Continuous Manufacturing

Batch manufacturing has been the standard in the pharma industry, however continuous manufacturing is now proving to be the better choice for efficiency, as well as waste and cost reduction. How can new technologies improve this method further?

Maria Grahm at Siemens

The pharmaceutical industry is constantly facing major challenges, such as shorter development times, strict cost controls and increased regulatory requirements. To remain flexible and agile, and keep pace with these challenges, the implementation of continuous manufacturing (CM) processes is crucial. This method offers significant advantages over traditional batch production.

Traditionally, batch manufacturing has been the cornerstone of pharmaceutical production since the early 20th Century, primarily due to its simplicity and the limited technological capabilities of the time. However, as medical science has advanced and the demand for more complex drugs has increased, the limitations of batch processing – such as longer production times and higher costs – have become more pronounced. Many manufacturers have recognised this and are converting their processes to CM.

CM in the pharma industry means that active ingredients are produced in compact, closed units with a higher degree of automation and less manual intervention. Production steps that run one after the other in a classic batch process are integrated into a continuous process. Although this concept has been known for many years, it has recently experienced a new upswing. This is due to the new era in which increased computing power provides unbridled possibilities for new technologies, such as virtual environments, data models and all associated AI applications. In CM, raw materials are fed into the system at one end, and finished products emerge at the other in a seamless flow. This integration is achieved through advanced equipment like continuous reactors, real-time quality analysers and automated control systems that synchronise each stage of production.

A major advantage of CM is the increase in efficiency. The production time of a pharmaceutical product can be reduced from several months to just a few days using this method. This leads to a significantly faster market launch of pharmaceutical products. Another significant advantage is the cost saving: CM reduces operating costs and investments; lowers storage costs; and minimises waste. In addition, continuous production contributes to sustainability by reducing energy consumption and carbon footprint through more efficient processes and smaller facilities.

The pressure to implement CM has never been greater as pharma companies of all sizes develop fully integrated primary and secondary manufacturing capabilities. This technology is not limited to small molecules, but is also being applied to closed, integrated bioprocesses that combine upstream and downstream. Companies using continuous bioprocess technology are achieving promising results in record time, making batch manufacturing a thing of the past.

The technological basis of CM is a high degree of process automation, which reduces manual intervention and increases process reliability. The real key to CM is process analytics technology (PAT), which enables the quality inspection of pharmaceutical products to be integrated into the production process rather than taking place separately in a lab. PAT utilises tools such as near-infrared (NIR) spectroscopy and high-performance liquid chromatography (HPLC) integrated directly into the production line. These tools continuously monitor critical to quality attributes (CQAs) like concentration, potency and purity, enabling immediate adjustments to the process if deviations are detected. The introduction of PAT has been proven to reduce production costs, accelerate decision-making at the plant operations level, and improve the quality and efficiency of process steps.

“...continuous production contributes to sustainability by reducing energy consumption and carbon footprint through more efficient processes and smaller facilities”

Combined with digital twins for processes and production, PAT enables continuous quality control during the manufacturing process by using digital models for process optimisation. This leads to shorter batch runs and increased quality consistency, as the clinical efficacy of an active ingredient can be determined through direct online collection of quality data during the process. PAT reduces long laboratory analysis times by closing information gaps and shifting therapeutic drug performance analysis to in-process data and analytical tools that improve process understanding and control. Integrated process optimisation and quality assurance ensure right-first-time quality and reduce the risk of losing batches due to non-compliance. Overall, this leads to greater flexibility in production, as capacities can be adapted to market requirements and scaled more easily.

Digital twins of the installation, as well as the process and the product, are indispensable for the correct construction, usage and optimisation of such installations. A digital twin is a virtual replica of a physical system that can simulate real-world conditions. In pharmaceutical manufacturing, digital twins enable engineers to model production lines, test changes and predict outcomes, without disrupting actual operations. This applies already during the design phase, where processes can be tested much faster, better and more cost-effectively.

It is possible to propose installations virtually and carry out experiments on them to establish connections between all kinds of process parameters and CQAs at a very early stage, and to realise process optimisation without having to build expensive installations and carry out costly experiments.

When using a simulation software for processes, mechanistic models of each process step can be generated, used and linked to each other via flowsheet modelling to simulate the processes and make connections between the various process steps. This allows for overwhelming possibilities at an early stage, such as line start-up and shutdown, feed backward and forward control, residence time distribution, disturbance rejection, and equipment limitations.

Using digital twins, companies can anticipate equipment failures before they occur, schedule maintenance proactively and optimise process parameters for maximum efficiency. They also serve as valuable training tools for staff, allowing them to familiarise themselves with new systems in a risk-free environment.

Other data models and multiphysics computational fluid dynamics tools can be used to make these high-tech simulations possible as well. Moreover, these simulation platforms can be seamlessly linked to existing distributed control systems (DCS) or supervisory control and data acquisition (SCADA) systems, so that they can be used as test and training platforms without much extra cost. The involvement of module predictive controllers (MPCs), and the ability to link these virtual environments to the real plant during the commercial phase, and thus be able to make predictions in real time and adjust them if necessary, makes CM even more attractive.

The reliability associated with PAT also comes with other benefits: significantly lower costs for warehousing and quality control; reduction of equipment sizes; and reduced or even complete elimination of waste products. Small, fully closed processes with a high degree of automation allow companies to reduce variability, achieve higher yields and increase their profitability. This ultimately leads to lower operating, inventory and capital costs.

According to studies, CM can potentially save operating and capital costs by a corridor of 6%-40% and 20%-75%, respectively, compared to traditional batch operations depending on initial assumptions (including the costs of chemical intermediates and type of CM process).1 This is due to smaller, more cost-effective facilities operating at full capacity with minimal overhead. Time and cost savings are also achieved by eliminating the need for laboratory analysis of samples, which shortens the release time for products.

Pharmaceutical manufacturers are recognising that CM enables faster time-to-market for new drugs. Active ingredient production takes place in compact, closed units that are highly automated with minimal manual intervention. The integrated, CM process allows for bypassing scale-up testing. This leads to an increase in plant utilisation, so products that were previously in production for a long time are ready after two days. In addition, CM can also significantly reduce the building, energy and CO2 footprint.

CM in the pharmaceutical industry offers numerous benefits, ranging from efficiency gains to significant cost savings and improved sustainability measures. By integrating advanced PAT and digital twins, companies can significantly improve the quality and consistency of their products while drastically reducing production time. This innovative technology not only makes production more flexible and adaptable, but also promotes environmental sustainability through more energy-efficient operations and smaller facilities. CM is thus proving to be a key technology for successfully meeting the challenges of the modern pharmaceutical industry and increasing competitiveness.