Anton Middelberg, PhD, deputy vice-chancellor and vice-president of research at the University of Adelaide in Australia, believes industry reluctance to go continuous reflects the traditional focus on batch-mode production and, in some areas, the technical challenges.
“The complexity in continuous manufacturing is not trivial, and the industry has a well-established paradigm of batch processing which has worked well up to now and has been for a long time locked in by regulatory factors,” he says. The paradigm has been, Pharma is done in batches.
“In addition to regulatory considerations, the traditional lack of online measurement capacity has limited continuous processing—analysis is complex and has been done offline. To emphasize this point, product quality in chemical manufacture can largely be done online in a way that is not yet completely possible with large proteins.”
But there are signs of change according to Middelberg, who points out that “Measurement science and the ability to infer using related data sets means the goalposts have shifted in terms of enabling technology, so innovation is increasingly possible.”
Regulatory support, cultural change
Consistent regulatory support for continuous manufacturing is another positive for biopharmaceutical companies looking to switch to 24/7 production.
The FDA has been encouraging industry to consider the approach since at least 2015, issuing several guidance documents. Likewise, in Europe, the EMA has urged industry to look at ICH guideline Q13 on continuous manufacturing of drug substances and drug products.
With support in place, it is industry attitudes that need to change, notes Middelberg.
“The regulatory agencies have been supportive. The challenge is in adoption and in shifting to a culture that is cognizant of the shifted regulatory regimes, and building industry’s confidence about the approach,” he continues.
“There is still a lot of ‘Pharma is done in batches’ thinking, along with an incorrect understanding that regulation requires this [approach]. With the emergence of PAT and QBD, and the increasing sophistication of PAT, it now really is organizational culture rather than reality that is holding the industry back.”
Technical advances
In addition, Middelberg says, some of the technical challenges faced by the early adopters of continuous drug manufacturing have now been solved, citing chromatography as an area that has seen considerable innovation in recent years.
“There has been some superb work by people who have thought deeply about continuous chromatography, and the intellectual inputs have been significant, evolving from early approaches where the beds moved through to more elegant approaches where feed streams are shifted based on sophisticated mathematical models,” he tells GEN.
“This intellectual development has then enabled a maturation of the practical possibilities. In parallel, resins have improved to make them more robust and easier to regenerate, which is a key consideration in continuous processing.”
And for Middelberg, who recently co-authored a paper looking at how drug makers were warming to 24/7 production, it is likely use of the approach will continue to increase as its benefits become clear.
“As companies do innovate, they will likely see better outcomes in terms of economics, sustainability and even quality, and that will likely accelerate the further adoption of continuous process technology,” he says.
