Manufacturing Biotechnology Drugs: past present and Future

1
Manufacturing Biotechnology Drugs (past)
present and Future

• Images of Manufacturing
• Cranfield Management Development Centre
• 18th October 2007

2
2003 Licence Applications
In 2003 the FDA received more licence
applications for biotech products than for NCEs
3
Why making biotech drugs is not like making
widgets

• Images of Manufacturing
• Cranfield Management Development Centre
• 18th October 2007

4
What are biotechnology drugs?

• (predominately) Proteins
• Produced via recombinant DNA
• Produced from cells via DNA that was introduced
  artificially

5
What are biotechnology drugs?
6
Recombinant DNA
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Making biotech drugs
Analytical Support
8
Licensed expression platforms
9
Making biotech drugs
Analytical Support
10
Upstream processing
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Making biotech drugs
Analytical Support
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Downstream processing
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Making biotech drugs
Analytical Support
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Biotech drugs costs

• Importance of Fixed Costs

4,000
3,500
3,000
Total Cost
2,500
Fixed Cost
COG's (/g)
2,000
1,500
1,000
500
0
100
200
500
1,000
2,000
5,000
10,000
20,000
Production Scale (L)
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Biotech drugs facility costs
16
Biotech drugs distribution of costs
1kg/yr
10kg/yr
1Kg/g
DSP
Fermentation
Misc Consumables
QC
Utilities
17
Biotech drug manufacturing

• Characteristics
• Batch processes
• Expensive (100s - 1000s/g)
• Very high capital costs
• Very high fixed costs
• Sterile
• Just like making very expensive vodka

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Why making biotech drugs is not like making
widgets

• Images of Manufacturing
• Cranfield Management Development Centre
• 18th October 2007

19
External scrutiny

• Drugs are the most highly regulated manufacturing
  processes and biotech are the most regulated
  drugs.
• cGMP
• current Good Manufacturing Compliance
• prevents product adulteration
• The Regulators
• imagine what could go wrong and write long texts
  to make sure it doesnt
• Together they generate the forces of
  conservatism
• stifle innovation -
• tomorrows drugs will be made with yesterdays
  process.

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the process is the product

• Biotech products are large and complex.

21
Structure of an antibody
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the process is the product

• Biotech products are large and complex.
• The product is (often) heterogeneous
• heterogeneity could affect potency and/or safety
• heterogeneity is process dependent
• the product cannot be fully characterized

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IEF of Antibody 1
9.30 8.65 8.45 8.15 7.35 6.85 6.15 5.85 5.2 4.55
3.5
Expressed in NS0, CHO and HEK-293
1 2 3 4
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the process is the product

• Biotech products are large and complex.
• The product is (often) heterogeneous
• heterogeneity could affect potency and/or safety
• heterogeneity is process dependent
• the product cannot be fully characterized
• The Process is the Product
• process validation
• product characterization

25
The Case of Eprex

• Erythropoietin manufactured by JJ.
• Associated with PRCA
• Turns out that
• new product stabilizer (a detergent)
• leached organic compounds from the uncoated
  stopper
• that interacted with the EPO
• which made it immunogenic
• which lead to the production of neutralizing
  antibodies
• and caused a reduction of circulating EPO..
• which caused PRCA.
• Unpredictable and undetectable.

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Stakeholders

• The purchaser is not the consumer
• who is your customer?
• what do they want/value?
• Manufacturing as source of competitive advantage
• ease of administration
• patient compliance
• advanced formulations/devices
• How important are costs?
• Is manufacturing the best way to address costs?

27
Significnace of costs

• Avastin and Lucentis share molecular parents
• Lucentis costs 2,437/dose
• Avastin costs 687/dose
• Each dose of Avastin can be re-packaged to make
  10 doses equivalent to 1 Lucentis dose.
• Genentech have announced that they are
  restricting access to Lucentis.

28
Structure of an antibody
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Significnace of costs

• Avastin and Lucentis share molecular parents
• Lucentis costs 2,437/dose
• Avastin costs 687/dose
• Each dose of Avastin can be re-packaged to make
  10 doses equivalent to 1 Lucentis dose.
• Genentech have announced that they are
  restricting access to Lucentis.

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Biosimilars

• Biologic generics do not exist
• Process is the product
• But biosimilars do
• Based on characterization
• limited clinical testing
• HGF
• EPO
• EU/US divide
• Innovators dilemma

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Generation X

• Products of the future
• Nucleic acid
• Anti-sense RNA
• Naked DNA
• RNAi
• Gene therapy
• Cell based therapies
• Autologous
• Allogeneic
• Stem cells
• Xenotransplantation
• Personalized medicine

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Manufacturing personalized medicine?
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Generation X

• What will the manufacturing process of the future
  look like?
• Small scale (personalized)
• Commercially viable
• Deliver an appropriate dose of unadulterated
  product
• Sufficiently controlled that they can be
  demonstrated to provide a product with an
  acceptable riskbenefit ration for the patient o
  be treated

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Summary

• Biotechnology products are an increasingly
  important segment of todays pharmaceuticals.
• Their manufacture is simple in principle but
  complex in practice
• Product heterogeneity
• The relationship between maker and user.
• Regulation mitigates against innovation
• Tomorrows products will be more diverse than
  todays - and so will the processes that make
  them.

35
Manufacturing Biotechnology Drugs (past)
present and Future

• Images of Manufacturing
• Cranfield Management Development Centre
• 18th October 2007