Regulatory and Economic Challenges in Biotechnology Manufacturing
Gary Welch
Director of Biologics Production Abbott Bioresearch Center
Outline
Abbott Bioresearch Center and Humira®
Background
Manufacturing Challenges – Capacity Shortages – To Build or Contract Capacity – Decision Timeline – Regulatory Challenges Humira Case Study
Abbott Bioresearch Center Background
Founded as BASF Bioresearch Corp. in 1989 Worcester Facility opened in 1993
BASF Pharma acquired by Abbott Labs in March ‘01
Site houses both research and production activities
in the area of biotechnology
Expertise in immunology and monoclonal antibody
development and production
Workforce of 600+ (300 in manufacturing)
Humira® approved by FDA Dec.’02, EMEA Sept.’03 for
treatment of Rheumatoid Arthritis
Humira Background
Humira is the first fully human monoclonal
antibody to reach clinical development. It is an advanced-generation, anti-TNF (tumor necrosis factor) drug, which mimics natural human antibodies. TNF Alpha, is a small protein that plays a significant role in the regulation of the immune system. Humira binds specifically to TNF, reducing the inflammation, swelling, pain, and joint damage.
Rheumatoid Arthritis
•Affects about 2.5 million patients in U.S. •Two out of three patients are female •Peak age of onset between the ages of 45 and 65 years •Patients moderately disabled within two years of diagnosis and are severely disabled by 10 years •In patients with rheumatoid arthritis, TNF levels are very high, resulting in inflammation, swelling, pain, and joint damage.
Cell Line Development
Antibody Production:
Cell Culture Capacity Industry cycles between too little capacity versus too much Historically Capacity Utilization rates extremely high 2001 and 2002 – large number of products in pipeline drove companies to build capacity
– 2002: 160 Mabs in clinical development vs. 13 marketed products
2002 – 30 products failed clinical trials, plus downturn
in economy lead to an “in balance” capacity in 2003 Shortage predicted again in 2007-2008 timeframe
Biologics Manufacturing Capacity
Six Companies May Control 78% of the World’s Biologics Production Capacity by 2007 Estimated Mammalian Cell Capacity (liters) 2007 Abbott
344,650
All Other
84,000
192,000
Biogen
Boehringer Ingelheim
Genentech
150,000
250,000
Amgen/Immunex
125,000
IDEC
411,000
Total ~ 1.5 million liters
Source: JPMorgan (Feb 2002) and Abbott Estimates
Contract or Build?
Contract Manufacturing
– ADVANTAGES
Lower Capital Investment Reduces investment risk Company can focus on R&D and marketing Companies without manufacturing expertise avoid steep learning curve
– DISADVANTAGES
May be hard to find CMO with right fit of capacity and technology Developing long term strategy / commitments with uncertain outcomes Relying on 3rd party to be compliant to all regulatory bodies Higher Cost of goods decreases profit margin
Contract or Build?
Building Capacity
– ADVANTAGES
Design / build to optimize process Expertise in manufacturing leads to capacity and improvements for future products Control over quality and regulatory issues Enables flexibility in developing long term strategy for clinical and commercial production Maintain lower cost of goods Possible off-shore manufacturing to decrease tax burden
– DISADVANTAGES
Need to make decision long before capacity needs are finalized Large capital investment New technologies/process improvements may create obsolete or idle capacity
Outsourcing Strategies
Mixed: Outsource Large Volumes; Produce Early Phases In-House 18%
Most Production Outsourced 38%
Mixed: Outsource Early Phases, Then Decide to Outsource or Build 13%
Most Production InHouse 31%
Source: Genetic Engineering News Oct. 1, 2003
Manufacturing Strategy Timeline
Manufacturing Strategy needs to be in place early – Typically prior to Phase III in order to make registration batches and produce market launch material from same facility
Early Decisions means many uncertainties – Clinical Failures
34% success rate from pre-clinical to approval
– Regulatory failures – Commercial failures
Competition, patents
– Marketing Questions
How big is the Market? Dosing? More indications? Final process productivity
The Manufacturing Investment Challenge
“ You have to have the internal fortitude to invest in unique manufacturing sites. And if you want to be in biologics big time, it’s too late to start thinking about manufacturing once your molecules are in development. It takes a little bit of foresight and sometimes sticking your neck on the line”.
Large Molecules: Too Late for Big Pharma? (In Vivo, December 2001)
Timelines – Clinical vs. New Facility
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Typical Timeline for Antibody Project
Research Preclinical Phase I Phase IIa Phase IIb Phase III Registration Launch
Typical Timeline New Production Facility
Design Construction Commissioning and Validation Production Starts
Regulatory Issues
Facility Design and manufacturing systems must
consider
– Single product versus multiple products – Commercial as well as clinical production – Global manufacturing (meet expectations of FDA, EMEA, Japan…)
Major Regulatory Agencies concerns – Systems to control contamination – Systems to insure deviations are thoroughly investigated and corrective actions and product impact performed adequately – Use of animal derived raw materials
Humira Case Study
1996 – 1997 –
1997 –
First introduced into production in 1996 with a low productivity repeated batch process at 1000 L scale reactors Moved to 3000 L scale equipment Conceptual design started
» 2 x 6000 L in Worcester to meet registration timelines and market launch quantities » Invest in large scale “greenfield” facility for long term
1997 –
1998 –
Humira enters phase I clinical trials Major process change to “extended” batch process (50% improvement in specific productivity)
Humira Case Study 1998 – 1998 – Humira enters Phase II trials BASF delays approval of $40MM expansion in order to review alternatives, primarily contract manufacturing Decision to build a 2 x 6000 L “Launch Facility” in Worcester approved. Timing requires the 3000 L scale to be submitted for approval first Optimized extended batch process introduced (60% improvement in specific productivity)
1999 –
2000 –
Humira Case Study
2000 –
2000 –
Humira enters Phase III trials. Change in formulation necessitates a bioequivalence study
Additional 3000 L capacity is dedicated to Humira to ensure market launch demands are met 6000 L capacity is started up Abbott acquires BASF Pharma including BASF Bioresearch Abbott develops long term manufacturing strategy to build biologics facility in Puerto Rico primarily due to tax advantages
2001 – 2001 – 2001 –
Humira Case Study
2002 – 2002– 2002 – 2003 – 2003 –
File for US and European registration 3/28/02 Construction on commercial facility in Puerto Rico begun US approval for 3000 L scale received EU approval for 3000 L scale and US approval for 6000 L scale received File for EU approval for 6000 L scale