PAT for Biologics Ensuring Quality of Biologically Produced Drugs

1. PAT for BiologicsEnsuring Quality of Biologically Produced Drugs FDA Advisory Committee on Pharmaceutical Sciences April 13, 2004 Parrish Galliher and Elizabeth Fowler Xcellerex

2. Outline • Xcellerex View of PAT • Importance of PAT for Biologics • Value of PAT • Implementation of PAT – Xcellerex Program • Summary

3. 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. More biological variables Greater need for PAT 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

5. 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. Real-Time Process MonitoringBiotechnology Drugs Purpose Present Future API content API quality Impurities Bioburden & viruses Control product quality Ensure biosafety Cell growth Cell viability Metabolic parameters (dO2, pH, glucose) Fermentation Control product quality Ensure impurity removal Ensure biosafety API concentration API quality Impurity clearance Bioburden & viruses Process parameters (OD, pH, Flow rate, Conductivity) Purification API quality Content uniformity Excipient uniformity Impurity levels Sterility Ensure product Ensure uniformity Ensure safety API concentration Environment Fill volume Formulation Fill Finish

7. 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. Possible savings via on-line fermentation bioburden: $1,000,000/year 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

9. 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, DO2, 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 Xcellerex PAT ProgramProcess Development & Analytics

10. 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 DO2 On-line quality assurance Controlled environment modules Operator separation Disposables Xcellerex PAT ProgramManufacturing

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

12. Fractional Factorial Wells Center Point Wells Sigma Medium Wells Number of Wells 256 20 12 Average OD600 0.281 0.305 0.323 CV of OD600, avg 3.7% 3.6% 7.6% Approximate Cell Density at average OD600 (MM cells/ml) 1.2 1.5 1.7 CV based on approximate cell density, MM cells/ml 10.2% 8.7% 17.0% Process Optimization by DOE Best condition: 1.9 MM cells/ml Cells still 94% viable! Normal MHB ~ 0.8 MM cells/ml

13. Automation: eBatch RecordPurification

14. Step 1 Step 2 Step 3 Step 4 Statistical Process Control

15. 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. 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. 1000 800 600 400 200 0 27-Aug-02 09:37 26-Aug-02 17:52 26-Aug-02 21:48 27-Aug-02 01:44 27-Aug-02 05:41 27-Aug-02 13:33 27-Aug-02 17:30 27-Aug-02 21:20 28-Aug-02 01:11 28-Aug-02 05:10 28-Aug-02 09:15 28-Aug-02 13:12 28-Aug-02 17:08 28-Aug-02 21:04 Continual Environmental MonitoringTotal Particulates during Chromatography Step Particulates ≥0.5 µ per ft3 (x 10-3)

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