speeding medicines to people Potential Benefits of PAT for Biomanufacturing IFPAC 2005

Transcription

1 speeding medicines to people Potential Benefits of PAT for Biomanufacturing IFPAC 2005

2 Outline PAT for Biologics (Biotherapeutics) Mfg. What is a biotherapeutic? Converging trends in Biotech PAT player in overall biomfg. efficiency life cycle PAT for biomfg. current roadmap Rationale and potential benefits of PAT Challenges and risks applying PAT Conclusions

3 What is a Biotherapeutic? Small Molecule Biotherapeutic HOOOCH3NHOOOCH3NEtOOHOCH3HOCH3OCH3HNHOOOOHCH3SCH3OCH3OCH3IOOOOSONHNMeMeOCH3HN ,000 MW Primary, secondary structure 10,000 1,000,000 MW Primary, secondary, tertiary, quaternary structure

4 Challenges of a Biomfg. Process 0.01% pure $1,000/kg 3 quality assays 99% pure $1,000,000/kg 20 quality assays Cell Culture Primary Recovery Purification Formulation Filling 500 raw material components (99.99% impurities) 2 raw material excipients (1% impurities)

5 What is a Biotherapeutic? Biopolymer - protein, nucleic acid, carbohydrate, etc. Produced by cells fungi, bacteria, mammalian, plant, insect cells MW range: 10,000 1,000,000 daltons Potency may depend upon: Primary, secondary, tertiary and quaternary structure Glycosylation or Disulfide bridges between chains Conjugation to small molecule Degradation Susceptibility: Oxidation, deamidation, protease digestion, gas/liquid interface denaturation

6 Biotherapeutics Mfg. Huge Waste of Manufacturing Failed Drugs $40B sales worldwide, approx. 200 approvals 10 yrs to bring a drug to market, 7 yrs in clinic $1B total cost/drug, $900M is cost of failures $4B spent on manufacturing of sales) $2B spent on outsourcing manufacturing $3.6B spent on manufacturing failed drugs! Huge productivity gap for industry

7 Problem: Need for Faster, Better, Cheaper Mfg. Drug Pricing Pressure US Pricing controls imminent Biogenerics Reimbursement restrictions Downward COGS pressure Tighter FDA Regulations Tighter mfg. controls/quality FDA PAT quality expectations More analytical power More on-line quality Smaller Drug Markets Fewer blockbusters Genetic diagnosis based treatment Personalized medicine Smaller patient populations More potent, combination drugs New Paradigm -Smaller niche drug markets -Higher Efficiency Development - Faster drug development - Lower failure rate in clinic -Manufacturing - smaller mfg. batches - higher yield, lower cost - faster response, more flexible - more efficient operations - improve quality

8 Biomfg. Scale is Shrinking Niche markets Amt per drug Traditional Platform Scale 2,000L to 20,000L Xcellerex XDR Platform Scale 200L to 2,000L Improved potency Improving yields time

9 PAT Part of Mfg. Efficiency Improvement Product Facilities - Quality, PAT - Chemometrics -Process Knowledge - Operational Excellence Analytics Process

10 Xcellerex s Mfg. Improvement Strategy Process/Product Knowledge Process Control Contamination Reduction PAT Analytics - use HTS in PD to optimize process variables - use process knowledge for efficiency planning - automate control to reduce human error - real time analysis to reduce excursions - efactory monitors cgmp compliance - use disposable systems everywhere (simpler) - enclose mfg. systems in clean modules - miniaturize and apply to process if rational - adapt on-line analytics to disposable systems

11 Biomfg. PAT Current Roadmap OFF-LINE QC lab CHEMICAL, BIOASSAY QUALITY NIR, ph, DO2, HPLC AT-LINE On-floor CHEMICAL QUALITY ASSAYS NIR, ph, DO2, HPLC UPSTREAM PARAMETRIC QUALITY ASSAYS NIR, ph, DO2 IN-LINE DOWNSTREAM DIRECT QUALITY ASSAYS HPLC

12 Biomfg. PAT Current Practices Approach Upstream Mfg. Downstream Mfg. Product Quality assay At / Off line In-Line: HPLC Product Conc. Assay In-line: OD, NIR In-line: UV Parametric analysis yes yes Process Knowledge yes yes Operational Excellence yes yes

