Chemistry Reference
In-Depth Information
7.4.3.2 linearity and range
Linearity and range are established by preparing solutions of the drug, ranging in
concentration from below the lowest expected concentration to above the highest
concentration during release. Typically, solutions are made from a common stock
using serial dilutions. A range should be chosen (through appropriate dilutions as
necessary) so as not to exceed the linearity limits of the instrument.
Sometimes, organic solvents are necessary in the preparation of standards; how-
ever, no more than 5% (v/v) of organic solvent in the final solution should be used.
Linearity is typically calculated and reported by least-squares linear regression
analysis of the curve generated from a minimum of five points. Typically, a square of
the correlation coefficient (
r
2
≥ 0.98) demonstrates linearity. In addition, the
y
-inter-
cept must not be significantly different from zero. The ICH recommends that for
dissolution testing, linearity should be demonstrated ±20% over the range of the
dissolution test. For example, for a controlled-release drug product with a multiple
Q-factor of 20% after 1 h, and 80% after 24 h, the validated range should be from 0%
to 100% of label claim [6]. Additional general information on determining linearity
and range can be found in Chapter 4, Section 4.3.6.
7.4.3.3 Accuracy and recovery
Accuracy and recovery can be established by preparing samples containing the
drug and any other constituents present in the dosage form (e.g., excipients, coating
materials, capsule shell) ranging in concentration from below the lowest expected
concentration to above the highest concentration during release. The ICH recom-
mends a minimum of nine determinations over a minimum of three concentrations,
for example, three concentrations, three replicates each. An amount of stock solu-
tion equivalent to the targeted label claim may be added to the vessel instead of the
drug substance, particularly for very low strengths, as it may be more appropriate
to prepare a stock solution than to attempt to weigh very small amounts. The mea-
sured recovery is typically 95% to 105% of the amount added. Often, accuracy and
recovery experiments are carried out at the same time as linearity, using data from
the same samples. Additional general information on determining accuracy can be
found in Chapter 4, Section 4.3.1.
7.4.3.4 precision
For dissolution method validation purposes, precision is measured over two levels:
repeatability and intermediate precision. Repeatability refers to the application of
the procedure within one laboratory over a short period of time by one analyst using
one instrument. Repeatability is determined by replicate measurements of stan-
dard or sample solutions. It can be measured by calculating the RSD of the multiple
HPLC injections (peak area and retention time) or spectrophotometric readings for
each standard solution. Repeatability can also be measured from the same samples
used in the accuracy, recovery, and linearity experiments.
Intermediate precision is evaluated to determine the effects of random events
on the precision of the analytical procedure. This evaluation is typically done later
in the development of the drug product. The use of an experimental matrix design
