Biomanufacturing
Jim DeKloe
Biotechnology 101
Business and Regulatory Practices
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Biotechnology is the intersection of
Science
Business
Government
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Business and Regulatory Practices
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Business and Regulatory Practices
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Drugs versus “biotech”
Traditional Pharmaceutical
Biotechnology companies
“Big Pharma”
“Biotech”
Drugs
Proteins
Small molecules
Large Molecules
Produced by Chemistry
Produced by Living Organisms
Example: Aspirin
Example: EPO
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Business and Regulatory Practices
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History
Drugs
Biologics
Small molecules
Complicated Mixture of Large
Molecules
Produced by Chemistry
Difficult to Test Purity
Simple Pure Molecules
Emphasis on Consistent
Process
Easy to Test Quality
Examples:
Example: Aspirin
Vaccines, Plasma and Serum
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Business and Regulatory Practices
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Biotech clusters thrive when all elements of the
industry are represented
Technician Training
Until recently, the emphasis on R & D meant
that formal training targeting technicians was
rare
Community Colleges have moved into this niche
Technician training will be even more important
as more companies move from R & D into
biomanufacturing
Biotechnology 101
Business and Regulatory Practices
A Model Academic - Industry Collaboration
Building biomanufacturing curriculum
Tailoring curriculum to develop specific
required skills
Incorporating regulatory requirements
into curriculum
Biotechnology 101
Business and Regulatory Practices
Sabbatical
Experience
Genentech
supplied
Expertise
Donated Equipment
Presence on Advisory Committee
Guest Speakers
Biotechnology 101
Business and Regulatory Practices
Traditional versus Industrial
Traditional
Industrial
Education
Training
Lab Atmosphere
Pilot Plant Atmosphere
Set Times
Shifts
Lab Protocols
SOP
Lab Notebook
Batch Records
Individual
Team
Biotechnology 101
Business and Regulatory Practices
Question Authority!
Change Academic Paradigm
Borrow vocational tech and business ideas
Teach skills as well as educate
Emulate the industrial experience
Share the ideas that work
Biotechnology 101
Business and Regulatory Practices
Back to Basics - Cells
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Business and Regulatory Practices
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Eukaryotic Cells can be Engineered Also
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Business and Regulatory Practices
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Protein!
The
Protein is
the
Product!
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Business and Regulatory Practices
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Protein Structure
Proteins can be modified after
they are synthesized
The addition of sugars –
glycosylation – may be
important – it affects solubility
and pharmacokinetics (blood
half live)
Glycosylation patterns may vary
Repeat because it is so
important: If a protein loses this
shape, it loses its function
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Business and Regulatory Practices
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Protein!
The protein must not be unfolded (denatured) or it loses
its function. Proteins can be denatured by:
•pH extremes
•temperature extremes
•organic chemicals
•agitation
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Business and Regulatory Practices
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Protein!
DNA is the Flash
Protein is the Cash
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Business and Regulatory Practices
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Protein!
DNA is the Show
Protein is the
Dough
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Business and Regulatory Practices
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Protein!
DNA is the Bling
Protein is the Thing
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Business and Regulatory Practices
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Bacterial Cells – Prokaryotic Cells
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Business and Regulatory Practices
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Cells are grown in a large scale
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Business and Regulatory Practices
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Upstream
Cells Divide and are transferred to larger and larger
volumes
Cells are induced to produce protein
Many in-process samples are taken; some are sent to
QC for a variety of tests. For mammalian cells, they will
check for contamination by viruses and mycoplasma
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Business and Regulatory Practices
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Recovery - Downstream
Cells are separated from the medium surrounding them
by filtration or centrifugation.
Typically:
In E. coli culture (slang is fermentation), the cells are
retained and the medium is discarded
In cell culture (CHO cells), the cells have been
engineered to secrete the protein, so the cells are
discarded and the protein-containing medium is
retained
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Business and Regulatory Practices
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Protein Purification
The protein of interest must be separated from the other
proteins in the cells or medium until it is 99.99% pure.
This is accomplished by ultrafiltration and
chromatography
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Business and Regulatory Practices
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Ultrafiltration
In ultrafiltration the protein containing
solution is passed through a filter
with pores of a defined size. This
can separate proteins of different
sizes from one another, or can
separate protein from medium
components.
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Business and Regulatory Practices
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Chromatography
Chromatography methods use
resins of different types to exploit
the characteristics of the protein
to interest to separate it from
other contaminating protein
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Business and Regulatory Practices
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Types of Chromatography
Type of Chromatography
Protein Property
•Gel Filtration (Size Exclusion) - Size
•Ion Exchange (Cation or Anion) – Charge
•Hydrophobic Interaction Chrom. – Hydrophobicity
•Affinity Chromatography - Function or Special
Characteristic
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Business and Regulatory Practices
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Formulation
Once the protein has been purified, the bulk purified
protein will be placed in the formulation buffer and
sterile filtered. During formulation, adjuncts are added
to:
•Stablize pH
•Adjust osmolarity
•Prevent aggregation
•Cryoprotect (for lyophilized products)
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Business and Regulatory Practices
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Fill
Fill is completed in a special
facility that has highly filtered
air, gowned personnel with
special training, This process is
highly automated.
A measured amount of the
formulated protein is aliquoted
into sterile ampules
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Business and Regulatory Practices
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Finish
The protein may be lyophilized (freeze dried). This
makes it more stable, but physicians may find this form
of the drug less convenient to use.
Closures are added
Labels are applied.
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Business and Regulatory Practices
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Quality Assurance
The law requires a QA/QC department that is separate
from manufacturing
They will test:
Raw Materials
In-Process Samples
Utilities
Environmental Monitoring
The final protein product
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Business and Regulatory Practices
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Regulation
In the United States, the Food and Drug Administration
regulates pharmaceutical production
•Part of the executive branch
•Regulates $ 1 trillion of commerce a year
•Center for Drug Evaluation and Research
•Center for Biologics Evaluation and Research
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Business and Regulatory Practices
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What Are GMPs?
Subpart
Description
A
General Provisions
B
Organization and Personnel
C
Buildings and Facilities
D
Equipment
E
Control of Components and Drug Product Containers and Closures
F
Production and Process Controls
G
Packaging and Labeling Controls
H
Holding and Distribution
I
Laboratory Controls
J
Records and Reports
K
Returned and Salvaged Drug Products
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