Linearity over a Wide Range of Concentration.Since the areas of the related sub-

stances (typically, less than 1%) and drug substance (typically, more than 95%)

are summed, it is important that the method is linear from the concentration of

related substances (e.g., 1%) to that of the drug substance (e.g., 95%). However,

in some cases, the peak shape of the drug substance may not be totally sym-

metrical at such a high concentration. Therefore, the response may not be linear

in such a wide concentration range, and the use of area percentage may not be

appropriate. If the response of the analyte is nonlinear at higher concentrations,

the related substances would be overestimated. Although this is conservative from

a safety perspective, it is inaccurate and therefore unacceptable.