1. Xcellerex … speeding medicines to people … PAT for Biologics Ensuring Quality of Biologically Produced Drugs FDA Advisory Committee on Pharmaceutical Sciences April 13, 2004 Parrish Galliher and Elizabeth Fowler Xcellerex

2. …speeding medicines to people … Outline Xcellerex View of PAT Importance of PAT for Biologics Value of PAT Implementation of PAT – Xcellerex Program Summary

3. Xcellerex …speeding medicines to people … Xcellerex View of PAT Process knowledge gained through process analytics and statistically designed process optimization studies Processes designed for quality Continual monitoring ensures process control Risk based approach to quality; PAT provides data

4. Xcellerex …speeding medicines to people … Key Issues in Biologics Production Biological variation in production of material –Animal to animal variation –Cell culture variation Biological safety – unknown pathogens Unrelated impurities with unknown activities More biological variables Greater need for PAT

5. Xcellerex …speeding medicines to people … Product Risk Management Present: Minimal process change allowed Process parameters used as surrogates for product quality monitoring Release and some in-process testing used to ensure product consistency Future: Real-time monitoring provides increased assurance of process and product quality consistency Increased process understanding enables risk- adjusted evaluation of process & product data

6. Xcellerex …speeding medicines to people … Real-Time Process Monitoring Biotechnology Drugs Fermentation Purification Formulation Fill Finish Present Cell growth Cell viability Metabolic parameters (dO 2, pH, glucose) Process parameters (OD, pH, Flow rate, Conductivity) API concentration Environment Fill volume Future API content API quality Impurities Bioburden & viruses API quality Content uniformity Excipient uniformity Impurity levels Sterility API concentration API quality Impurity clearance Bioburden & viruses Purpose Control product quality Ensure biosafety Control product quality Ensure impurity removal Ensure biosafety Ensure product Ensure uniformity Ensure safety

7. Xcellerex …speeding medicines to people … Value of PAT for Biologics Ensure product quality remains consistent Assess deviation impact in real time –Avoid costs of processing unreleasable batches –Data justification of batch release Continual process monitoring obviates need for process validation Reduce testing requirements at end of process Increase process knowledge –Identify critical steps and parameters that impact quality –Improve risk assessment validity

8. Xcellerex …speeding medicines to people … Manufacturing Investment Risk Savings via On-Line Bioburden QC –Assumptions:  20 batches attempted/year  $20,000,000 annual budget, fully loaded  $1,000,000 cost per batch, fully loaded  90% overall batch success rate – 18 batches –Cost of lost batches: $2,000,000/year Possible savings via on-line fermentation bioburden: $1,000,000/year

9. Xcellerex …speeding medicines to people … Xcellerex PAT Program Process Development & Analytics Program Initiative Process Development –Automation - High throughput screening –Statistical process optimization Process Analytics –Product Quality – microarray glycosylation analysis –Process control via non- invasive sensors – pH, DO 2, optical density, IR –On-line environmental monitoring – non-viable particulates Benefit Optimized process from start of clinical manufacturing Examine more parameters in less time Real time assessment of product quality Non-invasive monitoring of process parameters Real-time assessment of environmental control

10. Xcellerex …speeding medicines to people … Xcellerex PAT Program Manufacturing Benefit Minimize operator errors Early detection of deviations Protect product quality Rapid batch release Minimize environmental contamination Increase flexibility Minimize cross-contamination Program Initiative Automation –Electronic batch records –Non-invasive sensors – pH and DO 2 –On-line quality assurance Controlled environment modules –Operator separation Disposables

11. Xcellerex …speeding medicines to people … Knowledge Management eFactory ™ eFACTORY™ Knowledge Management Data Experiments Methods PD Data Protocols Methods Quality Doc Approvals Doc Revisions Change control QA Documentation Lot release Exceptions Deviations QA Release Batch data Trending BPRs Mfg MyProject secure portal Supply Ops Vendors Mat. flow Inventory Quality Control Test Methods Sample status Trending Finance Contract Invoices Accruals Proj. Mgmnt Contract Phases Your project Reg Affairs FDA contact IND outlines Submissions

12. Xcellerex …speeding medicines to people … Fractional Factorial Wells Center Point Wells Sigma Medium Wells Number of Wells 2562012 Average OD6000.2810.3050.323 CV of OD600, avg 3.7%3.6%7.6% Approximate Cell Density at average OD600 (MM cells/ml) 1.21.51.7 CV based on approximate cell density, MM cells/ml 10.2%8.7%17.0% Normal MHB ~ 0.8 MM cells/ml Best condition: 1.9 MM cells/ml Cells still 94% viable! Process Optimization by DOE

13. Xcellerex …speeding medicines to people … Automation: eBatch Record Purification

14. Xcellerex …speeding medicines to people … Statistical Process Control Step 1 Step 3 Step 2 Step 4

15. Xcellerex …speeding medicines to people … Challenges in Applying PAT to Biologics Investment in bringing analytics on-line Innovation to develop analytical tools to assess critical attributes Extensive data accumulation needed during development to identify critical attributes and appropriate limits Regulatory uncertainty –More data may reveal more variation –Stringency of limits related to criticality of impact

16. Xcellerex …speeding medicines to people … Regulatory Risk with On-line Analytics Data –How much data is too much data –Collection interval - Continuous versus intermittent –How to use the data – speeding release or real-time release? Noise –How to handle spurious spikes in continuous on-line data –May need extra validation to ignore these Lost productivity, lower plant output, high mfg. costs

17. Xcellerex …speeding medicines to people … Continual Environmental Monitoring Total Particulates during Chromatography Step 1000 600 400 200 0 800 26-Aug-02 17:5226-Aug-02 21:4827-Aug-02 01:44 27-Aug-02 09:37 27-Aug-02 05:4128-Aug-02 05:1028-Aug-02 09:1528-Aug-02 13:1228-Aug-02 17:0828-Aug-02 21:0427-Aug-02 13:3327-Aug-02 17:3027-Aug-02 21:2028-Aug-02 01:11 Particulates ≥0.5 µ per ft 3 (x 10 -3 )

18. Xcellerex …speeding medicines to people … Summary Impact of PAT Measure product quality in process stream Increased understand of process – product quality relationship Continual process monitoring obviates need for process validation Enables science-based decision making in manufacturing Reduces batch release time, increases plant capacity Lower manufacturing risk and COGS Can be a very cost effective investment

19. Opportunity Process Knowledge Present Future Result: Better Quality & Lower COGS for Entire Industry Efficiency