Biomanufacturing Vision for the Future

(1)

Biomanufacturing Vision for the Future

Shou-Bai Chao, Ph.D.

Senior Vice President

Global Manufacturing and Technical Operations MedImmune (a Div of AstraZeneca)

NIPTE/FDA Research Conference “Future of Pharmaceutical Manufacturing”

Rockville, MD, June 18-19, 2013

“The views and opinions are those of the speaker and do not necessarily reflect those of MedImmune or AstraZeneca.”

(2)

Manufacturing Success

Manufacturing Success

Cost

Effective

Quality

Quantity

On Time

(3)

(4)

Biologics Versus Small Molecules

2011

₂₀₂₀

Share of Revenue: Bio vs. Small Molecules

Percent of Pipeline 43% 57% 80% 20% Biologics Small Molecules 5% 95% 50% 50% Biologics Small Molecules

(5)

Shift to Biologics

Higher success rates for large molecules

(6)

Patent Expiry Adds to Market

Source: Pharmaceuticals, 2012

By 2016, total mAb sales are expected to surpass $65B

(7)

Driving Forces for Biomanufacturing

of the Future

Productivity

(0.1 g/L to 10g/L)

Market

Segmentation

(e.g. PHC)

Globalization Addition of ROW – (emerging and developing) markets as more important for

biologics than in the past

Uncertainty of

product

approvals

(8)

The Capacity Conundrum

Uncertainty of product approvals

D el ta = A v ai lab le C ap aci ty D em an d Low capacity Start building Too much capacity Reduce Less utilization

(9)

Managing The Capacity Paradox

Projected (1993) Actual 1993 1994 1995 1996 1997 1998 0 50 100 150 200 250 $300M Betaseron revenues (Projected vs. actual)

Chiron built a plant it never used and was eventually sold

Projected (1993) Actual 1993 1994 1995 1996 1997 1998 0 50 100 150 200 250 $300M Betaseron revenues (Projected vs. actual) Projected (1993) Actual 1993 1994 1995 1996 1997 1998 0 50 100 150 200 250 $300M Betaseron revenues (Projected vs. actual)

Chiron built a plant it never used and was eventually sold

Wyeth & Immunex (now Amgen) lost potential sales in US and delayed launch in EU as US sales surpassed worldwide

sales within 6 months of launch

Actual/ forecast Unconstrained/ potential 0.0 0.5 1.0 1.5 2.0 2.5 $3.0B Enbrel revenues (actual vs potential) Actual/ forecast Unconstrained/ potential 0.0 0.5 1.0 1.5 2.0 2.5 $3.0B Enbrel revenues (actual vs potential)

(10)

Additional Challenges

• High degree of pipeline attrition

- Demand modeling

- Integrating manufacturing strategy into pipeline planning

- “Planning for success” – upsides have usually hurt manufacturing networks more than downsides

• Technical Leaps

- Yield enhancements in mAb production

- Most plants designed with <1 g/L productivity

- Currently averages are 3-6 g/L range with some in approaching 10 g/L - Related challenges; Domino effects

- Changes are not unilateral

- Upstream improvements may have downstream bottlenecks - Goal is overall optimal productivity

(11)

Late Phase Clinical Material in Commercial

Manufacturing Facility

• Many bio products need large scale production for Phase III

• Desire to make Phase III in commercial launch/ equivalent site

• Time/ quantity drivers different but overall manufacturing

optimization issue is same

• Manufacturing needs to consider not only bulk but Drug Product,

Packaging and supporting analytical/ QC requirements

• Flexible manufacturing network can also be built with

- Partnerships

(12)

Globalization

• Future may mean less mega sites and more regional sites for market

access

- Process intensification

- Smaller nimble facilities

- Cost – manufacturing at region

• More common for packaging/labeling globally • Drug product – fill/finish

- Global emerging market technical changes

(13)

Other Challenges; Diversification of Product

Considerations for New

Product Categories

• New product categories

- Traditional production facility concept may not work

• Need smaller modular facilities – e.g. for cell therapy

- Combination of biotech/ synthetic products

• Mix of potent facility/ API type facility – for Antibody drug conjugates

• Synthetic manufacturing – peptides and oligonucleotides

- Combination products

(15)

Facility of the Future

• Smaller, more focused markets

• As market demand decreases, and titers/yields increase, batch size decreases

• Flexibility must increase - Disposables

• Efficiency must increase

- Operational Excellence (OE)

• Downstream processes must improve

• More nimble, standardized and modular - Platform processes

- “Simpler” processes – less unique - Appropriate automation

• Balance flexibility with consistency

(16)

(17)

