How to Avoid Common Deficiencies in the ANDAs?

1. How to Avoid Common Deficiencies in the ANDAs? Laxma R Nagavelli, PhD Lead Chemist, Chem Division III, FDA/CDER/OPS/OGD Disclaimer: This presentation reflects the views of the presenter and should not be construed to represent FDA’s views or policies.

2. My Talk Covers • Generic Drug User Fee Amendments (GDUFA) and its impact on Abbreviated New Drug Application (ANDA) Reviews • Common recurring deficiencies in ANDAs • ANDA sections with inadequate/missing information • Representative ANDA applications with fatal flaws • References

3. Generic Drug User Fee Amendments (GDUFA)-July 9, 2012 With the enactment of GDUFA, Office of Generic Drugs (OGD) committed to expedite the availability of high-quality, lower cost generic drugs by bringing greater predictability to the review times for ANDAs, amendments and supplements.

4. GDUFA Goals Primary Goals: • Reduce the inspection parity between foreign and domestic establishments (ORA) • Reduce the time frame for generic approvals (OGD)

5. GDUFA – Goals (OGD) One of the GDUFA goals is to reduce the review time in bringing the generics to the market GDUFA Period: Oct 1, 2012 – Sept 30, 2017 First row: Goals for year 3 and 4 Second row: Goal for year 5

6. OGD # 1 Priority – Meeting GDUFA Goals Action items for meeting the GDUFA goals: • Quality ANDA submissions • Increase the FDA resources • Educate the industry about FDA expectations/requirements • Train the new reviewers • Reduce the backlog • Improve the review process/efficiency • Grants to advance regulatory science priorities/projects • Etc.,

7. OGD # 1 Priority – Meeting GDUFA Goals Increasing the Quality of ANDA submissions Refused-to-Receipt (RTR) applications for year 2012: • 40 (serious bioequivalence deficiencies) • 36 (serious chemistry deficiencies) • 13 (organization/formatting deficiencies) • 6 (clinical deficiencies) • 4 (inadequate sterility assurance) • 1 (incorrect basis of submission)

8. How to improve the quality of ANDAs? There is a Federal Registry Docket No. FDA-2014-N-0032 filed on Jan 23, 2014 for public comment (due date March 24, 2014) for improving the quality of ANDA submissions to the FDA.

9. Fed Reg Docket FDA-2014-N-0032 The purpose of this Docket is: • FDA is interested in hearing about difficulties that sponsors are having in preparing their ANDAs • FDA is willing to share/provide information to the industry in achieving the goal of quality ANDA submissions It is a two way street

10. Benefits of Quality ANDAs • Improved quality ANDA submissions will result in fewer refused-to-receive (RTR), fewer amendments, and easily correctible deficiencies instead of minors or majors and ultimately timely approval of generic drugs. • The more complete and improved quality of ANDA submissions will positively affect the availability of low-cost, high quality generic drugs to the public.

11. Lacking Quality in ANDAs…. Inadequate, incomplete or missing information in the applications prevents a reviewer from making a well informed regulatory decision leading to deficiencies Deficiencies

12. Types of Deficiencies • Easily Correctible Deficiency (ECD): The response from industry normally expected within 10 working days and requires modest FDA resources • NA-Minor: Most common form of deficiency typically including a DMF deficiency, normally expected to take more than 10 working days for preparing a response • NA-Major: A fatal flaw, normally takes longer time to send in the response as it generally requires additional data generation and sometimes may require reformulation (MaPP 5241.1 for Major/Minor) and requires substantial FDA resources

13. How to Reduce Deficiencies? FDA using the following methods of communication: • Speaking to industry at GPhA and other regulatory and scientific meetings • Issuing CDER/OPS/OGD Guidances • Issuing Manual of Policies and Procedures (MaPPs) • Publishing regulatory science articles

