…speeding medicines to people…

Potential Benefits of PAT for BiomanufacturingIFPAC 2005

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

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10,000 – 1,000,000 MW Primary, secondary, tertiary,

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What is a Biotherapeutic?Small Molecule Biotherapeutic

Challenges of a Biomfg. Process

Cell Culture PrimaryRecovery

Purification FormulationFilling

99% pure$1,000,000/kg

20 quality assays

0.01% pure$1,000/kg

3 quality assays

500 raw material components

(99.99% impurities)

2 raw material excipients

(1% impurities)

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

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 (COGS @10% of sales)• $2B spent on outsourcing manufacturing• $3.6B spent on manufacturing failed drugs!

Huge productivity gap for industry

Problem: Need for Faster, Better, Cheaper Mfg.Drug Pricing Pressure

US Pricing controls imminentBiogenerics

Reimbursement restrictionsDownward COGS pressure

Tighter FDA RegulationsTighter mfg. controls/quality

FDA PAT quality expectationsMore analytical powerMore on-line quality

Smaller Drug MarketsFewer blockbusters

Genetic diagnosis based treatment Personalized medicine

Smaller patient populationsMore potent, combination drugs

-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

New Paradigm

Biomfg. Scale is Shrinking

Niche markets

Improved potency

Improving yields

Traditional Platform Scale – 2,000L to 20,000L

Xcellerex XDR Platform Scale – 200L to 2,000L

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PAT – Part of Mfg. Efficiency Improvement

•

Facilities Analytics

Product

Process

- Quality, PAT- Chemometrics

-Process Knowledge- Operational Excellence

Xcellerex’s Mfg. Improvement Strategy• Process/Product - use HTS in PD to optimize process variables

Knowledge - use process knowledge for efficiency planning

• Process - automate control to reduce human errorControl - real time analysis to reduce excursions

- eFactory monitors cGMP compliance

• Contamination - use disposable systems everywhere (simpler)Reduction - enclose mfg. systems in clean modules

• PAT Analytics - miniaturize and apply to process if rational- adapt on-line analytics to disposable systems

Biomfg. PAT – Current Roadmap

UPSTREAMPARAMETRIC

QUALITY ASSAYSNIR, pH, DO2

DOWNSTREAMDIRECT QUALITY

ASSAYSHPLC

CHEMICAL QUALITY ASSAYS

NIR, pH, DO2, HPLC

AT-LINE On-floor IN-LINE

OFF-LINE QC lab

CHEMICAL, BIOASSAY QUALITY

NIR, pH, DO2, HPLC

Biomfg. PAT – Current PracticesApproach 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

PAT Enabling Technologies for BioMfg.• More enabling sensors on the horizon from genomics, proteomics, clinical diagnostics:

Upstream Cell Culture

PrimaryRecovery

Purification FormulationFilling

Bruker Optics, Biacore, Affinity Sensors, GWC Technologies, Nova BioMedical, Xantec, Texas Instruments, Waters, Applied BioSystems

HPLCNIROD

Surface Plasmon Resonance

IRFTIRNIRUV

HPLCIR

FTIRNIR

HPLCHPLCIR

FTIRNIRUV

Rationale - More Data Can Be Beneficial

Data set spectrum

Comprehensive Data SetNarrow Data Set

Full Process Spectrum

Rationale - Or a Curse if Mismanaged…Spurious Spikes in Continuous Data Stream

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Regulatory Risk with Biomfg. PAT• Data

• 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?

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

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.

• non-fouling, stability, calibration, etc.

• Correlation with other assays – avoid conflicts• Benefit – measure it!

Management Support

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

Potential $ Savings with PATExample 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

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!

Potential Result:

Faster, Better, Cheaper Mfg.Pr

oces

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e

Present

Future

Mfg. Efficiency

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

IFPAC- PAT for Biologics ManufacturingSession Speakers

Wyeth BioPharma - Jerry Justin - SPC

Baxter HealthCare - Paul Marshall - Oper. Excel

Siemens AG - Ingrid Maes - in-line NIR

Amgen - Duane Bonam - on-line HPLC

Eli Lilly - Rick Cooley - on-line HPLC

Outline PAT for Biologics (Biotherapeutics) Mfg.What is a Biotherapeutic?Small Molecule BiotherapeuticChallenges of a Biomfg. ProcessWhat is a Biotherapeutic?Biotherapeutics Mfg.Huge Waste of Manufacturing Failed DrugsProblem: Need for Faster, Better, Cheaper Mfg.Biomfg. Scale is ShrinkingPAT – Part of Mfg. Efficiency ImprovementXcellerex’s Mfg. Improvement StrategyBiomfg. PAT – Current RoadmapBiomfg. PAT – Current PracticesPAT Enabling Technologies for BioMfg.Rationale - More Data Can Be BeneficialRationale - Or a Curse if Mismanaged…Spurious Spikes in Continuous Data StreamRegulatory Risk with Biomfg. PATChallenges in Applying PAT to BioMfg.Road Map to Develop On-Line AssaysRationale – PAT Can Help Efficiency, COGSPotential $ Savings with PATExample of On-Line Bioburden AssayPotential Benefits - SummaryPath Forward for Biomfg. PATIFPAC- PAT for Biologics ManufacturingSession Speakers