Podcast
Questions and Answers
What distinguishes biosimilars from generic drugs in terms of their chemical composition?
What distinguishes biosimilars from generic drugs in terms of their chemical composition?
Which of the following is NOT a factor taken into consideration during the evaluation of biosimilars?
Which of the following is NOT a factor taken into consideration during the evaluation of biosimilars?
What is a potential safety concern specifically associated with biosimilars?
What is a potential safety concern specifically associated with biosimilars?
How does the administration route of biosimilars typically differ from that of generic drugs?
How does the administration route of biosimilars typically differ from that of generic drugs?
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What must be demonstrated for a biosimilar to be considered interchangeable with its reference product?
What must be demonstrated for a biosimilar to be considered interchangeable with its reference product?
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What does the isoelectric point (pI) of a protein indicate?
What does the isoelectric point (pI) of a protein indicate?
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How does a low pH environment typically affect protein charge?
How does a low pH environment typically affect protein charge?
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Which of the following processes involves the breakdown of peptide bonds by water?
Which of the following processes involves the breakdown of peptide bonds by water?
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Which amino acid sequences are identified as 'hot spots' for hydrolysis?
Which amino acid sequences are identified as 'hot spots' for hydrolysis?
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What effect does adding a base have on protein interactions in terms of charge?
What effect does adding a base have on protein interactions in terms of charge?
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What is the primary consequence of oxidation on proteins?
What is the primary consequence of oxidation on proteins?
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What is a consequence of minimizing protein-water interactions at pI?
What is a consequence of minimizing protein-water interactions at pI?
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What is a consequence of denaturation in proteins?
What is a consequence of denaturation in proteins?
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How does modification of cysteine sequences affect proteins?
How does modification of cysteine sequences affect proteins?
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Which of the following factors is NOT a cause of protein denaturation?
Which of the following factors is NOT a cause of protein denaturation?
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What is a primary role of stabilizers in protein formulations?
What is a primary role of stabilizers in protein formulations?
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What is the key advantage of administering protein drugs via the nasal route?
What is the key advantage of administering protein drugs via the nasal route?
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What characterizes the lymphatic system's role in drug administration?
What characterizes the lymphatic system's role in drug administration?
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What is the relevance of pH in protein drug formulations?
What is the relevance of pH in protein drug formulations?
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Which of the following best describes a challenge with oral administration of protein drugs?
Which of the following best describes a challenge with oral administration of protein drugs?
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What is a primary challenge encountered with generic biopharmaceuticals compared to small molecule drugs?
What is a primary challenge encountered with generic biopharmaceuticals compared to small molecule drugs?
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How does PEGylation affect protein stability?
How does PEGylation affect protein stability?
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Study Notes
Pharmaceutical Biotechnology: Stability and Biosimilars
- Isoelectric Point (pI): The pH where a protein's net charge is zero, crucial for stability. Proteins have positive amine and negative carboxyl groups. Low pH: protonated (positive charge), High pH: deprotonated (negative charge). pI influences stability, precipitation, and interactions. Manipulating pH affects protein interactions with water and precipitation tendency.
Factors Affecting Protein Drug Stability
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Chemical Instability:
- Covalent Modification: Bond formation/cleavage, affecting structure.
- Deamidation: Ammonia removal (asparagine/glutamine).
- Hydrolysis: Peptide bond breakdown by water.
- Oxidation: Reaction with oxygen, targeting cysteine residues, impacting stability. Storage conditions and buffer pH influence chemical instability.
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Controlling Chemical Instability:
- Hot Spot Amino Acids: Specific amino acids susceptible to hydrolysis (e.g., Asp-Pro sequences). Modifying sequences can enhance stability.
- Oxidation Control: Lyophilization under nitrogen, or modification of cysteine sequences reduce oxidation.
- Disulfide Bond Exchange: Oxidation can alter protein conformation.
- Maillard Reaction: Reaction between sugar and amino acid forming new structures.
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Physical Instability (Denaturation): Loss of native structure, leading to activity loss.
- Causes: Heating, pH changes, organic cosolvents, salt concentration, mechanical stress (e.g., shaking, freezing), drying, surfactants.
