What Impact should ICH Q8 have on ICH Q6A Decision Trees?

1. What Impact should ICH Q8 have on ICH Q6A Decision Trees? Ajaz S. Hussain, Ph.D. Deputy Director, OPS/CDER/FDA

2. Outline • An overview of ICH Q6A dissolution decision trees • Relationship between disintegration and dissolution test? • Mechanistic basis? Causal link? • Appropriate test conditions and acceptance criteria? • How ICH Q8 may help improve regulatory decisions? • Case example #1 DOE • Case example #2 New technology • Summary of an QbD approach

3. ICH Q6A: Decision Tree #7 (1) Establish drug release acceptance criteria: ER: Multiple time point MR: Two stage, parallel or sequential Modified release? Yes No High solubility? No Yes Rapid dissolution? Generally single-point dissolution acceptance criteria with a lower limit No No Yes Relationship between Disintegration - Dissolution? Generally disintegration acceptance criteria with an upper limit Yes

4. Test – Test Empirical Relationship • Disintegration time (DT) vs. % Dissolved at 10 and 15 minutes

5. Disintegration Time (DT) Disintegration Ft Fl Fs Fs* Tablet Surface (t) Large Fragments (l) Small Fragments (s) Total Dissolution = Ft + Fl + Fs + Fs* Prior to DT After DT Disintegration - Dissolution Relationship: Issues 10# screen Fraction dissolved Note: Disintegration and dissolution process in a dissolution apparatus may differ from that in a disintegration apparatus (different hydrodynamics and other conditions)

6. Mechanistic Understanding in ICHQ6A? • For example – “Particle size distribution testing may also be proposed in place of dissolution testing when development studies demonstrate that particle size is the primary factor influencing dissolution; justification should be provided.” • ICHQ6A 3.3.2.3 Parenteral Drug Products • Mechanistic understanding – identification and scientific justification of causal physical or chemical relationships between pharmaceutical materials and/or process factors • Note – establishment of “correlation” between two characteristics may not always be causal

7. ICH Q6A [EVENT] 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.

8. In absence of Pharmaceutical Development Information: Difficult to answer …. • Do changes in formulation or manufacturing variables affect dissolution? • Are these changes controlled by another procedure and acceptance criterion? • Adopt test conditions and acceptance criteria which can distinguish these changes. • Generally, single point acceptance criteria are acceptable. (tradition – risk based?) • Discriminating test conditions? What should the test discriminate?

10. 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

11. Drug M, IR Tablet

12. Pharmaceutical Development Information: Improves our ability to answer… • Do changes in formulation or manufacturing variables affect dissolution? • Yes, formulation composition and excipient functionality & variability; are these “critical”? • Are these changes controlled by another procedure and acceptance criterion? • Raw material certificate of analysis and weighing before charging – are these controls adequate? • Adopt test conditions and acceptance criteria which can distinguish these changes. • Test does distinguish these changes at 10 or 15 minutes; should the acceptance criterion be set at 10 minutes?

13. Need for a Comprehensive Control Strategy G.P. Migliaccio, FDA Science Forum 2005

14. Raw material variability: Certificate of analysis adequate? G.P. Migliaccio, FDA Science Forum 2005

15. Understanding and controlling critical variables DPA/FDA Unpublished data

16. Controlling Dissolution Rate: Options Dissolution = f (Ex1, Ex2, P1, P2, PS…) Drug Substance Formulation Process Bio PK/PD Disso Test NIR Product Stability Real Time Release (Stability?) “Market Standard”

17. What should the acceptance criteria be? • In the previous discussion we did not answer the question “should the acceptance criterion be set at 10 minutes?” • In QbD framework a design specification in vivo) is declared upfront, its suitability for the intended use justified and product/process designed with adequate controls

18. Design Specification • Current/Reactive: “dissolution significantlyaffect BA?” • QbD/Proactive: “Dissolution in vivo not rate limiting by design” or is “X ±Y by design” • Dissolution in vivo not rate limiting by design, i.e., sufficiently rapid such that blood levels from a tablet are essentially equivalent to that after administration of drug in a aqueous solution • Highly soluble drugs (e.g., control of critical variables using conventional formulation and manufacturing unit operations) • Low solubility drugs (e.g., novel technologies such as nanotechnology) • BA/BE studies conducted during development would then be used to test a “design specification” hypothesis

19. Is Dissolution Rate Limiting?

20. 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 (10 min selected for graphical clarity only) 0.0 0.1 0.2 0.3 0.4 0.5 Gastric Emptying Half-Time (h) Theoretical & Experimental Justification Drug M, IR Tablet Pharm Res. 1999 Feb;16(2):272-80

21. Drug M, IR Tablet: For BA/BE what are the critical variables? What should the specification be? Is a routine QC dissolution test necessary? All “BE” ? ?

22. Key Questions • What is the intended use? • What design specification delivers it? • IR tablet with rapid in vivo dissolution (~30 minutes) • What in vitro test system will be used for product development? • What is the in vitro acceptance criteria? (e.g., target 85% in 15 minutes and not slower than current regulatory standard of 85% in 30 minutes) • How is the design specification justified? • Phase I, relative BA with aqueous solution as ref. • What is the product design strategy? • Pre-formulation characterization – solubility, permeability, stability, compatability,..particle size needed for rapid dissolution • IR Tablet with a “super disintegrant”

23. Key Questions • What manufacturing science information is available to justify the design/selection of manufacturing process? • What are the critical variables with respect to manufacture-ability, stability, bioavailability? • What should be the regulatory specifications and control strategy to reliably deliver (state of control) the product quality and performance over the intend life-cycle of the commercial product?

24. In Vitro Acceptance Criteria: Product Optimization and also possibly for QC testing • Operating characteristics? • Although the test involves three stages, the behavior is dominated by the first and second stage. • In the figure (right) it can be observed that when the mean value is Q-0.6*standard deviation (10%) and less, the probability of acceptance (Pa) is insignificant, and when the mean value is Q+0.6*standard deviation and more, the Pa is almost 1. Statistical Properties of the Dissolution Test of USP. Carlos D. Saccone, Julio Tessore, Silvino A. Olivera, and Nora S. Meneces. Dissolution Technologies AUGUST 2004

25. Specifications - Standards and Continuous Improvement Current Regulatory Acceptance Range Alert Action OOS E.g., USP - Stage 2

26. Ensuring design specification are accepted as regulatory specifications • Characterize dissolution variability in acceptable clinical lots (base on clinical S&E) • Clinical lot should be in the state of control (e.g., from beginning to end of production, stratified sampling) with respect to critical variables (design specifications) • Gauge R&R type study to characterize “total” variability • Estimate of variability used to set “action” or “alert” limits within the design specification • Design specification (test method, and acceptance criteria = current public standard) then can be the regulatory specification

27. Summary • ICH Q8 has the potential to enhance utility of many aspects of ICH Q6A • Opportunity to convert the current “event” driven (reactive) decision process to an hypothesis based decision process • Design specifications – beginning with the end in mind – can focus attention on design process to exceed current regulatory standards or expectations without the need for such standards to be “tightened” based on process capability • Improved confidence in critical variables, their control strategy and achieving a state of statistical process control provide an effective means for continuous improvement within a companies quality system