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 kd kp kd = dissolution rate Formulated drug Solubilized drug Absorbed drug kd kp kd = dissolution rate function of solubility (including food), drug product quality attributes kp = 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 Of Drug Product Drug Release Rate Disintegration, Erosion and Granule Dissolution Swelling/ Water Penetration API Solubilization (rate/extent) Porosity Hardness Wetting API Form Selection (Salt, Polymorph, Particle Size) DP Excipient Selection, DP Process Selection API Form Selection, API Process Selection 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 2nd choice: direct comp. 3rd: dry granulation API Form Selection PS of API (match to excipients) Brittleness of API Counter ion selection Polymorph selection Solubility of API form API Process Selection N/A Crystallization/ Milling – mechanical property; shape/size Milling 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 Granulation Time Temperature Agitation Rate Seeding Cool down rate Solvent quality Filter heel Blow down time Cake thickness Slurry thickness Filter cloth/mesh Cake smoothing procedure Wash temperature Wash solvent quality Hold time Transfer procedures Agitation rate Inlet temperature Nitrogen blanketing Drying time Agitation blade Particle shape Drying vacuum Heel Transfer procedures Set up procedures Feed rate Screen size Mill speed Particle size Agglomeration Operator training Size measurement Particle shape Shape measurement Mill temperature 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