Quality by Design: Next Steps to Realize Opportunities?

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

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

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

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. 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 BCS Applications

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

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. DISSOLUTION OF GENERIC & RESEARCH TABLETS 110 100 90 ANDA1 ANDA2 80 ANDA3 ANDA4 70 % DRUG RELEASED ANDA5 60 ANDA6 ANDA7 50 ANDA8 40 ANDA8 74-217 30 UMAB-SLOW UMAB-MEDIUM 20 UMAB-FAST 10 0 0 5 10 15 20 25 30 35 TIME IN MINUTES Appropriate Specification or “Over-discrimination”All Bioequivalent to RLD

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

17. (weak acid, rapid dissolution in SIF) Capsule (Ref.) 1800 1600 Tablet 1 (wet-granulation - starch) 1400 1200 Tablet 2 (direct compression - calcium phosphate) 1000 Drug Concentration in Plasma (ng/ml) 800 600 400 200 USP Paddle 50rpm, Q 70% in 30 min 0 0 1 2 3 4 5 6 Time in Hours Failure to Discriminate Between Bio-in-equivalent Products: Inappropriate Test Method?

18. 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. NDA #X: Bioequivalent?

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. ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION What specific test conditions and acceptance criteria are appropriate? [IR] YES Develop test conditions and acceptance distinguish batches with unacceptable BA dissolution significantlyaffect BA? NO Do changes informulation ormanufacturing variables affect dissolution? Are these changes controlledby another procedure and acceptancecriterion? YES YES NO NO Adopt appropriate test conditionsand 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. aaps Annual Meeting

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

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

24. Is Dissolution Rate Limiting?

25. 110 1.2 100 Rapid 1.1 90 AUC 80 Slow 1.0 70 Cmax 60 0.9 AUC, AND Cmax RATIOS (T/R) 50 0.8 % DRUG RELEASED 40 30 0.7 SOLUTION 20 FDA-UMAB (931011) 0.6 10 0 0.5 0 5 10 15 20 25 30 35 0.2 0.4 0.6 0.8 1.0 1.2 RATIO (T/R) OF % DISSOLVED AT 10 MINUTES TIME IN MINUTES Metoprolol IR Tablets:In Vitro - In Vivo Relationship FDA-UMAB (931011)

26. Mean Intestinal Transit Time = 1.67 h 2.0 85% D I S S O L U T I O N T I M E (h) 0.70 0.75 0.90 AUC 1.5 1.2 Cmax 0.95 0.80 Plot 1 Regr 0.85 1.0 1.1 1.0 0.5 AUC, AND Cmax RATIOS (T/R) 0.9 0.0 Mean Intestinal Transit Time = 3.33 h 2.0 0.75 0.8 0.80 SOLUTION T 85% ~ 30 min in vitro 1.5 0.95 0.7 0.85 FDA-UMAB (931011) 0.90 1.0 0.6 0.5 0.5 0.2 0.4 0.6 0.8 1.0 1.2 RATIO (T/R) OF % DISSOLVED AT 10 MINUTES 0.0 0.1 0.2 0.3 0.4 0.5 Gastric Emptying Half-Time (h) Metoprolol IR Tablets: Experimental & Simulation Data

28. An hypothetical case study: Critical Formulation variables? Dissolution predominantly effected by disintegrant level and by interaction terms involving disintegant and dilutent and dilutent and mg stearate. 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. Low Medium High High Medium Low SUPAC-C: Quality Risk Classification (based on SUPAC and GAMP-4) Quality by design + Systems approach Risk Likelihood Level 3 Level 2 Impact on Quality Level 1

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

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?