中美仿制药研发和申报流程--涂家生2011.11.ppt

1、中美仿制药研发和申报流程,涂家生， Ph. D. 中国药科大学药剂学教授 Tel:Email: 2011.11 郑州,我国仿制药申报、审评和研发对策,主要内容,中美关于原研药和仿制药的背景,美国仿制药：申报、基于问题的审评和研发对策,展望,1,2,3,4,Company Logo,3,药物经济学催生美国仿制药制度,美国社会安全制度导致政府赤字严重 SSA已经破产：如何破局？ 降低医疗费用成为必然 Hatch-Waxman法案出台 美国FDA药品注册申请：新药（两类）、仿制药和非处方药申请,1984年后,New Drug Applications (NDAs),Abb

2、reviated New Drug Applications (ANDAs),“Full Reports” of Safety and Efficacy Investigations Applicant has right of reference to essential investigations?,Duplicate of an already approved product No safety/efficacy data permitted (only bioequivalence),505(b)(1),505(b)(2),505(j),NDA的研发和申报,505(b)(1) 新药

3、申报资料内容,Index Summary Chemistry, Manufacturing and Control Samples, Methods Validation Package and Labeling Nonclinical Pharmacology and Toxicology,6. Human Pharmacokinetics and Bioavailability 7. Microbiology ( for anti-microbial drugs only) 8. Clinical Data 9. Safety Update report ( typically submi

4、tted 120 days after the NDAs submission ),10. Statistical 11. Case Report Tabulations 12. Case Report Forms 13. Patent Information 14. Patent Certification,505(b)(2): 历史过程,Hatch Waxman法案：1984 Parkman Letter Phantom ANDA FDA Draft Guidance for Industry (1999) FDA Response to Citizens Petition (2003)

5、可以降低研发的费用和审评力量的浪费,505(b)(2)的关键: 可靠性,What is “Reliance” By whom? On what? Reliance and Exclusivity Market vs. Data Exclusivity Safety/Efficacy Data vs. CM Quality by Design Module 4: Nonclinical Module 5: Clinical (Bioequivalence),新药申报（NDA） 和仿制药申报（ANDA）的比较,NDA requirements,ANDA requirements,美国仿制药申报,F

6、DA仿制药部（OGD）鼓励申请人根据ICH对于人用药物的注册技术要求，即通用技术文件（CTD）的格式，提交ADNA。包括以下模块：,OGD QBR The question based review (QBR) serves as a general framework for the CMC assessment of ANDAs that focuses on critical pharmaceutical attributes of product quality. With justification, deviations or alternate approaches to thi

7、s framework can be utilize, as necessary, to ensure the adequacy of the assessment of product qualityFor ease of discussion, a simple dosage form is defined as a solution or an immediate release (IR) solid oral dosage form.,QBR: Drug Substance,Description and Characterization What are the nomenclatu

8、re, molecular structure, molecular formula, and molecular weight? What are the pKa, aqueous solubility (as function of pH), partition coefficient, polymorphism, hygroscopicity, and melting points? Control of Drug Substance Appearance and Identification Are the specifications for appearance and ident

9、ification appropriate? Assay Is the proposed drug substance assay limit acceptable? Is the analytical method validated and stability-indicating? Impurities and Residual Solvents Are all the possible impurities accounted for? What is the justification for the impurity acceptance limits? Are the analy

10、tical methods validated and suitable for their intended function? Additional Specifications Based on the review of the drug product and manufacturing process are specification(s) required on particle size, solid state form, moisture content, or other properties of the drug substance and why? For eac

11、h additional specification: What is the justification for the acceptance limit? Is it suitable for its intended function?,QBR: Drug Product,Description and Composition What are the components and composition of the final product? What is the function of each excipient? Do any excipients exceed IIG l

12、imits in the context of maximum daily dose and route of administration? If product is an NTI drug or a non-simple dosage form Are there significant differences between this formulation and the RLD that present potential concerns with respect to product performance? Control of Excipients What are the

13、 specifications for the inactive ingredients and are they appropriate per their intended function?,Simple Dosage Form: Either a solution or an IR solid oral dosage form,QBR: Drug Product (Continued),Manufacture For all products Does the batch formula accurately reflect the drug product composition?