14. Common Recurring Deficiencies Filing • Incomplete/missing 356h Form • Unjustified levels of inactive agents • Inadequate dissolution data • Insufficient/out-of-specification(OOS) stability data • Non Q1/Q2 parenteral formulations • Etc.,

15. Common Recurring Deficiencies Chemistry • Use of excipients beyond the Inactive Ingredient Database (IID) limits • Failure to list potential degradation impurities and/or missing justification when limits exceed QT levels • Inadequate validation/verification details for analytical methods • Failure to identify Critical Process Parameters • Failure to provide appropriate acceptance criteria for manufacturing yields

16. Common Recurring Deficiencies Sterility Assurance (parenteral) • Failure to describe or provide inadequate validation data for sterilization and/or depyrogenation of equipment and components • Failure to provide adequate validation data for sterilizing grade filters • Failure to provide process simulation data for the aseptic filling process/line/room

17. Common Recurring Deficiencies Bioequivalence • Inaccurate/incomplete information in e-tables • Submission of pharmacokinetic repeats • Incomplete/inaccurate bio-waiver requests • Lack of dissolution data for all strengths • Missing standard operating procedures (SOP) for analytical methods • Etc.,

18. Common Recurring Deficiencies Drug Master Files (DMF) • Containing multiple API manufacturing sites • Containing more than one manufacturing process • Failure to provide complete description of manufacturing process and controls • Failure to justify the appropriate starting materials • Inadequate justification for impurity limits • Time lapse since the original submission

19. CMC Essentials - ANDA Information Required On • Drug Substance • Drug Product • Container Closure System • Packaging and Stability • Dose and Administration (labeling)

20. Drug Substance-API • Molecular Structure • Physical and Chemical Properties • Manufacturing Process • Analytical Methods/Validations • Process/Degradation Impurities • API Specifications • Analytical methods/Validations • Reference Standards • Container Closure System • Stability

21. Drug Product • Components and Composition • Product Development Report • Manufacturing process - In-process controls • Drug Product Release • Analytical Methods/Validation/Verification • Container Closure System • Stability

22. Drug Substance – Common Deficiencies ANDA Holder’s Perspective S DRUG SUBSTANCE • S.1 General Information • S.1.1 Nomenclature • S.1.2 Structure • S 1.3 General Properties

23. Drug Substance – Common Deficiencies ANDA Holder’s Perspective S 1.3 General Properties Information missing: • Polymorphs • Particle size distribution (if BCS class II) • Chirality • Moisture sensitivity/Hygroscopicity • Solubility across pH range

24. Drug Substance – Common Deficiencies ANDA Holder’s Perspective • S.2 Manufacture • S.2.1 Manufacturers • S.2.2 Description of Manufacturing Process and Process Controls • S.2.3 Control of Materials • S.2.4 Controls of Critical Steps and Intermediates • S.2.5 Process Validation and/or Evaluation • S.2.6 Manufacturing Process Development

25. Drug Substance – Common Deficiencies ANDA Holder’s Perspective • S.3 Characterization • S.3.1 Elucidation of Structure and other Characteristics • S.3.2 Impurities • S.4 Control of Drug Substance • S.4.1 Specification • S.4.2 Analytical Procedures • S.4.3 Validation of Analytical Procedures • S.4.4 Batch Analysis • S.4.5 Justification of Specification

26. Drug Substance – Common Deficiencies ANDA Holder’s Perspective S.3.2 Impurities Not fully addressed: • Listing all USP impurities • Providing impurities table with origination (process vs degradation) • Identifying structural alerts for potential genotoxicity • Matching residual solvents limits to DMF holder’s specifications • Proposing limits to metal impurities

27. Drug Substance – Common Deficiencies ANDA Holder’s Perspective S.4.1 Specifications Incomplete information: • Counter ions • Chiral assay • Limit for unidentified impurities based on ICH Q3A • Limits for Class 1 metals if no DMF is filed • Controls for particle size distribution for BCS class II drugs • Test and control for desired Polymorph

