The following practical considerations for implementing ICH Q6B are based on a presentation from Health Canada, offering a regulator’s view on common challenges and best practices for biotechnological products.
- “The Process is the Product” Paradigm: A core principle for biologics is that “the process is the product.” The quality of the final drug is defined and assured by the entire, well-controlled manufacturing process itself, not just by the testing performed on the final product.
- The Lifecycle of Specifications: Specifications are not static; they evolve throughout the product lifecycle. They begin as minimal criteria in preclinical phases and are progressively tightened and refined as manufacturing experience and product knowledge increase through clinical trials and post-approval.
- Proactive Regulatory Engagement: Proactive communication with regulatory agencies through pre-submission meetings is highly recommended. Discussing characterization strategies, potency assay development, and the justification for specifications early on can prevent significant delays during the official review process.
Common Issues in Regulatory Submissions:
- Protein Concentration: A consistent trend of releasing batches near the lower limit of the acceptance range may indicate a systemic process control issue, even if the batches technically pass the specification.
- Identity Test Specificity: Identity assays must be specific enough to definitively distinguish the product from any other biologics that may be manufactured in the same facility.
- Modern Purity Methods: Regulators expect the use of modern, state-of-the-art analytical methods (e.g., HPLC-based methods) for purity testing. Older techniques like SDS-PAGE may no longer be considered sufficient on their own.
- Excipient Control: The concentration of critical excipients, such as polysorbates, must be monitored and controlled throughout the manufacturing process, as steps like filtration can impact their final levels and affect product stability.
- Inter-Laboratory Validation: When using multiple sites for testing (e.g., for product release and stability studies), a formal inter-laboratory validation study is essential to ensure that results are consistent and comparable across all locations.
