1. Critical Material Properties for Pharmaceutical Dosage Forms - Industry Perspective Tony Hlinak Abbott Laboratories North Chicago, IL

2. Phys Props of Pharm Powders April, 2006 2Company Confidential © 2006 Abbott Real World – Case 1 Spec Limits ?

3. Phys Props of Pharm Powders April, 2006 3Company Confidential © 2006 Abbott Real World – Case 2 ?

4. Phys Props of Pharm Powders April, 2006 4Company Confidential © 2006 Abbott Drug Product Manufacturing Formula Components Manufacturing Process Process Parameters Drug Product Physical Process Material Properties Process Model Quality Attributes Model Parameters Model-Based Process

5. Phys Props of Pharm Powders April, 2006 5Company Confidential © 2006 Abbott Material Properties Require Attention Affect processing behavior and final dose performance Can compromise an otherwise robust process –Reduce Reliability –Make Less Predictable Minimum Costs –Excessive waste, chronic rework, increased cycle times, uneven utilization of resources, and increased compliance risk Worst Case –Disrupt supply chain, exhaust technical and management resources, threaten relationship with regulatory agencies, weaken competitive position, and ultimately lose customers

6. Phys Props of Pharm Powders April, 2006 6Company Confidential © 2006 Abbott Material Property Effects - Realities Complex, Broad, Interrelated Many Characteristics Not True “Properties” in Thermodynamic Sense Relevant Property Information Not Available for Many Materials Even Those That are Widely Used in our Industry Many Properties of Interest Not Measurable Using Conventional Analytical Tools Variability in Some Methods are High and/or Highly Technique Dependent Property Impacts May Change with Processing Scale Property Impacts Depend on Both Amount Present in Formula and Other Components Present

7. Phys Props of Pharm Powders April, 2006 7Company Confidential © 2006 Abbott Property Example – Handbook of Excipients (2000) Compression characteristics of dibasic calcium phosphate anhydrous. Tablet weight: 750 mg Handbook of Pharmaceutical Excipients, First Edition Reprinted with permission from Marcel Dekker, Inc., to be published in Compaction of Pharmaceutical Excipients by Metin Celik, in press, 1999) : Microcrystalline cellulose, Emcocel 90M (Lot # 1037X. Mendell) at V = 100 mm/s : Microcrystalline cellulose, Emcocel 90M (Lot # 1037X. Mendell) at V = 300 mm/s

8. Phys Props of Pharm Powders April, 2006 8Company Confidential © 2006 Abbott Microcrystalline Cellulose Mechanical properties (a) Compression pressure: 9.84 kN/cm 2 Tensile strength: 0.8711 kN/cm 2 Permanent deformation pressure: 15.3 Brittle fracture index: 0.0821 Bonding index: 0.0571 Reduced modulus of elasticity: 1472 Flowability: 1.41 g/s for Emcocel 90M. (9) Calcium Phosphate Flowability: 18.9 g/s for A-TAB Property Example – Handbook of Excipients (2000)

9. Phys Props of Pharm Powders April, 2006 9Company Confidential © 2006 Abbott The Current State 1)Little or no information concerning relevant properties may be available on a particular component even those that are widely used within the industry 2)The properties of interest may not be measurable using conventional analytical tools or the results obtained are very technique dependent 3)Reliable mixing rules that allow estimates of mixture properties to be generated from the known properties of the components don’t generally exist 4)Physical models that link the output properties to the input properties are currently insufficient for most pharmaceutical unit operations 5)The impact of a particular property may change as the pharmaceutical manufacturing process is scaled or optimized, and will likely depend on both the amount of the component present in the formula as well as the type and amount of other components present

10. Phys Props of Pharm Powders April, 2006 10Company Confidential © 2006 Abbott The Flow Property Group Particle Size Distribution Particle Shape Distribution Bulk Density Surface Area Surface Energy Cohesiveness Surface Structure Static Charge Hygroscopicity

11. Phys Props of Pharm Powders April, 2006 11Company Confidential © 2006 Abbott The Uniformity Property Group Particle Size Distribution Particle Shape Distribution Surface Area Surface Energy Cohesiveness Surface Structure Static Charge Hygroscopicity

12. Phys Props of Pharm Powders April, 2006 12Company Confidential © 2006 Abbott The Wetting Property Group Particle Size Distribution Bulk Density Pore Size Distribution Surface Area Surface Energy Cohesiveness Surface Structure Static Charge

13. Phys Props of Pharm Powders April, 2006 13Company Confidential © 2006 Abbott The Drying Property Group Particle Size Distribution True Density Pore Size Distribution Surface Area Hygroscopicity

14. Phys Props of Pharm Powders April, 2006 14Company Confidential © 2006 Abbott The Mechanical Property Group Particle Size Distribution True Density Bulk Density Cohesiveness Elastic Modulus Compactibility Brittleness

15. Phys Props of Pharm Powders April, 2006 15Company Confidential © 2006 Abbott The Dissolution Property Group Particle Size Distribution Pore Size Distribution Surface Area Wetting Propensity Amorphous Content

16. Phys Props of Pharm Powders April, 2006 16Company Confidential © 2006 Abbott The Stability Property Group Particle Size Distribution Surface Area Amorphous Content Hygroscopicity

17. Phys Props of Pharm Powders April, 2006 17Company Confidential © 2006 Abbott Processing and Dosage Form Considerations

18. Phys Props of Pharm Powders April, 2006 18SPI - Bulk Properties Sub- ProcessCompany Confidential © 2006 Abbott High Level Map Select Property Particle Size Bulk Density Surface Area Particle Shape True Density Pore Size Surface Energy Flow Property Wetting Cohesiveness Surface Structure Amorphous Content Tensile Strength Elastic Moduli Compactibility Brittleness Static Charge Evaluate Property Property Critical? Select Another Property No Select Control Yes Demonstrate Control Property Database

19. Phys Props of Pharm Powders April, 2006 19Company Confidential © 2006 Abbott Recommendations 1.Currently available models for common pharmaceutical unit operations should be assessed and the relevant physical properties extracted 2.Available methods for quantifying the physical property list generated in the step above should be evaluated and the most promising approaches further developed specifically for pharmaceutical powders 3.As methods reach a sufficient state of maturity, the most commonly used pharmaceutical materials should be characterized and the results published in standardized tables. The results should include multiple vendors and include appropriate estimates of variation 4.The component results and the methods from the step above should be used to generate appropriate mixing rules for predicting the relevant properties of powder mixtures from the properties of the components 5.Iterate