Roche on Continuous Manufacturing at the PDA/EMA Joint Conference

Continuous manufacturing is now becoming a trend as its advantages are being increasingly recognized. At the PDA/EMA joint conference, which took place earlier this month, Martin Wunderlich from F. Hoffmann-La Roche presented an industry case study on solid drug product manufacturing based on this concept. He explained how a continuous wet granulation process for one of the company’s product (referred to as ‘product X’ hereafter) was developed using a quality-by-design (QbD) approach and a control strategy based on process analytical technology (PAT), as well as the technical challenges involved in the development of the process.

Continuous wet granulation offers significant advantages in terms of the general working principles and a straightforward scale-up versus batch manufacturing, says Wunderlich. In this example, product residence in the granulator was less than 10 seconds with continuous wet granulation compared with batch manufacturing, which took 15 to 30 minutes for the granulation of the entire batch of product X. More importantly, in continuous wet granulation, each subfraction of the batch was subjected to the same processing conditions, providing a steady state for the vast majority of processing, including the start-up and shut-down phases, whereas for batch granulation, one has to question whether the shear energy and granulation liquid distribution were even throughout the entire batch. For the same reason, scale-up effects are difficult to predict for batch granulation because the dramatic changes in equipment surface area and volume would mean that the product experiences different conditions in both small and large scales. In contrast, time scaling occurs under identical process conditions for small to very large batches in continuous wet granulation and the same equipment is used for both development and commercial manufacturing.

Several key drivers that led to the adoption of continuous manufacturing at Roche were highlighted, for example, process control was enhanced, apart from the reduction in development time and cost, to name a few. Continuous manufacturing also facilitated scale-up and offered high flexibility through variable batch size. The company’s experience with the process development of continuous wet granulation for product X demonstrated that a comprehensive process understanding could be achieved in a short time despite its challenges, such as the need for more complex equipment design and controls, as well as the professional data management system required for the various process controls and PAT tools. Data presented by the speaker showed that both continuous and batch processes resulted in similar product quality with comparable in vitro performance.

Continuous manufacturing is consistent with QbD efforts of the EMA and FDA, says Wunderlich. It has the potential to improve quality assurance and the consistency of drugs, and enables quality to be directly built into process design. For this industry, the door to implement continuous manufacturing in pharmaceutical R&D and commercial production is wide open.