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Liposome Drug Products: Chemistry Manufacturing and Control Issues

Liposome Drug Products: Chemistry Manufacturing and Control Issues. Arthur B. Shaw, Ph.D. Office of New Drug Chemistry Division of New Drug Chemistry II ACPS 7/20/2001. Introduction .

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Liposome Drug Products: Chemistry Manufacturing and Control Issues

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  1. Liposome Drug Products: Chemistry Manufacturing and Control Issues Arthur B. Shaw, Ph.D. Office of New Drug Chemistry Division of New Drug Chemistry II ACPS 7/20/2001

  2. Introduction • Definition of Liposome: A liposome is a microvesicle composed of a bilayer of lipid amphipathic molecules enclosing an aqueous compartment. • Liposome Drug Products (LDPs) are formed when a liposome is used to encapsulate a drug substance either within the lipid bilayer or in the interior aqueous space of the liposome Arthur B. Shaw CMC Liposomes ACPS

  3. Arthur B. Shaw CMC Liposomes ACPS

  4. Reasons for Making LDPs • Targeting and Site–specific Delivery of Drug • Extended Release: Entrapped drug released slowly over time • Delayed Release • Protect drug from degradative enzymes • Protect patient against detrimental toxic effects of drug • Internalization: Promote the intracellular delivery of drug, etc. Arthur B. Shaw CMC Liposomes ACPS

  5. Unique Physicochemical and Biopharmaceutical Characteristics • Characterization of Drug Product • Physicochemical Characteristics: • Particle Size • Lamellarity • Free/encapsulated in vitro • Biopharmaceutical Characteristics: Discussed by Dr. Kumi and Dr. Martin Arthur B. Shaw CMC Liposomes ACPS

  6. Influence of Lipids on Membrane Properties Permeability and stability of liposomes are influenced by the rigidity/stiffness of the lipid bilayer. Determined by: • size and shape of the liposome • lipid composition. Arthur B. Shaw CMC Liposomes ACPS

  7. Membrane Properties:Lipid Composition • Gel-liquid phase transition occurs in a narrow temperature range for pure lipids (Tc) • Tc is affected by • Fatty acid side chains • Degree of unsaturation • Chain length • Polar head group Arthur B. Shaw CMC Liposomes ACPS

  8. Issue for Concern • Demonstration that a liposome drug product is the same when there are manufacturing changes This includes changes by: • the same manufacturer and • a new manufacturer (generic) Arthur B. Shaw CMC Liposomes ACPS

  9. Classification of Liposomes • Size and Lamellarity • MPS Uptake • Coating • Classifications are not mutually exclusive Arthur B. Shaw CMC Liposomes ACPS

  10. Classification of Liposomes: Size and Lamellarity • Small unilamellar vesicles (SUV), 25 to 100 nm in size that consist of a single lipid bilayer • Large unilamellar vesicles (LUV), 100 to 400 nm in size that consist of a single lipid bilayer • Multilamellar vesicles (MLV), 200 nm to several microns, that consist of two or more concentric bilayers • Vesicles above 1 µm are known as giant vesicles Arthur B. Shaw CMC Liposomes ACPS

  11. Classification of Liposomes:MPS Uptake and Coating • Mononuclear-phagocytic System (MPS) = Reticuloendothelial System (RES) • MPS targeted • MPS avoiding • Plain or modified • Example: Antibody-coated Arthur B. Shaw CMC Liposomes ACPS

  12. Active Moiety The “active moiety” is the drug (e.g., doxorubicin) responsible for the therapeutic effect. The lipids are “functional excipients.” All approved liposome drug products use drugs already approved in other dosage forms. Arthur B. Shaw CMC Liposomes ACPS

  13. Demonstration of Sameness after Manufacturing Changes • Information needed to demonstrate that the drug product is the same when there are manufacturing changes. • The manufacturing procedure for the LDP may determine the clinical behavior of the drug product even if the components are the same and the finished product meets the same specifications. Arthur B. Shaw CMC Liposomes ACPS

  14. Uniqueness of LDPsCharacterization • LDPs are unique compared with most other drug products • LDPs require characterization (similar to a drug substance) to include tests that may not be part of the specifications e.g., lamellarity, particle size, charge Arthur B. Shaw CMC Liposomes ACPS

  15. Uniqueness of LDPs:Characteristics Some characteristics may affect clinical performance • LDPs of the same composition may have different characteristics • Even if LDPs have the same characteristics by the current available tests they may not have the same clinical performance. Arthur B. Shaw CMC Liposomes ACPS

  16. How can Changes in Manufacturing be Assessed? • Changes for the Same Manufacturer: Manufacturer has experience with process • Pre-approval Changes • Post-Approval Changes • Changes for a New Manufacturer: Manufacturer has no experience with process. Arthur B. Shaw CMC Liposomes ACPS

  17. Factors Affecting Sameness • Raw Material • Manufacturing Process and Controls • Storage and Reconstitution Arthur B. Shaw CMC Liposomes ACPS

  18. Factors Affecting Sameness:Raw Materials and Their Specifications • Lipids From Natural Sources: Egg lecithins can vary in fatty acid composition • Modified Natural Lipids • Semisynthetic Lipids • Synthetic Lipids • Examples: • Fatty Acid Composition • Degree of Fatty Acid Unsaturation Arthur B. Shaw CMC Liposomes ACPS

  19. Factors Affecting Sameness:Manufacturing Process and Controls • Removal of Residual Organic Solvent • Removal of Endotoxin • Removal of Free Drug • Protection of Lipids From Oxidation • Control of Liposome Size Distribution / Osmolality • Encapsulation Control • Sterilization • Scale up and Economic Feasibility Arthur B. Shaw CMC Liposomes ACPS

  20. Factors Affecting Sameness:Storage and Reconstitution • Liposome preparations can be stored: • frozen, in liquid form • as a freeze dried powder. • Reconstitution of freeze-dried liposomes may affect particle size and size distribution. Arthur B. Shaw CMC Liposomes ACPS

  21. Release of Drug • Release controlled by: • Fluidity/stability (lipids/co-lipids): • Size: MLV or a SUV • Physicochemical properties of drug • Drug/lipid interaction Arthur B. Shaw CMC Liposomes ACPS

  22. Stability/Compatibility with infusion Fluids and Plasma • Any change in particle size can affect targeting, RES uptake, safety and efficacy. • In vivo stability of whole liposome is particularly important for targeted liposomes, since they should remain stable in the plasma without loss of contents until uptake at the target site. Arthur B. Shaw CMC Liposomes ACPS

  23. Approved Liposome Drug Products Arthur B. Shaw CMC Liposomes ACPS

  24. CMC Issues for Liposome Drug Products • Attributes in specifications/characteristics • Changes in manufacturing Arthur B. Shaw CMC Liposomes ACPS

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