1. Ajaz S. Hussain, Ph.D. Office of Pharmaceutical Sciences CDER, FDA 17 September 2003 Quality by Design: Next Steps to Realize Opportunities?

2. Outline “Quality by Design” (QbD) –What is QbD from a pharmaceutical science perspective? –How is/should QbD be achieved? –When is/should QbD achieved? –How is/should level of QbD be evaluate and measured? –How should QbD communicated? –What is the relationship between QbD and Risk? –What are/should be the regulatory benefits of QbD? –What steps should FDA take to realize the benefits of QbD?

3. What is QbD from a pharmaceutical science perspective? Traditional –Dosage form Immediate release –Direct compression –Wet granulation –Dry granulation Buccal tablets Sub-lingual tablets Capsules –Hard gelatin –Soft gelatin Product Design Process Design Design features of these conventional products and processes have essentially been defined over the last several decades and toady we often do not consider these as a “design” issue. Thinking or rethinking in terms of Quality by Design offers significant opportunities.

4. “Dosage form Design” “A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug substance.” –DOSAGE FORM DESIGN: A PHYSICOCHEMICAL APPROACH. Michael B. Maurin (DuPont Pharmaceuticals Company, Wilmington, Delaware, U.S.A.), Anwar A. Hussain and Lewis W. Dittert (University of Kentucky, Lexington, Kentucky, U.S.A.)

5. MODERN TABLET FORMULATION DESIGN AND MANUFACTURE Larry L. Augsburger and Mark J. Zellhofer “Tablet dosage forms have to satisfy a unique design compromise. The desired properties of rapid or controlled disintegration and dissolution of the primary constituent particles must be balanced with the manufacturability and esthetics of a solid compact resistant to mechanical attrition.” “The objective of preformulation studies is to develop a portfolio of information about the drug substance to serve as a set of parameters against which detailed formulation design can be carried out. Preformulation investigations are designed to identify those physicochemical properties of drug substances and excipients that may influence the formulation design, method of manufacture, and pharmacokinetic- biopharmaceutical properties of the resulting product.”

6. Design Features: TABLET FORMULATION Larry L. Augsburger and Mark J. Zellhofer Optimal drug dissolution and, hence, availability from the dosage form for absorption consistent with intended use (i.e., immediate or extended release). Accuracy and uniformity of drug content. Stability, including the stability of the drug substance, the overall tablet formulation, disintegration, and the rate and extent of drug dissolution from the tablet for an extended period. Patient acceptability. As much as possible, the finished product should have an attractive appearance, including color, size, taste, etc., as applicable, in order to maximize patent acceptability and encourage compliance with the prescribed dosing regimen. Manufacturability. The formulation design should allow for the efficient, cost-effective, practical production of the required batches.

7. Achieving Quality by Design? Integrity Uniformity Weight Control In vitro Dissolution Chemical Purity API, Excipients, Manufacturing Process Pharmaceutics Profile API Particle Size API Salt Selection Chemical Compatibility Degradation Pathway Prediction Material Property Characterization Process Simulation Design Christopher Sinko, Ph.D. Pfizer Global Research & Development

8. Example Attribute: Bioavailability Objective: Maximize & reproducible –Absorption mechanism (passive, active, site specific) –Physico-chemical attributes (solubility, dissolution rate, salt selection, particle size, morphic form, stability of drug substance ….) –Formulation design (disintegrating agent, wetting agent, solubilizer, pH modifiers, absorption enhancers,..) –Process design (wet/dry granulation, lubrication, compaction,….) –Specifications and controls on all critical variables

9. BA Data from pre-CAN and Exp Toxicology Studies Simulations Using Dissolution Absorption Model** BA is expected to be significantly PS Dependent** Tablet Content Uniformity Model BA is expected to be PS Independent** In vivo studies in animals PS Analysis Drug Substance Delump (e.g. pass through 20 mesh) Is desired PS readily achievable? Consistent with Model ? No Yes Improve Model No Yes Recommend Appropriate PS In-process Sample Done PS Reduction ** At expected dosing range in humans integrating data from pre-clinical studies. Christopher Sinko, Ph.D. Pfizer Global Research & Development