28. Drug Substance – Common Deficiencies ANDA Holder’s Perspective S.4.3 Validation of Analytical Procedures Information missing: • Verification for compendial methods or methods transferred from DMF holder • Equivalence for in-house methods to the USP S.4.5 Justification of Specifications (impurities) • Qualification data for impurities over Q3A QT levels or for potential genotoxic materials over the CDER guidance limits

29. Drug Substance – Common Deficiencies ANDA Holder’s Perspective Information missing/unjustified: S.5 Reference Standards or Materials • Qualification data for impurity standards S.7 Stability • Unjustified API retest date

30. Drug Product – Common Deficiencies P DRUG PRODUCT P.1 Description and Composition of the Drug Product P.2 Pharmaceutical Development P.3 Manufacture

31. Drug Product – Common Deficiencies P.1 Composition/Components of the Drug Product Information missing: • Justification for overage of API – it should be based on RLD and label but NOT based on manufacturing loss or drug substance instability or to increase the shelf-life • Information on N2/C02 when used as blanketing agents • Intended function of the excipients selected • Amounts of excipients based on total daily intake of drug • w/w% and amounts for each of the excipients for unit dose • Excipient standards (USP, NF and FCC etc.,) • Type of starch (ex. pre-gelatinized starch derived from maize)

32. Drug Product – Common Deficiencies P.2 Pharmaceutical Development Inadequate information: • API-excipient compatibility - study conditions • Preservative Effectiveness Test – supporting range • Extractable and leachable data - stoppers and filters • Drug product physical attributes - size and shape (beads, tablets and capsules - CDER guidance)

33. Drug Product – Common Deficiencies P.3 Manufacture P.3.1 Manufacturers P.3.2 Batch Formula P.3.3 Description of Manufacturing Process and Process Controls P.3.4 Controls of Critical Steps and Intermediates P.3.5 Process Validation and/or Evaluation

34. Drug Product – Common Deficiencies P.3.4 Controls of Critical Steps and Intermediates Inappropriate or unjustified In-process tests and controls: • Granulation end point (feel/touch – subjective) – quantitative end point is recommended • Blend uniformity analysis (BUA) mean and release assay • USP<1151> for excess volume (parenteral) • Particle size distribution (PSD) controls for blend to eliminate potential segregation

35. Drug Product – Common Deficiencies P.4 Control of Excipients P.4.1 Specifications P.4.2 Analytical Procedures P.4.3 Validation of Analytical Procedures P.4.4 Justification of Specifications P.4.5 Excipients of Human or Animal Origin P.4.6 Novel Excipients

36. Drug Product – Common Deficiencies P.4 Control of Excipients Information missing: • Applicant’s specifications and CoA • Analytical methods/validations for residual solvents • Meeting the USP, National Formulary (NF) or Food Chemicals Codex (FCC) specifications (ex: test and limits for N-vinly pyrrolidone and peroxides for povidone) • Statement for melamine content • Reduced testing

37. Drug Product – Common Deficiencies P.4.1 Specifications Tests missing and/or limits unjustified: • Counter ion ID and content, specific ID test, chiral assay, enantiomer/stereoisomer limits, XRPD etc., • Quantitative color test for parenteral solutions with color • Reconstitution Time for solid oral powders/parenterals • Listing process impurities with higher limits compared to DS • Not listing known degradation impurities or providing no explanation for not listing or listing with higher limits over QT with no justification • Higher limits over CDER guidance limits for structural alerts with no pharm/tox data for qualification • Limit for Total impurities is not justified • Same assay and impurity limits for release and stability?

