Are "Do-Overs" Practical In Biopharmaceutical Manufacturing?

By Josh Eaton

What should a manufacturer do when an API (drug substance) or intermediate from a biopharmaceutical manufacturing process does not meet specification, or when a process has operated outside the validated operating range?  What if, for instance, a chromatography step does not reduce the host-cell protein content to the required amount due to overload of protein or a variation in buffer pH? This scenario does not always result in a product failure, after all, so salvaging the material is definitely the preferred option. One path may be reworking the material, which, per ICH Q7, would entail the use of processing steps different from the established manufacturing process (such as recrystallizing the material with a different solvent). However, this practice would then be subject to additional, and potentially extensive, validation and justification exercises.

A better solution may be reprocessing the nonconforming material via the associated and previously validated process, such as a distillation, filtration, or chromatography step. However, there is limited literature currently available to guide manufacturers in properly implementing a reprocessing procedure. Additionally, not all regulatory authorities are comfortable with all aspects of reprocessing — for example, repeating a simple virus filtration after failure of filter integrity testing, versus repeating an entire chromatography process.