What Impact should ICH Q 8 have on

What Impact should ICH Q 8 have on ICH Q 6 A Decision Trees? Ajaz S. Hussain, Ph. D. Deputy Director, OPS/CDER/FDA

Outline • An overview of ICH Q 6 A dissolution decision trees – Relationship between disintegration and dissolution test? – Mechanistic basis? Causal link? – Appropriate test conditions and acceptance criteria? • How ICH Q 8 may help improve regulatory decisions? – Case example #1 DOE – Case example #2 New technology • Summary of an Qb. D approach

ICH Q 6 A: Decision Tree #7 (1) Modified release? Yes No Establish drug release acceptance criteria: ER: Multiple time point MR: Two stage, parallel or sequential High solubility? Yes Rapid dissolution? Yes Relationship between Disintegration - Dissolution? 3/18/2018 No No Generally single-point dissolution acceptance criteria with a lower limit No Yes Generally disintegration acceptance criteria with an upper limit

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

Disintegration - Dissolution Relationship: Issues Disintegration Time (DT) Disintegration Fraction dissolved Ft Fl Tablet Surface (t) 10# screen Fs Large Fragments (l) Fs* Small Fragments (s) Total Dissolution = Ft + Fl + Fs* Prior to DT After DT Note: Disintegration and dissolution process in a dissolution apparatus may differ 3/18/2018 from that in a disintegration apparatus (different hydrodynamics and other conditions)

Mechanistic Understanding in ICHQ 6 A? • 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. ” • ICHQ 6 A 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

ICH Q 6 A [EVENT] DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION What specific test conditions and acceptance criteria are appropriate? [IR] YES dissolution significantly affect BA? Develop test conditions and acceptance distinguish batches with unacceptable BA NO Do changes in formulation or manufacturing variables affect dissolution? Are these changes controlled by another procedure and acceptance criterion? YES NO NO 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. aaps Annual Meeting 7

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?

Tablet Formulation

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 Unpublished Data from DPQR/CDER/FDA

Drug M, IR Tablet

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?

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

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

Understanding and controlling critical variables DPA/FDA Unpublished data

Controlling Dissolution Rate: Options Dissolution = f (Ex 1, Ex 2, P 1, P 2, PS…) Drug Substance Formulation Process Product NIR Disso Test Bio PK/PD Stability Real Time Release (Stability? ) “Market Standard”

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 Qb. D framework a design specification in vivo) is declared upfront, its suitability for the intended use justified and product/process designed with adequate controls

Design Specification • Current/Reactive: “dissolution significantly affect BA? ” • Qb. D/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

Is Dissolution Rate Limiting?

Drug M, IR Tablet Theoretical & Experimental Justification Mean Intestinal Transit Time = 1. 67 h 0. 70 0. 75 85% 1. 2 D I S S O L U T I O N Cmax Plot 1 Regr 1. 1 1. 0 0. 7 0. 6 0. 5 0. 2 T 85% ~ 30 min in vitro 0. 8 SOLUTION 0. 9 FDA-UMAB (931011) AUC, AND Cmax RATIOS (T/R) AUC 0. 4 0. 6 0. 8 1. 0 T I M E 1. 2 RATIO (T/R) OF % DISSOLVED AT 10 MINUTES (10 min selected for graphical clarity only) 2. 0 0. 90 1. 5 0. 95 0. 80 0. 85 1. 0 0. 5 2. 0 0. 0 Mean Intestinal Transit Time = 3. 33 h 0. 75 0. 80 1. 5 0. 95 0. 85 0. 90 1. 0 0. 5 (h) 0. 0 0. 1 0. 2 0. 3 0. 4 0. 5 Gastric Emptying Half-Time (h) Pharm Res. 1999 Feb; 16(2): 272 -80

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” ? ?

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”

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?

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

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

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

Summary • ICH Q 8 has the potential to enhance utility of many aspects of ICH Q 6 A – 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