Closed systems: Data driven equipment and facility design case study

This document reports on the learnings from bioburden reduction studies on hybrid (stainless steel and disposable) functionally closed bioprocessing systems developed over three years in collaboration with the Biomanufacturing Training and Education Center (BTEC) at NC State University.

The study sought to demonstrate that for low bioburden processes, operating a functionally closed system in a CNC environment is equal to or better than operating an open process in a grade C environment. This approach offers significant benefits for biopharma manufacturers in terms of capital and operational costs as well as reduced facility complexity.

The study concluded that measures as simple as flushing with WFI may be successfully employed to effectively mitigate the risk of assembling and operating a modern hybrid closed bioprocessing system in a controlled, non-classified environment. Over a five log reduction in bioburden was achieved with some cleaning agents.

The report argues that it is in fact superior to operate a functionally closed system in a CNC environment in this manner, versus an open system in a grade C environment as the potential microbial contamination from the environment entering the system would be lower.

The aim of the BioPhorum Drug Substance ‘Closed Systems in CNC Space’ workstream is to provide data driven arguments and risk based approaches to support implementation of closed or functionally closed systems, and to operate those systems within CNC environments.

Moving from inflexible operations in a grade C environment to a modern, flexible multi-product facility in a CNC environment will result in significant reduction in costs for the industry.

Such designs provide superior benefits like energy conservation, reduced facility capital and operating cost, shorter facility construction and qualification times, enhanced facility throughput and operational flexibility, reduced cost of goods and speed to market; all while maintaining the highest product quality standards.

Capital costs may reduce by 45 per cent and operational costs by between 50 per cent (energy) to 100 per cent (Environmental Monitoring) as per figures 1 and 2 (ref bioprocess international article 123):

However, to enable this shift to happen, the industry needs confidence from data, tools and processes born from risk based approaches that demonstrate it is acceptable to operate in this manner. One such area where data is lacking is other than steam, how can you render a low bioburden processing system functionally closed when open connections are made?

As such, the study was designed to assess what log reduction in bioburden could be obtained by flushing or cleaning open connections in a CNC environment to render a process system functionally closed. The results gained clearly demonstrate that this method of functional closure gives an acceptable reduction in bioburden, and arguably results in a lower amount of environmental contamination entering the process than a comparable open operation in a Grade C environment.

Organizations should now use this concept and data to develop their own cleaning development and validation strategy for their specific processes. This would support their own risk based approaches to implementing use of closed systems in a CNC environment