science of biologics & the characteristics of biotech
TRANSCRIPT
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Science of biologics & the
characteristics of biotech
production process
Andres F. Zuluaga, MD, MSc
Head. Department of Pharmacology & Toxicology
University of Antioquia
Medical School
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Why are we here?Importance of Biologic Drugs
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MODERN BIOTECHNOLOGIES & THE DISCOVERY OF DNA MANIPULATION
Biotechnology:
The commercial
application of living
organisms or their
products (Bio-), which
involves the deliberate
manipulation of their DNA
molecules (Technology) to
solve problems or make
useful products.
INNOVATION (R&D) NEW PRODUCT BENEFITS
Source: http://www.accessexcellence.com/RC/VL/GG/biotechnology.html
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Applications of Biotech to Healthcare
� Diagnosis
� Therapy
� Vaccination
� DNA testing
� Diagnostic kits
� Drugs & novel therapies
� DNA fingerprinting
For drugs (to treat or to prevent): Biopharmaceuticals
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EJHP Practice Vol 13 2007/1
Pavlovic M. Horm Res 2008;69:14-21
Vaccines, blood products or derivates (including heparins), hyperimmune
serum, hormones (rhGH), toxins, monoclonal antibodies, peptides,
cellular therapy.
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Time-line of Biopharmaceuticals
� Establishment of an alliance (“merger”) between the start-up
biotech companies (technical expertise) and big pharmaceutical
companies (pharmaceutical experience) in 1980s –> Biotech
sector
� i.e. Genentech & Eli Lilly: development of recombinant human insulin,
clinical trials and large-scale marketing (Humulin)
� The vast majority of recombinant proteins are produced in E. coli, S.
cerevisiae or in animal cell lines (Chinese hamster ovary (CHO) or
baby hamster kidney (BHK) cell lines). The use of additional modern
biotechnologies such as protein engineering in conjunction with an
increased understanding of structure-function relation of proteins has
facilitated the development of more potent and safe B&B drugs..
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PROTEIN ENGINEERING COMMONLY USED TO PRODUCE BIOPHARMACEUTICALS
1. Alteration of single amino acid
residues at specific sites.
2. Insertion or deletion of a single
amino acid residue.
3. Alteration or deletion of an entire
domain.
4. Generation of a novel fusion protein.
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ISSUE #1: PATENT PROTECTION FOR MANY 1ST GEN. BIOPHARMACEUTICALS HAS NOW COME/IS COMING TO END.
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ISSUE #2: CHEMICAL VS BIOLOGICAL DRUGS: WHICH IS BETTER?10-Year Trends in Major Drug and Biological
Product Submissions to FDA
Novel chemical structure
Biological drugs
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ISSUE #3: THERE IS A COMPLEX CRITICAL PATH FOR MEDICAL PRODUCTS
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Why are Biotech products expensive?
High R&D + high Return = high Risk
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Which is/are the difference(s) with Chemical drugs?
Características Chemical Biologic
Active ingredient (MW)Small molecules (tipically
<500-1000 kDa)
Large macromolecules (peptides ,
often >1000 kDa)
Manufacture
Typically chemically
synthesized with high degree
of purity and
characterization. Can be
analyzed from a structure-
function perspective
Inherent Heterogeneity. Product
Process
Relationship. Activity may be affected
by minor changes in bioprocessing and
post-translational
modifications.
Production
A well defined synthetic
pathway that can be scaled
to large quantities
Potential for complex production
process, scale up, purity, batch
variability issues. Process yields can be
small.
Pharmaceutical forms
Variable (oral, topical, etc),
concentration & potency can
be established
Usually injectable forms. Potency
more difficult to quantify.
Comparison criteria for
version different to
innovator
Bioequivalency (AUC)Preclinical test, PK, PD, clinical trials to
assess safety & eficacy, PV
Immunogenicity
Potential
Usually too small to be
considered as immunogenic
Immunogenic potential is high for
macromolecules that are recognized as
foreign
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Why Are Biotechnology Products Different From Simple Organic Chemicals?
Synthetic Drugs
Small molecules
Easy synthesis
� Aspirin
� Oligopeptides
Hemi-synthesis
Need of active stereo-isomers
� Steroids
� Anticancer
� Antimetabolites
� Cyclosporin
Extraction Biologicals
Complex & rare molecules
Animal source possible
� Insulin
� Heparins
Human source necessary
� HGH
� Coag. Factors
� Albumin
Implies a purification Process prior to human use.
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Manufacturing Processes Are Different
Biotech Products
� Produced by purification
� Starting material variable
� Many in-process tests
� Complex End-product tests
� Process is product-specific
� Batch sizes are small (g or kg of finished product)
Conventional drugs
� Produced by formulation
� Starting material defined
� Few in-process tests
� End-product tests simple
� Process is product type specific (generalizations possible)
Molecular identity can be tested only for Conventional drugs
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Ten key questions that drug regulatory agencies have to solve to license a biologic drug
1. Does the manufacturing process or materials raise
concerns about product safety (impurities, infectious
agents, lack of stability)?
