While 2020 is an incredible and very difficult year, it has also been a year of remarkable biopharmaceutical accomplishments. Developments from vaccine development to new models of pharmaceutical R&D have transformed the biopharmaceutical industry. Here, we review the top five trends that have impacted the biopharma industry in the last year and that will continue to influence the industry in 2021 and long beyond.
1.More biologics analysis than ever before
Traditionally engineered proteins and monoclonal antibody drugs still account for a large percentage of new biologics development, but the next generation of therapeutics, including cell and gene therapies, multi-specific drugs, and genetic vaccines and therapies, are experiencing explosive growth.
As a result, there is a growing need for highly sensitive analytical systems that can be used to rapidly characterize multiple types of analytes with sensitivity, precision, and high resolution. These systems must be able to separate, detect, and characterize multiple analytes simultaneously across complex matrices and a wide range of concentrations.
Often, analytes have highly similar structures, such as nanobodies that can be distinguished by only one or two deamidations; protein contaminants from host cells and media that may negatively impact safety and efficacy also present analytical challenges; and it is not possible to develop an effective single assay capable of analyzing different host cell protein (HCP) profiles (up to 1000 or more quantities per host cell) using conventional ligand binding assays.
A simple, rapid, and effective technique with excellent separation capabilities and high precision, such as capillary electrophoresis (CE), is increasingly used to check and confirm the purity, heterogeneity, and glycan conjugation of all types of biological drugs. Specialized and standardized reagents and kits optimized for specific CE methods have also been generated, such as Capillary Isoelectric Focusing (CIEF), Capillary Zone Electrophoresis (CZE), CE Sodium Dodecyl Sulfate (CE-SDS) and CE – Laser Induced Fluorescence (CE-LIF) provide complete workflows and solutions that are both accurate and flexible enough for quality control applications.
CE is also combined with mass spectrometry methods for a range of analyses required during next-generation model development and commercialization. At the same time, liquid chromatography tandem mass spectrometry (LC-MS/MS) using data-independent acquisition techniques has proven to provide more comprehensive coverage, and analytical methods are faster and simpler to develop, being used for better biotransformation and analyte characterization indications. The analytical results are less likely to be false negatives, and the combination of multiple reagents is more affordable. For example, the CE method allows simultaneous detection of HCP from different organisms and the identification and quantification of all HCP in a single injection feed, regardless of their concentration. In addition, it can be applied to any biological agent, including cell and gene therapies, without the need for much more time-consuming development work.
2.Demand for new vaccines is at an all-time high
The COVID-19 pandemic has stimulated an unprecedented boom in the field of new vaccine development. A range of traditional and cutting-edge approaches to vaccine development are being sought. Naked DNA plasmid-based, viral vector and mRNA gene vaccines have leveraged robust, scalable platform manufacturing concepts and integrated processes that have dramatically reduced the time to vaccine development. As these new vaccines are rapidly developed and commercialized, advanced analytical technologies play a critical role in ensuring the safety and efficacy of these new vaccines.
3.Uncharted areas and therapeutic approaches with new paradigms
In addition to new gene vaccines, many new RNA- and DNA-based therapies, such as oligonucleotide antivirals, viral and other gene therapies, various types of cellular and gene-modified cellular therapies, bispecific and trispecific antibody drugs. Today, conjugates of bispecific T-cell bridging substrates, peptidomes and nanoantibodies are being developed.
These novel drug therapies overcome some of the limitations of monoclonal antibodies (mAb), such as the ability to bind multiple sites simultaneously, higher stability and the ability to enter solid tissue and cross the blood-brain barrier. However, these new modalities and the complexity of the process may give rise to many variants. These therapeutic agents also typically have lower titers than mAb (10-50%).
The diversity and higher complexity places a greater burden on the analysis from the clone selection stage to the production process development and commercial production. At low concentrations, it is necessary to distinguish molecules with less structural differences. Therefore, higher sensitivity and separation are essential when developing analytical methods for these new approaches.
In order to overcome these challenges, existing reliable mAb methods are being optimized and tuned for variations in the analytical development process. For example, CE-SDS, cIEF, CZE, and rapid polysaccharide analysis for peptide and nanobody analysis can be optimized by increasing the percentage of reagents in the sample, using different reagents, lowering the pH, and changing the temperature and time of analysis.
The industry has struggled to find alternative orthogonal techniques that can address the specific complexities of mAb variants (rather than just using modified mAb methods). Techniques such as capillary electrophoresis coupled with mass spectrometry (CE-MS) can support the analysis of charge variants of intact nanobodies, even if the mass difference is only 1-2 daltons.
High resolution mass spectrometry (HRMS) ensures adequate resolution of the parent oligonucleotides as well as the major and minor metabolites of oligonucleotide antivirals.
To characterize multi-specificity at the subunit level, higher throughputs can be achieved using LC-MS/MS systems with differential mobility separation (DMS) technology. This technique allows the separation of protein subunits with a single injection and unambiguous identification of each strand without the need for chromatographic separation, thereby reducing the total time required to complete the study.
4.Patients need faster-achieving therapies
Time to market is critical for developers of both traditional and next-generation therapies. For new therapies targeting specific genes, the urgency is even greater. The companies that win first will be able to win in a highly competitive market.
Therefore, the key to improving process preparation for genes and other new therapies is to develop consistent, scalable, high-yield platform approaches and rapid analytical methods. Without rapid analytical methods, it is impossible to fully understand all relevant process parameters and how they affect product quality attributes, which will prevent the development of well-marketed processes.
Advances in automation and data analysis have the potential to reduce analysis time and simplify analysis while improving consistency and accuracy. Given the typically low production volumes of next-generation therapeutics, these assays must also have greater sensitivity and accuracy.
CE solutions have proven to provide the high sensitivity and high resolution required for GMP release for a variety of applications. For example, the purity of AAV coat proteins can be determined using CE-LIF with four orders of magnitude greater sensitivity than traditional SDS-polyacrylamide gel electrophoresis (PAGE) methods, while the use of smaller sample volumes allows for improved throughput detection.
5.Proven and reliable analytical methods
The need for pharmaceutical companies to develop mature, qualified processes and assays provides a new paradigm for monoclonal antibody drugs, which have well-defined process and analytical requirements. Developers of gene, cell, and other next-generation therapeutics lack platform solutions, regulatory guidance, and skilled and experienced personnel, and must therefore create their own pathways to commercialization.
However, the U.S. Food and Drug Administration (FDA) continues to develop guidance documents to support the development and commercialization of these novel, life-changing drugs. the FDA encourages progress by creating opportunities to discuss the best ways to ensure optimal product safety. Various coalitions of technology providers, drug developers and regulatory agencies are working together to modify existing methods and develop new technologies to streamline and reduce the time required to analyze new studies. Combining the best analytical technologies with the smartest therapeutic thinking will bring the latest and most effective therapies to patients as quickly as possible.