Exam 3 Biologics: Lyophilized Powders for Reconstitution

Question 1

What percentage of approved biologics are marketed as lyophilized powders in the past 10 years?

Answer 1

40%

Question 2

What is the type and indication of Remicade?

Answer 2

type: MAb
indication: rheumatoid arthritis and others

Question 3

What is the type and indication of Nulojix?

Answer 3

type: MAb fusion protein
indication: renal transplant

Question 4

What is the type and indication of Herceptin?

Answer 4

type: MAb
indication: breast cancer

Question 5

What is the type and indication of Orencia?

Answer 5

type: MAb fusion protein
indication: rheumatoid arthritis

Question 6

What is the type and indication of Benlysta?

Answer 6

type: MAb
indication: lupus

Question 7

What are the advantages of lyophilized powders?

Answer 7

1. proteins, drugs, and other materials in lyophilized powders have reduced rates of chemical and physical degradation → the most important advantage!!
2. improved drug stability and longer shelf life
3. refrigerated storage is not usually needed
4. can use lyophilized formulations in pre-filled syringes, pens, autoinjectors (“dual chamber”)

Question 8

How do dual chamber inserts typically work?

Answer 8

one chamber for the powder and one chamber for the solution in which once you push the button, you break the barrier and so the powder and the solution mix and gets reconstituted

Question 9

What are disadvantages of lyophilized powders?

Answer 9

1. must be reconstituted prior to injection → less convenient than solutions
2. more expensive and slow/time consuming to manufacture → low temp and low pressure is needed!

Question 10

What is lyophilization?

Answer 10

1. also known as freeze drying
2. removes water by sublimation → water goes from ice phase to vapor phase without going through liquid water phase in between
3. occurs at low temperature and low pressure
4. gentler than other methods of removing water (ex. boiling) and is better for fragile drugs → protein is more stable and is more gentle on the protein
5. same process is used for some foods (like instant coffee, dried fruits in breakfast cereals) → preserves the delicate flavors of the food

Question 11

What is the reason for a product to be lyophilized?

Answer 11

it was not stable in solution → if it was stable in solution, a solution product would have been made (look at the drug as a stability risk!)

Question 12

What is the main mechanism behind lyophilization?

Answer 12

operates at a low pressure so that it goes from ice to vapor phase without going through liquid phase

Question 13

What is the phase diagram of water?

Answer 13

y axis is pressure and x axis is temperature (atmosphere pressure of 1 atm is living conditions)

Question 14

What are the different phases that can occur with the phase diagram of water?

Answer 14

1. freezing → from water to ice (right to left)
2. vacuum → to lower pressure (up to down in ice phase)
3. sublimation → from ice to water vapor (left to right)

dry powder to ambient if going from water vapor to water

Question 15

What are the different stages of lyophilization?

Answer 15

1. the first stage is freezing → take product and decrease temp while staying at the same atmospheric pressure to make ice
2. reduce pressure and go through sublimation
3. drying stage → ice to water vapor phase (a dry powder)
4. back to atmospheric temperature and pressure

Question 16

What do lyophilizers look like?

Answer 16

big programmable machines that look like autoclaves that can hold thousands of vials in which vials are loaded in and cycles occur in a closed chamber to freeze dry the product in the vials

Question 17

How can lyophilization cause instability?

Answer 17

1. freeze concentration can promote aggregation → concentrated solution of stuff that hasn’t freezed yet can promote aggregation
2. disulfide bond scrambling can be accelerated by freezing and drying
3. protein structure can be perturbed by lyophilization → certain excipients can inhibit this
4. aggregated and/or degraded protein can be observed on reconstitution → via cloudiness or haziness so look at it before giving it to the patient!

Question 18

What are some excipients that can inhibit the protein structure from being perturbed by lyophilization?

Answer 18

lyoprotectants → drying protectant

cryoprotectants → freezing protectant

Question 19

What are some clinical considerations regarding lyophilized formulations?

Answer 19

biologics are usually marketed in lyophilized form because they are unstable in solution so caution is needed

Question 20

What are certain instances when you should use caution in regarding lyophilized formulations?

Answer 20

1. when reconstituting
2. when storing and handling the reconstituted solution → have limited shelf life once reconstituted (example is that glucagon fibrillates at room temp)
3. when administering so visually inspect for particulates (anything floating in solution that is weird or abnormal looking)

do not swirl or shake!!!

Question 21

What do particulates look like under the microscope?

Answer 21

they look like long irregular shaped clumps

Question 22

What is an overall summary about lyophilized formulations?

Answer 22

1. lyophilized (freeze-dried) formulations are often used for biologics that are unstable in solution
2. they must be reconstituted prior to injection → adds extra cost and hassle
3. use care when reconstituting and when handling reconstituted solutions → can be subject to aggregation once they are back in solution