# Presentation: 481971

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

- Ajaz S. Hussain, Ph.D.
- Deputy Director, OPS/CDER/FDA

## 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

## ICH Q6A: Decision Tree #7 (1)

- Modified release?

- High solubility?

- Rapid dissolution?

- Relationship between
- Disintegration - Dissolution?

- No

- Yes

- Yes

- Generally single-point
- dissolution acceptance criteria
- with a lower limit

- Generally disintegration
- acceptance criteria with
- an upper limit

- Establish drug release
- acceptance criteria:
- ER: Multiple time point
- MR: Two stage, parallel
- or sequential

- Yes

- No

- No

- No

- Yes

## Test – Test Empirical Relationship

- Disintegration time (DT) vs. % Dissolved at 10 and 15 minutes

## 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)***

## 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 *

## What specific test conditions and acceptance criteria are appropriate? [IR]

- ICH Q6A [EVENT] 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. **

- aaps Annual Meeting

## 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?

## Slide 9

|  |  |  |
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|                                  Tablet Formulation |
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## 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*

## Drug M, IR Tablet

**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

- Drug Substance

- Formulation

- Process

- Product

- NIR

- Disso
- Test

- Bio
- PK/PD

***Dissolution = f *****(*****Ex1, Ex2, P1, P2, PS...*****)**

- Real Time Release
- (Stability?)

- 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 QbD 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 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

## Is Dissolution Rate Limiting?

## Theoretical & Experimental Justification

**Drug M, IR Tablet**

- Pharm Res. 1999 Feb;16(2):272-80

## Drug M, IR Tablet: For BA/BE what are the critical variables?

**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 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