The World Health Organization has long recognized the need for a global harmonization of standards for biologics worldwide. In response, the United Kingdom's National Institute for Biological Standards and Control has developed the first international standard for infliximab.
The World Health Organization has long recognized the need for a global harmonization of standards for biologics worldwide. In response, the United Kingdom's National Institute for Biological Standards and Control (NIBSC) has developed the first international standard (IS) for infliximab, which targets tumor necrosis factor (TNF).
A recent paper describes how a candidate preparation coded 16/170 was found to be suitable as an IS for bioactivity for infliximab. The hope is that future continued studies such as these, examining standardization, will help promote biosimilar development, leading to lower drug costs worldwide, the authors said.
The issue has arisen because postapproval manufacturing changes in highly regulated markets can potentially result in changes in the product over time. Reference infliximab, for example, has gone through approximately 50 such changes since approval. As multiple biosimilars of a given reference product enter the marketplace, these individual products will all undergo their own changes, and could experience drift from the originator product.
Every product’s manufacturer has its own reference standards (a term not to be confused with reference product) against which it measures a product’s consistency over time. As such, there is an increasing need for harmonization of these in-house standards with a public standard that can serve as a benchmark for the reference product and all biosimilars.
The infliximab IS from NIBSC is intended to support in vitro bioassay calibration and validation by defining international units (IU) of bioactivity. The authors noted that the proposed units are not intended to revise product labelling or dosing requirements, since these decisions are made by regulators.
In this study, each ampule was assigned values of 500 IU of TNF neutralizing activity and 500 IU of binding activity. Two preparations of infliximab were formulated and lyophilized at NIBSC. The study involved using in vitro cell-based bioassays (TNF neutralization, antibody-dependent cell-mediated cytotoxicity, and complement-dependent cytotoxicity) and binding assays.
For TNF neutralization, between 74% and 83% of the assays performed were valid depending on the standard and the assay readout type. The assays proved to be very robust, even in the absence of a common standard. No one particular assay method was more variable; in addition, all reported potencies were similar.
The most variable assays in this study were the binding assays. Although this might be due to the smaller number of assays performed compared to the TNF neutralization assays, there could be several other contributing factors. Unlike TNF neutralization, the methods used were diverse and included ELISA, FRET and SPR platforms.
Overall, when infliximab products were assayed relative to in-house standards, there was significant variation in the relative potency estimates reported. However, the introduction of a common bioassay reference standard reduced inter-laboratory variability.
As more infliximab products come to market, they will all adopt their own lifecycle. It is important to ensure that the quality of products are aligned after different authorizations. Of note, this was the first international collaborative study, consisting of 26 participants in 15 countries.
Metcalfe C, Dougall T, Bird C, et al. The first World Health Organization international standard for infliximab products: A step towards maintaining harmonized biological activity. [published online November 5, 2018]. mAbs. doi:10.1080/19420862.2018.1532766.