Scientific Publications by FDA Staff

J Pharm Sci 2020 Apr;109(4):1519-28

An NMR based similarity metric for higher order structure quality assessment among U.S. marketed insulin therapeutics.

Wang D, Park J, Patil SM, Smith CJ, Leazer JL Jr, Keire DA, Chen K

Protein or peptide higher order structure (HOS) is a quality attribute that could affect therapeutic efficacy and safety. Where appropriate, the HOS similarity between a proposed follow-on product and the reference listed drug (RLD) should be demonstrated during regulatory assessment. Establishing quantitative HOS similarity for two drug substances (DS), manufactured by different processes, has been challenging. Herein, HOS differences among US marketed insulin drug products (DP) were quantified using NMR spectra and principal component analysis (PCA). Then, the unitless Mahalanobis distance (DM) in PCA space was calculated between insulin analog RLDs and their recently approved follow-on products and all DM values were 3.29 or less. By contrast, a larger DM value of 20.5 was obtained between the two Insulin Human DPs independently approved. However, upon mass-balanced and reversible dialysis of the two Insulin Human DPs against the same buffers, the DM value was reduced to 1.19 or less. Thus, the observed range of NMR-PCA derived DM values can be used as a robust and sensitive measure of HOS similarity. Overall, the DM values of 3.3 for DP and 1.2 for DS using insulin therapeutics represented realistic and achievable similarity metrics for developing generic or biosimilar drugs, quality assurance or control.