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No Straight Line: Confronting API Scale-Up Challenges

scaleupIn many of the blog posts we’ve written over the last few years, we’ve referenced the growing complexity of active pharmaceutical ingredients (APIs).

It isn’t just mindless chatter intended to fill our blog, we promise! API production times are longer, production processes are growing more complex, and practical paths from R&D to production are growing more and more challenging. Services such as Alternate Route Scouting  are no longer obscure offerings from complex chemistry providers. In fact, such services are standard operating procedure for firms looking to manufacture less-expensive and safer drugs quickly and with less effluent and waste.

Technology & Innovation to Blame?

If we’re looking for something to blame for the increasing complexity of today’s drugs (and aren’t we always?), the pace of technological and scientific innovation comes to mind. Things considered impossible (or – at least – too difficult to achieve commercially) twenty years ago are tried-and-true practices today. Drugs are evolving and becoming more complex, as are their individual parts – notably, the active ingredients that comprise them.

APIs – The Sum of All Parts

Producing an API is best described as a series of discrete steps which require scaling as volumes grow (e.g., the transition from R&D to late clinical or full-scale production stages). While each distinct production step may be scalable, the entire process – taken as a whole – may face challenges that aren’t visible when designing or scaling each individual step.

That’s because many of those challenges aren’t related to individual processing steps per se, but rather related to the combination of those steps at large scales. Many of the challenges that emerge later in scale-up and commercialization barely attract notice at earlier stages. A great example would be the handling and storage of raw or finished materials. It’s easy to store a liter of a reagent under specific environmental conditions. Ten thousand liters becomes an entirely different matter.

Sometimes not noticed (or noticed, but not managed) earlier in development are potential heat generation & dissipation issues. Even with significant infrastructure, some heat generation problems are serious enough to warrant process modifications.

Processing and reaction times are another frequent issue, especially at bulk scales. Larger volumes often require longer reaction times, something that can – depending on the process – lead to other issues. These types of challenges can be magnified at larger scales, and they demand solutions that don’t affect the performance and safety of the finished active.

Each Step May Scale Up Linearly, While the Overall Process May Not.
This is one of the reasons scale-up rarely leaps from micrograms to tons in a single bound, but rather requires multiple scaling stages (micro or milligram scale, gram scale, pilot scale prior to full production, etc.) to successfully translate bench processes to manufacturing. Scale-up is rarely a linear process (wouldn’t that be nice and convenient!), and at each scale new complications typically emerge that must be worked through.

I read recently (I don’t remember where) that the unexpected problems which arise during scale-up are signs of the very contradiction that exists in scale-up: that scaling each individual step within a process won’t always achieve – at larger scale – what has been previously accomplished at a smaller scale.

Bottom line – the steps or processes may individually be linear, but the sum total often is not. And while some of these issues may be unavoidable as scale-up progresses, others can definitely benefit from a bit of planning and foresight. Not to be repetitive, but we at Neuland huge proponents of incorporating scale-up planning and forecasting as early as possible into the R&D process to reduce the likelihood of unexpected challenges as much as possible.

 

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