In progressing through the developmental and clinical stages for a biologic drug product, it is common to need to alter the processing scheme for the product, or to re-engineer the recombinant line for increased expression or construct stability. Such modifications may result in structural alteration of the biological drug. A Comparability Program is necessary to establish that the expressed molecules are the same. The regulatory agencies will require that a Comparability Program is thoughtfully designed and employed to discern measurable differences in the products.
A Comparability Program may include:
- Peptide mapping via HPLC with in-line mass spectroscopy for primary structure and side chain modification comparison
- UV-Vis, CD, and Fluorescence or other Spectroscopies for comparison of secondary structural features
- Chromatography and ELISA-based techniques for analysis of purity and impurities
- Size Exclusion Chromatography (SEC) for comparison of oligomeric structures and levels of aggregation
- Chromatographic or LC/MS/MS Oligosaccharide (Glycan) Profiling for carbohydrate comparison
- Quantitative Sialylation Determination
- In-vitro biological and ELISA/immunological assays for potency evaluation
By establishing a high-quality Comparability Program, even subtle changes, such as glycosylation or minor post-translational modifications may be detected, thereby avoiding potentially substantial effects on efficacy and safety.
What analytical methods should be employed to distinguish variations in structure? What is considered a significant change? What validation is required? What metrics can be developed to detect structural variation, and how do you determine its significance? Blue Stream can apply its expertise in the design and execution of a first-rate Comparability Program. Please call Blue Stream at 617.234.0001 for further information.