Biopharmaceuticals Flashcards
What are biopharmaceuticals?
Biopharmaceuticals are medical drugs produced using biotechnology.
They are proteins (including antibodies), nucleic acids (DNA, RNA or oligonucleotides) used for therapeutic or diagnostic purposes.
Majority of biopharmaceutical products are pharmaceuticals that are derived from life forms.
The first such biopharmaceutical approved for therapeutic use was recombinant human insulin.
What are biological products ?
Biological products are generally derived from living materials; human, animal or microorganisms.
They are usually complex in structure, and thus are usually not fully characterized.
What are some examples of biopharmaceuticals?
Haematopoietic factors.
Cytokines including interferons (for cancer, Alzheimer’s
disease, arthritis, major depression).
Monoclonal antibodies.
Hormones & derivatives.
Enzymes.
Recombinant proteins for vaccines / DNA vaccines.
What are haematopoietic factors?
Used for the formation of blood cellular components.
They regulate the proliferation and maturation of cells that enter the blood from the marrow, and cause cells in one or more committed cell lines to proliferate and mature.
An example is erythropoietin; a hormone that regulates red blood cell production.
What are cytokines?
They are regulators of host responses to infection, immune responses, inflammation and trauma.
Include some proteins, peptides or glycoproteins which regulate hormones or help in cell signalling.
They include monokines, lymphokines and interleukins.
Some biologic drugs are cytokine inhibitors.
E.g. Anakinra (Kineret®) inhibits IL-1 or TNF-α is for the treatment of rheumatoid arthritis and works by inhibiting IL-1 binding to its receptor.
What are monoclonal antibodies?
Are monospecific antibodies (MAbs) that are the same.
They are made by identical immune cells that are all clones of a unique parent cell.
Can be used for cancer as the monoclonal antibodies for cancer bind only to cancer cell- specific antigens and induce an immunological response against the target cancer cell.
Can be modified for the delivery of a toxin, radioisotope, cytokine or other active conjugate.
Approved MAbs include bevacizumab, tratuszumab, cetuximab, panitumumab.
May also be used for autoimmune diseases (rheumatoid arthritis, IBD etc), E.g. infliximab.
What are recombinant proteins for vaccines?
Recombinant protein vaccines consist of protein antigens that have either been produced in an expression system (e.g., bacteria or yeast) or purified from large amounts of the pathogenic organism.
The vaccinated person produces antibodies to the protein antigen, thus protected from disease.
There are a limited number of recombinant/purified protein vaccines currently in use.
Examples of successful recombinant/purified protein vaccines include cholera, diphtheria, tetanus and hepatitis B vaccines.
How are living cells used in order to produce a protein product?
Insert gene encoding the protein of interest.
Cells require proper conditions for optimal growth (temperature, pH, oxygen, medium etc).
Culture and fermentation can take weeks.
Complex purification steps.
Safe product with desired potency.
How are protein therapeutics different from small molecule drugs?
May contain intrinsic infectious agents.
Aseptic techniques are required during production (terminal heat or gamma sterilization rarely applied).
Usually have heterogeneous composition.
Numerous process and product-related impurities.
Change in the manufacturing process can cause change in product composition.
Exact structure may be unknown (e.g. all possible variants often not fully characterized).
What are some distinct attributes of biopharmaceuticals?
Relatively unstable in solution.
High molecular weight, complex structural organization and delicate conformation.
Sensitive to environment (temperature, pH, oxidation, non-polar solvents etc).
Prone to enzymatic degradation (proteases and nucleases).
Susceptible to adsorption, unfolding, aggregation and inactivation.
Prone to microbial contamination.
Increased viscosity and low solubility at high concentrations.
Needs special care during fill-finish, storage and shipping.
Short half life (in vivo) - Results in their frequent administration and ultimately poor patient compliance
Varying potencies.
Cytokines, Enzymes, Hormones (High): Need low concentration.
Antibodies (Low): Need high concentration.
Limited absorption /Low mucosal permeability.
Low bioavailability.
Immunogenic.
What are the problems with the manufacturing of biopharmaceuticals?
Very Expensive.
Low production yields.
Sterile suites for cell culture, purification and fill-finish.
Cold chain.
What are the disadvantages of biologic drugs?
Relatively unstable in solution.
High molecular weight, complex structural organization and delicate conformation.
Sensitive to environment (temperature, pH, oxidation, non - polar solvents etc).
Prone to enzymatic degradation (proteolysis).
Susceptible to adsorption, unfolding, aggregation and inactivation.
Prone to microbial contamination.
Increased viscosity and low solubility at high concentrations.
Needs special care during fill-finish, storage and shipping.
Why do biologic drugs have poor bioavailability?
Short half life (in vivo).
Varying potencies.
Cytokines, Enzymes, Hormones (High) Need low concentration.
Antibodies (Low) Need high concentration.
Limited absorption / Low mucosal permeability.
What are the major issues for biologic product formulation:
Solubility - Proper pH should be considered if solubility enhancement is required. Excipient choice is important.
Stability - Physical instability (misfolding, aggregation…etc.) Chemical instability (oxidation, isomerization, degradation…etc.)
Sterility - Meet sterility requirement for parenteral
Special considerations for sterilization methods that can be utilised.
Safety + Purity - Viral decontamination and endotoxin/pyrogen removal are necessary.
Explain the challenge of insolubility:
Low aqueous solubility is the major problem encountered with formulation development of biologics.
This is because of the high molecular mass of biologics, and great tendency to aggregate.
This leads to difficulties in obtaining adequate, reproducible absorption from the gastrointestinal tract after oral administration.
Poor solubility and variable absorption are associated with low bioavailability, and ultimately affect the efficacy and safety of the product.
2 big issues:
Cannot give particles by IV.
Poor bioavailability by oral.