13 PAT Enabling Technologies for BioMfg. More enabling sensors on the horizon from genomics, proteomics, clinical diagnostics: HPLC NIR OD Upstream Cell Culture HPLC IR FTIR NIR Primary Recovery HPLC HPLC IR IR FTIR FTIR NIR NIR UV UV Surface Plasmon Resonance Purification Formulation Filling Bruker Optics, Biacore, Affinity Sensors, GWC Technologies, Nova BioMedical, Xantec, Texas Instruments, Waters, Applied BioSystems

14 Rationale - More Data Can Be Beneficial Narrow Data Set Comprehensive Data Set Data set spectrum Full Process Spectrum

15 Rationale - Or a Curse if Mismanaged Spurious Spikes in Continuous Data Stream Particulates 0.5 µ per ft 3 (x 10-3 ) Aug-02 17:52 26-Aug-02 21:48 27-Aug-02 01:44 27-Aug-02 05:41 27-Aug-02 09:37 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

16 Data Regulatory Risk with Biomfg. PAT What is the rationale for more data - how much data is too much data? What is the right collection interval? Continuous data versus intermittent collection? How to use the data speeding post batch release or enabling real-time release? Noise How to handle spurious spikes in continuous on-line data May need extra validation to ignore these What if On-line and Off-line assays don t agree?

17 Challenges in Applying PAT to BioMfg. 20 different assays define product quality! Large investment in bringing analytics on-line Innovation in on-line analytical tools technology feasible? Extensive data 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 Interpretation by Field Inspectors uncertain

18 Road Map to Develop On-Line Assays Rationale and sanity check: Speed? Technology? Risk? Start with a standard lab QC assay Miniaturize and/or automate, make it robust Software development - Part 11/GAMP compliant Validation road testing Calibration, precision, linearity, accuracy, etc. Management Support non-fouling, stability, calibration, etc. Correlation with other assays avoid conflicts Benefit measure it!

19 Rationale PAT Can Help Efficiency, COGS Ensure product quality remains consistent, live Assess mfg. deviation impact in real time Kill bad batches fast, save downstream manufacturing cost Could help rescue batches heading to failure Can reduce process validation requirements Reduce testing requirements at end of process Speed batch release, more batches per year Overall strong potential to reduce COGS

20 Potential $ Savings with PAT Example of On-Line Bioburden Assay Assumptions: 20 batches attempted per year, $20M annual budget $1,000,000 total cost per batch, 50% in purification ($500,000/batch) 90% overall batch success rate 18 batches/yr, 2 fail due to bioburden Cycle time of off-line bioburden assay: 14 days; to bulk: 7 days Cost of lost batches if processed all the way to bulk: $2,000,000/year Cost of lost batches if stopped at harvest: $1,000,000/year Potential Savings with on-line bioburden assay: $1,000,000 / year

21 Potential Benefits - Summary PAT can be part of overall manufacturing improvement strategy PAT rationale should be sound, regulatory risk needs clarity Technology still very challenging, enabling sensors on horizon Science-based management of manufacturing excursions Product quality monitoring can save questionable batches Potential to reduce batch release time, increases plant capacity Potential lower manufacturing risk and COGS May be big business opportunity for sensor and analytics firms!

22 Potential Result: Faster, Better, Cheaper Mfg. Process Knowledge Present PAT Future Mfg. Efficiency

23 Path Forward for Biomfg. PAT Biopharm Industry s role Leaders provide examples of successful PAT Present to industry followers Invest in new technologies where rational Vendors of Sensor Technology adapt to biotherapeutics FDA s role Listen to Industry develop Guidance that is balanced, Recognize complexity of biotherapeutics, take long term view Harmonize Field Inspectors and international regulatory bodies

24 IFPAC Biomanufacturing Session Speakers (Thursday) Amgen - Duane Bonam - on-line HPLC Wyeth - Jerry Justin - SPC Eli Lilly - Rick Cooley - on-line HPLC Siemens - Ingrid Maes - in-line NIR Baxter HealthCare - Paul Marshall - Oper. Excel