# Presentation: 326159

## Quality By Designand DissolutionPhRMA10/25/05

- Presented by
- Christopher Sinko, Ph.D.
- at the Advisory Committee for Pharmaceutical Science meeting
- on October 25, 2005

## PhRMA Contributors

**R. Baum****	****	****	****Pfizer**
**L. Dias****	****	****	****Abbott**
**M. Diener****	****	****	****Sanofi Aventis**
**M. Oates****	****	****	****Pfizer**
**Parr****	****	****	****Glaxo Smith Kline**
**S. Poehlein****	****	****	****Merck**
**R. Poska****	****	****	****Abbott**
**R. Reed****	****	****	****Merck**
**C. Sinko****	****	****	****Pfizer**
**Till****	****	****	****PhRMA**
**E. Warner****	****	****	****Schering Plough**
**C. Wilson****	****	****	****Glaxo Smith Kline**

## Agenda

**Quality by Design (QbD) Approach for Understanding Drug Release**
**Advantages and Challenges of QbD**
**Next Steps/Path Forward**

## Dissolution Testing and Drug Release

**Dissolution testing has been widely used as the primary tool to evaluate drug release**
**Other attributes may be more meaningful and should be explored**
**Dissolution testing may not be needed if other attributes are more predictive of drug release**

## Quality by Design for Drug Release

**Two primary aspects**
**Clinical relevance of release and stability specifications**
**Correlation between process parameters and ability to achieve specifications (and therefore remain clinically relevant)**

## Where Do We Start?

**Begin with immediate release dosage forms**
**Extended release out of scope at this time**
**Early clinical studies used to determine drug release needs **
**Well-established concepts, such as the Biopharmaceutics Classification System (BCS), can provide context regarding...**
**Drug product quality attributes**
**API quality attributes**

## Basic Concept of BCS

**Formulated**
** ****drug**

**Absorbed**
** ****drug**

**Solubilized drug**

***k******d***

***k******p***

***k******d***** = dissolution rate**
**function of solubility (including food), drug product quality attributes**
***k******p***** = permeability rate**
**major function of API molecular structure**
**minor dependence on salt form, food?, excipients, etc. **

## Basic Concept of BCS

**Attributes that can affect the dissolution and permeability rates include those**
**Related to API solubilization**
**API salt form, polymorph, particle size, surface area or wetting**
**Related to cohesive properties of the drug product that influence disintegration**
**Porosity, hardness, wetting, swelling/water penetration**

## Quality Attributes

**Drug Release Rate**

**Disintegration, Erosion and Granule Dissolution**

**API Solubilization**
**(rate/extent)**

**Porosity**

**API ****Form Selection**
**(Salt, Polymorph, Particle Size)**

**Hardness**

**Wetting**

**Swelling/**
**Water Penetration**

**DP Excipient Selection, DP Process Selection**
**API Form Selection, API Process Selection**

**Quality Attributes**
**Of Drug Product**

- Features of “Quality by Design”:  doing things consciously*

- *A Quality by Design Approach to Dissolution Based on the Biopharmaceutical Classification System, R. Reed

## The Logic of QbD

**Once a formulation scientist understands the patient’s requirements, they can design a formulation using either or both approaches:**
_**Prior knowledge**_**:  choose API form, excipients and processes that will achieve the expected release profile**
_**QBD**_**:  select API form, excipients and processes that have greatest impact on quality attributes that affect release of drug**
**Selections based on theoretical/fundamental understanding, alternative measurements and heuristic development**

## Connecting QbD to Quality Attributes

| QBD Factors | Porosity | Hardness | Wetting | Swelling/
Penetration | API Solubilization |
| --- | --- | --- | --- | --- | --- |
| DP Excipient Selection | PS of excipients (match to API)
Hardness/
Brittleness of excipients
Granule strength | Bonding Index
Brittle Fracture Index
Compression force profile via simulation
Other mechanical properties | Contact angle measurements | Solubility of excipients
Microscopic evaluation of swellability | Analysis described in porosity, wetting and swelling |
| DP Process Selection* | 1st choice: wet granulation
2nd choice: dry granulation
3rd:  direct comp. | 1st choice: dry granulation
2nd choice: wet granulation/direct compression | 1st choice: wet granulation
2nd choice: direct comp.
3rd:  dry granulation | 1st choice: wet granulation
2nd choice: direct comp.
3rd:  dry granulation | 1st choice: wet granulation
2nd choice: direct comp.
3rd:  dry granulation |
| API Form Selection | PS of API (match to excipients)
Hardness/
Brittleness of API | Bonding Index
Brittle Fracture Index
Compression force profile via simulation 
Other mechanical properties | Contact angle measurements | Counter ion selection
Polymorph selection
Solubility of API form
Microscopic evaluation of swellability | Counter ion selection
Polymorph selection
Analysis described in porosity, wetting and swelling |
| API Process Selection | N/A | Crystallization/
Milling – mechanical property; shape/size | Milling | N/A | Crystallization/
Milling – shape/size |

- *use DP excipient selection measurements to facilitate DP process selection

## Processing Variables, Influence and Design Space

**Each quality attribute is affected and/or influenced by processing variables**
**Processing variables can be generically categorized as process parameters**
**Machine parameters, methods, people, operating environment**

## Definition of Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs) Describing the Design Space

**It is necessary to identify the quality attributes that are critical, i.e. those defining **
**Purity**
**Potency**
**Surrogate for Bioavailability**
**Identify CQAs that have strong bearing on the drug release rate**
**Identify critical few processing parameters that ensure CQAs are met**

## Processing Variables, Influence and Design Space

**One definition of “Design Space” may be the functional relationship between the attributes and process parameters**
**Closer to the current reality**
**Another may be that the boundaries of Design Space are defined by the CQAs**
**Would mean that any modifications made to the product that allowed the CQAs to be met would be acceptable**
**This definition requires that the CQAs serve as a surrogate for clinical performance**
**Closer to the “desired state”**

## Design Space ExampleAPI Particle Size

**Design Space in this context is defined as the functional relationship between CQAs and CPPs**
**It is determined that Particle size of the API is a critical quality attribute that serves as a measure of release rate**
**Process parameters can then be evaluated to determine their impact on this CQA and if they are critical**

## Design SpaceAPI Particle Size

- Crystallization/
- Filtration

- Wash/Drying

- Milling

- Represents a known interaction

## Advantages of QbD for Dissolution

**If we only focus on the dissolution test we miss an opportunity to gain a better fundamental understanding of other attributes and their associated process parameters that can significantly influence drug release**
**A ****greater understanding of the underlying scientific connection between factors of the design and the attributes will be achieved**
**Will result in enhancement to the already high quality of today’s pharmaceutical products**

## Current Challenges

**How do we define release and stability specifications that are clinically relevant and not limited to a reflection of process capability?**
**Only when this is achieved will the full benefits of a QbD approach be realized**
**Broad understanding of and commitment to the “desired state” by industry and regulators**

## Next Steps/Path Forward

**Continue industry/FDA collaborations to make the concept of “Design Space” more tangible**
**A focused effort to ****define a mechanism that will allow development of clinically relevant specifications is necessary**