 Is this API obtained from Free acid/base salification and purification

 □Yes     □  □No

不适用(原料药为无机化合物及起始原料为已批准上市原料药的情况)      

□N.A.(in case that API is inorganic product and the raw material is those API approved for marketing)

S2.3 = 1 \* ROMAN I类溶剂的使用是否是必须的

S2.3 Is it necessary to use class I solvents

 □Yes     □No 

不适用 □N.A.

 

S2.4起始原料

S2.4 Starting material    

2.4.1是否提供了重要起始物料的制备工艺

2.4.1 Is manufacturing process for starting materials been provided?

全部提供  □All provided

部分提供/未提供

□partially provided/ not provided

 

2.4.2是否制订了重要起始物料的内控标准

2.4.2 Are in-house specification & limit justificationCOAs for starting materials provided

全部提供  □All provided

部分提供/未提供

□partially provided/ not provided

 

S2.5    生产工艺和过程控制

S2.5 Control of manufacturing process

2.5.1是否提供了中试以上规模的生产工艺,包括反应物料的投料量、工艺参数和收率

2.5.1 Is scale-up manufacturing process been provided, including input of all materials, process parameters and yield rate

2.5.2是否提供工艺路线的选择依据(实验依据和/或文献依据)

2.5.2 Is the selection of process route been justified (by study results and/or references) 

2.5.3是否提供了主要生产设备信息(型号、生产厂、关键技术参数等)

2.5.3 Is information of manufacturing equipment provided, including Mold NO., manufacturer, critical technique parameter, etc.?

    □Provided     

  □Not provided

 

 

 

    □Yes        

  □No

 

 

   □Provided      

  □Not provided

 

S2.6关键步骤和中间体的控制

S2.6 Control of critical steps and intermediates

2.6.1是否明确了关键工艺步骤和关键工艺参数

2.6.1 Have critical steps and critical steps parameters been established?

2.6.2是否提供了关键工艺步骤和关键工艺参数确定依据

2.6.2 Is the establishment of critical steps and critical steps parameters been justified?

2.6.3是否制定了全部中间体的控制标准

2.6.3 Have specifications for all intermediates been established?

□Yes      □No

     

 

□Yes       □No

      

 

全部提供 □All provided

部分提供/未提供

□Partially provided/ not provided

 

S2.7试制规模                     未提供

S.2.7 Batch scale                     □Not provided

S2.8商业批量          未提供

S2.8Commercial scale    □Not provided

 

S2.9工艺验证方案

S2.9 Process validation protocol

提供 □Provided 批量     batch size     

未提供  □Not provided

S2.10□无菌原料药

S2.10□Sterile API

工艺验证报告

Process validation report

提供 批量        

□Provided batch size        

未提供□Not provided

S2.11□其他原料药

S2.11□Other API

工艺验证报告/空白的批生产记录

Process validation report/ Master Batch Production Record (BPR)

提供            □提供Provided

批量            Batch size       

未提供        □not provided

S3.特性鉴定 CHARACTERIZATION

 

S3.1是否与对照品进行了结构确证对比研究

S3.1 Comparative study of structure elucidation with the reference standards

□Yes      □No

 

S3.2是否对自制杂质对照品的结构进行了研究

S3.2 Structure elucidation on self-developed impurity standards 

           □不适用

□Yes       □No   □N.A.

 

S3.3结构确证样品是否提供纯度数据

S3.3 Is the purity of sample for structure elucidation provided?

S3.4精制工艺是否与产品工艺一致

S3.4 Is purification method of this sample same with the manufacturing process?

□Yes        □No

 

□Yes         □No 

未说明     □Not justified

 

S3.5是否提供元素组成研究信息  S3.5 Is report of element analysis provided?

□Yes    □No

 

S3.6是否提供平面结构研究信息

S3.6 Is planar structure elucidation provided?  

红外 IR             □ Yes   No

紫外 UV            □ Yes   No 

核磁 1H & 13C-NMR  □ Yes   No

质谱 MS            □ Yes   No

其他 Other              

 

S3.7是否对立体构型进行了研究

S3.7 Is Stereo configuration study provided? 

□ Yes       

   □ No        □不适用    □N.A.

 

S3.8是否对晶型进行了研究   S3.8 Is polymorphisms study provided?  

□Yes        □No     □不适用  □N.A.

 

S3.9是否对粒度进行了研究  S3.9 Is particle size study provided

   □Yes      □No     □不适用   □N.A.

 

S3.10是否对溶解性进行了研究  S3.10 Is solubility study provided?

