Ok, so there wasn’t really a war on at the 4th PDA Europe Workshop on Monoclonal Antibodies, though there was plenty of mildly heated discussion. I simply could not resist the Lucas reference.
Conducted in Basel (Switzerland) in mid-June, the workshop was fully attended, but relatively small, such that it could “foster a feeling of closeness and networking”, according to Richard Levy, senior vice president, scientific and regulatory affairs at the Parenteral Drug Association (PDA). And indeed it did; the numerous coffee breaks were a great opportunity for industry peers and regulators to mix and continue discussions initiated in presentations. Perhaps any bigger, and the sense of relaxed community would be lost… The workshop kicked-off with a wonderfully candid and standout presentation by an assessor from the Danish Medicines Agency, and, as with many of the regulators, it came with a disclaimer: the contents herein are “not a promise of approval!” The presentation focused on the regulatory perspective of a control strategy in the QbD paradigm, and elicited a number of gasps from the attendees. Not least the statement that shifting quality control upstream as part of a risk-based control strategy could, in theory at least, mean an end to product release testing—something that, the speaker said, would come as a surprise, even to regulators!
There was a call for more openness and transparency in application dossiers. The situation was likened to an iceberg, of which the tip represented release tests (specifications) and the actual contents of the dossier, and where the bulk of the iceberg was hidden underwater: extended characterisation, process controls (procedures, materials, in-process testing, monitoring, validation)—all information and knowledge within the company not routinely included in the dossier and yet some parts of which are accessible at inspections. (A further comical analogy was made to a teenage daughter, the tip being what the daughter told her mother, and the rest being what she was thinking of doing…) Either way, the message was made quite clear: companies cannot provide too much information about process knowledge gained in terms of control strategy.
Another question that raised interest was “how do we determine critical quality attributes (CQAs)” in terms of control strategy. Of course, this has no straight answer, but the message here was that it may change over time as knowledge is gained or if even small changes are made to the production process. From regulatory experience, it seems that the definition and understanding of CQA is clear in the dossier, but the rationale and designation is often lacking or absent.
The second presentation of the day was from Stephanie Schnicke of Roche Diagnostics (unsurprisingly, being in Basel), and also focused on control strategy, putting forward strategic considerations for design. Roche has addressed the difficulty of determining CQAs and non-CQA by assigning an “impact score” to all using a risk-based approach, which took into account four impact areas: pharmacokinetics/dynamics, biological activity, safety and immunogenicity. The latter of which caused debate for the entire conference, and by necessity perhaps the subject of an entirely separate blog post…
Throughout the post-presentation discussions (and to certain extent within the presentations) it was clear that regulatory bodies had limited experience (by their own admission) in QbD applications, put down to the simple fact that so few “full-blown” applications have been seen. European regulators have looked to FDA for advice and example, where the QbD paradigm shift has far more momentum—FDA absence at the workshop was no oversight, however, as it would have “substantially changed the atmosphere” of the workshop, according to Jim Lyda, Senior Science & Regulatory Affairs Advisor for PDA.
Questions over what should or should not be included in dossiers is clearly a sensitive issue for companies who feel the need to protect certain information for future process flexibility, but, as the first presentation concluded very poetically, “Let us, together, find the right balance.”