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...

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.

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The process of assembling regulatory documents for submission to multiple global health agencies can present a repetitive cycle of authoring, editing, and data verification, which increases in complexity as changes are made for approved products, particularly from a chemistry, manufacturing, and controls (CMC) perspective. Currently, pharmaceutical companies rely on a workflow that involves manual CMC change management across documents. Similarly, when regulators review submissions, they provide feedback and insight into regulatory decision making in a narrative format. As accelerated review pathways are increasingly used and pressure mounts to bring products to market quickly, innovative solutions for assembling, distributing, and reviewing regulatory information are being considered. Structured content management (SCM) solutions, in which data are collated into centrally organized content blocks for use across different documents, may aid in the efficient processing of data and create opportunities for automation and machine learning in its interpretation. The US Food and Drug Administration (FDA) has recently created initiatives that encourage application of SCM for CMC data, though many challenges could impede their success and efficiency. The goal is for industry and health authorities to collaborate in the development of SCM for CMC applications, to potentially streamline compilation of quality data in regulatory submissions.

The field of human therapeutics has expanded tremendously from small molecules to complex biological modalities, and this trend has accelerated in the last two decades with a greater diversity in the types and applications of novel modalities, accompanied by increasing sophistication in drug delivery technology. These innovations have led to a corresponding increase in the number of therapies seeking regulatory approval, and as the industry continues to evolve regulations will need to adapt to the ever-changing landscape. The growth in this field thus represents a challenge for regulatory authorities as well as for sponsors. This review provides a brief description of novel biologics, including innovative antibody therapeutics, genetic modification technologies, new developments in vaccines, and multifunctional modalities. It also describes a few pertinent drug delivery mechanisms such as nanoparticles, liposomes, coformulation, recombinant human hyaluronidase for subcutaneous delivery, pulmonary delivery, and 3D printing. In addition, it provides an overview of the current CMC regulatory challenges and discusses potential methods of accelerating regulatory mechanisms for more efficient approvals. Finally, we look at the future of biotherapeutics and emphasize the need to bring these modalities to the forefront of patient care from a global perspective as effectively as possible.