1. Understanding Critical Material Properties for Pharmaceutical Dosage Forms Current vs. Desired State Ken Morris Professor of Industrial and Physical Pharmacy Professor of Chemical Engineering (by courtesy) Physical and Mechanical Properties of Excipients: Workshop Summary April 5- 7, 2006

2. The Problem Pharmaceutical development and manufacturing processes have become so complex that it is increasingly difficult to provide safe and effective drugs at a significantly lower cost to patients. The science of pharmaceutical product development and manufacturing is not as advanced as in other industries such as the chemical industry, the aircraft industry, other engineering industries, etc. where Quality by Design concepts are applied more routinely A paradigm shift is required to change how pharmaceutical products are designed and manufactured once a new molecule is discovered. The ultimate choice is whether we want to invest in developing science or to have more regulation

3. Drug vs. Dosage Form Typically you dont give the pure drug to the patient? –Small doses, Unstable, Patient compliance The active pharmaceutical ingredient (API) is combined with excipients to produce a dosage form which allows the delivery of a drug in the safest and most efficacious way A dosage form relies on two elements: 1- Formula and 2 - Process A formula without a process is a pile of powder hence the need for pharmaceutical engineering

4. API is the Drug, what are Excipients? Any component intentionally added to a formulation still present in the final dosage form is an excipient Excipients must provide some necessary function in the dosage form manufacturability, stability, performance, or elegance Typical functions include: bulking agents, disintegrants, lubricants, binders, buffers, preservatives Excipients are selected to either amplify desired properties OR mask undesirable properties of the API to obtain the desired dosage form performance

5. Preformulation-Materials Sciences in Product Development: e.g., tablets

6. High Shear Granulator Fluid Bed Dryer Tumble Mixer Rotary Tablet Compression Co- mil granulation wet milling drying dry milling mixing tableting Co- mil Accela-Cota coating Tablet Imprinter imprinting Process combine the Drug and excipients into the dosage form Courtesy of Steve Nail, Eli Lilly

7. API/RM Property Selection Rationale/Process (ASTME55.02 in cmte) Define CAs Review CAs

8. So whats the problem? Variability is still the Enemy Process RM InputProduct Adapted from Rick Cooley, Eli Lilly, and Jon Clark CDER-FDA variable FIXED!! ??? You CANNOT have a constant output from a fixed process and variable input Adjustable! Variability

9. Formulation Specific IVIVC Peak Concentration Vs. % Dissolved in vitro Clarke et al. J. Pharm. Sci. 66: 1429, 1977 % Dissolved in 40 minutes 20406080100 Peak Concentration (ug/100ml) 12 14 16 18 20 22 24 26 28 30 A B H I D F J C G E Different filler

10. Current vs. Desired State: in light of FDA enabling initiatives Currently one can only either process to erase RM variability or reject much material if it isnt exactly with in spec (very expensive). The Desired State includes process solutions but also allows control to a desired endpoint! But: the process has to be designed to allow incorporation of the variability and you have to monitor critical control points!

11. NIPTE, April 2006 Understanding Product Variability: Where are we? API Variability Excipients Variability Process Variability Product ?? R. Christian Moreton, Ph.D - Idenix Pharmaceuticals, Cambridge, MA Making progress New ground Getting there

12. NIPTE, April 2006 Sources of Excipient Variability Scale – capacity of the equipment train Variability of raw materials (often of natural origin) Conditions during growing season Conditions at harvest Variation in growing season year upon year Changes in raw material source due to Drought Flood War Accident Weather at the time of manufacture Hot or cold - Dry or humid R. Christian Moreton, Ph.D - Idenix Pharmaceuticals, Cambridge, MA

13. Associated Frustrations of Excipient Suppliers Cant make a different product for EVERY Industry, Client, Product Lack of understanding of what variables are critical for a given use Lack of methods to determine many critical variables AND Customers dont always know what they want/need anyway

14. The Kicker!! There is No Pharmaceutical Excipient Industry Majority of Pharmaceutical Suppliers are Chemical Industry subsidiaries Small fraction of Parent Production Varying degrees of dedicated R&D Specifications-driven Global Market and Manufacturing Base Distributors and Repackagers No general purpose New Chemical Excipients for oral solid dosage forms since the early 70s (Moreton RC, Eur Pharm Rev Sep 1997)

15. Pharmaceutical Materials Science traditionally focused ONLY on SOLUBILITY Which is of course vital, but we know theres more –Handling –Compaction –Flow –Size –Shape –MW –etc... We lack the Materials Science tools in place for traditional materials