10. Formulation & Process Design Starting at small scale – pilot – clinical/prod. Need tools to screen/evaluate various design prototypes –In Vitro Dissolution Test bio-studies to ensure relevance of in vitro dissolution test Relevance based on physico-chemical aspects of the drug and formulation Observations (personal) –Often a dissolution test is used to screen/evaluate experimental formulations without sufficient considerations or verification of its in vivo predictability (relevance)

11. August 2000 FDA Guidance

12. BCS Applications PRE-CLINICAL PHASE I PHASE II PHASE III CLINICAL-TRIAL- FORMULATION MARKETED FORMULATION POST-APPROVAL CHANGES MULTI-SOURCE PRODUCTS POST-APPROVAL CHANGES INITIAL CLASSIFICATION CLASS CONFIRMED PRODUCT CONFORMS TO BCS SPECIFICATION EQUIVALENCE IN VITRO EQUIVALENCE IN VITRO - LEVEL 3 EQUIVALENCE IN VITRO EQUIVALENCE IN VITRO - LEVEL 3

13. Dissolution Test & Bioequivalence: Risk Assessment Dissolution generally “over- discriminating” Dissolution fails to signal bio-in-equi ~ 30% (?) NO YES Bioequivalent Dissolution Specification Why?

14. False Positives and False Negatives!!! Test/Ref. Mean I. J. MacGilvery. Bioequivalence: A Canadian Regulatory Perspective. In, Pharmaceutical Bioequivalence. Eds. Welling, Tse, and Dighe. Marcel Dekker, Inc., New York, (1992)).

15. Appropriate Specification or “Over- discrimination” All Bioequivalent to RLD

16. Failure to Discriminate Between Bio-in- equivalent Products: Inappropriate Acceptance Criteria 01020304050 % Drug Dissolved 0 10 20 30 40 50 60 70 80 90 100 110 USP Specification Product A Product B Time in Minutes Product B was not bioequivalent to Product A Log(AUCinf): CI 94.6 - 123.6 Log(AUC): CI 89.1 - 130.0 Cmax: CI 105.3 - 164.2

17. Failure to Discriminate Between Bio-in- equivalent Products: Inappropriate Test Method?

18. NDA #X: Bioequivalent? Drug X (100 mg dose, volume required to dissolve the dose at pH 8, lowest solubility, is 230 ml, extent of absorption from a solution is 95%) Weak base exhibits a sharp decline in solubility with increasing pH above 3 Clinical-trial formulation: Wet granulation, drug particle size (D50%) 80 microns, lactose MCC, starch, Mg-stearte, silicon dioxide. Tablet weight 250 mg. Dissolution in 0.1 N HCl 65% in 15 min and 100 % in 20 minutes. Disintegration time 10 minutes. The company wants to manufacture the product using direct compression. To-Be-Marketed formulation: Direct compression, drug particle size (D50%) 300 microns, dicalcium phosphate, MCC, Mg-stearate, silicon dioxide. Tablet weight 500 mg. Dissolution in 0.1 N HCl - 85% in 15 min., and 95% in 20 min. Disintegration 1 min. Clincal product exhibits poor dissolution in pH 7.4 media (about 30% in 60 minutes). Data for T-b-M not available.

19. Failure of Dissolution Tests to Signal Bio-in-equivalence Inappropriate “acceptance criteria” –One point specification –Set “too late” Inappropriate test method –media composition (pH,..) –media volume –hydrodynamics Excipients affect drug absorption Other reasons

20. aaps Annual Meeting20 ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION What specific test conditions and acceptance criteria are appropriate? [IR] dissolution significantly affect BA? Develop test conditions and acceptance distinguish batches with unacceptable BA YES NO YES NO YES NO Do changes in formulation or manufacturing variables affect dissolution? Are these changes controlled by another procedure and acceptance criterion? Adopt appropriate test conditions and acceptance criteria without regard to discriminating power, to pass clinically acceptable batches. Adopt test conditions and acceptance criteria which can distinguish these changes. Generally, single point acceptance criteria are acceptable.