38. Drug Product – Common Deficiencies P.4.4 Justification of Specifications Adequate justification missing: • Specified identified, specified unidentified per USP/RLD/ICH Q3B QT, single unknowns including unspecified with RT per ICH Q3B IT, and structural alerts per CDER guidance • Not listing the lesser of two [0.X% or xxx mg Total Daily Intake (TDI)] for impurities • Limits for enantiomer/stereoisomers, Quantitative color test, Reconstitution time based on RLD label • Accelerated stability data or batch analysis data can’t be used to set the specification limits

39. Drug Product – Common Deficiencies P.6 Reference Standards or Material P.7Container Closure System P.8 Stability P.8.1 Stability Summary and Conclusion P.8.2 Post-approval Stability Protocol and Stability Commitment P.8.3 Stability Data

40. Drug Product – Common Deficiencies P.7 Container Closure System Inadequate or Information Missing: • Light/Moisture permeation data • Glass delamination data • Use of colored container closure system (CCS) • Use of multiple moisture absorbents • Extractable and leachable data • Stability of the drug product is packaging • dependent invariably in all cases

41. Drug Product – Common Deficiencies P.8 Stability Information/Justification Missing: • Critical tests of release not selected for stability (APHA color test, reconstitution time, preservative test, particulate matter etc.,) • Justification for the total impurities • Data for inverted position (parenteral) • Change of analytical methods during the stability study • Root cause reports for out-of-specification (OOS) results • Freeze thaw study data for refrigerator products • Content uniformity (CU) and Dissolution data for scored tablets • Forced degradation/stress study

42. REGIONAL INFORMATION R1 Executed Batch Records • Data missing or not properly recorded • Excess weighing of materials for loss during the process • Missing Master Batch Records R2 Comparability Protocols R3 Methods Validation Package These are only some of the common deficiencies found in the ANDA applications and does NOT represent the comprehensive list

43. ANDA Example-1: Specifications Applicant submits an application for topical solution drug product that has a USP monograph. The proposed DP specification has pH range one unit lower (acidic) compared to the USP and secondly, the product does not meet the sterility as recommended by the USP.

44. Review Outcome • Applicant’s reasoning that the drug substance is unstable at higher pH is not acceptable. A USP product is recommended to meet all the USP compendial requirements such as, identity, strength, quality, purity and consistency. • Applicant was recommended to reformulate the drug product to meet the USP • A MAJOR deficiency was issued

45. ANDA Example-2: Impurity Limits Applicant submits an application in which the drug product is sensitive to oxygen and it is expected to form oxidative degradation product. There is literature to support the formation. The firm identifies the impurity and proposes the limit at ICH QT limits. However, forget to identify that it is a structural alert for potential genotoxicity and provided no justification for the proposed limit.

46. Review Outcome A deficiency was cited requesting the firm to provide pharm/tox data to demonstrate safe level for this impurity or alternatively propose an acceptance criterion to meet the CDER guidance recommendations for potential genotoxic/carcinogenic impurities. This is a MAJOR deficiency per MaPP 5241.1

47. ANDA Example-3: Formulation Applicant proposes formulation for a parenteral drug product involving carbon dioxide as sparging agent to adjust the pH of the formulation whereas the NDA product use no pH adjusters.

48. Review Outcome The applicant fails to comply with the 21 CFR 314.94(a)(9)(iii) requirement. (iii)”……….an applicant may seek approval of a drug product that differs from the reference listed drug in preservative, buffer, or antioxidant ……”. The applicant was cited a MAJOR deficiency recommending to reformulate the product without the pH adjuster (carbon dioxide) and provide all appropriate CMC data to support the application

49. ANDA Example-4: DP Attributes Multiple Examples: Applicant submitted an ANDA for an immediate release solid dosage form with tablet sizes that are almost double the size of the RLD. In a second case the ANDA applicant used ‘000’ size capsule for their DP compared ‘00’ capsule for RLD. In another case, the applicant proposes a generic product without score whereas the RLD is scored.

50. Review Outcome A MAJOR deficiency was cited to apply the CDER guidance in selecting the tablet or capsule sizes for the generic products. A MINOR deficiency was cited regarding the scoring to provide a commitment for not marketing the unscored product and submit a supplement with CU/dissolution data for scored product prior to marketing.