1. Yongtian Ni Sino-American Regulatory Consulting Alliance December 4, 2011

2. Topics ICH and CTD ANDA Checklist for CTD and eCTD format CTD Modules OGD’s ANDA Filing Process Refusal to Receive Issues Regulations for ANDA Submissions

3. International Conference on Harmonization (ICH) ICH brought together the regulatory authorities from Europe, Japan and the United States to discuss scientific and technical aspects of product registration. ICH developed guidelines for the Common Technical Document for Registration of Pharmaceuticals for Human Use (CTD).

4. CTD and eCTD Format New ICH-CTD format, preferably electronic to support Question-based Review (QbR) Pre-assigned ANDA numbers are issued only for true electronic CTD submissions. http://www.fda.gov/cder/ogd/request_preassigned_ ectd.htm

5. CTD and eCTD Format Module 1Administrative - Specific for FDA - Contains regulatory information (356h, Cover Letter, Debarment & Financial Cert, Patent, LoA, Basis for Submission, Comparison to RLD, EA, BA/BE Waiver, Labeling) Note: FDA will soon charge user fee for ANDA. Details have not been finalized.

6. CTD and eCTD Format Module 2Summaries - Contains the summaries of chemistry and bioequivalence information - 2.3 Quality Overall Summary (QOS), QbR (2.3.S and 2.3.P) for OGD - 2.7 Clinical Summary- Bioequivalence Studies http://www.fda.gov/cder/ogd/Summary_ BioTables_CTD.htm

7. CTD and eCTD Format Module 3Quality (Chemistry) - Drug Substance - Drug Product - Pharmaceutical Development - Regional Information

8. CTD and eCTD Format Module 4Nonclinical Study Reports - Not required for ANDAs

9. CTD and eCTD Format Module 5Clinical Study Reports Not required if there are no BA/BE studies and if a request for waiver of BA/BE studies was submitted in Module 1.12.15.

10. ANDA Filing Process

11. ANDA Checklist for CTD or eCTD Format for Completeness and Acceptability of an Application for Filing http://www.fda.gov/cder/ogd/anda_checklist.pdf

12. ANDA Checklist This checklist was created to follow the Comprehensive TOC Headings and Hierarchy for the CTD format. Inclusive of the CFR requirements for ANDA filing Consultation with individual divisions of OGD as well as references to the multiple guidances for industry were used in the development of this checklist Sections not listed on the checklist are not required for ANDA filing, but may be included if deemed necessary for review

13. Module 1- Administrative 1.1.2Signed and completed Application Form 21CFR314.94(a)(2)Form 356h Firms should defer to the Electronic Orange Book when identifying the Holder of the Approved Application Firms should utilize USP nomenclature when the finished drug product is USP.

14. Module 1- Administrative 1.2Cover Letter Only required for paper submission Address any issues or previous communication with the Agency TOC Only required for paper submission See Comprehensive TOC (Headings & Hierarchy)

15. Module 1- Administrative 1.3.2Field Copy Certification Only required for paper submission Requires original signature 1.3.3Debarment Certification-GDEA Firms must declare that they have not and will not use in any capacity any individual that has been debarred pursuant to Section 306(k)(1) and (2) of the GDEA.

16. Module 1- Administrative 1.3.4Financial Certifications BA/BE Financial Certification (Form 3454), or BA/BE Disclosure Statement (Form 3455) 1.3.5Patent and Exclusivity 1.3.5.1 Patent Information Patents listed for the RLD in the Electronic Orange Book

17. Module 1- Administrative 1.3.5.2Patent Certification Patent number/s Certification (Paragraph based on FD&C Act) PIPIIPIIIPIVMOU No Relevant Patents Expiration of the Patent/s Exclusivity Statement

18. NCE Exclusivity NCE Exclusivity- only exclusivity that blocks submission of ANDAs for a period of 5 years from the date of approval of the first approved NDA. If an ANDA contains a PIV certification to a listed patent covering the NDA for which an NCE applies, then the application may be submitted one year prior to the expiration of the NCE exclusivity.

19. Module 1- Administrative 1.4.1Letters of Authorization Allows FDA to review the referenced DMF - Type II (API) - Type III (CC) - US Agent LoA must be submitted by all firms residing outside of US. US Agent is granted authority by the DMF holder to act as an intermediary between FDA and the applicant

20. Module 1- Administrative 1.12.11Basis for Submission Must include name of RLD as designated by the Orange Book Include the NDA number on the Basis for submission If utilizing an approved Suitability Petition as Basis of Submission, the applicant must provide a copy of the approval letter for the Suitability Petition. 21 CFR 314.93

21. Module 1-Administrative 1.12.11Basis for Submission (Cont’d) 314.122ANDAs that rely upon an RLD that is no longer marketed. An application may be filed pending the outcome of the Agency’s determination that a drug product was removed from the market for reasons other than safety or efficacy. This petition must be submitted under 10.25(a) and 10.30.

