Pyrogens & Particulates

What are pyrogens?

Fever-inducing

Non-volatile

Thermostable,

Water-soluble lipopolysaccharides from gram-negative bacteria cell walls

What are the sources of pyrogens in sterile products?

Solvents, excipients, and manufacturing apparatus'

What physiological responses can pyrogens cause?

• Reddening of injection site

• Pain in legs and trunk

• High temperature

• Multiple organ failure

Which products require pyrogen testing?

Injections over 15 ml

Powders for reconstitution, especially large-volume IV infusions

What is the rabbit test for pyrogens?

Inject rabbits with the formulation and observe for a temperature rise; fails if 3 rabbits have a combined increase of >2.65°C'

What are two advantages of the rabbit test for pyrogens?

Febrile response similar to humans; reliable for detecting pyrogens'

What are two disadvantages of the rabbit test for pyrogens?

Expensive and time-consuming; difficult to quantify and affected by some injections like insulin'

What is the Limulus Amoebocyte Lysate (LAL) test?

An in vitro test for bacterial endotoxins using horseshoe crab amoebocytes, detecting gel formation'

What are two advantages of the LAL test for pyrogens?

Quick and sensitive; quantifiable and inexpensive'

What are two disadvantages of the LAL test for pyrogens?

Results affected by pH and cations; requires careful control'

What indicates a positive response in the LAL test?

Coagulation or gel formation when LAL reacts with endotoxins'

What is particulate contamination in parenteral fluids?

Presence of visible and subvisible mobile, undissolved substances unintentionally present'

How does particulate contamination differ from microbial contamination and pyrogens?

Particulates are any particles (not necessarily living); microbial contamination involves living organisms; pyrogens are non-living endotoxins'

What are the origins of particulate matter in parenteral solutions?

Raw ingredients like drugs, solvents, or materials not filtered out during clarification'