Formulation and delivery of monoclonal antibodies Flashcards
what do proteins and macromolecules consist of
4 polypeptide chains
describe the stability of proteins and macromolecules
not very stable compared to small drug molecules
what is the route of administration of infliximab
IV infusion
what is the route of administration of rituximab
IV infusion
what is the route of administration of tocilizumab
IV infusion, sc injection
what is the route of administration of abatacept
IV infusion
what is the route of administration of adalimumab
sc injection
what is the route of administration of golimumab
sc injection
what is the route of administration of certolizumab pegol
sc injection
what is the route of administration of etanercept
sc injection
what are the advantages of sc route for delivery of mabs
- Can self administer treatment following training
- better self management - useful to treat chronic diseases with frequent dosing
- can use prefilled syringes/pens/autoinjectors
- better patient comfort than IV infusion
- longer dosing interval - reduced healthcare costs
- reduced hospital visits
- increased compliance
what are the disadvantages of sc route for delivery of mabs
- limited volume can be delivered to sc space
- relatively high dose required
- need stable, highly concentrated antibody formulation
- can have high viscosity
- can increase injection force, time and pain at injection site
- can reduce compliance - can also adversely affect bioprocessing during manufacture
what are the challenges of high concentration formulation development
- high concentration
- >0.1 of solution volume is occupied by solute
- molecular size and distance between van Der waal surfaces is of a similar magnitude to size of molecule - refers to molecular proximity
- can result in interaction between proteins
- reversible self association, increase in viscosity, aggregation
what is viscosity at a macroscopic level
rate of transfer of momentum in a liquid
- how readily it pours
what is viscosity at a microscopic level
resistance to solute mobility
- how solute molecules move around relative to solvent molecules
what needs to be considered in concentrated solutiosn
- molecular crowding
- intermolecular interactions
how does dose of monoclonal antibody affect viscosity
a high dose of mab required leads to high viscosity solutions
what is the pairwise intermolecular interactions
- difference in viscosity due to different intermolecular interactions
- considers behaviour of pairs of molecules
- DVLO
what is pairwise intermolecular interactions dependant on
- overall charge on solute molecule and charge distribution
- proximity of molecules
what are higher order intermolecular interactions
considers behaviour of groups of molecules
what are the approaches to avoid high viscosity
- predict or study concentration dependant viscosity of mab
- could reconsider use of mab if early enough and alternatives exist - understand effect of sequence and structure of mab on viscosity at high concentrations
- optimise sequence while still retaining activity - understand role of excipients in controlling viscosity
what are buffers used for
regulating pH
what are salts and charged amino acids used for in excipients
reduce tendency for proteins to self associate
what is the role of surfactants in excipients
replace proteins at interfaces
- both are surface active
what is the role of stabilisers In excipients
anti oxidant, metal chelator, cyroprotectant
what is the isoelectric point in proteins
pH at which a protein has no net charge
- when ph>pl, a protein has a net negative charge
name the 6 categories of excipients
- buffers to keep ph levels between 4.7 and 7.4
- most formulations use 1 of 3 surfactants
- sodium chloride is commonly used
- 2 amino acids
- antioxidants
- all lyophilised formulations used 1 or a mixture of polysaccharide/disaccharide
give examples of buffers
acetate, histidine, phosphate
give examples of surfactants
polysorbate 80, polysorbate 20
give examples of amino acids used as excipients
glycine and arginine
give examples of antioxidants
ascorbic acid, methionine and EDTA
Give examples of disaccharides/polysaccharides
- sucrose, sugars provide bulk and serve as a stabilising agent, mannitol
what devices can be used for delivery of mabs
- conventional needle and syringe
- combination product- drug and device
- drug solution (viscous)
- device: needle technology, ergonomic design (shape, size, actuation mechanism) - certolizumab pegol pre filled pen/syringe
- adalimumab (humira) pre filled pen/syringes, injection vials
- golimumab pre filled pen/syringes and pre filled disposable devices
- etanercept:
- benepali: pre filled disposable injection
- enbrel: pre filled disposable injection, powder and solvent for solution for injection vials
- erelzi: pre filled disposable injection
what are the requirements of using a drug and device combination product
- bolus injector- not multi use
- pre filled plastic syringe
- needle safety device
