RX422: Formulation of biologics

What are the routes of administration of biologics?

Parenteral (IV, SC, IM)

Inhalation

Depot

Nasally

Topical

Very few oral

Why can’t you give biologics nasally?

Sneezing reflex can’t be controlled

• Insulin and other things that need precise dosing can’t be given nasally

How is REGULAR heparin given?

IV

Can biologics cross BBB?

Yes. It’s just hard to do

• Carrier proteins

When do you take oral GLP-1s?

First thing in the morning for a consistent pH in stomach with a SIP of water

• Don’t want to flush it out of the stomach

How many units of pH needs to be moved to give 99% charge?

2

What is the isoelectric point (IP)?

pH at which the net charge is 0

What happens when you mix biologics with electrolytes (NaCL, KCL, etc.)?

Decrease solubility

What happens when you combine Organic solvents to proteins?

decrease solubility

What is lyophilization?

Freeze drying

Why does freeze drying increase stabilization?

Skips a phase (Liquid) so reduces loss

Which one of these is how freeze drying should look?

On the left

Which of the following is a result of moisture?

The one on the right

How do you package freeze dried products and why?

In an ampule because you want to avoid moisture

What is the risk of crystallization when freeze-drying?

There is none because there is no water in the process

What is the role of NaCl in a formulation?

Adjusts tonicity (NEVER CALL IT A BUFFER)

What excipient will monoclonal antibodies never be packed with?

Preservatives

What are monoclonal antibodies packaged as and why?

Single-use

No preservatives

What are the 4 stability problems in biologics?

Denaturation (Unfolding)

Aggregation

Surface adsorption

Oxidation

How do you prevent denaturation (Unfolding)?

DO NOT SHAKE

Minimize exposure to air

Add surfactants, buffers, and cosolvents.

What are common surfactants?

Poloxamers

Polysorbates

What cosolvents alter preferential hydration / preferential binding?

Polyethylene glycol

Glycerol

How do you overcome aggregation?

Make pH at lease 0.5 unites above or below IP

What is the most common range for IP?

5-7

How do you overcome Surface adsorption?

Coat surface of container

Add serum albumin

Add surfactants

What is the purpose of serum albumin in biologic formulations?

Compete with the therapeutic protein for binding sites to reduce adsorption

How do you overcome oxidation?

Reduce temperature to prolong time of the reaction

Minimize oxygen exposure

Control pH (Buffer)

Opaque or amber containers if photo-oxidation

Eliminate metals

What puts a biologic at risk of aggregation?

Changes in pH and temperature

Silicone vials

Stainless steal

• some proteins just don’t like it

Vibration during shipping

Change in air pressure

What is GRAS?

PEG agent

How does PEG protect a protein from degradation?

PEG associates with water forming a protective layer of water around the protein

What is particulate technology?

Formulating proteins without modifying protein structure

What is most common use of PLGA microspheres?

Particulate technology (Deopts)

What is the route of administration of particulate technology (Depots)?

IM and SUBQ

What is a big manufacturing issue in biologics?

Fogging

How do you prevent fogging?

Siliconize it

How do you test for fogging?

Monitor leak test by sampling rubber stopper in random batch