Chemistry Reference
In-Depth Information
7.3.1 d
eveloPIng
And
v
AlIdAtIng
SImS
A SIM is a quantitative analytical procedure used to detect a decrease in the amount
of the active pharmaceutical ingredient (API) present due to degradation. According
to FDA guidelines, a SIM is defined as a validated analytical procedure that accu-
rately and precisely measures active ingredients (drug substance or drug product)
free from potential interferences such as degradation products, process impurities,
excipients, or other potential impurities, and the FDA recommends that all assay
procedures for stability studies be stability indicating [4]. During stability studies,
HPLC is routinely used to separate and quantitate the analytes of interest. There are
three components necessary for implementing a SIM: sample generation, method
development, and method validation.
7.3.1.1 generating the sample
SIMs are routinely developed by stressing the API under conditions exceeding
those normally used for accelerated stability testing. In addition to demonstrating
specificity in SIMs, chemical stress testing, also referred to as forced degradation,
can also be used to provide information about degradation pathways and products
that could form during storage, and help facilitate formulation development, manu-
facturing, and packaging. Stressing the API in both solutions and in solid-state
form generates the sample that contains the products most likely to form under
most realistic storage conditions, which is in turn used to develop the SIM. In sim-
plest terms, the goal of the SIM is to baseline resolve all the resulting products (the
API and all the degradation products) each from the other (i.e., no co-elutions).
Table 7.4 lists some common conditions used in conducting forced degradation
studies for drug substances [13].
Samples should be stored in appropriate vessels that allow sampling at timed
intervals (if desired), and that protect and preserve the integrity of the sample.
Thermostated and humidity-controlled ovens should also be employed. Generally,
the goal of these studies is to degrade the API from 5% to 10%; any more, and
relevant compounds can be destroyed, or irrelevant degradation products produced
(e.g., degradation products of the degradation products!); any less, and important
tAble 7.4
common conditions used in Forced degradation studies
study
conditions
Acidic pH
0.1 N HCl
Neutral pH
pH 7.0 phosphate buffer
Basic pH
0.1 N NaOH
Oxidation
O
2
Atmosphere, or H
2
O
2
Photolysis (UV)
1000 watt-h/m
2
(ICH-Ref. 2)
Photolysis (Fluorescence)
6 × 10
6
lux h (ICH-Ref. 2)
Note:
Acid and base solutions should be neutralized before analysis. Initial
sample concentrations in the range of 1-10 mg/mL are normally used.
