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.