Chemistry Manufacturing and Controls in Human Gene Therapy Products: FDA Guidance Part 2

Last year’s guidance from the FDA regarding human gene therapy products (Human Gene Therapy Products: Incorporating Human Genome Editing Guidance for Industry, FDA January 2024) gives in-depth recommendations for Chemistry, Manufacturing, and Controls (CMC) for Human Genome Editing (GE) product development. In this article we will look specifically at the CMC aspects of the guidance. For an overall summary of the guidance, please read Part 1.

The guidance details safety and quality requirements, including comprehensive manufacturing and testing processes and stability assessments. It also recommends analytical procedures, potency assays, and detailed processes to optimize the safety and efficacy of human gene therapy products.

Below are the key steps companies need to know to comply with the latest guidance.

• General: Follow the general CMC considerations for product manufacturing, testing, and release as outlined in the 2020 Human Gene Therapy (GT) CMC Guidance and integrate the new guidance with existing CMC practices.
• Design:
  • Use design platforms suitable for the genomic target and intended modification
  • Provide descriptions and rationales for design and screening processes in the Investigational New Drug application (IND)
  • Include sequences of GE components and/or expression constructs
  • Optimize GE components to minimize off-target modifications and inhibit degradation, and include detailed optimization strategies in the IND
• GE component Manufacture and Testing:
  • Consider GE components as active pharmaceutical ingredients or drug substances when administered in vivo
  • Treat GE components in their final formulation for in vivo administration as drug products (DPs)
  • Apply recommendations to GE components used routinely in each DP lot
  • Provide detailed descriptions of manufacturing, purification, and testing processes in the IND
  • Include flow diagrams, detailed narratives, lists of raw materials/reagents, and representative certificates of analysis
  • Summarize quality control and assurance programs, tracking and segregation procedures, and shipping protocols
  • Ensure compliance with Current Good Manufacturing Practices (CGMP)
  • Test GE components for sterility, identity, purity, and activity
  • Include additional testing for process residuals as needed
  • Provide descriptions of analytical procedures, including sensitivity and specificity
  • Assess the stability of GE components during storage and provide stability study protocols and data
• DP Manufacture and Testing:
  • Include detailed descriptions of the DP manufacturing process and in-process controls in the IND
  • Provide flow diagrams, detailed narratives, lists of reagents, and certificates of analysis
  • Ensure aseptic processing for sterile DPs
  • Develop a DP testing plan that addresses safety concerns arising from manufacturing or identified in nonclinical studies
  • For ex vivo-modified cells, determine GE efficiency and assess specificity
  • Test the DP for sterility
  • Describe analytical procedures for DP testing, including accuracy, precision, sensitivity, and specificity
  • Develop DP specifications based on starting materials, manufacturing process, desired final product attributes, and nonclinical studies
• In Vivo-Administered Human GE Drug Products:
  • Provide complete descriptions of plasmid/vector manufacturing and testing in the IND
  • Include detailed descriptions of nanoparticle formulations and manufacturing processes
  • Conduct release testing to evaluate the efficiency of GE component incorporation into nanoparticles
  • Develop potency assays to measure multiple aspects of activity for in vivo human GE DPs
  • Include potency assays in DP stability studies
• Ex Vivo-Modified Human GE Drug Products:
  • Indicate the timing of the GE step within the manufacturing process
  • Include descriptions of process controls and in-process testing for critical steps
  • Provide acceptance criteria and/or limits
  • Conduct release testing for on-target editing efficiency and a total number of genome-edited cells
  • Perform additional characterization of editing events at the on-target site
  • Assess off-target editing frequency, chromosomal rearrangements, and residual GE components
  • Monitor the number of edited cells or frequency of GE during stability testing
  • Develop potency assays to measure the properties of cells and intended downstream biological modifications
  • Include potency assays in DP stability studies
  • Additional DP testing should be included for allogeneic human cell products, and stringent acceptance criteria should be established

These steps will help companies align with the new guidance and ensure compliance with the CMC components of their GT product development.

Do you need help with your GE product development? Please reach out by email at info@windshire.com or call +1 844-686-5750 to explore how we can assist with your development needs.