Process development service tackles QC issue in biopharma
biological entities (NBEs) has been one of the major trends in the
pharmaceutical sector over the last few years, but their production
can be said to be more of an art than a science.
One reason is that unlike small molecule drugs, proteins are typically not manufactured in a crystalline form (with the obvious exception of insulin). This is unfortunate as crystalline structures are the preferred form for pharmaceuticals, as they allow stringent batch-to-batch quality control, are easier to formulate into dosage forms for delivery and tend to be more stable.
The problem is that the complex structures of proteins, and in particular the folding and re-folding interactions in these large molecules, make efficient, repeatable crystallisation extremely difficult at an industrial scale. But faced with the huge number of NBEs coming through the product pipelines, regulators around the world are starting to look at the issue of quality control.
Now, a collaborative effort between UK companies Accentus C3 Technology and Chiralabs has come up with a new protein crystallisation process development service, dubbed ProteinXL, which should make it easier for companies to develop NBEs in crystalline forms that are scalable to commercial production.
David Hipkiss, Accentus' general manager, told In-PharmaTechnologist.com that "it has been long recognised that there is an absence of internationally agreed standards for the control, production and analysis of biopharmaceuticals."
And on the whole, the biopharmaceutical industry has been happy with this situation, as it has afforded them a lot of leeway in quality control terms and provided a built in protection against generic competition. There are as yet no agreed standards to prove 'bioequivalence' for biologics as there are for small molecule drugs, but this could change if proteins are made in crystalline form, facilitating QC analysis.
Forward-thinking biopharma companies are recognising that this situation cannot continue forever, and are starting to appreciate that having a stable crystal structure for a protein can pay dividends. This includes a higher chance of securing regulatory approval, but also other factors such as improved formulation (for example a smaller crystal structure may be suitable for inhaled rather than injected delivery), longer shelf lives and the possibility that lower-dose, extended-release formulations could be developed.
ProteinXL is targeted at small and large biopharmaceutical companies who want to see if it is feasible to develop a crystalline form of their NBE - a process that should take two to three months - and ultimately to develop a scaled-up process for production. Of course, the originator company will have to show that any new crystal form developed behaves in the same way as the original material.
At the heart of the ProteinXL service is a technique called circular dichroism, a technique for the determination of the three-dimensional structure of proteins and the way they interact with their environment, and the firms' microcrystallisation screening technology, unveiled at the end of last year.
Circular dichroism is of particular value in this setting as it will help ensure that there has been no change in protein structure or loss of activity as a result of the crystallisation.
George Tranter, an acknowledged expert in circular dichroism and director of Chiralabs, said: "efficient production of NBEs represents a tremendous industrial challenge and the desire for reliable crystalline forms is growing from both an innovator and regulatory perspective."