New Biomanufacturing Technologies

“process intensification” – doing more in less

• Buffer handling - Key limitation in high volume Mab products - More justification for in-line buffer dilution

- Save on making and storing high volume buffers

• Higher throughput processing

- Flow through membrane based separation technologies - Potential for faster processing

• Continuous processing

- DS processes – alternate perfusion type processes - Continuous purification processes

• Simulated moving beds • Flow through schematics

(18)

Single-Use Technology

• “Single-use bioprocessing equipment…is providing the biopharmaceutical industry with cost-effectiveness and flexibility”1

• Greater flexibility1

- “…purchase, ship, store and install complete manufacturing systems as needed”

• Cost of manufacturing reduction

- No steam/clean/sterilize equipment1

- Cheaper equipment (plastics vs. stainless) 1

- Waste management: Cost to incinerate disposables is a fraction of production cost and waste water treatment2

• 68.1% of companies report current in-house use of single-use bioreactors (however, no mainstream biopharmaceutical product is manufactured using this equipment) 1

• Supplier management is a key success factor for disposable technology due to extractables concerns. 3

1. E. Langer, President, BioPlan Associates, Inc., “Biomanufacturing Morphs, (a summary of 8th_{Annual Report and}

Survey of Biopharmaceutical Manufacturing Capacity and Production): BioPlan Associates, April 2011 2. S. Aldridge, “Biopharm turns plastic,” March 1, 2007

(19)

Changing Face of Biotech Drug Substance

Facilities

• Large, single product dedicated

plants

• Built for blockbusters • Inflexible, fixed pipe • Costly to modify

• Few products, large volumes

• Lower capital cost • Lower operating cost • Disposable

• Flexible

• Many products, smaller volumes

(20)

New Trend: Single Use/Disposables

250L Stainless Steel Bioreactor 1000L Single Use Bioreactor

(21)

(22)

Lifecycle of Biomanufacturing

• Collaborations (The next chapter)

- Industry maturation – established industry leading Biologics

products

- Strategic collaborations taking form, global capabilities established

- Product differentiation based on therapeutic performance and end

user experience

- Mfg processes in large are using similar medias, incoming material

specifications, and equipment to achieve common cost point

- Standardized facilities and convergence to platform technologies

(processes and analytics)

• Enhanced process yields & controls enabled via process characterization

• Enables broader use of available capacity to hedge portfolio risk

(23)

Opportunity - TPN

• TPN – Trusted Partner Network

• “Flexible Manufacturing Network”

- Share capacity to better balance the demand curve - Closer relationship than traditional CMO relationship

(24)

Manufacturing Capacity Sharing Model –

A Relationship Built on Trust & Transparency

• A capacity consortium sharing available manufacturing capacity

- Enabled by facility and process similarities

- Partnership across a portfolio of programs rather than ad-hoc product based agreements

- Open book capacity requirements for small network of partners

- Biosimilars may offers broader portfolios for entry into multi-product manufacturing collaborations

• Business Benefits

- Financially responsible use of available capacity – Increase ROA

- Hedging pipeline risk across broader portfolio of opportunities – Managing the Capacity Paradox - Capital avoidance/deferral

- Aligned incentives to maximize asset utilization - drives innovation

(25)

Merck Signs 15 Year Manufacturing Capacity

Sharing Agreement with MedImmune

(26)

(27)

Business Case (Why now for MedImmune?)

• Three to five year delay in delivering on the

commercialization of products

- Contrary to original plan, plant would not be

fully utilized until 2022

• Under-utilization would leave it empty until

2014-2016

• Result: $100M annual depreciation to

manufacturing

• Best in Class facility and staff would be in “hot

standby” status for five years

(28)

(29)

Manufacturing Process: Purification

Pilot Scale

60 cm diameter columns

Commercial Scale

1.4 meter diameter columns

(30)

Why Did Merck Choose MedImmune?

Licensure achieved in June, 2011 as planned

>ZERO 483’s

ISPE Facility of the Year Award (FOYA) for Project Execution

>Jan 2011

Near Perfect

Production startup records

(31)

$

_Q

Maintain High Quality While Reducing Cost

of Goods (COGS)

• Cost containment/reduction will

always be important to our

continued business

• But our industry requires and

assumes 100% reliable Quality as

a foundation for survival of the

(32)

Understand Cost Components to

Identify Areas of Potential Reduction

that Do Not Impact Quality

0 20 40 60 80 100 2011 Best Target P er cen t C O G M ( % )

COGM

After understanding is gained, COGM components identified as “low hanging fruit” can be addressed

Biomanufacturing Vision for the Future