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FDA Doubles Down on QbD

After a 13 year gap the US FDA has updated its guidance on Comparability Protocols bringing it in line with contemporary thinking on modern pharmaceutical development practices. So what are the implications?

The key changes in this version of the guidance document involve updates to put the guidance in line with QbD, PAT, and Process Validation principles. FDA has long voiced its support for QbD to industry, but industry itself has not fully come around. For FDA to clearly state that things like continuous improvement, understanding the process, and risk management over the course of a product’s lifecycle are significant represents a shift from merely holding QbD up as an idealized model to actually spelling it out in what will eventually be a binding document. The potential for flexibility in product development offered by QbD is closer to being in reach with this guidance. FDA has made a clear statement that they are all-in for QbD with this document.

Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information has, significantly, been brought into alignment with the principles of Quality by Design (QbD) outlined in ICH guidelines Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, Q10 Pharmaceutical Quality System, and Q11 Development and Manufacture of Drug Substance. The updated guidance has received a significant facelift, but, like renovators of a cherished historical home, the FDA has taken care to ensure that the foundations and original character of the document remain.

In Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information the FDA shows the level to which it has embraced QbD and clearly wants people to take notice. The updated guidance contains notable references to the QbD guidelines listed above, as well as FDA’s Guidance for Industry: PAT and the 2011 Guidance for Industry: Process Validation. In some cases, the QbD guidelines are referenced directly, while in others the texts have a similar feel.

The Federal regulations that govern comparability, 21 CFR 314.70 and 21 CFR 601.12, have been updated four and six times respectively since 2003, when the comparability guidance was last updated. In addition to the QbD and federal regulation updates, new to Comparability Protocols is the inclusion of language that mandates the adherence to cGMP protocols when making any post-approval changes. This guidance is now relevant to anyone filing an NDA or BLA.

The greater embrace of QbD, PAT, and Process Validation may be easily absorbed for larger companies, but may place a significant burden on smaller firms with limited resources. It is, however, important to note that QbD principles should not be abandoned due to cost. Hiring a consulting firm to handle multiple aspects of the CMC operations or filing can be advisable and definitely affordable in the long run. As Ben Franklin quipped, “remember time is money”.


Blog article by: Brendan Cooney