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Manufacture Bioprocessing - Upstream & Downstream, Standards & Regulation

Continuous Progress

Continuous manufacturing is on the rise in pharma. Recent advances have made it possible to formulate a final drug product from base ingredients much faster without halting production. Continuous has proven its benefits for the manufacture of small molecule drugs, but there is now increasing interest in applying the technology to large molecules, too. The prospect of increased regulatory clarity and harmonization is also driving more organizations to take a hard look at continuous manufacturing.

Although manufacturers generally acknowledge the potential of continuous, there are barriers to adoption. In the last few years, the greatest challenge companies have had to contend with is working the upfront costs into business cases. The integrated lines required for a continuous process have a significant capital cost due to the need to bring in experienced personnel to handle the new technologies. For example, process development now requires more automation, as well as the use of process analytical technology and changes to the pharmaceutical quality systems. In addition, the lengthy timelines for setting up and qualifying a new line make it challenging to link a single product to a business case.

One of the uncertainties that hampers the adoption of continuous manufacturing is regulatory considerations. Though major agencies like the FDA, EMA, and PDMA have put forth guidance elements and strongly advocated for the adoption of continuous approaches, uncertainty remains regarding global market requirements. Years ago, it was a question of acceptance that stemmed from an overall lack of familiarity in many markets. Today, there is less concern about whether a continuous process will be approved; instead, concerns have shifted to questions about timelines and clarity on what information is really needed. For instance, ICH Q13, which has been in the works for a few years now and should be published within the next year, is intended to provide greater clarity for CM processing of both small and large molecules. Due to COVID-19, the group was unable to meet in person, somewhat delaying progress.

Another key consideration is understanding what batches are and how they are defined for continuous. “Batchless'' operations are not necessarily possible in the strictest sense, because there still needs to be a way to delineate quantities of material produced to allow for alignment with traditional regulatory and PQS approaches. Where defining a batch is concerned, the degree of flexibility can present a challenge. Current guidance states that there are multiple acceptable ways to define a batch, as long as the definition remains consistent. It is often recommended that drug developers conduct a risk analysis and keep the batch size on the higher end of what would have been done with a traditional batch process. The tradeoff for shorter batch sizes is additional testing and documentation. For longer batches, higher development costs are expected.

In the end, however, batch size is not a critical factor, because what really matters is run time. Because batches can be produced in succession, many batches can be run in a series without stopping the process. Currently, the intended maximum run time is part of a submission and going beyond requires a filed plan or a post-approval change.

Many companies have stated, “We know we will be using continuous manufacturing in the future; we just don’t know when that will be.” The ability to wait is a function of the fact that the same product is being produced by either a continuous or a batch process. If these companies were enabling a new product using continuous manufacturing, adoption would be much faster. Those on the sidelines are always looking for ways to stick their toes in the water.

Today, continuous processes have been approved for both solid doses and drug substances. The gap from the initial approvals observed in the last few years seems to have resulted from first adopters’ initially focusing on a single product and then turning to their early-stage pipeline. There are currently many late-stage compounds using continuous processes and we should see another round of approvals in the somewhat near future. This is an exciting prospect because it will demonstrate how first adopters have reorganized to embrace the technology.

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About the Author

Doug Hausner

Doug Hausner is Associate Director for Industrial Relations and Business Development at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), Rutgers University, NY, USA.

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