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. Arthur B. Shaw CMC Liposomes ACPS2 Introduction uDefinition of Liposome: A liposome is a microvesicle composed of a bilayer of lipid amphipathic molecules enclosing an aqueous compartment. uLiposome 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

3. Arthur B. Shaw CMC Liposomes ACPS3

4. 4 Reasons for Making LDPs zTargeting and Site–specific Delivery of Drug zExtended Release: Entrapped drug released slowly over time zDelayed Release yProtect drug from degradative enzymes yProtect patient against detrimental toxic effects of drug zInternalization: Promote the intracellular delivery of drug, etc.

5. Arthur B. Shaw CMC Liposomes ACPS5 Unique Physicochemical and Biopharmaceutical Characteristics zCharacterization of Drug Product zPhysicochemical Characteristics: yParticle Size yLamellarity yFree/encapsulated in vitro zBiopharmaceutical Characteristics: Discussed by Dr. Kumi and Dr. Martin

6. Arthur B. Shaw CMC Liposomes ACPS6 Influence of Lipids on Membrane Properties Permeability and stability of liposomes are influenced by the rigidity/stiffness of the lipid bilayer. Determined by: zsize and shape of the liposome zlipid composition.

7. Arthur B. Shaw CMC Liposomes ACPS7 Membrane Properties: Lipid Composition zGel-liquid phase transition occurs in a narrow temperature range for pure lipids (T c ) zT c is affected by yFatty acid side chains xDegree of unsaturation xChain length yPolar head group

8. Arthur B. Shaw CMC Liposomes ACPS8 Issue for Concern zDemonstration that a liposome drug product is the same when there are manufacturing changes This includes changes by: ythe same manufacturer and ya new manufacturer (generic)

9. Arthur B. Shaw CMC Liposomes ACPS9 Classification of Liposomes zSize and Lamellarity zMPS Uptake zCoating Classifications are not mutually exclusive

10. Arthur B. Shaw CMC Liposomes ACPS10 Classification of Liposomes: Size and Lamellarity zSmall unilamellar vesicles (SUV), 25 to 100 nm in size that consist of a single lipid bilayer zLarge unilamellar vesicles (LUV), 100 to 400 nm in size that consist of a single lipid bilayer zMultilamellar vesicles (MLV), 200 nm to several microns, that consist of two or more concentric bilayers zVesicles above 1 µm are known as giant vesicles

11. Arthur B. Shaw CMC Liposomes ACPS11 Classification of Liposomes: MPS Uptake and Coating yMononuclear-phagocytic System (MPS) = Reticuloendothelial System (RES) xMPS targeted xMPS avoiding yPlain or modified xExample: Antibody-coated

12. Arthur B. Shaw CMC Liposomes ACPS12 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.

13. Arthur B. Shaw CMC Liposomes ACPS13 Demonstration of Sameness after Manufacturing Changes zInformation needed to demonstrate that the drug product is the same when there are manufacturing changes. zThe 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.

14. Arthur B. Shaw CMC Liposomes ACPS14 Uniqueness of LDPs Characterization  LDPs are unique compared with most other drug products zLDPs require characterization (similar to a drug substance) to include tests that may not be part of the specifications e.g., lamellarity, particle size, charge

15. Arthur B. Shaw CMC Liposomes ACPS15 Uniqueness of LDPs: Characteristics Some characteristics may affect clinical performance yLDPs of the same composition may have different characteristics yEven if LDPs have the same characteristics by the current available tests they may not have the same clinical performance.

16. Arthur B. Shaw CMC Liposomes ACPS16 How can Changes in Manufacturing be Assessed? zChanges for the Same Manufacturer: Manufacturer has experience with process yPre-approval Changes yPost-Approval Changes zChanges for a New Manufacturer: Manufacturer has no experience with process.

17. Arthur B. Shaw CMC Liposomes ACPS17 Factors Affecting Sameness zRaw Material zManufacturing Process and Controls zStorage and Reconstitution

18. Arthur B. Shaw CMC Liposomes ACPS18 Factors Affecting Sameness: Raw Materials and Their Specifications zLipids From Natural Sources: Egg lecithins can vary in fatty acid composition zModified Natural Lipids zSemisynthetic Lipids zSynthetic Lipids Examples: yFatty Acid Composition yDegree of Fatty Acid Unsaturation

19. Arthur B. Shaw CMC Liposomes ACPS19 Factors Affecting Sameness: Manufacturing Process and Controls yRemoval of Residual Organic Solvent yRemoval of Endotoxin yRemoval of Free Drug yProtection of Lipids From Oxidation yControl of Liposome Size Distribution / Osmolality yEncapsulation Control ySterilization yScale up and Economic Feasibility

20. Arthur B. Shaw CMC Liposomes ACPS20 Factors Affecting Sameness: Storage and Reconstitution zLiposome preparations can be stored: yfrozen, in liquid form yas a freeze dried powder. zReconstitution of freeze-dried liposomes may affect particle size and size distribution.

21. Arthur B. Shaw CMC Liposomes ACPS21 Release of Drug zRelease controlled by: yFluidity/stability (lipids/co-lipids): ySize: MLV or a SUV yPhysicochemical properties of drug yDrug/lipid interaction

22. Arthur B. Shaw CMC Liposomes ACPS22 Stability/Compatibility with infusion Fluids and Plasma zAny change in particle size can affect targeting, RES uptake, safety and efficacy. zIn 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.

23. Arthur B. Shaw CMC Liposomes ACPS23 Approved Liposome Drug Products

24. Arthur B. Shaw CMC Liposomes ACPS24 CMC Issues for Liposome Drug Products zAttributes in specifications/characteristics zChanges in manufacturing