A Quadrupole Dalton-based multi-attribute method for product characterization, process development, and quality control of therapeutic proteins

Abstract

During manufacturing and storage process, therapeutic proteins are subject to various post-translational modifications (PTMs), such as isomerization, deamidation, oxidation, disulfide bond modifications and glycosylation. Certain PTMs may affect bioactivity, stability or pharmacokinetics and pharmacodynamics profile and are therefore classified as potential critical quality attributes (pCQAs). Identifying, monitoring and controlling these PTMs are usually key elements of the Quality by Design (QbD) approach. Traditionally, multiple analytical methods are utilized for these purposes, which is time consuming and costly. In recent years, multi-attribute monitoring methods have been developed in the biopharmaceutical industry. However, these methods combine high-end mass spectrometry with complicated data analysis software, which could pose difficulty when implementing in a quality control (QC) environment. Here we report a multi-attribute method (MAM) using a Quadrupole Dalton (QDa) mass detector to selectively monitor and quantitate PTMs in a therapeutic monoclonal antibody. The result output from the QDa-based MAM is straightforward and automatic. Evaluation results indicate this method provides comparable results to the traditional assays. To ensure future application in the QC environment, this method was qualified according to the International Conference on Harmonization (ICH) guideline and applied in the characterization of drug substance and stability samples. The QDa-based MAM is shown to be an extremely useful tool for product and process characterization studies that facilitates facile understanding of process impact on multiple quality attributes, while being QC friendly and cost-effective.

Comprehensive characterization of monoclonal antibody by Fourier transform ion cyclotron resonance mass spectrometry

“…27 Multiple-attribute method (MAM), which combines high-end MS and dedicated software to provide highly specific and quantitative information for monitoring different attributes of biotherapeutics, could also be used in characterization and quality control of biotherapeutics, as FTICR might not be readily accessible in some cases. [45][46][47] Materials and methods…”

A View on the Importance of “Multi-Attribute Method” for Measuring Purity of Biopharmaceuticals and Improving Overall Control Strategy

“…Similarly, MAM can facilitate the monitoring of host cell proteins (HCPs) with immunogenicity or safety risks, and for any HCPs at unacceptable levels, MAM can aid the optimization of purification processes for greater clearance (32). In addition to being an excellent formulation screening tool, MAM is now widely used to monitor specific oxidation, deamidation, isomerization, and/or succinimide formation events that can impact product potency and establish appropriate product expiries to mitigate their impact (8,10,(12)(13)(14)32,33).…”

Technology outlook for real‐time quality attribute and process parameter monitoring in biopharmaceutical development—A review

“…Instrumentation with a smaller footprint and less‐complicated methods are preferred for implementation in both process development and manufacturing. A single quadrupole dalton‐based (QDa®) multiattribute method for product characterization and quality control of therapeutic proteins was recently reported (W. Xu et al, 2017). This technology features automated Protein A purification of clarified harvest from bioreactors followed by the mass spectrometric analysis of potential CQAs such as deamidation, afucosylation, and oxidation (W. Xu et al, 2017).…”