1 Overview of Pharmaceutical Technology and Education Areas: Industrialization Pharmaceutical Technology Manufacturing Science Pharmaceutical Engineering Education

2 The Pipeline Problem  Despite the most sophisticated drug discovery methods and the largest expenditures ever, fewer new drugs are reaching the market  Last year only 20 (not 50) New Molecular Entities reached the market  This is termed “the pipeline problem”  New technologies for bringing Molecules to Market are needed  Pharmaceutical Technology will achieve this goal

3 The Pipeline Problem

4 Critical Path Concepts

5 Critical Path Initiative  Tools for increasing the number of drugs reaching the market  Tools for speeding drugs to market  Modernize tools for product development  Create new tools

6 Critical Path Critical Path Research and Translational Research are related

7 Three Areas on the Critical Path (FDA) Scenario 1: The Pharma Industry will Fragment into these three areas and Discovery

8 Critical Path

9 The Amlodipine Story Nifedipine Amlodipine

10 Amlodipine Industrialization  Initially the maleate salt was made  Maleate salt had a biologically active degradation product  Switched to besylate salt late in development  Amlodipine besylate (Norvasc is the most successful heart drug ever developed)

11 Status of Pharmaceutical Technology HISTORICAL DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION HEURISTIC RULES “Rules of Thumb” EMPIRICAL MODELS MECHANISTIC MODELS Rules Current Level of Knowledge Desired Level of Knowledge

12 Tools and Strategies  Approaches to dealing with problem compounds  Product design concept and quality by design  Predictive capabilities Solubility Bioavailability Stability  FDA – predictive capabilities could save $100 million per drug

13 Critical Path Dimensions  Physical design Screening and Simplified Formulations ► Toxicology ► Clinical trials ► Example – salt, disintegrant, lubricant  Characterization XRPD  Specifications GMP Analytical methods

14 Critical Path Dimensions  Lack of trained personnel  Few educational programs  Very little fundamental research on pharmaceutical materials

15 Key Concepts Improve quality 1. Know what you have 2. Make the same thing every time (within the design space) Reduce costs Cost of goods sold is up to $80 billion dollars A 20% reduction leaves $16 billion to discover new drugs or reduce costs

16 Educational Strategies  Pharmaceutical Engineering  Molecules to Market educational strategy  Allen Chao GMP Center  Regulatory Programs National GMP Curriculum

17 Outcomes  More drugs on market  Reduced time to market  Improved quality  Reduced costs of drugs

18 Extras

19 Dimensions of the Pipeline Problem  Patient deaths and unfavorable outcomes because of delays in marketing new drugs  At least $100,000,000 per drug under development ($2-4 billion per year)

20 Pipeline Problem - Related Issues  Higher risk manufacturing processes (variability is two sigma not six sigma)  Reduced flexibility in manufacturing  Major manufacturing problems and issues Disastrous CMC inspections by the FDA

21 Pipeline Problem - Related Issues  Significance /Insignificance of Validation Is validation just a well rehearsed demonstration lacking any significant value?  Difficulty in scaling up Numerous bridging bioequivalence studies  Insufficient size and personnel in existing centers and programs to address these issues

22 Status of Pharmaceutical Technology HISTORICAL DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION HEURISTIC RULES “Rules of Thumb” EMPIRICAL MODELS MECHANISTIC MODELS Rules Current Level of Knowledge Desired Level of Knowledge

23 Detector Filter Wheel Optical filters Sensors for Process Understanding and Control: Fixed-Wavelength (Filter) NIR Gauge NDC-Infrared Engineering Irwindale, CA

24 Heat and Mass Transfer Modeling of Drying: Two-Stage Drying In a UniGlatt APAP Granulation at 60 °C Time (min) NIR Linear Region (Evaporative Cooling) Exponential Region (Diffusion Limited) P.L.D. Wildfong, A.-S. Samy, J. Corfa, G.E.Peck, and K.R. Morris J Pharm Sci –639 (2002).

25 Temperature vs Time for APAP Granulation: The Opportunity for Innovation Critical moisture Temperature Moisture Content Drying Time (min) MM55 Reading Temperature (°C) T MM K.R. Morris, S.L. Nail, G.E. Peck, S.R. Byrn, U.J. Griesser, J.G. Stowell, S.-J. Hwang, K. Park Pharm Sci Tech Today –245 (1998).

26 Fast-Drying Trials of an Ibuprofen Granulation Comparison of Average MM55 Values Between Fast Drying and Traditional Drying Time (min) MM55 Fast-Drying Average MM55 Traditional-Drying Average MM55 P.L.D. Wildfong, A.-S. Samy, J. Corfa, G.E.Peck, and K.R. Morris J Pharm Sci –639 (2002).

27 A National Center to Address these Issues  Materials science – fundamental understanding  Pharmaceutical engineering  Process understanding and control  Design for six sigma  Informatics  Industrialization Physical design Characterization Scale-up & small scale production Specifications  Build on success of current centers/consortia

28 National Center Current Consortia & Programs New Programs

29 Current Consortia & Programs CAMP NSF CPPR PTCC 21 st Century GMP Regulatory Education

30 New Programs ERC Mater. Sci. Infor- matics Anal. Chem. Six Sigma Prediction Pharm. Engr.

31 Science and Engineering Expertise at Purdue  Leading basic and applied science programs in Engineering Chemistry Pharmacy Materials science  Top Pharmacy School and Industrial Pharmacy Department  Leading Chemical Engineering Department  Leading manufacturing program  Top analytical chemistry program  Ability and willingness to collaborate

32 Regulatory Expertise  Purdue faculty participation in Pharmaceutical Sciences Advisory Committee of the FDA Garnet Peck Steve Byrn (former Chair) Ken Morris  Training FDA “Patriot Team” in process analytical technology (PAT), receiving international kudos  Teaching courses to FDA and the only academics advising major CMC revisions (Ken Morris)  Purdue IPPH faculty are members of United States Pharmacopoeia Committee of Experts (Byrn and Peck)  Harvey Wiley a Purdue Professor was the first commissioner of the FDA

33 Multi-university Programs  Collaborator via CAMP – MIT  Collaborator via PTCC – IIT  Collaborators via NSF CPPR – Univ. of Puerto Rico, U. Conn., Minnesota, Rutgers  Collaborators via ERC and National Center (Proposed) - Rutgers

34 Conclusion – Strategy National Center for Pharmaceutical Technology  Establish a Center patterned after the National Center for Food Safety and Technology and/or Argonne Laboratory  Establish facilities and infrastructure  Obtain programmatic support from FDA (for FDA employees) and a consortium of companies  Investigate scientific issues of mutual interest to the FDA, companies and academia  Establish educational programs

35 Administration of National Center  Not for profit  Administered by Purdue  MOU with several universities in process  Run by full time professional project manager  Board integrated by academics, industrialists, government rep.  Funding in the $20 M per year range

36 Extra

37 Hierarchy of Projects 1. Materials Science 2. PAT – Process understanding 3. Informatics 4. Prediction 5. Low Variability – 6 Sigma