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lec21_formulation of biotech products (I)(1)

Learning Objectives

Major Problems of Protein Drugs

  • High Molecular Weight:

    • Large molecules increase difficulty in cellular uptake.

  • Poor Stability:

    • Native biologically active structure maintained by weak noncovalent forces; easily disturbed by mild manufacturing or storage conditions.

  • Factors Affecting Stability:

    • Temperature

    • pH

    • Humidity

    • Ionic Strength

    • Enzymes

    • Mechanical Forces: pressure, shearing, and shaking.

Protein Folding

  • Definition:

    • Physical process where linear polypeptides fold into their 3D structure.

  • Initial State:

    • Proteins start as unfolded polypeptides (random coils) post translation from mRNA.

  • Folding Process:

    • Amino acids interact to produce a well-defined native state.

  • Importance of 3D Structure:

    • Correct folding is essential for functionality; improper folding leads to inactive proteins.

Physical & Chemical Instability of Protein Products

  • Physical Instability:

    • Changes in secondary, tertiary, or quaternary structures.

  • Chemical Instability:

    • Formation of new chemical entities via bond cleavage or formation.

  • Examples of Instability:

    • Aggregation, hydrolysis, surface adsorption, oxidation, precipitation, deamidation, and disulfide exchange.

How to Stabilize Protein Formulations?

  • Avoid Degradation Factors:

    • Physical and chemical factors that lead to instability (e.g., pH, temperature, enzyme activity).

  • Natural Conditions:

    • Proteins stabilize better in environments resembling their natural habitats.

  • Additives:

    • Use stabilizers to maintain native protein structure, reducing aggregation risk.

  • PEGylation:

    • Addition of polyethylene glycol (PEG) to improve stability.

  • Nanotechnology Formulation:

    • Use of nanoparticles for stabilization.

    • Examples include protein encapsulation and adsorption on nanoparticles.

Storage of Protein Drugs

  • Solution State:

    • Unstable and requires storage at -30°C to -80°C (-22F to -112F), complicating handling and transportation.

  • Dried Form Advantages:

    • Stable even at room temperature, easier for transportation, and more cost-effective.

How to Get Dried Form of a Protein Product?

  • Need for Dry Formulation:

    • Aqueous liquid forms are unstable and have limited shelf life, often requiring freezer storage.

  • Drying Methods:

    • Spray Drying

    • Freeze Drying (Lyophilization)

The Spray Drying Process

  1. Solution Feed:

    • Pumped as a fine droplet mist into drying chamber via an atomizer.

  2. Droplet Drying:

    • Liquid evaporates rapidly after atomization.

  3. Dry Powder Formation:

    • Formed in the drying chamber by heated gas; particles fall for collection.

  4. Cyclone Separator:

    • Induces separation of powder from air, collecting the final powder product.

CT

lec21_formulation of biotech products (I)(1)

Learning Objectives

Major Problems of Protein Drugs

  • High Molecular Weight:

    • Large molecules increase difficulty in cellular uptake.

  • Poor Stability:

    • Native biologically active structure maintained by weak noncovalent forces; easily disturbed by mild manufacturing or storage conditions.

  • Factors Affecting Stability:

    • Temperature

    • pH

    • Humidity

    • Ionic Strength

    • Enzymes

    • Mechanical Forces: pressure, shearing, and shaking.

Protein Folding

  • Definition:

    • Physical process where linear polypeptides fold into their 3D structure.

  • Initial State:

    • Proteins start as unfolded polypeptides (random coils) post translation from mRNA.

  • Folding Process:

    • Amino acids interact to produce a well-defined native state.

  • Importance of 3D Structure:

    • Correct folding is essential for functionality; improper folding leads to inactive proteins.

Physical & Chemical Instability of Protein Products

  • Physical Instability:

    • Changes in secondary, tertiary, or quaternary structures.

  • Chemical Instability:

    • Formation of new chemical entities via bond cleavage or formation.

  • Examples of Instability:

    • Aggregation, hydrolysis, surface adsorption, oxidation, precipitation, deamidation, and disulfide exchange.

How to Stabilize Protein Formulations?

  • Avoid Degradation Factors:

    • Physical and chemical factors that lead to instability (e.g., pH, temperature, enzyme activity).

  • Natural Conditions:

    • Proteins stabilize better in environments resembling their natural habitats.

  • Additives:

    • Use stabilizers to maintain native protein structure, reducing aggregation risk.

  • PEGylation:

    • Addition of polyethylene glycol (PEG) to improve stability.

  • Nanotechnology Formulation:

    • Use of nanoparticles for stabilization.

    • Examples include protein encapsulation and adsorption on nanoparticles.

Storage of Protein Drugs

  • Solution State:

    • Unstable and requires storage at -30°C to -80°C (-22F to -112F), complicating handling and transportation.

  • Dried Form Advantages:

    • Stable even at room temperature, easier for transportation, and more cost-effective.

How to Get Dried Form of a Protein Product?

  • Need for Dry Formulation:

    • Aqueous liquid forms are unstable and have limited shelf life, often requiring freezer storage.

  • Drying Methods:

    • Spray Drying

    • Freeze Drying (Lyophilization)

The Spray Drying Process

  1. Solution Feed:

    • Pumped as a fine droplet mist into drying chamber via an atomizer.

  2. Droplet Drying:

    • Liquid evaporates rapidly after atomization.

  3. Dry Powder Formation:

    • Formed in the drying chamber by heated gas; particles fall for collection.

  4. Cyclone Separator:

    • Induces separation of powder from air, collecting the final powder product.

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