biotech intro
TRANSCRIPT
BIOPROCESSING IN THE PHARMACEUTICAL
INDUSTRY (An Engineering and Technological Overview)
Erick Prado, P.E. 18-Sep-07
UNIVERSIDAD INTERAMERICANA, BAYAMON
THE INTRODUCTIONWhat is Biotechnology?
Traditional vs. Modern BiotechnologyPharmaceutical Industry at Glance
BIOPHARMACEUTICALSSmall Molecules vs. Macro-MoleculesBiotechnologies for API ManufacturingBiotechnology-based Pharmaceuticals ENGINEERING ASPECTS
cGMP RequirementsEquipment Design Considerations
Facility Design ConsiderationsCommissioning and Qualification
BIOPROCESSING TECHNOLOGIESTypical Biopharmaceutical ProcessUpstream Processing: Cultivation
Fermentation: Bio-reactionDownstream Processing: Recovery
Downstream Processing: PurificationFill and Finish Operations
WHAT’S NEXT?Future Directions
Knowledge-based Economy: The Bio-Island
SCIENCE BEHIND MODERN BIOTECHThe Chemistry of Life
The DNAGenetic Engineering
SEMINAR MAPPING
THE INTRODUCTION
What is Biotechnology?
Biotechnology
• Technology based on biology
• Biotechnology is the integration of natural sciences and engineering sciences in order to achieve the application of organisms, cells, parts thereof and molecular analogues for products and services
Disciplines of Biotechnology
Biotechnology Color Code
RED BIOTECHNOLOGY: Medicine / Pharmaceuticals• Gene therapy• Production of proteins, antibodies, and vaccines• Tissue engineering
WHITE BIOTECHNOLOGY: Chemical industry• Basic chemicals• Biopolymers• Biorefinery
GREEN BIOTECHNOLOGY: Agriculture• Crops improvement• Natural pesticides• Pest and disease resistance
• There are 20 different amino acids
• Within a gene, each specific sequence of three DNA bases (codons) directs the cell's protein-synthesizing machinery to add a specific amino acid
1930
1970
1990
1910191519201925
1935194019451950195519601965
197519801985
199520002005
19051900
CLASSICAL GENETIC
MICROBIAL GENETIC
GENE MANIPULATION
Genetic mapping
Transformation demonstrated
Molecular genetics
Development of technologies
Applications
TH
E H
ISTO
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F G
EN
ETIC
S
Traditional vs. Modern Biotechnology
THE INTRODUCTION
Traditional vs. Modern Biotechnology
Traditional• Based on microorganisms• Cells are not manipulated• Production of antibiotics by fermentation
Modern• Based on microorganisms and cell culture• Cells are manipulated• Production of protein products based on recombinant
DNA and cell culture• Modern biotech refers to Molecular Biology, Molecular
Genetics and Genetic Engineering
Biotechnology
• Broad definition can include many traditional food preparation processes
– Beer and wine
– Leavened bread
• Usually refers to recombinant DNA or tissue culture based processes
– emphasizes modern technology
– generate genetically modified organisms
THE INTRODUCTION
Pharmaceutical Industry at Glance
Pharmaceutical Industry Main Customers
Medicines
Return
Documents
Patient
Shareholders
Regulatory Agencies
Pharmaceutical Industry
FDA OSHA EPA
From Molecule to Patient
DiscoveryResearch and Development
FDA Approval
API ManufactureDistribution
Therapeutic Target
Final Dosage ManufacturePatient
ACTIVEPHARMACEUTICA
LINGREDIENT
API
PROVIDES THE THERAPEUTIC EFFECT
ACTIVE PHARMACEUTICAL INGREDIENTS = DRUG SUBSTANCES
API Sources
Chemical Synthesis
Micro-organisms
Natural Sources
Fermentation Biotechnology
Extraction Purification
Chemical reactions
Synthetic APIs
Biological/Biotech APIs
Natural APIs
+API
DOSAGE FORM
EXCIPIENTS
INERTACTIVE
Pharmaceutical Commercial Chain
PRIMARY PHARMACEUTICAL
PRODUCTION
CHEMICAL SYNTHESIS
MICRO-ORGANISM
PLANT ANIMAL
TABLETS
CAPSULE
SYRUPS
SUSPENSIONS
EMULSIONS
CREAMS
OINTMENTS
SUPPOSITORIES
DROPS
SPRAYS
INJECTIONS
SECONDARY PHARMACEUTICAL
PRODUCTION
RAW MATERIALS
APIFINAL DOSAGE DISTRIBUTION
CHAIN
TABLETS
CAPSULE
SYRUPS
SUSPENSIONS
EMULSIONS
CREAMS
OINTMENTS
SUPPOSITORIES
DROPS
SPRAYS
INJECTIONS
SECONDARY PHARMACEUTICAL
PRODUCTION
RAW MATERIALS
API
PRIMARY PHARMACEUTICAL
PRODUCTION
CHEMICAL SYNTHESIS
MICRO-ORGANISM
PLANT ANIMAL
FINAL DOSAGE DISTRIBUTION
CHAIN
RATE-LIMITING STEP
R&D Costs for a Biopharmaceutical
Small Molecules vs.
