Ex 3. L4: Biologics: Prefilled Syringes, Pens, and Autoinjectors

Question 1

Examples of dosage forms

Answer 1

Lantus
Tx: Diabetes
Form: pre-filled pen

Humira pen:
Tx: rheumatoid arthritis
Form: Pen; (pre-filled syringe)

Aranesp:
Tx: Anemia of renal failure
Form: prefilled syringe; pen

Rebif:
Tx: Ms
Form: prefilled syringe; auto-injector

Question 2

Reminder about prefilled syringes, pens, etc

Answer 2

Technically, prefilled syringes, pens, and autoinjectors are NOT formulations

The pen (or syringe/autoinjector) itself is a medical device

The solution inside the pen/injector is the formulation

Together: They are called a combination product

Question 2

Advantages of pre-filled syringes, pens, and autoinjectors

Answer 2

-Ease of use, convenience
-Easier to transport than vial and syringe
-Discrete
-Increased patient compliance
-Reduced risk of dosage error
-Reduced risk of product contamination

Question 3

Disadvantages of pre-filled syringes, pens and autoinjectors

Answer 3

-Higher cost than vial plus syringe
-Cannot mix two drugs (e.g. insulin types)
-Drug waste due to priming
-Greater surface-to-volume ratio, presence of lubricants, can induce aggregation of protein drugs

Question 4

Pre-filled syringe components

Answer 4

Relook at slide 46
-Syringe barrel
-Luer lock
-Finger grip
-Plunger
-Gasket
-Top cap

Question 5

Insulin pen: Components

Answer 5

Relook at slide 48
-Pen cap
-Outer needle cap
-Inner needle cap
-Protective seal
-Rubber seal
-Insulin reservoir
-Dose window
-Dosage knob
-Injection button

Question 6

Common features of prefilled syringes, auto-injectors and pens

Answer 6

These are usually solution dosage forms within a device for admin, common features include:
-Drug solution
-Needle
-Piston or plunger
-Housing

Question 7

Special concerns for prefilled syringes, auto-injectors, and pens

Answer 7

When compared to vials containing solutions for injection, these devices have:
Higher surface-to low volume

Lower total volume

Syringe lubricants, oils
-Change interaction of proteins with solid surface
-Droplets in solution

proteins are surfactants and can unfold when exposed to surfaces or interfaces

Question 8

Aggregation and surfaces: Prefilled syringes, pens and autoinjectors

Answer 8

Hydrophobic syringe lubricants coat inside of barrel surface

Suspended oil droplets provide additional hydrophobic surface area

Folded, native protein
Hydrophobic surface promotes greater unfolding

Desorbed, partially unfolded protein

Dimer

Aggregates

Question 9

Part 3 summary

Answer 9

-Pre-filled syringes, pens and auto-injectors are used (usually) to deliver solution formulations of biologics
-Formulation concerns for biologics in solution apply
-Higher surface-to-volume ratio than in vials, and the use of lubricants, may promote aggregation

Question 10

Examples of Lyophilized Powders for reconstitution

Answer 10

Remicade
Tx: Rheumatoid arthritis and others
Type: mAB

Nulojix
Tx: renal transplant
Form: mAB infusion protein

Orencia
Tx: Rheumatoid arthritis
Form: mAb fusion protein

Herceptin
tx: breast cancer
type: mAb

Benlysta
tx: lupus
type: mAb

Question 11

Advantages of lyophilized powders

Answer 11

Reduced rates of chemical and physical degradation
Improved drug stability and longer shelf-life
Refrigerated storage is not usually needed
Can use lyophilized formulations in pre-filled syringes, pens, autoinjectors (dual chamber)

Question 12

Disadvantages of lyophilized powders

Answer 12

Must be reconstituted prior to injection; less convenient than solutions
-More expensive and time-consuming to manufacture

Question 13

What is lyophilization

Answer 13

-AKA freeze drying
-Removed water by sublimation
-Occurs at low temp and low pressure
-Gentler than other methods of removing water (e.g. boiling), better for fragile drugs
-Same process is used for some foods (instant coffee, dried fruits in some breakfast cereals)

Question 14

How does lyophilization work?

Answer 14

Relisten

Question 15

Lyophilization can Cause instability

Answer 15

“Freeze-concentration” can promote aggregation
-Disulfide bond scrambling can be accelerated by freezing and drying
-Protein structure can be perturbed by lyophilization. Excipients to inhibit this
-Lyoprotectants
-Cryoprotectants

-Aggregated and/or degraded protein can be observed on reconstitution

Question 16

Clinical Considerations: lyophilized

Answer 16

Biologics are usually marketed in lyophilized form because they are unstable in solution. Use caution….
-When reconstituting
-When storing and handling the reconstituted solution
-When administering; visually inspect for particulates

Question 17

Lyophilized powders for reconstitution summary

Answer 17

Lyophilized (free-dried) formulations are often used for biologics that are unstable in solution
-They must be reconstituted prior to injection
-Use Care when reconstituting and when handling reconstituted solutions