   □Yes      □No

 

3.11是否列明产品中可能含有的杂质及来源

Has all the potential impurities and their sources been provided?

有机杂质 Organic impurities

无机杂质 Inorganic impurities

残留溶剂 Residual solvents

重金属 Heavy metals

 

 

Yes      No   □不适用 N.A.

Yes      No      

Yes      No   □不适用N.A.

Yes      No   □不适用N.A.

 


S4.质量研究与质量标准 S4. Quality study and specification

 

S4.1已收载标准情况

S4.1 Specification already adopted by monograph

中国药典   ChP          □国家药品标准  State-specification

进口药品注册标准  IDL   □USP           □BP              □EP

□JP                      □其他 Others

 

S4.2

有关物质与杂质谱分析Related substance and impurity profile analysis

S4.2.1工艺来源杂质研究分析资料:S4.2.1 Study on process impurities

提供 Provided                                        

     □物料Raw materials   □中间体 Intermediates    □副产物by-products   □其它others

未提供 Not provided

 

S4.2.2降解杂质研究分析资料:S4.2.2 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

  □其它降解 others degradation                

未提供Not provided

 

S4.2.3与参比品的杂质谱对比研究资料

S4.2.3 Has impurity profile been compared with that of originator products?

提供      □Provided

未提供  □Not provided

 

S4.2.4超鉴定限杂质的定性研究和限度控制

S4.2.4 Has characterization and control strategy been provided for impurities over identification threshold?

提供        □Provided

未提供    □Not provided  

无超限杂质 

□No impurities over identification threshold

 

S4.2.5分析方法研究与验证

S.4.2.5 Method development and validation

S4.2.5.1标准中分析方法的来源与筛选、优化过程  S4.2.5.1 Have the development, selection and optimization of analytical procedure been provided?

提供      □Provided

未提供  □Not Provided

 

S4.2.5.2ICH成员国药典/中国药典同品种标准方法的对比 S4.2.5.2 Has the method comparison with those adopted in ICH members monograph / ChP for the same product been provided?

提供    未提供

□Provided   □Not Provided

未收载

□Not adopted yet

 

S4.2.5.3分析方法学验证  

S.4.2.5.3 Method validation

提供  Provided      

基本全面  complete

缺项较多 incomplete with deficiencies

未提供Not provided

 

S4.2.5.4杂质谱对比用分析方法的研究与验证资料 S.4.2.5.4 Have method for impurity profile comparison and corresponding validation been provided?                          

提供    未提供

□Provided   □Not Provided

 

S4.2.6基因毒性杂质的研究与控制

S4.2.6 Study and control on genotoxic impurities 

研究并列入   □Studied and controlled     

研究未列入  □Studied but not controlled             

未研究      □Not studied

不适用      □N.A.

 

S4.2.7标准中杂质的控制

S4.2.7 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   未提供依据

   □Justification     □No Justificaton

 

S4.2.8杂质限度与已有最严格标准对比 S4.2.8 Impurity limit comparison with the tightest specification ever adopted

相当或严格 □Equivalent or tighter     

 

宽松  □Looser     

提供依据                   未提供依据

□ Already justify such looser limit □ Not yet justify such looser limit

 

未比较□ Not compared yet

     已有最严格标准可以获得   □不可获得                                           

     The tightest specification   □obtainable  □not obtainable

 

S4.3□

β-内酰胺类抗生素聚合物

S4.3□

β-lactam antibiotic polymer

S4.3.1是否进行聚合物研究

S4.3.1 Has polymer been studied?  

    (注射用和青霉素类原料药)

□Yes   □No(API for injection and penicillin group API

 

S4.3.2方法学研究与验证资料

S.4.3.2 Method validation

提供  Provided      

基本全面  complete

缺项较多 incomplete with deficiencies

未提供Not provided

 

S4.3.3是否与原研产品进行了聚合物含量水平对比考察

S4.3.3 Has content of polymer been compared with that of originator product?  