Macro-Molecules
BIOPHARMACEUTICALS
Small vs. Macro Molecules
Small Molecule Products• Molecular weight in 10² order of magnitude• Produced by:
– Traditional chemical synthesis– Microorganisms (fermentation or biotransformation)– Extraction from plants and animals
• Most of the medicines today• N-heterocyclic compounds most important• Administration: oral, dermal, inhalation,
parenteral
Small vs. Macro Molecules (cont.)
Macro Molecule Products• Molecular weight in 10³ order of magnitude• Very fragile molecules• Obtained mainly from modern biotechnology• Most of the biopharmaceuticals today• Proteins and peptides most important• Administration: parenteral
Biotechnologyfor
APIs Manufacturing
BIOPHARMACEUTICALS
• Known as biotransformation and bioconversion• Production of small molecules by use of:
– Natural or modified isolated enzymes– Enzyme extracts– Whole-cell
• A starting material is converted by the enzyme in the desired product
Biocatalysis (enzymes)
• Known as microbial fermentation• Part of the traditional biotechnology• Used for the production of:
– Small molecules – Antibiotics– Peptides– Less complex big molecules
• Bioreactor called fermenter• Microbes are allowed to grow by:
– Supplying the appropriate nutrients – Maintaining the proper conditions (pH, temperature,
agitation, etc.)
Biosynthesis
• Old technology for product isolation:– Solvent extraction of the medium containing the
product
• Modern technologies for product isolation:– Membrane (reverse osmosis, ultra- and nanofiltration) – Chromatography
• Final purification by conventional crystallization
Biosynthesis (cont.)
• Use of animal or plant cells, removed from tissues
• Cells are allowed to grow by:– Supplying the appropriate nutrients – Maintaining the proper conditions (pH, temperature,
etc.)
• Used for the generation of high molecular weight proteins
Cell Cultures
• Contrary to microbes, cell culture can performs post-translational modifications required by large proteins production
• Typical post-translational modifications:– Protein folding– Disulfide linkages– Glycosylation– Carboxylation
Cell Cultures (cont.)
Biotechnology-based Pharmaceuticals
BIOPHARMACEUTICALS
Biopharmaceutical
• A therapeutic product created through the genetic manipulation of living things, including (but not limited to): – Proteins– Monoclonal Antibodies– Peptides
• Monoclonal Antibody (MAb)– Highly specific antibody that is derived from only one
clone of cells and recognize only one antigen– Antigen: agent that stimulates production of antibody
that will react specifically with it
Peptide Drugs
• Many hormones are actually small peptides (2-40 amino acids)
• Calcitonin (Calcimar, Miacalcin, 32 res.) – Thyroid hormone to enhance bone mass
• Oxytocin (Pitocin, 9 residues)– Pituitary hormone to stimulate labor
• Vasopressin (Pitressin, 9 residues)– Pituitary h. for antidiuretic/vasconstriction
Protein Pharmaceuticals
• Insulin (diabetes)
• Interferon (relapsing MS)
• Interferon (granulomatous)
• TPA (heart attack)
Protein Pharmaceuticals
• Actimmune (If )• Activase (TPA)• BeneFix (F IX)• Betaseron (If )• Humulin• Novolin• Pegademase (AD)
• Epogen• Regranex (PDGF)• Novoseven (F VIIa)• Intron-A• Neupogen• Pulmozyme• Infergen
Protein Pharmaceuticals
• Insulin Pigs or cattle (pancreas)
• Albumin Human blood (donated)
• HGH Human brains
• Factor VIII Human blood (donated)
• Calcitonin Salmon
• Anti-venom Horse of Goat blood
Protein Drug Original Source
Protein Pharmaceuticals
• Natural sources are often rare and expensive – Difficult to keep up with demand– Hard to isolate product– Lead to immune reactions (diff. species)– Viral & pathogen contamination
• Most protein pharmaceuticals today are produced recombinant– Cheaper, safer, abundant supply
Categories of Biopharmaceuticals
• Hematopoietic growth factors and coagulation factors – Stimulate production of certain blood cell types and
clotting agents– Epogen®,Neupoeng®, Benefix®, Neulasta®
• Interferons and cytokines for anti-infective and cancer therapy– Antiviral and anti-prolifertation activity– Avonex®, Betaseron®, Rebil®
Categories of Biopharmaceuticals (cont.)
• Hormones – Pre-recombinant from slaughtered animals– Humulin®,Glucagon®, Somatropin®, Synarel®
• Enzymes– Catalyze unique biochemical reactions with high
substrate specificity– Enzyme replacement, thrombolytich enzymes, DNAse
therapy, cancer therapy– Actovase®, Pulmosyme®, Oncaspar®
Categories of Biopharmaceuticals (cont.)
• Antibodies and Derivatives – Chimeric, Humanized, Fully human– Enbrel®, Remicade®, Rituxan®, Herceptin®
• Vaccines (for viral and bacterial infections)– Smallpox, polio, measles, mumps,rubella, chicken
pox, flu, rabies, hepatitis, etc.– TB, typhus, cholera, lyme, pertussis, tetanus,
diphtheria, pneumonia, etc.