Podcast
Questions and Answers
What is a key consideration when evaluating the biosimilarity of a proposed product to the reference product?
What is a key consideration when evaluating the biosimilarity of a proposed product to the reference product?
Which factor is most crucial for large molecules when selecting injection sites for subcutaneous administration?
Which factor is most crucial for large molecules when selecting injection sites for subcutaneous administration?
What role do surfactants and buffers play in biologics formulations?
What role do surfactants and buffers play in biologics formulations?
Which ingredient is essential for the lyophilization process in protein formulation?
Which ingredient is essential for the lyophilization process in protein formulation?
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What is the typical concentration range for IgG antibodies in protein solutions?
What is the typical concentration range for IgG antibodies in protein solutions?
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Which of the following is NOT a target requirement for injectable formulations?
Which of the following is NOT a target requirement for injectable formulations?
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What makes long-acting injectables more susceptible to variation in drug absorption?
What makes long-acting injectables more susceptible to variation in drug absorption?
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Which of the following processes is known to use high shear forces to mill particles?
Which of the following processes is known to use high shear forces to mill particles?
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What is a critical issue associated with high pressure homogenization?
What is a critical issue associated with high pressure homogenization?
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What distinguishes biologics from conventional chemical products in terms of their manufacturing processes?
What distinguishes biologics from conventional chemical products in terms of their manufacturing processes?
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Why is aseptic filtration particularly important for thermolabile liquids in pharmaceutical production?
Why is aseptic filtration particularly important for thermolabile liquids in pharmaceutical production?
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How do biosimilars relate to reference biologic products?
How do biosimilars relate to reference biologic products?
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What are the key cleanliness requirements for working with open products in parenteral administration?
What are the key cleanliness requirements for working with open products in parenteral administration?
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What is the significance of using a 0.22 µm pore size in aseptic filtration?
What is the significance of using a 0.22 µm pore size in aseptic filtration?
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Study Notes
Course Information
- Course code: PR5217
- Course topic: Injectables 2
- Instructor: Associate Professor Matthias G. Wacker, PhD
- Department: Department of Pharmacy, Faculty of Science, National University of Singapore
- Email: [email protected]
Learning Outcomes
- Learn about formulation aspects relevant to biologics and biosimilars
- Understand the biopharmaceutics and production of long-acting injectables
Aseptic Production
- Clean environment with different cleanroom grades (e.g., grade A) is crucial, depending on the risk involved in the operations
- Sterile materials are used
- Operators cannot contaminate the product
- Stringent cleaning and disinfection protocols are conducted
Aseptic Filtration
- Terminal sterilization is the safest method, but aseptic filtration (also known as sterile filtration) is also suitable for certain situations
- Suitable for thermolabile liquids
- Removes pyrogens
- Conditions follow Ph. Eur. standards, using 0.22 µm pore size
Aseptic Manufacture
- Diagram illustrating aseptic manufacture process
- HEPA filter, protective screen, light fixtures, air flow, work surface, room wall, floor, supply plenum, sub-plenum, blower, and pre-filter and exhaust plenum are components present in the diagram
Cleanroom Sinovac
- Image of a technician wearing cleanroom attire
Biologics
- Biologics are partially manufactured by living organisms
- Their synthesis does not follow conventional chemical processes
- Biosimilars show very similar clinical performance to the reference product but with a more complex composition
Biologics and Biosimilars
- Biologics are at least partially manufactured by living organisms
- Their synthesis follows different pathways from conventional chemical reactions, and thus biologics compositions can be more complex
- Biosimilars are biologics which clinically resemble already-approved reference products
Formulation Science Biosimilars
- Biosimilars typically use the same dosage form and excipients as their reference product
- Small differences in excipients such as human serum albumin do not exclude a finding of biosimilarity if clinical data show a high similarity between the products
Injection Sites
- Injection sites for subcutaneous tissues may include the arm, abdomen, or thigh
- Injection site differences are more relevant for large molecules
Subcutaneous Tissue
- Diagram illustrating the process of subcutaneous injections, including formulation, injection site, inflammation and immune response, lymphatic drainage, tissue retention, and metabolism, and blood capillary.