16. NIST/NIPTE workshopBruno Hancock16 Where do we start? Scale of scrutiny QUANTUM BULK TABLET SINGLE TABLET MOLECULAR (CRYSTAL) PARTICULATE Scale-up Blending, granulation, compression Crystallization, spray drying, lyophilization Crystal structure

17. NIST/NIPTE workshopBruno Hancock17 Predictive approaches Atomic/Molecular Particle Bulk Powder Dosage Form

18. NIST/NIPTE workshopBruno Hancock18 Where are we? Lack of MSE knowledge for our materials makes 1 st principles prediction/design a long term goal Empirical methods give relative values but rely on anecdotal data We have NO reliable mixing rules!! Standard methods dont exist or arent agreed upon for determination of many properties Lack of an excipient physical and mechanical properties database prevents Bayesian prior knowledge approaches

19. Enter NIPTE and NIST: Standards, Measurement Science, and Property Prediction Anne Chaka Chief, Physical and Chemical Properties Division Chemical Science and Technology Laboratory Second half: Ram D. Sriram Manufacturing Metrology and Standards for the HealthCare Enterprise Leader, Design and Process Group Manufacturing Systems Integration Division Manufacturing Engineering Laboratory

20. NIST Mission To promote U.S. innovation and industrial competitiveness by advancing measurement science, standards, and technology in ways that enhance economic security and improve our quality of life

21. NIST Measurements and Standards Measurement Research 2,100 publications/years Standard Reference Data 90 types available; 5,000 units sold/ year Standard Reference Materials >1,200 products available; 30,000 units sold/year Calibrations and Tests 3,200 items calibrated/year Laboratory Accreditation 826 accreditations Standards Committees 390 NIST staff, 450 committees Metrology Training Courses 25 per year

22. Collaborative Effort Between NIPTE and NIST In any product design project, the first step ought to be to fully characterize the materials that go into the product. Properties of excipients, which form the biggest part of pharmaceutical dosage forms, are not well defined and characterized. It is also not well understood how intrinsic properties of these excipients impact processing or manufacturing This is an area of fundamental research for NIPTE – without this understanding, one cannot really do Quality by Design NISTs mission is to advance measurement science, standards and technology This project is a perfect example of collaboration for these two organizations for the advancement of science in a critical area of mutual interest

23. The Needs Methods for quantifying potentially critical attributes (NIST-NIPTE collaboration)Methods for quantifying potentially critical attributes (NIST-NIPTE collaboration) Database of physical and mechanical properties of our excipients and their grades (all partners)Database of physical and mechanical properties of our excipients and their grades (all partners) Models for the drug product manufacturers to use to create a production or design space that can accommodate reasonable variation in the RMs (NIPTE)Models for the drug product manufacturers to use to create a production or design space that can accommodate reasonable variation in the RMs (NIPTE) QbD implementation in the companies to take full advantage of the above! (everyone, FDA has done its part)QbD implementation in the companies to take full advantage of the above! (everyone, FDA has done its part)

24. The Benefits of getting to the Desired State Less uncertainty in demands and less wasteLess uncertainty in demands and less waste Meaningful, reliable analytical methods based on materials understanding for determination of potentially critical attributesMeaningful, reliable analytical methods based on materials understanding for determination of potentially critical attributes Pharmaceutical Scientists and Engineers then choose their desired materials and build the appropriate design spacePharmaceutical Scientists and Engineers then choose their desired materials and build the appropriate design space Ability to identify value added changesAbility to identify value added changes Ability to recognize and meet the need for new and/or niche productsAbility to recognize and meet the need for new and/or niche products

25. Progress and Next Steps Planning committee established: Ann Chaka (NIST) and Gerald Thone (FMC) cochairs. Charge: to develop a plan for the next steps leading to a NIST-FDA-NIPTE industry CRADA Establish Steering Cmte with industry Champions Establish working groups Organize follow up workshops with more stake holders ID expertise in other fields that might help our effort Investigate the limits of testing devices

26. Next Steps Start by investigating a simple tertiary system: market drug, carrier-MCC, Mg- stearate and gradually increase complexity Round-robin testing at various companies Investigate the limits of testing devices Consider models and mixing rules Combine to do particle design to lead to the optimal behavior Map out the various stages where variability could occur

27. Acknowledgements NIPTE OPS-CDER-FDA