IFPAC and the ‘State-of-the-Art’ in PAT

Continuous manufacturing’s rising star has process analytical technologies at its heart.

By Emil W. Ciurczak, contributing editor

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Everybody uses (and mostly misuses) this term. What does state-of-the-art (SOTA) really mean? If you live in a developing country, a bicycle may be SOTA transportation. Just because an instrument or piece of machinery is “new” doesn’t mean it is “improved.” I have seen the same electronics (from a 5-year-old instrument) in a newer, often smaller box … and its makers make believe that, because it is so, it is an “improvement.”

As with most technologies, almost all instruments and software improve with time, albeit often in tiny increments. Some truly make significant leaps technologically. For example, making a grating-based instrument’s resolution move from 10nm to 8.5nm is nice, but changing to a diode-array or AOTF (acousto-optic tunable filter) is a real jump. Overall, individual advances continue in most all analytical equipment. To paraphrase the Olympic slogan, instrument designers continue to pursue goals of “smaller, faster and cheaper.”

But no matter which piece of equipment one examines, it is still a tool to measure and control. The real star(s) of the show were the many papers on continuous manufacturing (CM). (There are a few manufacturers of commercial equipment which may be seen, if you review the IFPAC program online.) At least a dozen presentations showcased the concept, not only for final product, but in product development, where the size and speed of making varied batches lends itself to performing a Design of Experiment (DoE) in far less time, using far less materials.

Martin Warman (Vertex) presented two papers where he showed the huge savings in API alone, when using CM for DoE. Using “normal” or full-factor DoE for, say, three levels (high, nominal, low) of nine factors (API, lubricant, temp., etc.), we would have to produce 512 (29) lots. If we used a DoE with a Plackett-Burman equation, we would only need to produce 29 batches. Using conventional batch-wise production techniques, this could still take several weeks. Using CM, the same number of “batches” would only take a day or two. The size of the batches would also differ greatly. Since we need to do a DoE on “production-size” lots, the cost of materials would be strikingly different.

In CM, the development lot size is the production lot size, saving huge amounts of both API and excipients, not to mention cleaning time of the equipment between batches. Assume a 100 kg “normal” batch versus a 10 kg CM batch, for example. If we have 10% API in the formulation, the former uses 10 kg of API, while the latter only needs 1 kg. If we assume a mere $100/kg for the API, the “normal” sized lots would cost 29 lots x $1,000/lot = $29,000 just for the API. Using CM, the API cost would be only $2,900, and that doesn’t include time, equipment and labor savings.

The other benefit is that, since the CM batch size is the same for development as for production, over a year may be saved in scale-up efforts for each product. This means a quicker filing and faster time-to-market for the product, whether it is on a NDA or ANDA. The former allows for longer production under patent protection, while the latter allows a generic company to be quicker to market. Since many formulations may be made in a short time period, there is also a chance to optimize the formulation (which sugar, for example) for optimum blood levels and time to that optimum for far less money.
Best of all, when using correct CM, all portions are under control. There are PAT devices at every step, measuring and controlling the process. The size of the “lot” allows for faster response to and potential OOS event. Should the process make an excursion, at worst only a small amount of material is at risk. In a conventional process, several hundred kilos of material are at risk in an OOS event.

Finally, the space needed for a CM suite is far smaller than a standard production facility. The “footprint” can be the size of a normal conference room and need only be two stories high. Compare this with the standard rooms needed for blenders, granulators/dryers, tableting machines and such. Also, since the process is continuous, warehouse facilities — normally used to store intermediates — will no longer be needed. We have a win-win-win situation when CM is properly used. Time, space, utilities and labor are all saved by using CM in lieu of current production methods. That is really the “state of the art” in Pharma.

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