  □Yes                 

   含量水平        □不高于原研  高于原研

   Polymer content   □ not higher than that of originator product

□ higher than that of originator product

No

 

S4.4 □残留溶剂

S4.4 Residual solvents

S4.4.1溶剂使用情况:

S4.4.1 Usage of residual solvents :

 

使用了 = 1 \* ROMAN I类溶剂

□ Class = 1 \* ROMAN I solvents are used

 

精制步骤使用了 = 2 \* ROMAN II类溶剂

□ Class II solvents are used in purification

 

其它步骤使用了 = 2 \* ROMAN II类溶剂

□ Class II solvents re used in other steps

 

精制使用了有机溶剂

□ Organic solvents are used in purification

 

使用了其它无类别溶剂

□ Use of other not-classified solvents

列入质量标准的残留溶剂:  Solvents controlled in specification

 

 

研究并列入        研究未列入             未研究

□Studied and controlled □Studied but not controlled  □Not studied

 

研究并列入        研究未列入             未研究

□Studied and controlled □Studied but not controlled   □Not studied

 

 

研究并列入         □研究未列入              未研究

□Studied and controlled □Studied but not controlled   □Not studied

 

 

研究并列入         研究未列入          未研究  

□Studied and controlled □Studied but not controlled  □Not studied

 

 

研究并列入          □研究未列入            未研究

□Studied and controlled  □Studied but not controlled □Not studied

 

S4.4.2方法学验证

S4.4.2 Method validation

提供  Provided      

基本全面  complete

缺项较多 incomplete with deficiencies

未提供Not provided

 

S4.4.3 残留溶剂限度确定的依据

S.4.4.3 Justification on limit of residual solvents

 

提供      □Provided    

未提供   □Not Provided

 

S4.5□ 金属杂质

S4.5 □ Metals

S4.5.1金属使用情况:

S4.5.1 Metal profile

□1类金属  Class I metals

□1A

( PtPd)

 □1B

IrRhRuOs

□1C

MoNiCrV

S4.5.1.1列入质量标准的金属杂质

S4.5.1.1 Metals controlled in specification

 

研究并列入  

□Studied and controlled in specification

 

研究未列入

□Studied but not controlled

 

未研究

□Not studied

S4.5.1.2所用分析方法 :

 S4.5.1.2analytical procedure:

重金属检查   □Heavy metal method 

电感耦合等离子色谱法

□Inductively coupled plasma chromatography

原子吸收光谱法 Atomic Absorption Spectroscopy

其它 □Others

 

S4.5.1.3方法学验证

S4.5.1.3Method validation

提供  □Provided

  □全面  □ Complete

缺项较多    

□Lots deficiencies    

未提供

□Not provided

 

S4.5.2 

□2类金属  Class 2 metals

□3类金属  Class 3 metals

 

研究并列入 Studied and controlled in specification

研究未列入Studied but not controlled in specification

未研究  Not studied

 

S4.6含量测定

S4.6 Assay

S4.6.1标准中分析方法的来源与筛选优化 S4.6.1 Have the development, selection and optimization of analytical procedure been provided?

提供           未提供

 

S4.6.2ICH成员国药典/中国药典标准方法的对比

S4.6.2 Has the method comparison with those adopted in ICH members monograph / ChP for the same product been provided?

提供       未提供        □未收载

□Provided    □Not Provided   □Not adopted yet

 

S4.6.3分析方法学验证资料

S4.6.3 Method validation

提供  Provided      

基本全面   complete  

缺项较多Lots deficiencies

未提供Not provided

 

S4.6.4与已收载最严格标准的比较

S4.6.4 Comparison with the tightest specification ever adopted

相当或严格 □Equivalent or tighter 

 

宽松                          提供依据     未提供依据

□Looser_________ □Already justify such looser limit  □Not yet justify such looser limit

 

未比较 Not compared yet       

 

S4.7其他关键质量属性

S4.7 Other critical quality attributes

S4.7.1□试验项目  Impurity D 

S4.7.1 □ item               

 

S4.7.2提供了分析方法的来源与筛选优化过程

S4.7.2 Have the development, selection and optimization of analytical procedure been provided?

S4.7.3分析方法学验证

S4.7.3 Method validation

 

S4.7.4ICH成员国药典/中国药典标准的对比

S4.7.4 Has the method comparison with those adopted in ICH members monograph / ChP for the same product been provided?

 

 

 

提供     未提供

□Provided   □Not provided

 

 

 

 

提供      未提供

□Provided   □Not provided

 

提供 Provided     

相当或严格 □Equivalent or tighter 

宽松                □Looser_________

提供依据      □Already justify such looser limit 

未提供依据   □Not yet justify such looser limit

未提供   □Not yet provided   

未收载    □Specification not adopted yet

 

S4.8质量标准

S4.8 Specification

是否提供与已收载最严格标准的对比

Has the specification been compared with the tightest specification ever adopted

提供       未提供

□Provided    □Not Provided  

 

S4.9标准物质

S4.9 Reference standards

S4.9.1法定对照品

S4.9.1 Official reference standards

标签/样品照片/说明书  Label, picture, package inset    

        □提供     未提供

□provided  □Not provided

 

S4.9.2 □试剂公司商品:

公司名称            

S4.9.2 □From Reagent company:

Manufacturer              

S4.9.2.1结构确证资料      □提供       未提供

S4.9.2.1 Structure elucidation  □Provided   □Not provided

S4.9.2.2标定赋值资料    □提供     未提供      不适用

S4.9.2.2 Calibration process □Provided  □Not provided  □N.A.