22. Module 1- Administrative 1.12.12Comparison Between Generic Drug and RLD- 505(j)(2)(A) Conditions of Use Active Ingredients- must be same as innovator Inactive Ingredients Route of Administration Dosage Form Strength

23. Module 1- Administrative 1.12.14Environmental Analysis Firms should submit a statement that they are in compliance with all federal, state and local environmental laws Categorical exclusion under 25.31 (a) Environmental Assessment for substances that occurs naturally in the environment http://www.fda.gov/cder/guidance/1730fnl.pdf

24. Module 1- Administrative 1.12.15Request for Waiver of In-Vivo BA Studies For certain drug products, the in vivo BA/BE of the drug product may be self-evident and meets one of the criteria defined in 21CFR 320.22(b)(1).

25. Module 1- Administrative 1.14.1Draft Labeling Proposed draft labeling (electronic format); including SPL S X S container labeling with differences annotated and explained Electronic submission requirements ANDAs submitted after June 8, 2004 are required to provide their labeling in electronic format

26. Module 1- Administrative 1.14.3Listed Drug Labeling (RLD) S X S Labeling of Package and Patient Insert with all differences annotated and explained 1 RLD label and 1 RLD container label

27. Module 2- Summaries 2.3Quality Overall Summary QOS should include sufficient information from each section in Module 3 to provide the reviewer an overview of the application Chemistry/Bio Division requests submission in PDF and MS format Model QOS and Model Bio Summary Tables available in OGD website

28. Module 2- Summaries 2.7Clinical Summary (Bioequivalence) Summary of results of BA/BE studies Bioequivalence Division request submission in PDF and MS format

29. Module 3- Quality 3.2.S.1 General Information (Drug Substance) Nomenclature Structure General Properties

30. Module 3- Quality 3.2.S.2Manufacture (Drug Substance) Name and full address of facilities (Summary table of all facilities- contacts, addresses, phone/fax numbers, CFN #, etc.) Function or Responsibility Type II DMF No. for API * DMF for API must be stamped received by Agency prior to submission of an ANDA that relies upon said DMF.

31. Module 3- Quality 3.2.S.4Control of Drug Substance Specifications Test Procedures Validation Spectra and chromatograms Sample statement in accord with 21 CFR 314.50 (e)(i) CoA/Batch Analysis Justification of Specifications

32. Module 3- Quality 3.2.P.1Description and Composition of the Drug Product Unit composition Inactive ingredients and amounts as compared to IIG

33. Components and Composition of the Drug Product Inactive ingredients not previously approved or higher than previously approved (Most prevalent RTR issue) OGD will not consider GRAS/GRAE status conclusive evidence; use in food products will not persuade FDA to allow its use in drug products Exception Excipients: changes in preservative, buffer or antioxidant: 314.94(a)(9)(iii) Note that pH adjusters in parenterals are not exception excipients.

34. Module 3- Quality 3.2.P.2Pharmaceutical Development Should contain information on the development studies conducted to establish that the dosage form, formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application. See Guidance for Industry Q8

35. Module 3- Quality 3.2.P.3Manufacture (Drug Product) Name and full address of manufacturers, contract labs, contacts and specific functions All firms performing any testing, packaging, sterilization, etc. of DS or DP must be ID’ed so that a request may be initiated for inspection cGMP certification with signature FDA inspection information

36. Module 3- Quality 3.2.P.3.2Batch Formula (Drug Product) List of all components of the dosage form to be used in the manufacturing process, amounts on a per batch basis, including overages and a reference to their quality standards.

37. Module 3- Quality 3.2.P.3.3Description of Manufacturing Process and Process Controls (Drug Product) Flow Diagram showing the process steps and where materials enter the process Blank Master Production Batch Records - Maximum production scale-up of 10 x the theoretical yield of the exhibit batch may be requested.

38. Module 3- Quality 3.2.P.3.3Description of Manufacturing Process and Process Controls (Cont’d) Reprocessing Statement - Forms should certify that it does not utilize reprocessing procedures in the manufacturing of the drug product. If the firm does wish to reprocess the drug product, they will submit a Prior Approval Supplement to the Agency describing the process. Release of the reprocessed product will be withheld until the PAS is approved by the Agency.

39. Module 3- Quality 3.2.P.3.4Controls of Critical Steps and Intermediates (Drug Product) All critical process controls and their associated numeric ranges, limits, or acceptance criteria should be identified and justified and a brief description of the test provided

40. Module 3- Quality 3.2.P.3.5Process Validation and/or Evaluation (Drug Product) Description, documentation, and results of the validation and/or evaluation should be provided for critical steps or critical assays used in the manufacturing process - Microbiological sterilization validation - Filter Validation Must have complete filter validation present upon submission of an ANDA, this information may not be submitted at a later date.

41. Module 3- Quality 3.2.P.4Controls of Excipients (Inactive Ingredients) Identify source of supplier for all inactive ingredients (tabular format) CoA 3.2.P.4.1Specifications Testing Specifications

42. Module 3- Quality 3.2.P.4.2Analytical Procedures Test procedures should be provided, when appropriate 3.2.P.4.3Validation of Analytical Procedures Normally not needed for excipients Should be submitted in special circumstances (i.e., characteristic of excipient is critical to product quality)

43. Module 3- Quality 3.2.P.4.4Justification of Specifications Applicant’s CoA Pharm/Tox studies when appropriate to justify the safety of an inactive ingredient IIG database, compendial, etc.