Biological vs. Biosimilar Development
- A diagram contrasting the regulatory emphasis for biological vs biosimilar production routes
Protein Formulation
- Biologics often need formulations which increase chemical stability (shelf life)
- Commonly used stabilizers include surfactants and buffers to maintain pH and reduce interactions in concentrated protein solutions (e.g., IgG antibodies).
- Lyophilization requires specific ingredients like cryoprotectants and lyoprotectants
Case Studies Antibodies
- Case studies on antibody formulations
Pharmaceutical Development
- Describes the factors associated with pharmaceutical formulation development including route of administration, physical form and functional requirements
Erbitux
- Erbitux (Cetuximab) is an antibody used to treat recurrent or metastatic squamous cell carcinoma of the head and neck in patients who have failed platinum-based therapy.
Regulatory Requirements European Pharmacopeia
- Parenteral preparations (e.g., injections, infusions, and implantations) are sterile preparations intended for administration
- Containers must be sufficiently transparent for visual inspection
- Injections are sterile solutions, emulsions or suspensions
Excipients in Erbitux
- Inactive ingredients for Erbitux solution for injection
- Include Glycine, polysorbate 80, sodium chloride, citric acid monohydrate, sodium hydroxide, and water for injections
Excipients Antibody Solutions
- Antibody solutions are typically highly concentrated
- Sodium chloride and amino acids are commonly used
- Buffers adjust pH between lyophilized and non-lyophilized products.
- Excipients like Lysine, Tromethamine, Adipic acid, Mannitol, Arginine HCI, Proline, Citrate, Trehalose, Arginine, Glycine, Sucrose, Histidine, Acetate, Sodium Chloride, Phosphate are listed and their functions based on their use
Excipients in Erbitux
- Adsorption to various materials is reduced by polysorbates.
- Steric stabilization decreases larger agglomerates in antibody solutions.
Excipients Erbitux
- Glycine weakly interacts with proteins, contributing to stability.
- Water competition between the unfolding protein and glycine increases stability.
- All amino acids exhibit a degree of buffering capacity
Injection Site
- Absorption of large molecules (like antibodies) varies based on injection site
- Bioavailability differences in different injection sites (abdomen, arm, thigh, muscle, IV)
Case Study: Long-acting Injectable
- Case study on long-acting injectable formulations
Dosage Form MPA
- Aqueous solubility of MPA is approximately 1.54 ± 0.60 µg/mL
- Formulation of MPA used in injectable suspensions are at 160 mg/mL
- Suspensions are intended for subcutaneous injection into the abdomen or thigh.
Biopharmaceutics MPA
- Low blood levels of MPA are needed for its medicinal effects
- Intramuscular administration of MPA ensures a long duration of effect following a single injection
Selected Target Requirements
- Important requirements for safety and efficacy in formulations, such as sterile and non-pyrogenic preparations, stability, controlled particle size, optimized dissolution rate and syringability
Injection Site
- Small molecules are less affected by injection site differences
- Long-acting injectables are potentially more susceptible to injection site differences because of their longer absorption process
Depo-SubQ Provera
- Formulation type is a suspension for injection
- Inactive ingredients include Medroxyprogesterone acetate, methylparaben, propylparaben, sodium chloride, polyethylene glycol, polysorbate 80, and monobasic sodium phosphate
Process Technologies
- Sterilization techniques
- Hot melt extrusion
- Homogenization technologies
- Lyophilization
High Pressure Homogenization
- High shear forces are utilized to mill down particles to a micrometer scale
- Useful for closed-batch production, potentially creating a sterile product
- Product stability can be an issue, especially with proteins
Wet Bead Milling
- Grinding and shearing creates particles
- Ultra-crosslinked milling beads are used
Summary
- Injection type is frequently decided based on desired pharmacokinetic properties
- Parenteral formulations require adherence to stringent chemical, physical, and microbiological contamination standards
- Protein formulations are complex due to stability issues
- Long-acting injectable formulations are developed to respond to specific medical needs, and their release behavior is critical
Questions in PR5217
- Course questions are provided twice a week
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