Development of a pioneering analytical platform for the characterisation of biotherapeutic and biosimilar drugs in Brazil

Abstract

Biological medical products (biopharmaceutical, biotherapeutics or biologics) are an innovate family of therapeutic drugs that have revolutionized the treatment of many serious disease such as cancer, autoimmune disorders or diabetes. Biologics are complex macromolecules that are produced from genetically modified living organisms, hence expensive to produce and purchase. Consequently, and in spite of their benefits in disease treatments, their prescriptions in developing countries are still very limited. Recently, as many biologic patents have expired and other will expired in the next years, an attractive biosimilar market is arising. Biosimilars are copy versions of original protein drugs which are highly similar in safety, potency and purity profile to the reference biological products, while providing a lower-cost option for patients and health care systems. In this context and in order to avoid a burden on the healthcare budget, the Brazilian Authorities have promoted a long-term benefit scheme to encourage the local manufactures of biosimilars (The Productive Development Partnership PDP program). Several agreements between private and public institutions as well as strategic market policies are being addressing to enhances competitiveness and price equilibrium. However, the task of ensuring an efficient and safe pathway to bring biosimilar to market is extremely challenge. As expected from their complex structures, comparing two biopharmaceutical products to demonstrate biosimilarity requires extensive analytical studies and techniques. An exhaustive characterization and a comprehensive study of the Critical Quality Attributes (CQAs) tightly regulated by the International Committee of Harmonization (ICH) guidelines must be performed on the biopharmaceutical. As mentioned above, the analytical characterization of protein biotherapeutics is a critical step in the biosimilar assessment and product development and registration. Meeting the regulatory requirements implies an arsenal of orthogonal analytical techniques that allows the characterization of the desired protein and the multiple impurities and variants in the biotherapeutic. The application of this holistic approach reveals several challenges for both industry and regulatory agencies, which requires state-of-the-art techniques and specialized personnel to yield a reliable and accurate characterization of the product. To address these concerns, in this project we propose the development and implementation of a comprehensive analytical platform to in-depth characterization of biopharmaceuticals and biosimilars using state of the art high-resolution mass spectrometry (HRMS) methods. Special attention will be paid to practical considerations such as minimizing artefact formation during sample preparation, characterization of product-related substances and process-related impurities, such as host cell proteins, search for efficient sequencing strategies, automation, quantitative peptide mapping, and the implementation of a LC-HRMS multi-attribute method workflow for characterization and quality control. The overall workflow must be extremely reproducible and reliable, capable of obtaining accurate and reliable comparison between the original and the biosimilar in a time and cost-efficient way. As a result, the proposed workflow is suitable applied to assess and monitoring the Control Quality Attributes (CQAs) required for national regulatory agencies (National Health Surveillance Agency, ANVISA) with focus on the biologics and biosimilar development and approval process and quality control. Therefore, we will contribute to the successful biotherapeutic licensing and continuous pharmaceutical level supply of the actual demand for affordable and specialized biopharmaceutical therapies. Ultimately, increased access to biosimilars could save up to R$ 0.4 billion per year to the Health Ministry while expanding treatment options to patients. (AU)