Roundtable Part 2: Overcoming Barriers to Adopting Continuous Processing Practices

According to the BioPlan annual reports, a great majority of the of the industry is more comfortable with batch operations, and sees the complexity, training, and logistical requirements associated with continuous processes, such as perfusion bioreactors to be daunting. Rightly or wrongly, the impression of the risks and complexity associated with these devices exists.  The industry has moved toward unit operations focusing on ‘process intensification’ rather than fully continuous, end-to-end processing.

While there are a number of advantages that drive the adoption of continuous processing, there can be some concerns, some of which are true challenges and others may be perceived barriers.

Those include:

• Alignment around the business case for moving to continuous processing, especially when a significant amount of existing batch process capacity or existing products are made reliably by batch processes.
• Questions around regulatory agency support or other concerns outside of the large market regions, which may be less familiar with the technology.
• Unfamiliarity with the technology in general and working through development of appropriate control strategies and supporting systems that come with transition to any new technology. For example, the level of process automation, use of Process Analytical Technology (PAT) and use of models can all contribute to some of the key advantages of the technology, yet they may require a different level of understanding and expertise from what some are doing today.
• Ability to integrate the technology into business and quality systems appropriately.
• While there are some questions (e.g., definition of a batch, management of larger process data sets, control and release of material, etc.) that need to be answered, we believe these are all manageable.

Barriers are combination of confidence, unwillingness as well as regulatory bodies. Once the product is commercial no one wants to change as they have to spend money to convince regulators of bio-equivalency. Since significant monies are being made with batch process, why take on un-necessary aggravation of dealing with regulators.

FDA generally gets favorable feedback on continuous processing. That said, implementing continuous manufacturing does require a capital investment up front. There is also a learning curve involved the first time a company implements a continuous manufacturing process. Constraints like these may pose a challenge for some companies, particularly when considering their existing investment in batch manufacturing. It is up to each company to decide whether continuous manufacturing is a practical approach for a specific product in their portfolio.

The monetary advantages of continuous manufacturing are more likely to be realized over a longer timeframe. Continuous manufacturing facilities and equipment are significantly smaller compared to batch manufacturing. These can reduce operational costs such as utility usage, waste, solvent use, and staffing, among other considerations. Continuous manufacturing also naturally lends itself to rapid process development, and a batch size increase is usually achieved by increasing run time without requiring a change to equipment size. This can help reduce the time from development to market. Since continuous manufacturing also allows for more nimble testing and control, it can help reduce the likelihood of manufacturing failures.

Next Generation Processing, as we consider it, is an evolutionary manufacturing approach beginning with unit operation optimization and evolving to connected, intensified processes with the potential of a fully continuous process – hence the uptake of this methodology takes time. Despite the fact that enabling technologies already exist, some still need to be improved and current technological gaps filled. System complexity, in-line monitoring and online analytics (e.g. PAT), or holistic, integrated process development expertise, are only a few known hurdles to adoption. The same applies for regulatory guidance which requires further evolution. For example, how will regulators define a batch in the framework of Next Generation Biomanufacturing? Also, this industry paradigm shift towards Next Generation Processing represents a new mind-set for both management and process developers – even a totally new company culture for some of our stakeholders. The fact that there is no templated approach yet for the successful implementation of Next Generation Bioprocessing, versus a well characterized and heavily regulated pharma industry, may outweigh the clear potential this new way of manufacturing drugs will bring.

It’s a risk adverse industry to some extent because of the regulated nature of drug production. However, due to market changes, the time frame for accepting new, enabling technologies has become shorter. The industry is facing demand to produce more complicated molecules more efficiently and at a lower cost, so acceptance of more efficient approaches is not just nice to have – in some cases it is critical.

About three years ago, I would have argued that adoption was hindered by the lack of successful examples, but not today. As everyone knows, it takes eight to ten years to successfully launch an approved and innovative molecule. I would attribute the cause to the process and time required. There have been technological challenges, which had to be expected but that are being overcome. Scientific progress in clone development, and cell culture media that express proteins in higher quantities all have an impact as well. Cost has a direct impact on the demand and demand drives innovation. If fed batch cultures produce sufficient quantity to satisfy demand, it limits the need for value offered by continuous processing. This applied to all innovative molecules, biosimilars and bio-betters.