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Chapter 1- Introduction to Biomanufacturing
Northeast Biomanufacturing
Center and Collaborative
What is Biomanufacturing ?
 Advanced-technology manufacturing
industry within biotechnology that is
responsible for making biopharmaceuticals
(biologics) and other bioproducts such as
biofuels and human tissues.
 A biopharmaceutical/biologic is any
biotechnology-based therapeutic that
structurally mimics components found in a
living organism.
Examples of Biopharmaceuticals
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Hormones (Insulin)
growth factors
blood proteins
clotting factors (tPA)
enzymes
antibodies
DNA and RNA
stem cells
Applications of Biopharmaceuticals in
Health & Medicine
• Therapeutic proteins for treatment of disease
• Vaccines to prevent disease
• Protein or DNA-based diagnostics
• Regenerative medicine technologies
• Gene therapy
Approved Biologics
Biopharmaceutical
Date of Commercial Production,
Indication
Company
Humulin (human insulin)
1982, diabetes
Eli Lilly
tPA (tissue plasminogen activator
1987, myocardial infarction
Genetech
Humatrope (human growth hormone)
1987, human growth hormone deficiencies
Eli Lilly
Epogen
1989, anemia
Amgen
Energix-B
1989, hepatitis B vaccine
SmithKline
Beecham
Betaseron
1989, multiple sclerosis
Berlex
Laboratories/
Chiron
Ceredase
1991, Type I Gaucher’s disease
Genzyme
Proleukin (Il-2)
1992, kidney carcinoma
Chiron
AHF (recombinant anti-hemolytic
factor)
1992, hemophilia A
Baxter
Healthcare
Pulmozyme (DNAase)
1993, cystic fibrosis
Genentech
Biopharmaceutical Drug Development
Objective
 To develop a robust, scalable, reproducible, and cost-effective
process that results in safe and efficacious biopharmaceuticals
 Time consuming and expensive!
• 8-15 years
• $500 million to $1 billion
• 1/10,000 drug candidates makes it
Drug Development Process
Discovery/ Research
 Identify gene/protein of interest
 Create an “expression vector” that includes the
gene of interest
 Select cell type to transform
 Cellular machinery transcribes DNA into mRNA and
mRNA into protein via the Central Dogma
Expression Vector: The basis of modern
biopharmaceutical manufacturing
Bacterial Transformation in Biomanufacturing
Central Dogma of Biology
Expression Systems- Considerations
Post-translational modification
– Modification of an amino acid of the polypeptide chain
– Addition of sugar moieties to certain amino acid side
chains(glycosylation)
– Approximately 70% of human proteins are glycosylated
and biological activity is highly affected without this
modification
– Majority of prokaryotic cells lack the ability to make
glycoproteins
Prokaryotic Expression Systems
Bacterial Systems (e.g E.Coli)
• Less time consuming/expensive to culture
• Unable to perform post-translational
glycosylation
Yeast Cultures
• Less time consuming/ Inexpensive
• Can add non-human glycans which are
immunogenic
Recombinant DNA Expression Systems
Expression System Application (%)
CHO
35.5
E. Coli
29
Miscellaneous
mammalian
16.5
Yeast
16.5
Miscellaneous
8.5
Human
4
Blockbuster Drugs made in CHO cells
Product
Sales
(USD in billions)
Approved
Patent Expiry (US)
Company
Humira (anti- TNF)
11.0
2002
2016
AbbVie, Eisai
Enbrel (anti-TNF)
8.76
1998
2026
Amgen, Pfizer, Takeda
Rituxan (anti CD20)
7.91
1997
2016
Biogen Idec, Roche
Avastin (anti-VEGF)
6.97
2004
2017
Roche/Genentech
Herceptin (anti-HER2)
6.91
1996
2019
Roche/Genentech
Epogen (epoetin alfa)
3.36
1989
2013
Amgen, Johnson &
Johnson
Avonex (IFN-b-la)
3.00
1996
2016
Biogen Idec
Rebif (IFN-b-la)
2.59
1998
2013
Merck Serono
Aranesp/Nesp
2.42
2001
2024
Amgen
Eyla
1.86
2011
2021
Regeneron; Bayer
Healthcare
Table taken from website Brief history of CHO cells
Eukaryotic Expression Systems
Mammalian Systems – Chinese Hamster Ovary Cells
(CHO)
 Have the ability to perform post-translational glycosylation
 Widely used but expensive and more time consuming to
culture
 Protein products are easier to process later in production
because they are secreted into culture media
Process Development and Scale-Up
Determine best processes to produce the most protein/drug as efficiently as
possible.
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Upstream Processing- develop equipment and processes used in
production to culture the cells that make the biopharmaceutical
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Downstream Processing –recovery & purification of drug from cell
culture media
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Formulation/Distribution –product is filled, tested for purity and
sterility and distributed for clinical use
Upstream Processing
 Develop equipment and processes used in production to culture
the cells which produces the biopharmaceutical
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Culture Flasks
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Spinner Flasks
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Bioreactors
Downstream Processing
Recovery and purification of drug product from cell
culture
• Centrifugation- Ultracentrifuges
• Filtration-TFF Units
• Chromatography- FPLC/HPLC
Testing Finished Product
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The biopharmaceutical is placed in solution, with excipients, for
parenteral injection. Product tested for purity, stability, and sterility
before distribution
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Purity Tests
• Chromatography
• Electrophoresis
• ELISA
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Sterility Tests
• Microbial Tests for endotoxins
Regulation of Biopharmaceutical Manufacturing
• The manufacture of all pharmaceutical products are
regulated by the Food & Drug Administration (FDA)
to ensure quality and safety.
• FDA requires that all pharmaceuticals be
manufactured and quality of drug products using
Current Good Manufacturing Processes or cGMP
Ensuring Quality
Drug Manufacturing Facilities have departments/groups that ensure
quality:
– Quality assurance (QA) Dept ensures that the manufacturing
facility complies to all regulations and maintains all
documentation for compliance
– Quality Control (QC) Dept is responsible for testing the raw
materials and the product during many stages of the
manufacturing process
Documentation in Pharmaceutical
Manufacturing
Documentation can take many forms:
 Process and production document (SOPs, batch records, manufacturing
operations)
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Operational and equipment log books (documentation of maintenance,
cleaning)
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Training documents
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Electronic Documents
Biopharmaceutical Biomanufacturing
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The production of a new biopharmaceutical may require a facility to
be prepared for its manufacture and 400 to 600 people hired; 50%
may be technicians
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The largest bioreactor in such a facility could be 20,000 L (scaledup is from a 1-2 mL cryovial taken from the working cell bank)
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Once constructed and commissioned, the facility’s equipment and
process SOPs must undergo validation
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The set up, maintenance and use of each piece of equipment is
logged; the equipment must be calibrated
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Environmental Health and Safety (EH&S) requirements are of
central importance.
Amgen-Biomanufacturing Facility Tour
Visit Amgen website for a virtual tour of their manufacturing facility
http://www.amgenbiotech.com/tour/amgen-manufacturing.html
Top of 20,000L Bioreactor