1. Title: Plan for Approach to the Understanding and Predicting Excipient Properties and Functionality NIPTE - National Institute of Pharmaceutical Technology and Education Excipient Database Development Project August 15, 2011 update

2. Today’s Agenda  Introductions  Database overview  PharmHub overview & database demonstration  Test methods overview  Feedback summary – Wish list for features – Future steps

3. NIPTE Participants NIPTE PersonnelAffiliationRole Stephen W. Hoag Ting Wang University of Maryland, Baltimore School of Pharmacy PI Data collection Data modeling Carl Wassgren Kristine Alston Purdue University Dept. of Mechanical Engineering Data collection Data modeling Ann Christine Catlin Sumudinie Fernando Sudheera R. Fernando Purdue University Rosen Center for Advanced Computing Database technology and development Hub Cyber Infrastructure Linas MockusNIPTE/PurdueDatabase data entry development Prabir BasuNIPTEDirector of NIPTE Administrative

4. Raw Material Inputs → CQA Critical Quality Attributes Hardness Disintegration time Dissolution CU/mixing Excipient Properties Crystal form Particle size Bulk density Etc. Relationships Not well understood

5. Excipient Variability Process Step Design Space Inputs Process Parameters Inputs Materials API Excipients Product (or Intermediate) Product Variability Process Variability Unforeseen/unknown excipient variability at the heart of many surprise product failures during production

6. Excipient Characterization  Key issues – Measurement variability sources  Method differences  Technique differences  Test conditions – Excipient variability  Within supplier  Between suppliers – Critical Quality Attributes (CQA) not always known  E.g., degree of substitution of HPMC – Surface area of Mg Stearate – Unknown factors Trying to account for in database Trying to catalog in database

8. Development Strategy  Won’t solve problem of excipient functionality with one project – Thus, focus on first step which is material properties of excipients  Goal to develop database infrastructure with finite resources  Start with DC and will expand to other categories as database grows – Current properties  Chemical Description  Flow  Compactability

9. PH-200 PH-102 SCG PH-102 PH-101 PH-105 PH-103PH-113 PH-112 Decrease moisture content NMT 1.5% NMT 2% NMT 3% NMT 5% Particle size 180 um 150 um 100 um 50 um 20 um PH-302 PH-301 0.3g/cc 0.4g/cc Loose bulk density Increase stability of moisture-sensitive drugs NMT= not more than Comparison of different grades of MCC Increase flow Increase batch size FMC

10. Comparison of different grades from different manufacturers--MCC ManufacturesGrades Particle Size, µm Moisture, % Loose Bulk Density, g/cc FMCAvicel PH101503.0-5.00.26-0.31 JRS Vivapur 101 65-- 0.26-0.31 Emcocel 50M0.25-0.37 AKC PH-101 502.0-6.0 0.22 UF-7110.21 KG-8020.12 KG-10000.29 FMCAvicel PH-1021003.0-5.00.28-0.33 JRS Vivapur 102 100-- 0.28-0.33 Emcocel 90M0.25-0.37 AKCPH-102902.0-6.00.30 FMC = FMC BIOPOLYMERS AKC = Asahi Kasei Corporation JRS = J Rettenmaier & Söhne GmbH and Co.KG

11. Database Structure Excipients - MCC Products - PH101 Lots - Lot # 1 Properties - particle size Test method - Light scattering Equipment - Malvern ← USP compendial category ← Actual product on the market

12. Handbook of Excipients  Handbook of excipients – 1. Nonproprietary Names – 2. Synonyms – 3. Chemical Name and CAS Registry Number – 4. Empirical Formula and Molecular Weight – 5. Structural Formula – 6. Functional Category – 7. Applications in Pharmaceutical Formulation or Technology – 8. Description – 9. Pharmacopeial Specifications – 10. Typical Properties  Angle of repose  Density (bulk, tapped and true)  Flowability  Melting point  Moisture content  NIR spectra  Particle size distribution  Solubility – 11. Stability and Storage Conditions – 12. Incompatibilities – 13. Method of Manufacture – 14. Safety – 15. Handling Precautions – 16. Regulatory Status – 17. Related Substances – 18. Comments – 19. Specific References

13. Database Structure Catalog of properties and measurements Raw data, chemical & test descriptions Measurement presentation of data Derived from raw data Eg CI, particle size, histogram Tools for usage Eg how to ID excipients to solve problems User Interface

14. Database Features Cont.  With PharmHub we can: – Create online community of users to share information  i.e., gives us the ability to pool user excipient experiences and data  Discussion boards, forums etc.  Online lectures  Become the and Facebook ® of excipients? – Capture information in real time  Have the capability to gather product info. directly from manufactures production in real time – Blind information  Can put producers and usurer information in blinded from in database  Gives capability to correlate users and producer data, which is not done currently

15. Database Partners  Worked with individuals and organizations for database guidance – IPEC – Pharm IQ – Knowledgeable individuals in Pharma  Database sustainability

16. Presentation Style  We would like this to be interactive discussion not a lecture – Please feel free to interrupt at any time!!!  Can you…  What would happen if….  Can you show me….