1. Office of New Drug Chemistry, OPS, CDER, Food and Drug Administration Establishing Dissolution Specification Current CMC Practice Vibhakar Shah, Ph.D. Office of New Drug Chemistry Office of Pharmaceutical Science Center for Drug Evaluation and Research, FDA Advisory Committee for pharmaceutical Science May 3-4, 2005

2. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 2 Outline:  Overview of Current Practice  CMC Assessment ICH Q6A Principles  Case Study Example  Extended-Release Oral Suspension Original Drug Development strategy Dissolution Results Critical Issues Recommendations Improvements Dissolution Results: Post-Improvements  Concluding Remarks

3. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 3 Current Practice:  Establishing dissolution specification(s) is a shared responsibility between the Office of New Drug Chemistry (ONDC) and the Office of Clinical Pharmacology and Biopharmaceutics (OCPB)

4. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 4 CMC Assessment: Scientific Analysis and Assessment:  Physico-chemical properties of the formulation components: drug substance(s) and excipients  Solubility  pKa  particle size distribution  Polymorphic forms  Others  Impact of these physico-chemical properties on  Processibility of the formulation components  Safety, efficacy, (BA/BE, dissolution), and stability of the drug product  Manufacturing processes, especially those having potential to influence the release profile of the drug substance  Control strategy of critical process parameters  In-process testing

5. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 5 CMC Assessment:  Relationship of in-process testing to critical quality attributes (e.g., dissolution) of the drug product:  Particle size distribution  Release rate  Compression force, tablet hardness, friability etc.  Development and validation aspects of the proposed in-vitro dissolution method (e.g., UV, HPLC etc.):  Chromatographic parameters  Specificity, linearity, accuracy, precision, ruggedness, etc.  Release time point intervals  Available in-vitro dissolution data from development, clinical, bio-, and primary stability batches for a discerning trend on storage  The proposed shelf-life of the drug product on the basis of the stability data analysis of dissolution as well as other DP attributes

6. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 6 OCPB Assessment:  Results of in-vivo studies (PK, food effect, etc.)  Results of IVIVC studies  Development/optimization of the proposed in- vitro dissolution method:  Dissolution medium (Components)/Medium pH  Release time point intervals (e.g., 1, 3, 6, 12 Hr)  Apparatus

7. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 7 CMC Assessment: In coordination with OCPB, appropriate dissolution specifications (test method and acceptance criteria) that are reflective of the dissolution data from various batches (clinical, bio-, stability) of the drug product are recommended.

8. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 8 ICH Q6A Principles:  Quality Attributes with potential relevance to dissolution within ICH Q6A:  Particle size (DS): Decision Tree #3  Polymorphic content (DS): Decision Tree #4  Polymorphic change (DP): Decision Tree #4  From the forgoing discussion (CMC assessment) it should be apparent that ICH Q6A principles for setting specifications (e.g., dissolution) are well integrated in the quality assessment of the drug product

9. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 9 ICH Q6A Decision Tree #3 Drug Substance Particle Size Distribution Acceptance Criteria

10. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 10 ICH Q6A Decision Tree #4 Drug Substance Polymorphic Content Acceptance Criteria

11. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 11 ICH Q6A Decision Tree #4 Drug Product Polymorphic Change Acceptance Criteria

12. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 12 Case Study Example Extended-Release Oral Suspension

13. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 13 Extended-Release (ER) Oral Suspension:  505(b)(2) application:  Safety and efficacy of the proposed active ingredients for the proposed indication established through immediate release products available under the Tentative OTC Monograph for the same indication  Therefore, no clinical trials required  Proposed Dose:  Single dose (Q12h) to patients 6 years of age or older  Equivalent to the nominal OTC monograph doses, given Q6h X 2

14. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 14 Drug Product Formulation:  Two different active ingredients: DS1 and DS2  DS1 is anchored to a drug carrier support and coated separately with semipermeable polymer to prevent dose dumping and to impart extended release (ER) profile  DS2 binds to the drug carrier support in-situ during the manufacturing process, but it is not coated  Both active ingredients along with other excipients are suspended in aqueous based solution  Concerns:  Safety implications due to potential dose dumping  Efficacy implications due to insufficient rate and extent of release of the actives

15. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 15 Drug Development Strategy:  Demonstrate bioavailability of the drug product formulation (6% coating of DS1) to a reference drug, an immediate-release (IR) Solution, containing the same two active ingredients  Formulate three experimental drug product formulations, each differing only by the coating level of semipermeable polymer on DS1:  Low (2% w/w): Fast release formulation  Medium (5.5% w/w): Intermediate release formulation  High (9% w/w): Slow release formulation  Establish IVIVC for each active among these three experimental formulations  Establish dissolution specifications for both actives based on generated dissolution profiles from the slow and fast release drug product formulations

16. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 16 NDA Submission Data:  Manufactured five formulations of the DP containing DS1 coated with varying levels of semipermeable polymer: 2% (low), 5.5% (medium), 9% (high) as well as 6% and 10%  Performed following PK studies:  Multi dose bioavailability (BA) study with IR solution and Single dose food effect study DP Formulation containing DS1 with 6% polymer coating  Single dose IVIVC study: DP Formulations containing DS1 with 2%, 5.5% and 9% polymer coating  In-vivo results from 4 Batches (PK studies) and in-vitro dissolution data from nine batches (4 PK and 5 stability)

17. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 17 Applicant’s Claims:  Level A IVIVC established for both the actives of the ER suspension  The mean and individual Level A IVIVC models for DS2 met the FDA validation criteria and can be used for setting dissolution specifications and biowaivers  The mean and individual Level A IVIVC models for DS1 failed the FDA validation criteria in that the predicted values had a larger error than recommended  However, if the dissolution criteria remain within the dissolution profiles tested in IVIVC study, the DS1 results can serve as a mapping study for the formulation

18. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 18 Agency’s Findings of PK Results:  BA and Food Effect Studies: (6% coating of DS1):  Systemic exposures of both actives were favorable between the ER suspension and multiple dose of reference IR solution  Observed no food effect for both actives  IVIVC Study: (2%, 5.5% and 9% coating of DS1):  DS1: Failed to establish in-vivo in-vitro correlation (IVIVC) Observed more than 20 % of difference in Cmax for formulations of fast and slow dissolution profile  DS2: Level “A” IVIVC established, but failed to validate the IVIVC The formulations used in IVIVC study were found bio- inequivalent, i.e., Cmax of the formulations used in the IVIVC study were different by more than 20% The proposed dissolution specification and the approach to set a dissolution specification based on IVIVC by mapping was found unacceptable

19. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 19 Stability Results Analysis:  Contradictory release profiles observed between drug product formulations containing 6% and 9% coated DS1  DS2 showed more decrease in dissolution than DS1  Observed substantial (up to 20%) decrease in dissolution (% release) at 1 hr, 3 hr, and 6 hr time points for both actives from their corresponding initial values among bio- and primary stability batches at all storage conditions  The decrease in dissolution was most notable at 3 hr and 6 hr time points  The decrease in dissolutions is minimum at 12 hr time point  The decrease in dissolution for both actives levels off by nine months on storage

20. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 20 Dissolution Results of DS1 6% 9% 5.5% 2%

21. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 21 Dissolution Results of DS2 6% 9% 5.5% 2%

22. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 22 Potential Critical Issues:  Raw materials Controls (including excipients):  Particle size distribution control of drug carrier support  Particle size distribution control of excipients  Manufacturing Process & In-process controls:  Binding of DS1 to drug carrier support  Coating level and coating process for DS1  Other manufacturing Processes  Particle size distribution of coated DS1  Release profile of DS1  Controls:  Particle size distribution (PSD) Criteria (drug carrier support, coated drug bound carrier support) Method (e.g., sieving vs. laser diffraction)  Dissolution method

23. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 23 Revised Drug Development Strategy:  Abandon IVIVC approach to set dissolution acceptance criteria  Conduct PK studies (BA/BE) on commercial scale bio-batch containing DS1 at the specified target coating level (rather than a range) and compare it to the reference IR solution  Manufacture additional three pilot scale primary stability batches of the drug product containing DS1 at the specified target coating level  Propose dissolution acceptance criteria based on in-vitro dissolution profiles obtained for both actives from the bio-batch

24. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 24 Applicant’s Improvements:  Process Improvements:  Specified the target coating level of semipermeable polymer within X±1% for the DS1  Revised coating and subsequent manufacturing processes  Instituted appropriate process controls to stabilize binding of both actives to the drug carrier support in the suspension  Manufactured 1 commercial scale bio- and 3 pilot scale stability batches  Controls:  Instituted appropriate particle size measurement method (e.g., laser diffraction) for drug carrier support, and coated drug (DS1) bound carrier particles  Revised PSD acceptance criteria for drug carrier support, coated drug (DS1) bound carrier support particles and suspension stabilizing excipients

25. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 25 Agency’s Findings of PK Results: Post-Improvement  Three PK Studies conducted utilizing DP formulation containing X±1% coating of DS1:  BA/BE assessment  PK at steady state  Food effect study  Results:  The PK profiles of DS1 and DS2 from test ER suspension were found similar/comparable to the reference IR solution following single and multiple dose administration  Food had no effect on bioavailability of both actives

26. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 26 Post Improvement Stability Results Analysis:  Observed stable and consistent release profiles (1hr, 3hr, 6hr and 12hr time points) for both DS1 and DS2 on storage within each of the bio- and three primary stability batches  Observed no discernible trend in release profiles of DS1 and DS2 among bio- and primary stability batches at all storage conditions  Comparable release profiles for both DS1 and DS2 among bio- and three primary stability batches

27. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 27 Post-Improvement Dissolution Results of DS1

28. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 28 Post-Improvement Dissolution Results of DS2

29. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 29 Concluding Remarks:  Identified probable causes of discrepant and inconsistent dissolution results for DS1 and DS2  Recommended corrective measures to address the issues  End results:  Consistent manufacturing process  Acceptable BA/BE results  Stable and consistent release profiles without any discernible trend on storage for both drug substances DS1 and DS2  Dissolution criteria better reflective of the data  Improvement in the quality of the drug product  Improvement in assurance against the safety and efficacy concerns

30. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 30 Concluding Remarks:  The case study example highlighted:  Lack of/poor understanding of the raw material properties and manufacturing processes that were critical to be controlled for consistent quality and thereby desired performance (e.g., extended- release/dissolution) of the drug product  Inadequate efforts invested by the applicant during the drug development to understand the causal links of dissolution failures

31. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 31 Concluding Remarks:  The case study example stresses a dire need for improvement to the existing drug development efforts to understand:  The relationship between the raw material properties of formulation components and critical quality attributes of the drug product (which and how)  The effect of raw material properties of formulation components on their processibility for selected manufacturing processes  The effect of manufacturing processes and associated critical process parameters on the critical quality attributes of the drug product

32. Office of New Drug Chemistry, OPS, CDER, U.S. Food and Drug Administration Advisory Committee for pharmaceutical Science, May 3-4, 2005 32 Concluding Remarks: There is no substitute to a systematic and scientific approach to a drug development for a safe, efficacious and quality drug product.