21. Average # of BE Studies: At a Major Pharmaceutical Company mean ~ 24 mean ~ 7

22. In Vivo BE* for Justifying Changes During Development Capsule Tablet (WG) Film Coat Site Change in Drug Manuf. Solvent -Coat Site Change Tablet (DC) Multi- Strength Scale-up Multi- Strength BE Study Failed BE To-Be-Marketed Approval *Generally 3-6 clinical bioequivalence tests are conducted in a NDA

23. Tablet Formulation

24. Is Dissolution Rate Limiting?

25. Metoprolol IR Tablets: In Vitro - In Vivo Relationship FDA-UMAB (931011) RATIO (T/R) OF % DISSOLVED AT 10 MINUTES 0.2 0.40.60.81.01.2 AUC, AND Cmax RATIOS (T/R) 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 SOLUTION FDA-UMAB (931011) AUC Cmax

26. Metoprolol IR Tablets: Experimental & Simulation Data RATIO (T/R) OF % DISSOLVED AT 10 MINUTES 0.20.40.60.81.01.2 AUC, AND Cmax RATIOS (T/R) 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 AUC Cmax Plot 1 Regr FDA-UMAB (931011) SOLUTION T 85% ~ 30 min in vitro

28. Dissolution predominantly effected by disintegrant level and by interaction terms involving disintegant and dilutent and dilutent and mg stearate. An hypothetical case study: Critical Formulation variables? Unpublished Data from DPQR/CDER/FDA

29. What is QbD? Design decisions based on through formulation and process understanding as these relate to the intended use What is the relationship between QbD and Risk? –Within a given quality system and for a product: inverse relationship between level of QbD and Risk

30. QbD Questions (Contd.) How is/should QbD be achieved? –In a structured manner guided by scientific information/knowledge gathered during pre-formulation, development, scale-up, and in production When is/should QbD achieved? –Ideally for clinical trial material (all major/critical aspects), fine- tune over the life-cycle How is/should level of QbD be evaluate and measured? –Established relationships (preferably – quantitative /mathematical) between product & process variables and quality attributes (as in draft PAT Guidance) How should QbD communicated? –As part of the original submission (e.g., CTD-Q; P2 – Pharmaceutical Development) and/or –Post-approval (supplement or comparability protocol )

31. QbD Questions (Contd.) What are/should be the regulatory benefits of QbD? –Product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product performance –Risk-based regulatory approaches recognize the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance and the capability of process control strategies to prevent or mitigate the risk of producing a poor quality product –Example: Customized SUPAC [SUPAC –C]

32. What steps (is) should FDA (taking) take to realize the benefits of QbD? Start to build elements of “Pharmaceutical Development” in all relevant guidance documents (e.g., Draft Drug Product Guidance) Support development of ICH guideline on “Pharmaceutical Development” Train FDA staff on how to evaluate the knowledge content of “Pharmaceutical Development Reports”

33. What steps (is) should FDA (taking) take to realize the benefits of QbD? While the ICH process on Pharmaceutical Development is ongoing –Focus on SUPAC-C concept –Work with/within the draft Comparability Protocol Guidance Is this format too restrictive? –In addition to Comparability Protocol concept develop additional guidance on SUPAC-C Appendix to Comparability Protocol? Planned revisions of current SUPAC guidance? Independent SUPAC-C guidance?

34. SUPAC-C: Quality Risk Classification ( based on SUPAC and GAMP-4) High Medium Low Medium High Risk Likelihood Impact on Quality Level 3 Level 2 Level 1 Quality by design + Systems approach

35. Quality Risk Priority 3 2 1 Low Medium High Probability of Detection Risk Classification High Medium Low Quality by design + Systems approach

36. Level of QbD: Metrics Achievement of pre-determined product and process performance characteristics that are adequate for the intended on every batch and in an established cycle time Performance characteristics are selected or developed through scientific studies –to identify target characteristics –of all relevant sources of variability in the target characteristics –to evaluate the effectiveness of testing/controls strategies to mitigate the risk of variability Metrics –Right-first-time –Process Time/Cycle time –Ability to reliably predict impact of changes

37. “Quality by Design” (QbD) What is QbD from a pharmaceutical science perspective? How is/should QbD be achieved? When is/should QbD achieved? How is/should level of QbD be evaluate and measured? How should QbD communicated? What is the relationship between QbD and Risk? What are/should be the regulatory benefits of QbD? What steps should FDA take to realize the benefits of QbD?