Regenerative medicine

Regenerative medicine therapy, including cell therapy, gene therapy, and therapeutic tissue engineering, provides unprecedent potential to treat, modify, reverse, or cure previously intractable diseases, such as cancer and organ failures. This class of therapy has completely changed the paradigm and the trajectory for medical treatment. Broad clinical translation and patient access requires advances in manufacturing technologies and measurements to ensure the safety, quality, and consistency of the therapy and to reduce the cost.

NIST is committed to solving the measurement challenges of this fast-moving sector of the bioeconomy by providing underpinning measurement infrastructure and platform technologies, as well as standards to promote manufacturing innovation, improve supply chain resilience, and support characterization and testing to facilitate regulatory approval.

The NIST Regenerative Medicine program is working closely with the U.S. Food and Drug Administration's Center for Biologics Evaluation and Research (FDA/CBER) and the Standards Coordinating Body (SCB) as well as the broader industry to develop global manufacturing and measurement standards underpinned by a robust measurement infrastructure needed to advance product development and translation as directed by Sec. 3036 of the 21^st Century Cures Act.

The NIST laboratory programs support this growing industry as well as the broader industry ecosystem by:

• Developing new methods for quantitative measurement of quality attributes of a broad range of starting materials, products, and critically needed reagents for applications such as cellular immunotherapies as living drugs,  viral and non-viral vectors and delivery vehicles, and advanced genome editing tools and genome edited biological systems.
• Providing reference materials, including complex living reference materials, and documentary standards through international and national standards development organizations as well as professional societies.
• Applying measurement assurance strategies and associated tools to improve the performance of complex biological measurements systems.
• Convening stakeholders on precompetitive measurement and manufacturing challenges.
• Establishing partnership across the  public and private sectors to develop measurement solutions, platform technologies, and standards.

Selected Programs and Accomplishments

NIST has developed a suite of standards and tools for characterizing biological systems and components using advanced measurement science strategies that enable the generation of high-quality data.  Some recent examples of NIST’s work include:

• Design of Fit-For-Purpose Assays: As regenerative medicine therapy represents a broad and diverse range of products using living cells as the starting material and/or the product, NIST led the development of an ISO standard that provides considerations for characterization of cellular therapeutic products, including approaches to select and design analytical methods that are fit-for-purpose. These considerations are intended to guide the establishment of critical quality attributes for a cellular therapeutic product. NIST is developing similar concepts for the measurement of nucleic acids, viral vectors, and other biological systems and entities.
• Cell Counting Measurements: Count is the most foundational metric for assessing the attributes of cells, yet one of the least harmonized measurements. NIST developed innovative measurement solutions for evaluating the quality of cell counting measurements through experimental design and statistical analysis that led to two ISO international standards as well as tools to facilitate their adoption. The standards are used by industry for cell count and characterization to support CTP testing for safety and efficacy.
  • o ISO 20391-1:2018 Cell counting Part 1: General guidance on cell counting methods 
  • o ISO 20391-2:2019 Cell counting Part 2: Experimental design and statistical analysis
  • o Cell Counting Method Evaluation Tool (COMET): NIST developed an online Counting Method Evaluation tool for executing the statistical analysis and reporting outlined in ISO 20391-2:2019.
• NIST Flow Cytometry Standards Consortium: Flow cytometry is used to analyze individual cells to understand the proteins, nucleic acids, and other biomolecules they have or produce, and to analyze groups of cells to differentiate among different cell types and lineages. Flow cytometry is the most common analytical tool used in the characterization and testing of curative cellular immunotherapy products.  Established in 2020, the NIST Flow Cytometry Consortium is working with leaders in cell therapy development and manufacturing, U.S. government, global regulators, scientific societies, and the broader biotech industry to develop measurements, standards, and technology needed to accelerate the translation, manufacturing, and approval of new therapies (e.g., CAR-T and emerging stem cell derived allogenic therapy).  The Consortium coordinates strategic inter-laboratory testing and comparisons to develop critical standardized flow cytometry assays for the regenerative medicine and biotechnology industry.
• NIST Rapid Microbial Testing Methods (RMTM) Consortium: Established in 2020, this Consortium is working with experts across the regenerative medicine field to address the need for measurements and standards, including reference materials, to increase confidence in the use of rapid testing for microbial contaminants in regenerative medicine and advanced therapy products.
• NIST Genome Editing Consortium: Established in 2018, this Consortium supports the development of groundbreaking tools and standards required to detect and monitor the accuracy and precision of genome editing technologies for the U.S. and global biotechnology sectors. The Consortium has developed a standard genome editing lexicon, with 42 defined terms, that is being referenced by industry in active regulatory filings.
  •  ISO 5058-1:2021 Biotechnology: Genome Editing – Part 1: Vocabulary
• VCN Interlaboratory Testing Program: The copy number of integrated genomic DNA is critical for assessing the safety and efficacy of engineered cellular therapeutic products such as CAR-T.  NIST is leading an interlaboratory testing program to evaluate the suitability and utility of cell lines with discrete number of integrated lentiviral vector copy number (VCN) and associated DNA materials to serve as reference materials or controls for a variety of cellular and genomic measurements.
• Quantitative and Advanced Bioimaging: NIST developed a comprehensive bioimaging program to support the use of imaging to better understand the fundamental mechanism-of-action of therapeutic cells and visualize dynamic and heterogeneous biological processes and interactions­­. Examples include the application of quantitative imaging and AI to assess the quality of tissue engineered medical products in a GMP setting as well as reference materials for instrument qualification and, data sets to benchmark AI/ML algorithm development.  NIST developed tools and guidelines for performing quantitative fluorescence imaging, supporting a critical measurement platform for the characterization of biological processes.
  • ASTM F3294 - 18 Standard Guide for Performing Quantitative Fluorescence Intensity Measurements
• Prototype Cell Assay Measurement Platform (P-CAMP): The NIST P-CAMP is a unique automated platform that enables multimodal analysis of large parameter spaces and guides the development of measurement assurance strategies for assays used for characterization and testing of biological products and processes.
• Assay for Monitoring Patient Response to Therapy: NIST is collaborating with NIH/NCI to develop quantitative and comparable flow cytometric procedures for establishing clinical cut-off points needed to monitor patient response to a broad range of therapies including cellular immunotherapies.