F3 Factory Case Study: Active Pharmaceutical Intermediates

As a F³ Factory Case Study Bayer Technology Services (BTS) investigated the transfer of a multi-step synthetic batch process for pharmaceutical intermediates to a fully continuous manufacturing process in a modular, flexible infrastructure including downstream processing. Working with other industrial and academic partners, Ehrfeld, Britest, TU Dortmund, University of Paderborn, Ruhr-University Bochum and RWTH Aachen, this case study successfully validated and demonstrated a major paradigm shift towards modular, continuous processing of active pharmaceutical intermediates.

The BTS project sought to assess the potential to replicate the cost, quality and efficiency benefits of large-scale continuous production in modular, flexible, small-scale container-based production units. In demonstrating a sequence of synthesis stages in a container environment, BTS also integrated a range of innovative, highly efficient process equipment solutions.

Starting from a five stage reaction sequence with intermediate isolation, key stages of the project included:

• chemical redesign against the paradigm shift of continuous processing
• simultaneous chemical and continuous process development
• integration of reaction and separation steps in the container unit  
• demonstration of the new process in the modular F³ Factory design

Cost and efficiency

Research and development activity in the first phase of the project demonstrated significant savings and efficiency gains with cross-project benefits for the wider F³ Factory programme.

Transfer of the chemical synthesis to an intensified fully continuous process led to a significant reduction in processing steps, reaction time and the amount of solvent used.

BTS operated the process sequence successfully for several days at bench scale, confirming the assumed benefits of the F³ Factory approach in terms of impact on footprint, resource consumption, continuous monitoring and process operability. Key benefits identified to date include:

• reduction in starting material costs (average 15% depending on transformations involved)
• increase in space time yield (up by factors >100)
• significant reduction in both reaction and processing time
• simplified work up processes due to elimination of intermediate isolation and purification stages
• unification of solvents and reduction in consumables
• reduction in equipment size
• reduction in design and installation costs (up to 30% depending on transformations involved)
• reduction in apparatus cost (approximately. 30% depending on intensification of the specific modules)

Modular, flexible production

This was the first industrial case study to be demonstrated in the INVITE backbone facility (see above), and therefore the BTS project led the way in establishing standards for process equipment assemblies (PEAs), the Process Equipment Container (PEC) and its integration with the backbone infrastructure services at INVITE.

To achieve maximum flexibility the standardised and scalable equipment used for the development and production phases enabled a fast and robust transfer from research to production in line with the development time line and with minimal effort.

Modular PECs can provide the required production capacity throughout the full product life-cycle. In addition, standardised chemical and physical processing PEA units can allow faster implementation of new manufacturing strategies in the highly regulated environment of pharmaceutical production.

In the latter stages of the project, BTS successfully demonstrated synthesis steps 1 and 2 in the case study’s PEC at the INVITE backbone facility.

The technological and economic benefits demonstrated through this case study provide a platform for the introduction of new technologies, production concepts and process equipment solutions for the European pharmaceutical manufacturing sector.

More information

For more information visit the F3 Factory Project website.