To date, no marketing authorization application (MAA) for a biologic that takes a QbD approach has been granted according to Dr. Keith Chidwick, Quality Assessor at the Medicines and Healthcare Products Regulatory Agency (MHRA).
He told delegates at last month’s Global Pharmaceutical Contract Manufacturing Event (GPCM) in London that so far four QbD-based biologic MAAs have been filed with the EMA and the QbD elements in most come across as “flights of fancy into an imaginary parallel world.”
One problem, according to Chidwick, is that some companies incorrectly see QbD as a route to accelerated approval.
In reality, “QbD is not a shortcut” he said, citing the “over 400 small scale runs using design of experiments type techniques” included in the most promising biologic MAA currently under review as evidence of the effort required.
QbD’s Biologic Failures
Dr. Brij Patel, a consultant at RegExcel Consulting and ex-MHRA Assessor, echoed this view.
He told Biopharma-Reporter.com most QbD-based biologic MAAs failed because the firm involved misunderstood ICH terminology, conducted inappropriate risk-assessments, failed to ensure the validity of small scale experiments or had asked for unreasonable flexibility.
One of the main issues, said another former MHRA Assessor, Dr. Christopher Bravery, is the uncertain and unpredictable nature of biologics. “Full application of QbD assumes a well-controlled and predictable manufacturing process” he told us.
“While I imagine it can work for small molecules,” he continued “I am unconvinced it is suitable for biologics – but I could be proven wrong.
“This of course ignores that biologics vary considerable in their nature, so maybe QbD would work in certain circumstances.”
Revolution in the Head
Though Patel said QbD “does not always equate to increased regulatory flexibility,” it “should lead to enhanced understanding of your product” which could be argued is needed for biologic success.
This was echoed by Jan-Gunnar Gustafsson, CEO of Swedish biopharmaceutical strategic and development services company, Bio Evaluation, who also spoke at the GPCM Event.
Going down the QbD route, he said, structurally improves process development and in the long run will be a cheaper, more controlled option as quality is guaranteed in every step, rather than having to constantly react when following traditional methods.
“QbD is a way of constructing a process by designing it,” said Gustafsson. “QbD is a state of mind – it is a 'revolution in the head'.”
Regulatory Allegiance
According to Chidwick, QbD application failings due to concerns about the definitions of critical quality attributes and critical process parameters have also been seen by the US Food and Drug Administration (FDA) who has been working with the EMA to harmonise the QbD application process, with variable results.
However, Chidwick and Patel both agreed at present there is a certain amount of confusion between the regulators and industry complicating the issue further.
“New guidelines say that you can mix the traditional and the QbD approach,” said Chidwick. “We find this rather confusing from a regulatory perspective.”
Patel, however, in one of his publications, blamed a “disconnect in expectations between Industry and regulators” for current regulatory experience with QbD.
“The key to success will be in Industry engaging the regulators early, basing requirements on appropriate scientific evidence and reasoning, conducting sound risk-assessments and requesting reasonable flexibilities.”