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Kris Schoeters of GEA Pharma Systems explains how pharma's uptake of continuous processing is changing.
In recent years, continuous processing has gained importance in the pharmaceutical industry, evidenced by the prevalence of seminars and conferences discussing this topic, as well as the increasing number of installations. Regulatory bodies have also elicited a large interest in moving to continuous processing as a method to improve the quality and efficiency of pharmaceutical production. In recent years, for example, speakers from the FDA have held presentations at numerous conferences and seminars, including ISPE meetings and AAPS 2010, that discuss the advantages of continuous processing. Recently, the agency even organised an internal seminar to educate their personnel about the latest developments in the technology.
One area of pharmaceutical manufacturing that has seen big advances in continuous processing is the production of oral solid dosage forms. However, there are many misconceptions about continuous processing that prevent pharma from investing in the relevant technologies.
Continuous processing in other industries is mainly used for the continuous production of one product for days, months or even years on end, so many people are under the perception that continuous processing is only suitable for large volume, monoproduction. In the past, many continuous production techniques also required a long startup or shutdown cycle, resulting in large losses of product both in startup and shutdown. In the pharma industry, which uses very expensive raw materials and APIs, losses must be minimised, if not avoided completely.
Another common misconception is the idea that continuous processing is not flexible. This belief stems from the chemical industry where a continuous process is often tailormade for a very specific process and product. The corresponding continuous equipment is also tailormade and often not suitable for other processes/products. In the pharma industry, tailoring equipment to a specific product is high risk, as a blockbuster can quickly become a mediocre selling product because of generic competition. In this case, if production equipment is not flexible enough to produce other products, it would mean a big loss for the company.
There is also an opinion that changing from batch production equipment to continuous production equipment will not bring a good return on investment. This view is principally driven by the pharma industry's high inventory of batch production equipment, which is under utilised in many cases. Pharmaceutical companies fear that the business case for investing in new continuous equipment is not strong enough compared with optimised utilisation of the currently installed base.
New continuous processing systems for producing solid oral dosage forms are now available that can be used for small volumes and multiple products. These new technologies also have minimal startup and shutdown losses because a steady processing state is reached quickly and the amount of product in the process is minimised. Upon process startup, only a negligible amount of product is often required before the correctly specified product is produced, thus minimising startup waste. Also, upon shutdown, almost no product is lost because of the minimal amount of product in the process at any one time.
Minimised losses make new technologies more flexible in terms of batch size because the size of the batch is not determined by the size of the equipment, but by the time of production. This means that manufacturers can produce to demand without having to use different kinds and sizes of equipment. For example, certain drugs may have high demand in the summer, but low demand in the winter. With batch equipment, the manufacturer must invest in a large machine to produce the product in the high season, but then the capacity of the machine will be underused for the low season. In this case, there are two options: either produce one big batch and (possibly) have problems with the shelf-life, or invest in a second, smaller machine.
Newer continuous processing equipment, however, can solve this problem; production can be 24/7 during the high season, while smaller batches (e.g. two hours of production every day) can be produced in the low season.
Another advantage in terms of flexibility is that many newer systems have been designed based on known production technology that has been adapted for continuous production and is, therefore, more flexible and much more capable of producing many different types of products. These benefits enable companies to invest in a new continuous processing system for a blockbuster product, for example, without the risk that it will no longer be used when the blockbuster comes off patent because other products can be produced on the same equipment as well.
We have made our own comparisons between a standard wet granulation production line (comprising highshear mixer and fluid bed dryer) and a continuous highshear granulation and drying line capable of producing the same amount of product (1.5 billion tablets/year). The continuous processing system took up 30% less manufacturing space and the overall investment cost was estimated to be only 40% of the cost for the standard line. Additionally, the continuous processing system offered expected labour savings of 40%.
One of the main advantages of continuous processing is that it is very easy to track the product continuously and reject any outofspecification product the moment it is detected before it can contaminate the whole batch. To do this, however, good online measurement tools are required, as well as good integration between the generated data and the control software. This will enable feedback and feedforward loops to automatically adjust process parameters to correct any change in the critical quality attributes, even before the product becomes outofspecification.
Although major advances have been made, there are still some challenges to be tackled. For instance, if online measurements are used for realtime release, where the product is released immediately after production based on the online analyses, the product will no longer be tested in the analytical laboratory. In this case, the measurements must be extremely accurate and reliable. Good integration with the machine control software and the manufacturing execution systems will also be crucial.
Implementing realtime release offers many advantages to the pharma industry because of the potential for reducing inventory and labour costs. It will, however, require close collaboration between pharma companies and equipment vendors.
Kris Schoeters is Product Manager Continuous Processing at GEA Pharma Systems — Collette.