2. What is known about the product and the purported
mechanism of action? (does this mechanism raise
concerns about impact on normal organs/tissues?)
3. Is there evidence in the laboratory and animal
studies that the product has the predicted action? If
not, why not?
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Ten key questions that drug regulatory agencies have to solve to license a biologic drug
4. Do preclinical data (or foreign experience in humans)
support the safety of:
� Starting dose, schedule, route of administration, duration of
exposure, proposed rate of dose escalation
5. Does the protocol appropriately monitor for toxicities (given
concerns based on chemical structure, toxicologic data or
prior human experience)?, Are risks acceptable for the
population to be studied?
6. Are there formulation issues, e.g., same formulation studied
in animals, toxic impurities?
7. Have phase 1 studies identified an optimal dose (safety and
activity) or should more dose exploration studies be done?
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Ten key questions that drug regulatory agencies have to solve to license a biologic drug
8. Do available activity data support efficacy assumptions
underlying Phase 3 (registration) trials?
9. Are trials designed to collect efficacy data; sources of
bias minimized?
10. Can be their safety monitored after massive use,
including the immune potential ? (i.e.
pharmacovigilance program)
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3 remarks about B&B
�Are they safe?
�Are they better than chemical
drugs on efficacy?
�Are biologic generics (biosimilars)
really equal (identical)?
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They are really equal?
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Bio-similar?
- Small-molecule drugs : generic form can be marketed if their
therapeutic equivalence to the original drug is proved
� pharmaceutical equivalence ( identical active substance) and bioequivalence ( comparable pharmacokinetics)
� no clinical efficacy and safety test
- Therapeutic proteins : the generic approach can not be applied to copies of therapeutic proteins because of complexity
� impossible to prove two protein products to be identical
� comprehensive clinical data : clinical equivalence
� approval by regulatory authority
� marketing
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How complex can be the process?Five Features of the Biotechnology Production Process
In summary, to produce a biologic drug we need:
1. Expression system of the gene
2. Production system compatible with the microorganism
3. Purification system
4. Nature of the active product
5. Pharmaceutical formulation and presentation
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Five Features For a Biotechnology Drug1. Expression System: Vector + Host
Identify, isolate and clone the gene coding for the desired protein
Construct a vector containing:� The gene
� The expression controls (promoter, secretion signal…)
Insert the vector into the selected micro-organism� Escherichia coli
� Saccharomyces cerevisiae
� Mammalian cells
� Genetically modified plants
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Expression System: Vector Construction + Host
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Five Features For a Biotechnology Drug2. The Production System
Purpose
� Optimize survival conditions for the genetically modified microorganism
� So that it produces the desired protein
� With acceptable yield
Materials & Methods
� Selection of cell culture media
� Selection of culture conditions
� Selection of culture equipment: i.e. fermenter
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Five Features For a Biotechnology Drug3. The Purification System
Purpose
� Extract protein from a complex growth medium
� Achieve close to 100% purity
� Without altering the protein
Materials & Methods
� Sequence of purification steps
� Filtration/ultrafiltration
� Precipitation/resolubilization
� Chromatography (ion-exchange, affinity, etc.)
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Five Features For a Biotechnology Drug4. Nature of Active Product
Proteins
� Chains of amino-acids
� Sequence of amino-acids encoded by genes
� Folded into 3-D conformation
� To obtain biological activity
� Host-dependent post-translational modifications (sugars…)
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Five Features For a Biotechnology Drug5. Pharmaceutical Formulation and Presentation
Purpose
� Maintain biological activity
� By keeping active protein conformation in solution
Materials & Methods
� Stabilization (albumin, glycerol)
� Storage at low temperature
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Aoki KR. Int Ophthalmol Clin 2005;45(3):25-37
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� Drug names of botulinum toxin products have changed to highlight the
different dose/potency ratios and emphasize that they are not
interchangeable
CARJ1
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Slide 30
CARJ1 Texto en Español! traduje el último párrafoCARJ; 20/10/2010
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Clinical Pharmacology
Immunogenicity: key-point for a good comparison of biopharmaceuticals
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Clinical Pharmacology
Immunogenicity: key-point for a good comparison of biopharmaceuticals
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http://www.nytimes.com/2008/04/30/health/policy/30heparin.html
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Conclusions
� Biologics are radically different to chemical drugs
in terms of molecular nature and size,
manufacturing process, purification and
immunogenicity, so they require different criteria
for clinical approval, specially in the case of
biosimilars, a fact that national drug regulatory
agencies are just beginning to recognize.
� Production of biologic drugs is so complex and
variation-prone that there is no
interchangeability, and each product has to
demonstrate its own efficacy and safety
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