44. Module 3- Quality 3.2.P.5Controls of Drug Product 3.2.P.5.1Specifications 3.2.P.5.2Analytical Procedures 3.2.P.5.3Validation of Analytical Procedures Sample statement- Sample drug product will be submitted upon request from FDA in accord with 21CFR 314.50(e)(1)

45. Module 3- Quality 3.2.P.5.4Batch Analysis CoA for each executed batch 3.2.P.5.5Characterization of Impurities List all expected impurities Identification of impurities 3.2.P.5.6Justification of Specifications Pharm/Tox studies to justify the safety of an impurity

46. Module 3- Quality 3.2.P.7Container Closure System 1. Summary of CC System (if new resin, provide data) 2. Components Specification (including Engineering Drawing) and Test Data 3. Packaging Configuration and Sizes 4. Container Closure testing 5. Source of Supply and Suppliers’ Address

47. Module 3- Quality 3.2.P.8Stability 3.2.P.8.1Stability Summary and Conclusion Stability Protocol Proposed expiration dating period - Tentative 24 month expiration date based upon 3 months of accelerated stability

48. Module 3- Quality 3.2.P.8.2Post-approval Stability Protocol and Stability Commitment Firm must commit to placing first 3 production lots as packaged in the largest and smallest container on long term stability Each year thereafter, a minimum of one lot packaged in the largest and smallest container will be added to long term stability. Firm must report the stability data as it becomes available (periodic reports).

49. Module 3- Quality 3.2.P.8.3Stability Data* Data from 4 timepoints should be submitted- 0, 1, 2, and 3 months 3 months of accelerated stability conducted per ICH Q1A, even if product fails under stressed conditions. RSB will file an ANDA with failing accelerated stability but may not file an ANDA if only unstressed stability is provided. Firm can bracket intermediate package sizes and only perform stability on largest and smallest package sizes if same CC system is used for multiple package sizes Batch number must be the same as the exhibit batch *FDA soon will require 12 months RT data and 6 months Accelerated/Intermediate data for three lots for each Package configuration.

50. Module 3- Quality 3.2.RRegional Information 3.2.RDrug Substance Executed Batch Records (if available) Comparability Protocols (optional) -used to demonstrate the lack of adverse effect for specified types of post-approval manufacturing changes Methods Validation Package

51. Module 3- Quality 3.2.RDrug Product Executed Batch Records - Parenteral products: Must package a minimum of 10% of the exhibit bulk size in each vial size proposed for marketing; scale-up based upon actual packaged amounts - Provide reconciliation detailing the disposition of all dosage units

52. Module 3- Quality 3.2.RDrug Product (Cont’d) Information on Components Manufacturer Information Function of Contract Facilities (Sterilization, etc.) CoA Comparability Protocols -used to demonstrate the lack of adverse effect for specified types of post-approval manufacturing changes Methods Validation Package

53. Certification to Accompany Drug, Biological Product, and Device Applications or Submissions The recently enacted U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007), Title VIII, Section 801 mandates the expansion of the clinical trials data bank (ClinicalTrials.gov). The new provisions require additional information to be submitted to the databank, including expanded information on clinical trials and information on the results of clinical trials.U.S. Public Law 110-85ClinicalTrials.gov Beginning no later than December 26, 2007, one FDAAA provision in Section 801, 42 U.S.C. 282(j)(5)(B), requires that a certification form (FDA 3674) accompany certain human drug, biological, and device product submissions made to FDA. At the time of submission of an application under sections 505, 515, or 520(m) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355, 360e, or 360j(m)), or under section 351 of the Public Health Service Act (PHS Act) (21 U.S.C. 262), or submission of a report under section 510(k) of the FD&C Act (21 U.S.C. 360(k)), such application or submission must be accompanied by a certification that all applicable requirements of section 402(j) of the PHS Act have been met. Where available, such certification must include the appropriate ClinicalTrials.gov identifiers (NCT numbers).

54. Refusal to Receive Issues Incomplete BE studies No dissolution data DMF not present or received by Agency by the stamped ANDA receipt date Missing or incomplete stability data No patent certifications Missing Citizen’s Petition or Suitability Petition

55. Refusal to Receive Issues (Cont’d) Inactive Ingredients Master production batch records not in accord with 10 x scale-up No information demonstrating that differences in inactive ingredients do not impact safety and efficacy.

56. Regulations for ANDA submissions 21 CFR 5.80Approvals of New Drug Applications and their Supplements 21 CFR 10.30Citizen Petition 21 CFR 50Protection of Human Subjects 21 CFR 56Institutional Review Boards 21 CFR 310.305Records and reports concerning ADEs on marketed prescription drugs for human use without approved new drug applications 21 CFR 314.70Supplements and other changes to an approved application 21 CFR 320BA/BE Requirements