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(An Engineering and Technological Overview)
UNIVERSIDAD INTERAMERICANA, BAYAMON
Erick Prado, P.E. 18-Sep-07
THE INTRODUCTION What is Biotechnology? Traditional vs. Modern Biotechnology Pharmaceutical Industry at Glance BIOPROCESSING TECHNOLOGIES Typical Biopharmaceutical Process Upstream Processing: Cultivation Fermentation: Bio-reaction Downstream Processing: Recovery Downstream Processing: Purification Fill and Finish Operations
BIOPHARMACEUTICALS Small Molecules vs. Macro-Molecules Biotechnologies for API Manufacturing Biotechnology-based Pharmaceuticals
SCIENCE BEHIND MODERN BIOTECH The Chemistry of Life The DNA Genetic Engineering
ENGINEERING ASPECTS cGMP Requirements Equipment Design Considerations Facility Design Considerations Commissioning and Qualification
WHAT’S NEXT? Future Directions Knowledge-based Economy: The Bio-Island
What is Biotechnology?
parts thereof and molecular analogues for products and services .Biotechnology • Technology based on biology • Biotechnology is the integration of natural sciences and engineering sciences in order to achieve the application of organisms. cells.
Disciplines of Biotechnology .
and vaccines • Tissue engineering WHITE BIOTECHNOLOGY: Chemical industry • Basic chemicals • Biopolymers • Biorefinery GREEN BIOTECHNOLOGY: Agriculture • Crops improvement • Natural pesticides • Pest and disease resistance . antibodies.Biotechnology Color Code RED BIOTECHNOLOGY: Medicine / Pharmaceuticals • Gene therapy • Production of proteins.
E HT 1900 1905 1910 1915 1920 1925 1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 CLASSICAL GENETIC Genetic mapping Transformation demonstrated MICROBIAL GENETIC Molecular genetics GENE MANIPULATION Development of technologies Applications .
THE INTRODUCTION Traditional vs. Modern Biotechnology .
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.Traditional vs. 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 Customers Pharmaceutical Industry Medicines Patient Main Shareholders Return Documents Regulatory Agencies FDA OSHA EPA .
From Molecule to Patient Therapeutic Target Discovery Research and Development FDA Approval Patient Distribution Final Dosage Manufacture API Manufacture .
API ACTIVE PHARMACEUTICAL INGREDIENT PROVIDES THE THERAPEUTIC EFFECT ACTIVE PHARMACEUTICAL INGREDIENTS = DRUG SUBSTANCES .
API Sources Chemical Synthesis Chemical reactions Synthetic APIs Microorganisms Fermentation Biotechnology Biological/Biotech APIs Natural Sources Extraction Purification Natural APIs .
API + EXCIPIENTS ACTIVE INERT DOSAGE FORM .
Pharmaceutical Commercial Chain PRIMARY PHARMACEUTICAL PRODUCTION SECONDARY PHARMACEUTICAL PRODUCTION TABLETS CHEMICAL SYNTHESIS CAPSULE SYRUPS SUSPENSIONS RAW MATERIALS API MICROORGANISM EMULSIONS CREAMS OINTMENTS SUPPOSITORIES FINAL DOSAGE DISTRIBUTION CHAIN PLANT ANIMAL DROPS SPRAYS INJECTIONS RATE-LIMITING STEP .
R&D Costs for a Biopharmaceutical .
BIOPHARMACEUTICALS Small Molecules vs. Macro-Molecules .
Small vs. inhalation. 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. parenteral . dermal.
) 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 .Small vs. Macro Molecules (cont.
BIOPHARMACEUTICALS Biotechnology for APIs Manufacturing .
Biocatalysis (enzymes) • 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 .
temperature. etc.Biosynthesis • 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.) . agitation.
Biosynthesis (cont.) • Old technology for product isolation: – Solvent extraction of the medium containing the product • Modern technologies for product isolation: – Membrane (reverse osmosis.and nanofiltration) – Chromatography • Final purification by conventional crystallization . ultra.
Cell Cultures • Use of animal or plant cells. removed from tissues • Cells are allowed to grow by: – Supplying the appropriate nutrients – Maintaining the proper conditions (pH. etc. temperature.) • Used for the generation of high molecular weight proteins .
cell culture can performs post-translational modifications required by large proteins production • Typical post-translational modifications: – – – – Protein folding Disulfide linkages Glycosylation Carboxylation .) • Contrary to microbes.Cell Cultures (cont.
BIOPHARMACEUTICALS Biotechnology-based Pharmaceuticals .
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 .
) – Thyroid hormone to enhance bone mass • Oxytocin (Pitocin. Miacalcin.Peptide Drugs • Many hormones are actually small peptides (2-40 amino acids) • Calcitonin (Calcimar. for antidiuretic/vasconstriction . 32 res. 9 residues) – Pituitary h. 9 residues) – Pituitary hormone to stimulate labor • Vasopressin (Pitressin.
Protein Pharmaceuticals • Insulin (diabetes) • Interferon β (relapsing MS) • Interferon γ (granulomatous) • TPA (heart attack) .
Protein Pharmaceuticals • • • • • • • Actimmune (If γ) Activase (TPA) BeneFix (F IX) Betaseron (If β) Humulin Novolin Pegademase (AD) • • • • • • • Epogen Regranex (PDGF) Novoseven (F VIIa) Intron-A Neupogen Pulmozyme Infergen .
Protein Pharmaceuticals Protein Drug Original Source • • • • • • Insulin Albumin HGH Factor VIII Calcitonin Anti-venom Pigs or cattle (pancreas) Human blood (donated) Human brains Human blood (donated) Salmon Horse of Goat blood .
species) – Viral & pathogen contamination • Most protein pharmaceuticals today are produced recombinant – Cheaper. safer.Protein Pharmaceuticals • Natural sources are often rare and expensive – Difficult to keep up with demand – Hard to isolate product – Lead to immune reactions (diff. abundant supply .
Categories of Biopharmaceuticals • Hematopoietic growth factors and coagulation factors – Stimulate production of certain blood cell types and clotting agents – Epogen®. Rebil® . Neulasta® • Interferons and cytokines for anti-infective and cancer therapy – Antiviral and anti-prolifertation activity – Avonex®.Neupoeng®. Benefix®. Betaseron®.
Somatropin®.Glucagon®.Categories of Biopharmaceuticals (cont. Pulmosyme®. DNAse therapy. Oncaspar® . thrombolytich enzymes. Synarel® • Enzymes – Catalyze unique biochemical reactions with high substrate specificity – Enzyme replacement. cancer therapy – Actovase®.) • Hormones – Pre-recombinant from slaughtered animals – Humulin®.
measles. Humanized. tetanus. etc. typhus.) • Antibodies and Derivatives – Chimeric. Rituxan®. etc. pneumonia. Remicade®.rubella. lyme. – TB. polio. rabies. diphtheria. flu. cholera. Herceptin® • Vaccines (for viral and bacterial infections) – Smallpox. chicken pox. .Categories of Biopharmaceuticals (cont. mumps. hepatitis. pertussis. Fully human – Enbrel®.
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