Implementing New Process Analytic Technologies: The underlying challenges PAT Subcommittee, June 12-13, 2002

1. Implementing New Process Analytic Technologies: The underlying challenges PAT Subcommittee, June 12-13, 2002 Justin O. Neway, Ph.D. Executive Vice President, Chief Science Officer Aegis Analytical Corporation http://www.aegiscorp.com

2. Outline • Background & information sources • Perceived benefits of PAT implementation • What are the underlying challenges? • What can manufacturers do? • What can vendors do? • What can the FDA do?

3. Background & Information Sources • ~15 Yrs in Process Development & Mfg. • Trained in Biochemistry & Microbiology • Worked in three Biotech/Pharma companies • Intimate with data problems in PD and manufacturing • ~5 Yrs with Aegis Analytical Corporation • Venture funded by GlaxoSmithKline, Merck, Aventis • Invited presentations to ~30 top Pharma & Biotech • Customer advisory panel & requirements consortia

4. Benefits of PAT Implementation • Greater control of product uniformity • Improved safety, quality compliance • Shorter cycle times, batch release times • Cost savings, supply chain stability • Moves us towards parametric release • Cost savings, lower inventory • Moves us towards continuous operations • Improved control, significant capital adjustment What about today’s failure rates, compliance & yield problems?

5. The Quality Compliance Challenge US Drug products are of high quality BUT: • Increasing trend towards manufacturing problems • Recalls, disruption of operations, drug shortages • Negative impact on New Drug Applications (NDA) • Low efficiency manufacturing and QA • Slow innovation and modernization Why do these problems occur? Janet Woodcock, M.D. FDA Science Board Presentation November 16. 2001

6. Data-intensive Decision-making Identify and control Critical Process Parameters • Quality & regulatory compliance (GMP): • Parameter review for batch release • Setting defensible specifications • Investigation of atypical batches • Manufacturing process validation • Production trend analysis • Annual Product Reviews (APRs) • Process control (stability): • Shorten process start-up/scale-up times • Shorten trouble-shooting time/adverse trend reversal • Improve process stability, productivity & quality • Improve Return on Net Assets (RONA)

7. The Real Manufacturing Data Environment The necessary data are in many separate locations Process yield & quality: discrete & replicate data LIMS PAT Instruments Process instrument measurements: discrete & continuous data Warehouse SCADA DCS PLCs Operators, times, volumes, quantities: discrete & replicate data Batch Records Material vendors, receive & release dates, equipment: discrete & replicate data ERP

8. Decision-making “Inefficiencies” • Several weeks of manual data retrieval • Not a priority for corporate IT, multiple data sources • Spreadsheet madness • “Excel add-ins”, discrete, continuous & replicate data • Bewildering choice of inadequate software • Too many packages with too little real usability • Programming required from non-programmers • Antiquated ways to communicate results • Tables of highlighted numbers • Traditional 2D plots

9. The World Around Us • Industry trends: • New instrumentation • Cheap data storage • Cheap computing power • Increased enforcement of GMP • Patent expirations • Industry consolidation, globalization The technology already exists to adequately deal with the “inefficiencies”

10. PAT Data Analysis Technology Example

11. Batch Release Technology Example - VPS Dissolution Rate Mixer Parameter Coating Parameter Dryer Parameter API Parameter

12. The Advantages of PAT A Good Balance - Compliance and Economics • FDA: • Wants better compliance to ensure safety and efficacy • Wants better manufacturing efficiency to lower drug prices • Industry: • Wants to comply but lacks necessary software capabilities • Has been building the cost of failed batches into pricing • Wants to shorten cycle times to improve economics For this to work, the realties of the manufacturing data environment must also be dealt with

13. What can we do? • Industry: • Boost manufacturing IT spending • Include mfg. users in budget prioritization • Implement underlying IT infrastructure needed for PAT • Vendors: • Make better software systems, work with industry • Be honest about software capabilities • Provide better training & support • FDA: • Continue emphasis on GMP compliance, outreach • Take opportunities to emphasize positive PAT economics

14. What can we do? • PAT subcommittee: • Continue “safe harbor” policy implementation • Account for additional necessary mfg. infrastructure • Publicize compelling economic justification • Account for hard costs, soft costs and social costs • Sponsor industry/vendor working groups • Define needs, develop requirements, provide feedback

15. Conclusions & Recommendations • PAT implementation, more difficult than expected • Requires much more than just new instrumentation • Challenges similar to other data-intensive decision-making “inefficiencies” • Poor data availability, inappropriate software systems • PAT – a unique economic incentive for quality compliance improvement • A good balance between compliance and improved economics • FDA - a catalyst for vendors, industry to work together • Gather data to show real world manufacturing software needs • Publicize the positive economics of PAT & quality compliance • Provide forums for industry/vendor collaboration