 

S4.9.3□自行或委托制备

S4.9.3□Self-developed reference standard 

S4.9.3.1制备工艺资料        □提供      未提供

S4.9.3.1 Manufacturing process  □Provided   □Not provided

S4.9.3.2结构确证资料       □提供       未提供

S4.9.3.2 Structure elucidation  □Provided    □Not provided

S4.9.3.3 标定赋值资料    □提供     未提供      不适用

S4.9.2.3 Calibration process □Provided   □Not provided  □N.A.

 


S5.稳定性研究 S5. Stability

 

S5.1影响因素试验:S5.1 Affecting factors test:            

批量:         Batch size: _______       未提供△     □Not provided   

是否裸样:If naked sample is used:     

□Yes        □No       未提供□Not provided              

 

S5.2加速试验与长期试验:S.5.2 accelerated and long-term stability test

 

S5.2.1是否市售包装:            □             未提供       

S5.2.1 Commercial packing or no:    □Yes    □No       □Not provided  

批次:___          批量:1.        2.        3.         未提供       批量过小

Batches: _____batches,   batch size: 1._____ 2._____3.______      □Not provided   □too small batch size

 

S5.2.2加速试验条件: □ 40±2/RH 75%±5%         □其他       /RH%      是否提供依据     □   

S5.2.2 Accelerated test conditions: □ 40±2/RH 75%±5%  □Other      /RH%       Why other condition □Justify  □Not justify

稳定性考察时间:  6  □6  □其他

Time interval      6M  □6M  □Others

 

S5.2.3中间试验(30±2/RH65%±5%):

S5.2.3 Intermediate test (30±2/RH65%±5%)                               

提供 Provided     

   稳定性考察时间:6  □6  □12  □其他   

Duration6M  □12M  □Others                

不适用 N.A.

 

S5.2.4长期试验条件:□25 ±2/RH 60 ±10%          □其他       /RH%     是否提供依据   □      

S5.2.4Long-term stability test□25 ±2/RH 60 ±10%    □Others      /RH%     Why other condition □Justify  □Not justify 

稳定性考察时间:  6  □6  □9  □12  □18  □24其他                

Duration  6M  □6M  □9M  □12M  □18M  □24M  □Others                

 

S5.2.5是否缺乏重要质量考察指标

S5.2.5 If Lack of key stability-indicating test items

Yes            

未考察项目       Items Not studied              

No

S5.2.6长期试验在拟定效期内考察指标是否出现显著变化

S5.2.6 If significant changes occur at test items during long-term stability test

Yes                  

No

S5.2.7长期试验是否出现超鉴定限杂质

S5.2.7 If over-identification limit impurity are present during long-term stability test?

Yes         

    □进行定性研究 Characterization

    未进行定性研究 No Characterization

No

 

S5.3有关物质相关图谱

S5.3 If chromatograms for related substance are provided?

提供 Provided

部分提供 Partially provided

未提供NP Not provided 

 

S5.4含量测定相关图谱

S5.4 If chromatograms for assay are provided?

提供或部分提供

Provided or partially provided  

未提供 Not Provided不适用 NA

 

S6.其他 S6.Others

 

S6.1研究数据及图谱真实性                    □              发现的问题:                                 

S6.1 Authenticity of Raw data and chromatograms   □No problems      □With problems, namely                                

 

S6.2包材依据是否提供                    □      

S6.2 Justification of selecting packing materials  □Yes     □No

 


审查结论 Overview conclusion

 

(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, : modest 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:

Modest deficiency(calculated as two minor deficiencies) and minor deficiency _____items

一、工艺研究 Manufacturing Process

1

2

二、特性鉴定 Characterization

1

2

三、质量研究和质量标准Quality study and specification

1

2

四、稳定性研究Stability

1

2

五、其他 Others

1

2

 

Acceptance criteria

评判标准

CTD with any significant deficiency, rejected.

CTD without any significant deficiency but minor deficiencies10, rejected.

CTD without significant deficiency and minor deficiencies ≤10: Accepted

(Note: Calculate 1 modest deficiency as 2 minor ones.)

 

Conclusion

审查结论

通过             □未通过

□Accepted         □Rejected