To develop a biosimilar product, it is essential to demonstrate the biosimilarity between the proposed biosimilar product and the reference product first in terms of quality in a stepwise approach that can then help inform the extent of safety and efficacy data that will be required to establish biosimilarity. These comparability studies should have direct side‐by‐side comparisons of the test and the reference products. In this paper, we develop a statistical method for unpaired head‐to‐head quality attribute comparisons. The method uses a plausibility interval derived from comparing the reference against the reference itself as the goalpost for claiming comparability. The idea behind this is that any observed difference between the reference and the reference itself should be considered as the random noise and as a part of the variability. We illustrate the performance of the proposed method by using simulation and real data sets. Copyright © 2012 John Wiley & Sons, Ltd.