Formulation and delivery of monoclonal antibodies

Question 1

what do proteins and macromolecules consist of

Answer 1

4 polypeptide chains

Question 2

describe the stability of proteins and macromolecules

Answer 2

not very stable compared to small drug molecules

Question 3

what is the route of administration of infliximab

Answer 3

IV infusion

Question 4

what is the route of administration of rituximab

Answer 4

IV infusion

Question 5

what is the route of administration of tocilizumab

Answer 5

IV infusion, sc injection

Question 6

what is the route of administration of abatacept

Answer 6

IV infusion

Question 7

what is the route of administration of adalimumab

Answer 7

sc injection

Question 8

what is the route of administration of golimumab

Answer 8

sc injection

Question 9

what is the route of administration of certolizumab pegol

Answer 9

sc injection

Question 10

what is the route of administration of etanercept

Answer 10

sc injection

Question 11

what are the advantages of sc route for delivery of mabs

Answer 11

1. Can self administer treatment following training
   - better self management
2. useful to treat chronic diseases with frequent dosing
3. can use prefilled syringes/pens/autoinjectors
   - better patient comfort than IV infusion
   - longer dosing interval
4. reduced healthcare costs
   - reduced hospital visits
   - increased compliance

Question 12

what are the disadvantages of sc route for delivery of mabs

Answer 12

1. limited volume can be delivered to sc space
2. relatively high dose required
3. need stable, highly concentrated antibody formulation
4. can have high viscosity
   - can increase injection force, time and pain at injection site
   - can reduce compliance
5. can also adversely affect bioprocessing during manufacture

Question 13

what are the challenges of high concentration formulation development

Answer 13

1. 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
2. refers to molecular proximity
3. can result in interaction between proteins
   - reversible self association, increase in viscosity, aggregation

Question 14

what is viscosity at a macroscopic level

Answer 14

rate of transfer of momentum in a liquid
- how readily it pours

Question 15

what is viscosity at a microscopic level

Answer 15

resistance to solute mobility
- how solute molecules move around relative to solvent molecules

Question 16

what needs to be considered in concentrated solutiosn

Answer 16

1. molecular crowding
2. intermolecular interactions

Question 17

how does dose of monoclonal antibody affect viscosity

Answer 17

a high dose of mab required leads to high viscosity solutions

Question 18

what is the pairwise intermolecular interactions

Answer 18

• difference in viscosity due to different intermolecular interactions
• considers behaviour of pairs of molecules
• DVLO

Question 19

what is pairwise intermolecular interactions dependant on

Answer 19

• overall charge on solute molecule and charge distribution
• proximity of molecules

Question 20

what are higher order intermolecular interactions

Answer 20

considers behaviour of groups of molecules

Question 21

what are the approaches to avoid high viscosity

Answer 21

1. predict or study concentration dependant viscosity of mab
   - could reconsider use of mab if early enough and alternatives exist
2. understand effect of sequence and structure of mab on viscosity at high concentrations
   - optimise sequence while still retaining activity
3. understand role of excipients in controlling viscosity

Question 22

what are buffers used for

Answer 22

regulating pH

Question 23

what are salts and charged amino acids used for in excipients

Answer 23

reduce tendency for proteins to self associate

Question 24

what is the role of surfactants in excipients

Answer 24

replace proteins at interfaces
- both are surface active

Question 25

what is the role of stabilisers In excipients

Answer 25

anti oxidant, metal chelator, cyroprotectant

Question 26

what is the isoelectric point in proteins

Answer 26

pH at which a protein has no net charge
- when ph>pl, a protein has a net negative charge

Question 27

name the 6 categories of excipients

Answer 27

1. buffers to keep ph levels between 4.7 and 7.4
2. most formulations use 1 of 3 surfactants
3. sodium chloride is commonly used
4. 2 amino acids
5. antioxidants
6. all lyophilised formulations used 1 or a mixture of polysaccharide/disaccharide

Question 28

give examples of buffers

Answer 28

acetate, histidine, phosphate

Question 29

give examples of surfactants

Answer 29

polysorbate 80, polysorbate 20

Question 30

give examples of amino acids used as excipients

Answer 30

glycine and arginine

Question 31

give examples of antioxidants

Answer 31

ascorbic acid, methionine and EDTA

Question 32

Give examples of disaccharides/polysaccharides

Answer 32

• sucrose, sugars provide bulk and serve as a stabilising agent, mannitol

Question 33

what devices can be used for delivery of mabs

Answer 33

1. conventional needle and syringe
2. combination product- drug and device
   - drug solution (viscous)
   - device: needle technology, ergonomic design (shape, size, actuation mechanism)
3. certolizumab pegol pre filled pen/syringe
4. adalimumab (humira) pre filled pen/syringes, injection vials
5. golimumab pre filled pen/syringes and pre filled disposable devices
6. etanercept:
   - benepali: pre filled disposable injection
   - enbrel: pre filled disposable injection, powder and solvent for solution for injection vials
   - erelzi: pre filled disposable injection

Question 34

what are the requirements of using a drug and device combination product

Answer 34

1. bolus injector- not multi use
2. pre filled plastic syringe
3. needle safety device