Midterm #1

Question 1

Pharmaceutical Biotechnology

Answer 1

• Any technology, advanced or otherwise, used to develop and test compounds-chemical or biologics- for therapeutic/clinical application
• Essentially it is the integration of science and know-how for biomedical applications
• Relationship to biopharmaceutics?

Question 2

Historical perspective of pharmaceutical biotechnology

Answer 2

• The path to new biopharmaceuticals
• Dramatic changes in the past 10-15 years

Question 3

What are biopharmaceuticals?

Answer 3

• Hormone (protein/peptide)
• Antibody (monoclonal/antiserum/immunoglobulin)
• Peptides
• Vaccines
• Cells
• Genetic material (nucleotides)

Question 4

Small MW drugs:

Answer 4

• pharmaceuticals
• small change>huge effects

Question 5

Biopharmaceuticals: change in amino acid sequences

Answer 5

• change in amino acid sequences > incremental effects
• The variants are still known by the same name and often for the same indication
  
  • insulin, hep B recombinant vaccine
• Same volume, different dose
• Name different but interchangeably used
• Substitutions/replacements at the end of the insulin. Used for similar indications

Question 6

Biopharmaceuticals refer to, where as pharmaceutic refer to:

Answer 6

• Biopharmaceuticals:
  
  • proteins
  • macromolecules
  • peptides >16-18 amino acids
  • enzymes
  • antibody
  • hormone
  • glycan or glycopolymers
  • nucleic acid polymers (DNA/RNA/Aptamers/Oligonucleotides)
  • Biologics
  • Biomolecules
• Pharmaceutical
  
  • Small molecule drugs
  • Chemical derrivatives

Question 7

Protein Biopharmaceuticals are:

Answer 7

• different from small molecule drugs, foods, or supplements
• Products that successfully transformed from proteins into drugs require
  
  • biopharmaceutic technologies and processes (Many steps)
  • Government and private funding of research and development (time and money)
• Regulated by FDA through evolving review and regulatory standards
• Important and growing areas of knowledge for pharmacists to best serve patients

Question 8

Large vs. Small Distinction

Answer 8

• Insulin products (MW>1000; large) versus
• Chemical drugs (i.e. acylovir and ganiciclovir; terfenadine and fexofenadine) (MW<1000; small)

Question 9

Differences between small chemical compounds and large macromolecules

Answer 9

• MW
  
  • Chemical: <1000
  • Protein Drugs: >1500
• Route of Admin
  
  • Chemical: All Routes
  • Protein Drugs: Mostly Parenteral (IV/IM/SC, etc)
• Volume
  
  • Chemical: Depends on hydrophobicity/protein binding
  • Protein Drugs: Limited to blood volume for most proteins
• Elimination
  
  • Chemical: Biotransformation
  • Protein Drugs: Protein filtration/aggregation/receptor binding
• Immunogenicity
  
  • Chemical: usually not important
  • Protein Drugs: May play a significant role
• Production:
  
  • Chemical: Synthesis
  • Protein Drugs: Cell and complex processes
• Fidelity:
  
  • Chemical: Excellent
  • Protein Drugs: Challenging
• Master Stock: (Cells that make the product day in and day out)
  
  • Chemical: Not required
  • Protein Drugs: Required
• Purity:
  
  • Chemical: Homogeneous
  • Protein Drugs: Non-homogeneous

Question 10

Differences in drug approval process

Answer 10

• Macromolecules produced by recombinant cells or tissues are unlikely to be homogenous-free of trace materials
• Therefore, FDA has two branches
  
  • CDER: Center for Drug Evalutation and Research
  • **CBER: **Center for Biologics Evaluation and Research to review new drug applications
• **New Drug Application (NDA): **Small molecules
• Biologic Liscence Application (BLA): Macromolecules and some vaccines
• Product Liscense Application (PLA): Vaccine and blood products

Question 11

“Responsible Head”

Answer 11

• Head of all processes such as contamination
• Responsible head will go to jail

Question 12

The difference in regulatory reviews are getting smaller

Answer 12

• While BLA and NDA still exist, as better preparation and detection techniques are available, some “well-characterized protein products” such as antibody molecules are now reviewed by CDER
• FDA announced it intention to consolidate the reveiw of biotech products under CDER-interferon alfa-2b (Intron A) was review by CDER
• Even with well-characterized proteins, the cost of production and detection of purity and contaminants remains challenging
• It is not only “what’s in the bottle” but more importantly, what not detectable in trace elements continues to challenge us

Question 13

Consequence of biopharmaceutics on pharmacy practice

Answer 13

• FDA approval based on risk/benefit consideration-who is the risk manager?
• Public expectation on “absolute” safety is not always consistant with FDA’s position
• Some of the added safegaurds may increase clinical development time; thus it adds to the overall medication cost

Question 14

Epogen vs. Eprex-recombinant Epoetin-alpha

Answer 14

• ​A change in manufacturing and packaging procedures causes production of antibody against both the endogenous erythropoietin as well as the recombinant drug
• As a result, erythropoietin made by patients is neutralized and they no longer can make RBCs—requiring life-long transfusion

Question 15

Summary of Distinction between biopharmaceutical and pharmaceuticals

Answer 15

• There are significant differences between chemical compounds and large macromolecules
• Unique properties of proteins and macromolecules require appropriate pharmaceutics principles and tools for development, evaluation, approval, and safety monitoring
• Evolving public expectation and regulatory standards may have impacts on the drug approval, dispensing, management and overall costs

Question 16

Basic Characterisics of Proteins

Answer 16

• Composed of defined sequence of amino acids linked together by peptide bonds
• Amino acid sequence may determine the secondary, tertiary, and quartenary structure of the protein-3D structure that exhibits the biologic activity
• Can be inactivated readily by:
  
  • Hydrolysis of peptide bonds: catalyzed by proteases
  • Denaturation: due to modification of the protein conformation

Question 17

Protein as Therapeutics

Answer 17

• Recombinant DNA technology enables large-scale and predictable production of biologically active proteins and peptides
• Refinements of robust pharmaceutical technologies have given us recombinant proteins in the scale, purity and quality for use as therapeutic agents.
• These recombinant proteins have opened a new class of drugs that could not otherwise be synthesized due to their complexity

Question 18

Rational for developing new and old protein drugs

Answer 18

• Existing (endogenous) proteins
  
  • Scarce-extremly low levels (tPA, DNAse)
  • Potential contamination-hGH, insulin, HepB vac
  • Reproducibility, predictability, qualtiy assurance
• New (innovative) proteins
  
  • Previously unavailable as extracted products
  • Could be proteins that mediate activity through binding, inhibition, induction, catalyzing or replacing defective bio/physiologic functions

Question 19

New innovation in therapeutics are products of public and private collaboration and investments

Answer 19