- Consequences: Aggregation, altered structure, increased antigenicity (possible toxicity).
- Visible signs: Precipitation, bubbles, cloudiness.
- Irreversible.
- Aggregation: May be caused by non-covalent or covalent forces (including disulfide bond changes), rendering drug unusable.
- Absorption to Surfaces: Denatured protein can adsorb to surfaces, leading to inactivation.
Formulation of Protein Drugs
- Formulation Complexity: More complex than traditional drug formulations due to protein nature.
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Key Factors:
- pH: Balancing chemical stability and avoiding aggregation, influencing solubility.
- Inorganic Salts: Enhancing thermal stability (e.g., zinc).
- Stabilizers: Protection against degradation, aggregation, precipitation, absorption & denaturation (e.g., Albumin, glycine).
- Antioxidants & Chelators: Maintaining stability.
- Preservatives: Commonly used.
Preservation of Protein Drugs
- Refrigeration: Prevents denaturation.
- Freezing: Requires cryoprotectants (e.g., sugars, amino acids).
- Lyophilization (Freeze-Drying): Uses cryoprotectants and water-replacing stabilizers.
- Novel Approaches: Site-directed mutagenesis, chemical modification (e.g., using PEG polymers).
Administration of Protein and Peptide Drugs
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Challenges: Physical barriers (intestinal/capillary endothelia), degradation. Varying permeability of capillary endothelia based on location (sinusoidal, fenestrated, continuous). Lymphatic system absorption (proteins >20 kDa).
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Chemical and Enzymatic Degradation: Protease enzymes (e.g., serine, cysteine, aspartate, metalloproteases) in various locations degrade proteins.
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Immunogenicity: Potential for immune response. Formulations can affect immunogenicity.
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Routes of Administration:
- Nasal: Advantages – rich vasculature, rapid absorption, avoids liver. Disadvantages – catabolism, mucosal clearance, limited surface area.
- Pulmonary: Advantages – large surface area, short capillary distance. Disadvantages – inconsistent delivery.
- Parenteral: Intravenous preferred. Challenges – vascular barriers.
- Oral: Most desired, but faces GI tract transport/degradation challenges.
Protein Delivery Improvement
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Protein Modification:
- Chemical Conjugation (e.g., Pegylation): Adding PEG polymers to increase stability.
- Site-Directed Mutagenesis: Altering amino acid sequences (e.g., insulin lispro - reversing Pro28/Lys29) for enhanced stability.
Generics vs. Biosimilars
- Generic Biopharmaceuticals: Chemical structure fixed in small molecule drugs, allowing for generic equivalents. Protein drugs (modifications) challenge this direct comparison. Generic drugs: chemically identical, bioequivalent to the originator.
- Biosimilars: Term for follow-on biologic products (complex proteins/antibodies). Not chemically identical to reference drugs, have potential modifications.
- Key Differences: Size & complexity, manufacturing method (living systems), structure (similar but not identical), administration. Biosimilars typically have longer half-lives.
Biosimilar Evaluation
- Requirements: Analysis (purity, structure, uniformity, potency, glycosylation, aggregation) and degradation mechanisms to assess similarity.
- Immunogenicity: Biosimilars can differ in immunogenicity profiles.
Biosimilar Cost
- Production costs remain high due to complexities in manufacturing and clinical studies.
- Not considered "cheap generics"
FDA Approval of Biosimilars
- Biosimilarity: High similarity to the reference product with no clinically meaningful differences in safety, purity, and potency.
- Interchangeability: Expected identical clinical results; substitution should not pose greater risks.
Conclusion
- The lecture covered biologics, protein drug stability, formulation, delivery, and FDA regulations. Key for pharmacists dispensing biologics and biosimilars.
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Description
This quiz explores the concepts of protein stability and the factors influencing the lifespan of drug products in pharmaceutical biotechnology. Focus areas include the isoelectric point, chemical instability types, and methods to control these instabilities to enhance drug efficacy. Test your knowledge on the critical aspects that affect protein interactions and stability.