14、If not, what are the differences and the justifications (e.g. potency adjustment, overage, excess coating solution, etc.)? If product is not a solution What are the key unit operations in the drug product manufacturing process? Are in-process tests identified by the sponsor appropriate? What is the

15、difference in size between commercial scale and biobatch and do they use the same unit operations? If product is an NTI drug or a non-simple dosage form What are the critical steps in the manufacturing process? What are the in-process tests/controls that ensure each critical step is successful? In t

16、he proposed scale up process what operating conditions will be adjusted to ensure the product meets all in-process and final product specifications? Why do you believe the sponsor has demonstrated a reasonable plan to scale up the process?,QBR: Drug Product (Continued),Control of Drug Product Identi

17、ty Is the specification for the identity of the drug product appropriate? Assay and Uniformity Are the proposed drug assay limits acceptable? Is the assay method validated and stability-indicating? How is the content uniformity evaluated? Is it acceptable? Impurities/Degradation Products Are the deg

18、radation products and their origins adequately described? What is the justification for the acceptance limits on degradation products? Are the analytical methods validated and suitable for their intended function? Dissolution What are the dissolution methods and acceptance criteria and how were they

19、 selected? What is the significant role of dissolution testing for this product? Additional Specifications Are there additional specifications that are required to ensure the product will perform as labeled and why? For each additional specification: What is the justification for the acceptance limi

20、t? Are the analytical methods validated and suitable for their intended function?,QBR: Drug Product (Continued),Reference Standard Are there a qualification report and COA provided for the reference standard or is this material purchased from an appropriate source? Container/Closure System Has the c

21、ontainer/closure system been used in a previously approved product or otherwise qualified for this dosage form? What specific container/closure attributes are necessary to ensure product performance? Drug Product Stability Data What stability data has been submitted? Has the sponsor provided stabili

22、ty data for the drug product packaged in the proposed container/closure? Acceptance limits Are all attributes that could change over time evaluated in the stability tests? What are the acceptable limits on these attributes? Shelf-life recommendation What is the justification of shelf life? Is the po

23、st-approval stability protocol acceptable?,QBR: Product Development Report for Complex Dosage Forms and NTI Drugs,Drug Substance Which properties or physical chemical characteristics of the drug substance affect drug product performance? Excipients Is there any evidence of incompatibility between th

24、e excipients and drug substance? Formulation What is the formulation intended to do? What mechanism does it use to accomplish this? Were any other formulation alternatives investigated and how did these perform? Were any formulation optimization or sensitivity studies carried out for variations in c

25、omposition around the final formulation? Were these studies sufficient to establish a design space for formulation composition? Is the formulation design consistent with the dosage form classification in the label? Drug Product What are the critical quality attributes that ensure the product will pe

26、rform as labeled?,QBR: Process Development Report,Process Description Why was this manufacturing process selected for this drug product? Were alternative unit operations investigated by process development studies? Critical Steps and Scale Up How were the critical steps in the process identified? Wh

27、at are the critical process parameters for each critical step and how were they identified, monitored and/or controlled? Were process development studies that varied starting materials or operating parameters conducted? Were these studies sufficient to establish a design space for process? In proces

28、s tests Why is each in process test required? How were the acceptance limits chosen? Why were the in-process tests identified as critical to product quality? What scale-up experience does the sponsor have with the unit operations in this process?,QBR: Risk Summary,NTI drug Classified as a non-NTI dr

29、ug, risk score = + 0 Classified as an NTI drug, risk score = +1 Dosage Form Simple Dosage Form, risk score = + 0 Other Dosage Forms and NTI drugs, risk score = + 1 Development Report If the sponsor submits a development report that addresses the FDAs questions: Risk score = + 0 Solution and IR Produ

30、cts: Product Development Report Other Dosage Forms: Product and Process Development Reports Insufficient or missing development report, risk score = + 1 If the application is of high overall quality Less than or equal to 2 cycles, risk score = + 0. Greater than 2 cycles, risk score = + 1,QBR: Risk-B

31、ased Conclusion,Should the application be approved? What post-approval waivers/commitments are appropriate for this product? If the total risk score is less than or equal to 1 CBE0 and CBE30 changes may be in annual reports Many PAS to CBE 30 If the total risk score is greater than 1 All supplements should be submitted as usual,生物等效性豁免,生物等效性豁免是指基于体外数据审批的管理程序。固体制剂往往采用溶出度、释放度作为证据。,I、基于药物剂型的生物等效性豁免,只有供试品和参比制剂的原料及其含量一致，辅料一致、用量相当，且符合如下规定时，可生物等效性豁免： 1、注射液；2、口服溶液，含量一致，且不含已知会影响胃肠道功能和主药稀释的辅料；3、气体；4、溶液散剂；5、耳用或眼用溶液；、6、外用溶液；7、采