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

Abstract

Abstract.Today, we are experiencing unprecedented growth and innovation within the pharmaceutical industry. Established protein therapeutic modalities, such as recombinant human proteins, monoclonal antibodies (mAbs), and fusion proteins, are being used to treat previously unmet medical needs. Novel therapies such as bispecific T cell engagers (BiTEs), chimeric antigen T cell receptors (CARTs), siRNA, and gene therapies are paving the path towards increasingly personalized medicine. This advancement of new indications and therapeutic modalities is paralleled by development of new analytical technologies and methods that provide enhanced information content in a more efficient manner. Recently, a liquid chromatography-mass spectrometry (LC-MS) multi-attribute method (MAM) has been developed and designed for improved simultaneous detection, identification, quantitation, and quality control (monitoring) of molecular attributes (Rogers et al. MAbs 7(5): 2015). Based on peptide mapping principles, this powerful tool represents a true advancement in testing methodology that can be utilized not only during product characterization, formulation development, stability testing, and development of the manufacturing process, but also as a platform quality control method in dispositioning clinical materials for both innovative biotherapeutics and biosimilars.KEY WORDS: biotherapeutic; mass spectrometry; multi-attribute method; quality by design.To date, multi-attribute method (MAM) has been applied to several early stage clinical programs with different classes of protein therapeutics and compared to current practices. This experience shows that the MAM technology can be utilized for different types of protein therapeutics delivering highly specific and quantitative information, which is invaluable during process development and essential for molecular characterization. Data has also been generated to support its use for release and stability in alignment with Quality by Design (QbD) principles. Utilizing recent advances in the technology, research, and development labs, in industry, has generated convincing data that MAM would be highly beneficial in a cGMP environment. This article will summarize the advantages of MAM relative to conventional product testing approaches. We recommend that MAM, unlike conventional purity methods, be used to specifically monitor and quantify molecular product quality attributes and product/process-related impurities. This increased specificity for attributes with increased relevance to safety and efficacy can lead to better product/process understanding, shorter process and product development timelines, and an improved control strategy by improving specificity of the measurement. MAM OVERVIEWReduced LC-MS-based peptide mapping methods have been used in academia and the industry for several decades. Biopharmaceutical companies are increasingly using quantitative LC-MS-based peptide mapping methods for clinical material characterization, as well as release and stability testing (1-7). Quantit...

Mass Spectrometry Advances and Perspectives for the Characterization of Emerging Adoptive Cell Therapies

“…LC-MS peptide mapping of mAb-based therapeutics has evolved from characterization towards quality control (QC), and has garnered widespread interest in the current state-of-the-art Multi-Attribute Method (MAM) [125]. Concurrently, the need for instrument control and system suitability has kept pace with translation of MAM analysis toward the QC environment [126].…”

Shifting Paradigms Revisited: Biotechnology and the Pharmaceutical Sciences

“…Through this approach, one can monitor several quality attributes by only one method, thereby reducing the number of assays required for QC release testing. 40 Besides the stability of the drug substance, it has been clear that excipients can have their own quality and stability issues, potentially compromising product quality; see Table 3 for examples. This implies that also the excipients should be characterized during product development.…”

Innovation in Chemistry, Manufacturing, and Controls—A Regulatory Perspective From Industry

“…The wide variety of novel therapies discussed in the previous sections are paving the path toward increasingly personalized medicine requiring us to leverage technological advancements, such as the liquid chromatographymass spectrometry multi-attribute method (MAM). As suggested by Rogers et al, 163 MAM peptide mapping principles provide a true advancement in testing methodology that can be used not only during product characterization, formulation development, stability testing, and development of the manufacturing process but also as a platform quality control method in releasing clinically produced and commercially manufactured materials for both innovative biotherapeutics and biosimilars. This method can monitor and quantify product quality attributes with increased specificity, linking attribute relevance to safety and efficacy indicators resulting in a more robust benefit: risk profile.…”