Continuous Manufacturing: Building an Evidence Base for Change

Continuous manufacturing (CM) has the potential to drive productivity and improve safety and product quality in the pharmaceutical sector, but the shift from batch processes requires a robust foundation of knowledge.

Organizations hoping to take advantage of CM, which could also be 40-50% cheaper to run than batch approaches, will need to learn how redesign individual processing steps, such as the blending of active pharmaceutical ingredients (API) with excipients. 

Successful implementation, then, will rely upon an in-depth understanding of how raw materials and their mixtures behave in this new world – which gives us an industry-wide responsibility to pool our expertise and build an evidence base for change.

The future paradigm 

CM offers numerous advantages over batch production, making it the future of pharmaceutical manufacturing.

It can significantly reduce lead, processing, and scale-up times, cut the volumes of API needed, and it requires less physical space, thereby decreasing plant footprint. At the same time, it minimizes contamination risks, reduces the likelihood of human error, and allows for real-time monitoring and release.

The model, which has the backing of both the FDA and EMA, as part of a quality-by-design (QbD) approach to pharmaceutical development, is also inherently flexible. This will be crucial as we move further into the personalized medicine era, when drug manufacturers will need adapt their processes to producing medicines in smaller volumes than have, up until now, been the norm.

Blend homogeneity 

If the industry is to embrace the benefits of CM, it first needs to thoroughly understand it. The traditional, batch-wise model has stood unchanged for decades, meaning our knowledge is due an update.

That’s why DFE Pharma teamed up with Gericke, a world-leading CM equipment supplier, to help build the evidence base. We already know that the material properties of excipients and APIs impact blend uniformity of pharmaceutical powder formulations for solid oral dose production. However, the data on the relationship between material properties and blend homogeneity comes from batch-wise blending trials. 

In this joint project, our researchers blended API and excipients in both a batch and a continuous process, before analyzing the homogeneity of the resulting mixtures. They found that whereas parameters such as particle size, density and flowability had a significant impact on blending performance in a traditional batch process, continuous blending was more robust, and resulted in uniform blends for a large variety of blend compositions.

In a paper published in the International Journal of Pharmaceutics, the authors concluded: “The limited effect of excipient material properties on blend uniformity presents a clear benefit for continuous processing. 

“The choice of excipients in a formulation can therefore be focused on their functional properties such as compactability or flowability without significantly affecting blending performance.”[1]

Excipient behavior

Of course, the knowledge need does not start and end at blending. When building CM processes that result in consistent end-products, the industry needs fundamental knowledge of how excipients behave throughout the journey. 

It’s important to remember that while any variation in how individual materials flow into the manufacturing line will affect the final product, excipient variation is inevitable. They can vary by type or grade, from vendor to vendor, and even from batch to batch.

Complicating this picture even further, the parameters that dictate control also vary according to the task in hand. While particle size distribution (PSD) may be crucial for one product, for example, beta content or surface area is vital to another. 

That’s why we have also been working on detailed research into how the specific properties of excipients affect continuous processes.

Accounting for variability

Next to understanding the critical material attributes it is important to understand the variability of those critical material attributes. Many organizations will assess the impact of excipient variability by testing multiple batches of excipients, however, this is a time-consuming, labour-intensive process and not always executed diligently. 

Instead, DFE Pharma advocates the use of multivariate data analysis (MVA) statistical techniques, which allow the simultaneous analyses of multiple parameters. DFE Pharma works with its pharma partners to identify major relevant sources of variation in the large, complex datasets, as well as noise variables that have no effect. Beyond the data share DFE Pharma is able to provide stretch batches, batches within specification that represent the full span of variation that might be expected based on historical product data. This data and stretch batches will contribute to Quality by Design (QbD) by informing risk assessment and focusing the experiments on the most important parameters. 

By effectively managing the variations that can impact on product performance, developers can slash the level of experimentation needed during product development and de-risk the use of excipients in continuous manufacturing. This will enable to quickly move up the development process.

Evidence for change

By enabling higher quality products at lower manufacturing costs, CM offers the pharmaceutical industry – and the people who rely on the life-changing medicines it supplies – a wealth of advantages.

But moving from batch to continuous processes will not be easy. It will require a huge volume of new information, knowledge, and data, on how the basic chemistry of drug development will work in this new environment.