Over the past several years, biologics have continued to make up an increasing proportion of biopharmaceutical sales and pipeline candidates. Biologics now account for more than half of the top selling drugs by revenue. In fact, 2018 saw a record 17 biologics license application (BLA) approvals and the 5-year annual average has more than doubled over the last decade (Figure 1). This trend is expected to continue for the foreseeable future with many different modalities of biologics in preclinical and clinical development. Currently, most global pharmaceutical companies’ pipelines consist of 20-40% biologics; the tipping point to a majority biologics pipeline is expected this decade.
But relative to synthetic small molecule therapeutics, the manufacturing process for biologics is far more complicated and requires the use of more intense characterization, from even the earliest stages of development through production and QA/QC to ensure safety and effectiveness. While liquid chromatography/mass spectrometry (LC/MS) has always had an important role in small molecule pre-clinical animal studies and in human clinical studies, expanded use is realized both upstream into target identification and downstream into manufacturing and QC release testing with biologics.
Just some of the characterization of biologics being performed in the LC-MS lab include: intact mass, glycan analysis, peptide mapping, impurity and degradant identity, and bioanalytical assays for DMPK purposes. The expansion of applications areas has also increased the types of mass spectrometers coupled to HPLC systems. The workhorse small molecule LC-MS system is based on a triple quadrupole spectrometer which provides excellent sensitivity for known compounds. This MS is ideal for the preclinical and clinical bioanalytical applications for small molecule therapeutics. Time-of-Flight (TOF) spectrometers are becoming more common instruments in pharmaceutical and biopharma labs because of their high mass resolving power. A TOF spectrometer allows for exact mass analysis on large molecules (~100,000 m/z) which is exceptionally useful in qualitatively characterizing biologics such as mAbs, ADCs and other large proteins.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from American Pharmaceutical Review – all delivered right to your inbox! Sign up now!
Beyond the capabilities of the mass spectrometer, consumables suppliers are now introducing novel sample preparation tools as well as isotopically labeled and certified reference standards for the biologics market. Specifically, for preclinical analysis of monoclonal antibodies, the introduction of immunoaffinity capture and release sample preparation kits are becoming popular. Furthermore, chromatography solvents and columns are tailored to meet the needs of large biologics. This trend includes large pore size (1000 Å) chromatography columns, smaller particles and smaller internal diameter columns all designed to couple biologics separations with mass spectrometers. Improvements include improved peak shape and faster analysis. Ultra-pure LC-MS solvents have been introduced to minimize unwanted fragmentation or ionization.
My expectation is that as biologics continue towards being a majority modality in the pharmaceutical pipeline, new and unique LC-MS tools will become available for use from discovery through QC.