BIOPROCESSING IN THE PHARMACEUTICAL INDUSTRY
(An Engineering and Technological Overview)
UNIVERSIDAD INTERAMERICANA, BAYAMON
Erick Prado, P.E. 18-Sep-07
SEMINAR MAPPING
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
WHATS NEXT? Future Directions Knowledge-based Economy: The Bio-Island
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
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
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 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. Macro Molecules
Small Molecule Products
Molecular weight in 10 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 10 order of magnitude Very fragile molecules Obtained mainly from modern biotechnology Most of the biopharmaceuticals today Proteins and peptides most important Administration: parenteral
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
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, temperature, agitation, etc.)
Biosynthesis (cont.)
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
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, temperature, etc.)
Used for the generation of high molecular weight proteins
Cell Cultures (cont.)
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
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
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
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
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.
