Transcript Dr. Sergio Perez Talavera

DESIGNING A
MULTIPRODUCT PLANT
FOR RECOMBINANT
BIOPHARMACEUTICALS.
MAJOR CONSIDERATIONS
Biotec India International, 2003
Why a Multiproduct Plant (MPP)?


Recombinant Biopharma Products (rBP)
have, in general, similar steps in their
production process.
One MPP is more economical than two or
more separate plants.
• It is possible to reduce up to 40% of the total
investment.


A MPP reduces the number of high
qualified personnel.
Can achieve better control.
Why not a MPP?


Regulatory agencies are more
concerned with cross contamination
in MPP than in dedicated plants.
Need to produce in campaign.
• It is necessary to have a higher stability
for the Active Principles & intermediary
products in the processes.
• Less flexibility for the production
management.
Recombinant biopharma products
(rBP).

More than 90% of the approved rBP are
proteins, most of them of human origin.
Therefore they are treated as biological.
• In future rBP can be DNAs or other nucleic acid
biomolecules.


Biomolecules are more labile.
Biomolecules are more difficult to
characterize and control.
• There is an intrinsic variability in the biological
response.
Timeline for launching a new rBP.
From lab to market

Biotechnology have reduced the time line
from R&D upto the market for a new
product. (10-12 years).
Production cell
engineering
Process
engineering
Plant design
and Production
CT I & II
CT III
Market
Engineering a rBP Production Cell
Genes

Structure: coding sequences &
regulatory sequences.
• Coding sequences are read by an
universal genetic code. (95% true)
• Regulatory sequences are more
differentiated.

Prokaryotes ≠ Lower Eukaryotes ≠
Mammals ≠ Plants
General structure of a gene
Start
Coding sequences
Regulatory sequences
Stop
Engineering a rBP Production Cell
Vectors

Auto-replicative multicopy plasmids
(mostly used in bacteria)

Integrative plasmids

Bacteriophages

Viruses

Artificial chromosomes.
(More used in yeasts)
(Integrative or not, higher eukaryotes)
(Yeast mainly)
Engineering a rBP Production Cell
Hosts



Prokaryotes
(Bacteria, mainly E. coli).
Lower eukaryotes (yeast).
Higher Eukaryotes cell lines
(Mammalians, Insects)

Living Organisms (Transgenic animals
& plants)
Regulatory Considerations

Are the rBP parenterals?.
• Have few sense to use a Plant designed to
produce a parenteral drug for producing a
non parenteral (np) one. Plant should be
designed according to the highest
requirements and then, production cost for
the np will run over.

Cleaning Validation.
• Additional to the cleaning procedure between
batches, inter-campaign cleaning procedure
should be validated.


No traces of the previous product.
No traces of the previous host.!!!!
Scale of the rBP production.

Are the commercial scale of the
products similar?.
• Difference of scale must be under a
factor of approximately 20.


Ex. Positive: Interferon and G-CSF
Ex. Negative: Interferon & Insulin
Insulin plant must be designed for not less than 50 kg of protein.
Interferon Plant 10 gram is a good commercial scale.
Are the bioproducts coming from
the same HOST?

Different host -> different equipment
design.
• Geometry of fermentors
• Disruption devices.



Different skills of the personnel for bacteria
or yeast then from MCL.
Equal host is easier to validate intercampaigns cleaning procedures.
Environmental aspects depend of the hosts.
• Effluents treatment
MPP Design Recommendations
General production scheme of a rBP
Formulation Section
Seed
Propagation
Live Section
Formulation & Filling
Biomas
multiplication &
Product Induction
Support
Activities
Section
QC & QA
Section
Purification Section
Harvesting,
Disruption &
Separation
Purification of the
Active Principle
(Several steps)
Plant Design Recommendations

Sectioned Plant
•
•
•
•
•
Live Section
Purification Section
Formulation & Filling Section
Support Activities Section
QC & QA Section
Steps 1-3
Steps 3-X
Steps X+1
Each Section should have independent:
• Personnel & material entrance,
• Differentiated HVAC systems,
• Differentiated treatment of supplies, RM,
Uniforms etc.
Actual layout of a MPP
PANHEBER BIOTEC LALRU PUNJAB
Advantages of Sectioned MPP?

Each section can be used in an
independent way.
• Different batches.
• Different products Simultaneously !!!


One MP Live Section for 2 or more
dedicated purification Section.
Design of Intermediary products.
It is recommended that at final step on
each section an stable well identify
intermediary product can be establish.