EXAM 2 L9 Flashcards
Review how to calculate half-life
Slide 83-85
Shelf life definition
the period of time that a drug product maintains its properties (e.g.) potency) within specified limits)
The shelf life is set…
During development, in negotiation between the FDA and the manufacturer
Shelf life is based upon the…
T90, the time for the drug concentration to decrease to 90% of its initial value
Review estimating shelf life equation
Slied 87*
How do protein drugs degrade?
Chemical degradation:
Breaks the “correct” covalent bonds and or forms “incorrect” ones
Hydrolytic reactions
Oxidation reactions
Physical degradation:
Changes protein structure, usually without breaking covalent bonds
Unfolding
Aggregation
Routes of Degradation
Physical:
Unfolding
Aggregation
Phase Separation
Precipitation
Chemical:
Oxidation
Hydrolysis
Condensation
Environment:
Solution , solid, pH, temp
Some common routes of protein degradation
Hydrolytic reactions (chemical):
Asparagine (Asn) deamidation
Peptide bond hydrolysis (“clipping”)
Oxidation reactions (chemical):
Methionine (met) oxidation
Disulfide bond scrambling
Aggregation (physical)
Review Asparagine structure
Slide 119-121 (deamidation causes the loss of this amine group, as ammonia)
Deamidation in IgG
Deamidation in the Fc domain
Four deamidation sites (of 25 Asn) in the Fc domain
Slow deamidation attributed to secondary structure
*Review Methionine Oxidation
Slide 122
Disulfide scrambling
A common route of covalent aggregation of proteins
In solution, the reactive species is the thiolate anion (RS-)
There are also oxidation paths that give the same products
Look at and listen to slides 124-125
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Look at and listen to slides 139-140
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