by Dr Margit Holzer, Scientific Director, Ulysse Consult
Minimizing operational costs and capital expenditures is a considerable challenge for production in the Biopharmaceutical industry. Many different contributions have to be taken into account when calculating these costs – capital investment, materials, consumables, labour, utilities, waste handling together with development, scale up, qualification and validation time and costs, etc – all add up to make production expensive.
One way to address this issue is to switch processes from batch ones to continuous ones; which are well established in other industries like food processing. When switching, the entire physical processing installation could be shrunk: necessary clean rooms, utilities, tank farms, processing and other equipment can often be reduced by half and operating costs for production, cleaning, analyses can be reduced significantly.
In 2007, Novasep published a cost study showing that a switch from batch to continuous downstream processing of Monoclonal Antibodies could reduce operational costs by 69% – a huge reduction and a very promising way to achieve a more economical production chain.
The question is then: how can one convert current batch processes into continuous ones? Related challenges include issues of quality and process control and the need for further process understanding and characterization. However, modern technologies using the approach of Process Analytical Technologies (PAT) for in-line/at-line/on-line controls allow getting the adequate level of information on process performance as well as a tighter control of product quality during development, scale up and production. A more structured & scientific approach of process characterization and design facilitated by using process simulation tools is equally desirable both for batch and continuous process, for developers and for regulatory bodies.
Switching a batch chromatography step to a continuous process has been challenging during many years. The main reasons were/are:
- the chromatographic process needs to be robust and integrate cleaning steps,
- the equipment (including that required for process monitoring/control strategy) needs to be extremely reliable, cleanable and easy to handle & maintained,
- it must be possible to qualify and validate the equipment, the software, the process and the cleaning to meet regulatory standards,
- the “where is my batch syndrome”: while the batch size is perceived as naturally defined in a discontinuous process, it requires definition with continuous processes. Let us notice that these definitions have already been accepted by authorities for several APIs.
Last but not least, regulatory bodies like the FDA support the implementation of continuous manufacturing using a science and risk-based approach because this can result in an improvement of critical quality attributes, more process control, less product holding time and processing in steady state conditions.