Biomanufacturing Program

Summary

Developing measurement science, standards, & technology to accelerate development & manufacturing of innovative, high-quality biotherapeutics

The NIST Biomanufacturing Program was initiated in 2012 to address infrastructural measurement science problems and biopharmaceutical reference material needs to support the development and manufacture of safe and effective biologic medicines (i.e., biopharmaceuticals). Through extensive stakeholder (industry, regulatory agencies, academia) engagement and feedback, NIST identifies broad infrastructural standards and measurement challenges faced by the biopharmaceutical industry and works to address these challenges and foster innovation by leveraging precompetitive collaborations and data sharing across stakeholder groups that are enabled by the availability of open-access, publicly available NIST reference materials.

The Result. NIST has filled a unique niche in supporting the biopharmaceutical ecosystem of the bioeconomy through the development of novel biopharmaceutical RMs and related measurement science and technology innovations, enabled by the availability of these standards.

Description

Image sources: SF Chronicle, Brant Ward (top); RSCB Protein Databank structure id 1IGT (right); National Cancer Institute, Rhoda Baer (bottom).

The NIST Biomanufacturing Initiative is designed to bolster the U.S. biopharmaceutical industry by providing the measurement science, standards, and analytical tools necessary to produce high-quality, low-cost protein drugs. The program focuses on the entire bioprocess lifecycle, aiming to foster innovation and ensure the safety and efficacy of complex biological products. By developing "biological rulers" and reference data, NIST helps manufacturers accurately characterize critical quality attributes, such as molecular structure and the presence of impurities, which are vital for reducing production costs and preventing adverse immune responses in patients.

Significant projects within this program include the creation of "NISTCHO," a specialized "living reference material" derived from Chinese Hamster Ovary cells that helps harmonize research and development across the industry. The initiative also addresses emerging medical frontiers, such as mRNA-based therapies, by developing research-grade test materials, such as RGTM 10202. Additionally, the program leads interlaboratory studies to investigate protein aggregation and immunogenicity, ensuring that biotherapeutic manufacturers can reliably detect and mitigate factors that might compromise drug stability or patient safety.

Major Accomplishments

Biomanufacturing Related Reference Materials

A key aspect of the NIST biomanufacturing program is the provision of a variety of high-quality reference materials and data products.

• RM 8671 - NISTmAb, Humanized IgG1κ Monoclonal Antibody
  NIST developed a recombinant IgG1κ monoclonal antibody (mAb) as a reference material for the biopharmaceutical industry, academia, regulatory authorities, and other standards organizations for a variety of uses, such as system suitability tests, establishing method or instrument performance and variability, comparing changing analytical test methods, and assisting in method validation.  The candidate reference material was graciously donated by an industrial partner. The results from this exhaustive characterization were collated and published in a three-volume ACS book series in 2014.
• RM 8634 - Ethylene Tetrafluoroethylene for Particle Size Distribution and Morphology. Protein particles, formed by the aggregation of protein monomers, may compromise drug stability and induce immunogenicity in patients, rendering the drug ineffective. Current methods used to assess these particles can vary by 10-fold in the measured particle counts. A particulate RM, used to normalize these disparate results, was developed from a stable fluoropolymer material (ETFE) that mimics the optical properties, size, and shape of protein aggregates. The material was evaluated for size and particle counts by 24 industrial and academic laboratories in a round-robin study and characterized by NIST for the number of particles per vial.
• RM 8675 - NISTCHO, Clonal CHO-K1 Cell Line Producing cNISTmAb. NISTCHO, a new mammalian cell line of interest to the biopharmaceutical and biomanufacturing communities, is now available. This Chinese hamster ovary (CHO) cell line has been engineered by MilliporeSigma to express a non-originator version of the widely-used monoclonal antibody (mAb) molecule, NISTmAb, named "cNISTmAb".
• SRM 3655 - Glycans in Solution (Frozen)
  This Standard Reference Material (SRM) is intended primarily for use as a calibration standard for the measurement of enzymatically released N-linked glycans. Potential applications of SRM 3655 include the benchmarking and comparability of analytical techniques, as a material for ensuring system suitability, and for analytical method validation. This material may also be used to value-assign in-house calibrators or control materials.
• Research Grade Test Materials developed in support of Biomanufacturing  - A NIST Research Grade Test Material (RGTM) is an exploratory, pre-calibration material developed by the National Institute of Standards and Technology (NIST) to support emerging measurement technologies, validation, and interlaboratory studies.
  • RGTM 10202 - FLuc mRNA is a newly developed NIST Research Grade Test Material with each unit consisting of one vial with ≈ 25 µg of mRNA in nuclease-free water, pH 6.4, frozen at –80 ^oC. This RGTM will be assessed during an interlaboratory study to determine the fitness-for-purpose as a reference standard or as a quality control material of the commonly accepted critical quality attributes for mRNA DS, including but not limited to: sequence identity, concentration, intactness, 5’ capping efficiency, 3’ poly(A) tail length, and product- and process-related impurities, as well as protein expression, safety, and other attributes
  • RGTM 10240 - RNA Encapsulated in Lipid Nanoparticles is currently engaged in an effort to produce a Research Grade Test Material (RGTM) consisting of ribonucleic acid (RNA) encapsulated in lipid nanoparticles (LNPs). The material is intended to support the standardization of analytical techniques for characterizing LNP / messenger RNA (mRNA) drugs.