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Manufacture Small Molecules

The Case for Continuous

The highest standards in quality and safety go hand-in-hand with pharmaceutical production (and rightly so), but this demanding regulatory environment has had one negative consequence; there can be a delay in implementing new technical innovations. This is a recognized problem in the industry and the FDA has tried to counteract this tendency with initiatives like Quality by Design (QbD) – as well as the recent draft guidance on Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base. 

One area where I feel that pharma is lagging behind other industries is continuous processing. The automotive industry is perhaps most famous for continuous processing, but batch processing is still very much the norm in pharma – even for very large quantities. Continuous processes have even been viewed with some scepticism from pharma manufacturers because of the perceived regulatory barriers and costs of equipment. In reality, however, regulators are becoming far more receptive to continuous processing. For example, QbD encourages the use of advanced process analytical technologies (PAT) to delve deeper into the know-how of processes. PAT is all about analyzing product quality continuously, in real time, and is an enabler of continuous processing. If you’re using PAT then why not go the extra mile and start considering continuous processes?

Traditionally, economic production of large quantities of product has been the main driver for implementing continuous processing (and we all know that pharma manufacturing is expensive, so any cost reductions are a benefit), but there are other advantages too. In my view, continuous processing is compelling even in the case of small production. Here are just some of the benefits:

  • Consistent product quality. Once validated, a continuous process should produce products of identical quality every time.
  • Production quantities are definable over time. As soon as the requested production quantity is achieved, the process is terminated. 
  • Smaller machines. As there is less product in the machine at any time compared with a batch process, drums and drives of a smaller size can be selected for the same output.
  • Less manual handling. Continuous machines can be integrated in comprehensive units with automatic process control, which makes manual handling redundant and saves money.
  • Less cleaning. With batch processing, cleaning can be necessary after each batch. In continuous processes the unit only needs to cleaned after a product change. 

I am a big advocate of continuous processing and I enjoy discussing the advantages. But this doesn’t mean that batch processing is obsolete. Batch and continuous processes offer individual benefits. The decision as to which process is best in a specific case is contingent on a precise analysis of the task at hand. Implementing continuous processes also involves a number of challenges. The most important point is to fully understand your product’s characteristics, such as porosity and flow behavior. You’ll also need to define your throughput. In general, continuous machines in the pharmaceutical industry are designed for throughputs from 5 to 500 kg per hour, so they can be used for small quantities or the development of new recipes, as well as high volumes of drugs. Small quantities can be produced within a couple of minutes and large quantities within several hours, days, or weeks, depending on the process.

I believe that continuous processes will be increasingly used in the pharma industry; in recent years, there has been a great improvement in the number of systems and machines available for this purpose. In reality, you don’t need anything truly specialized – all continuous machines and units can be used in the pharmaceutical industry, as long as they comply with GMP requirements.

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About the Author
Reiner Lemperle

Reiner Lemperle, Authorized Officer, Gebr. Lödige Maschinenbau GmbH, Paderborn, Germany.

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