Biologic medicines represent the largest sector of the U.S. bioeconomy, with a global market of $145 billion, growing at greater than 15% annually and employing more than 810,000 workers. In 2013, seven out of ten of the top-selling drugs were biologics, specifically protein therapeutics, and it is projected that by 2020, 50% of all prescription drugs sales will be biologics. A general unmet need in the development and manufacturing of these products is the inability of the current state-of-the-art in measurement technology to characterize these complex protein products with sufficient precision and accuracy to ensure desirable clinical performance.
NIST seeks the development of new or improved measurement tools and methods that can more quickly, accurately, and precisely characterize the structure of biologic drugs. Advances in such measurement technology will:
· Enable faster and more confident assessments of the potential effects of changes in the manufacturing process, equipment, or raw materials.
· Aid development of biosimilars that will lead to greater competition and improved access to many medications for US patients.
· Increase general knowledge in the field of biopharmaceuticals and allow industry to develop improved and next generation protein therapeutics.
New analytical methods that can more accurately assess finished products, as well as analytical tools that can monitor attributes biologic throughout the manufacturing process are desirable. This opportunity applies to all types of analytical methods including those used for process monitoring, characterization, or lot release. New analytical tools or methods to be developed should have some advantage over current analytics in terms of higher resolution (greater sensitivity, orthogonality, or specificity), reliability, or the clinical relevance of the product attribute that is measured.
The development of new or improved analytical technologies to assess the product quality attributes below are of interest in this opportunity.
• Post-translation Modifications
Many protein therapeutics have post-translational modifications that are critical to their clinical activity. These modifications are typically complex and heterogeneous, and analytical methods for fast qualitative or quantitative assessment of these modifications and how they relate to potency and clinical performance need to be improved. For example, glycosylation of the Fc region of many monoclonal antibody therapeutics is important for their mechanism of action in cancer treatment. Of particular interest in this opportunity are improved methods for quickly analyzing and quantifying glycosylation and other modifications known to affect the efficacy and safety of these types of products. Analytical technologies to improvement measurement of other post-translational modifications including deamidated species, glycated species, sialylated species, C-terminal variants (HC -Lys, HC-Pro Amide), N-terminal variants (Gln vs pyro Glu), and oxidized forms would also be of interest.
• Higher Order Structure
Protein therapeutics must be folded into a three-dimensional structure to become functional and often a three-dimensional structure can be misfolded. It is possible that a distribution of three dimensional structures can exist for a product where there will be one major three-dimensional structure present with other minor variants differing in three-dimensional structure. We seek the development of new or improved higher order structure measurement tools that can detect and quantify the properly folded three-dimensional structure along with misfolded variants of protein therapeutics.
• Protein Aggregation and Particulates
Protein molecules can stick to each other to form aggregates which are thought to be the precursors to formation of larger particulate species. It is believed that these species have the potential to stimulate adverse immune responses in patients that can lead to neutralization of the protein therapeutic. Aggregation and particulate formation are particularly problematic for monoclonal antibody therapeutics that are typically formulated at high concentrations of 100 mg/ml or greater. In order to better understand adverse immune reactions, the ability to measure and quantify different types of aggregates in products needs to be improved. We seek the development of new or improved analytical tools that can directly measure the size and shape of protein aggregates or particulates, or assess their composition.
For assessment of all the product attributes above, new or improved analytical technologies or methods that require minimal sample preparation, or are capable of interrogating high concentration, formulated protein therapeutics, or protein therapeutics in raw process streams are also of particular interest in this opportunity.
Phase I expected results:
Establish proof of concept of new or improved analytical technology to measure desired product quality attribute (s) of protein therapeutics. Optimize and establish performance characteristics of new or improved analytical technology including sensitivity, resolution, quantitation, measurement speed (including sample preparation steps), accuracy, precision, and reproducibility.
Phase II expected results:
Directly compare results of new or improved analytical technology with results from a current state-of-the art analytical method (can be conceptually similar or orthogonal analytical method) used for characterization or product release testing of protein therapeutics. Demonstrate a factor of 2X or greater improvement in sensitivity, resolution, accuracy, precision, or speed of the new or improved analytical technology.
NIST will be available to consult or for potential collaboration with the awardee depending on the measurement technology to be developed. NIST will also be willing to provide where appropriate reference materials to better compare performance of the proposed new method or technology with that of the current state-of-the-art.