Continuous manufacturing has been gaining acceptance as a method of manufacturing OSD products. What is its current level of acceptance in the biopharmaceutical industry and what are some critical industry issues that need to be addressed before it can achieve widespread usage?
Small molecule drug manufacturers have been applying semi-continuous processes with success for some years now. However, the key shift in acceptance arguably came this year as the Food and Drug Administration (FDA) approved a switch from batch to continuous processing for Janssen’s Prezista (darunavir) for the treatment of HIV-1 infection. FDA further commented in a blog posted in April 2016 by Lawrence Yu, PhD, Deputy Director of the FDA Office of Medical Products and Tobacco Center for Drug Evaluation and Research, and Office of Pharmaceutical Quality that continuous processing offers “greater reliability, safety, efficiency, responsiveness/flexibility, and reduced costs”.
Yet, even as continuous processing becomes a hotter topic with large molecule manufacturers, it remains in the early stages of acceptance. Some of the key drivers of this interest in continuous biopharmaceutical production are:
- Single-use technologies: Ideally suited for use in continuous operations now that they are more widely adopted at the commercial scale.
- Process intensification: Bioreactors can now make product at higher titers, making continuous a more viable option.
- Targeted applications: The drive for drugs that are targeted for smaller populations means that effective production at a smaller scale is needed (which is best accomplished with continuous processes).
Right now we are seeing more biopharmaceutical companies evaluating or establishing programs for continuous downstream processing solutions. However, in this industry, one of the greatest challenges is inflexibility due to an aversion to risk, which makes early adoption tricky. Because of this hesitance, we expect more hybrid approaches at first (with a mix of continuous and batch steps), mimicking the adoption curve we saw in the transition from hard piped to single use systems.
Do you believe the entire biopharmaceutical manufacturing process can be adapted to continuous manufacturing? Or are there specific processes and/or applications that can be linked into a continuous process? If so, what are they, and what benefits can be realized by biopharmaceutical companies that convert these processes to continuous manufacturing?
As mentioned above, yes, I do believe so, but there is a great deal of work to be done to get there. At Pall Life Sciences, we decided first to take on the critical task of addressing producer challenges in the downstream. Our work over the past few years has been very focused on innovations that allow key unit operations to be connected in a continuous fashion.
Semi- or fully-continuous manufacturing of large-molecule drugs offers the potential to reduce footprints and overall costs of pharmaceutical operations up to a bioreactor volume of 2000L while increasing efficiency and product quality and consistency. It depends on the type of company and what they are looking to achieve, but benefits can be realized in both semi- or fully-continuous mode for a company of any size. Established biopharma manufacturers may be more likely to adopt tack-on hybrid approaches, where they can see immediate impact in areas such as monoclonal applications. For new (often small, start-up) biotechs with no process history, there is more flexibility to adopt newer technologies.
Regardless, there is a time advantage across the board as process steps and downtime are removed. Continuous processes are monitored on an ongoing basis to ensure that process parameters are maintained at optimal values, delivering more consistent processes and product quality. Reductions in waste generation and product losses are key benefits, but there are also cost savings via optimized resource usage, and minimized facility footprints. The smaller plant footprint reduces overall CAPEX, and OPEX is also reduced since buffer volumes are reduced in downstream processing. In addition, continuous processes streamline human resources as they are less labor intensive.
If a biopharmaceutical company is considering continuous processing, what are some of the important factors they need to bear in mind, and where should they start? Is there such a thing as “low hanging fruit” that a company can start with to gain experience with continuous manufacturing technologies?
Even as the FDA has been outspoken in support of moving towards continuous bioprocesses, they realize it can be a complex transition. Part of the work we have done here at Pall is aimed at easing that burden of transition. We see three main challenges associated with the transition:
- A need for cost-effective continuous technologies for unit operations.
- A need for clearly demonstrated performance under cGMP conditions at the commercial scale.
- A need for unit operations that provide reliable and reproducible performance to address validation requirements.
For a company interested in implementing continuous processes, it is imperative to work closely with their equipment suppliers. Each participant needs to understand the unique challenges associated with continuous manufacturing of pharmaceutical drug substances and drug products.
As companies consider this transition, it is also important to think strategically about the longevity of the drug products, and how earlier adoption might pay off. Lifecycle management is crucial to the success of many drugs today, and technologies that help increase efficiencies and reduce costs can have a significant impact on the profitability of off-patent products. Manufacturers that are late to adopt continuous processing may see their product portfolios losing competitiveness. In addition, at the process development scale, continuous processing offers a flexible, platformable process that is expected to translate into reduced development time and a faster time to market for new drugs.
How can a company like Pall Life Sciences help a biopharmaceutical company move towards a more continuous processing system? What continuous processing products/technologies and services do you offer that can help a biopharmaceutical company meet its quality, efficiency and market goals?
Our team has actively worked to expand our portfolio of continuous technologies. In 2016 alone, we have achieved a number of new continuous downstream product launches under a portfolio referred to as Cadence™. This portfolio includes the Cadence BioSMB PD and Process systems — the first simulated moving bed multi-column chromatography systems of their kind designed for any scale of biopharmaceutical manufacturing. The Cadence Inline Concentrator, based on single-pass tangential flow filtration (SPTFF) technology, is available for continuous concentration of bioprocess fluids at various process steps. And for clarification, our Cadence Acoustic Separator (CAS) — based on acoustic wave separation — allows for a reduction of 75% of the buffer volume required to perform large-scale depth filtration. These technologies are easy to integrate into bioprocesses separately, or in a continuous fashion.
In addition to these technologies for specific unit operations, Pall continues to develop single use, as well as filtration and separation technologies, that offer improved performance and are enabling for continuous processing. Pall is also very involved in industry discussions about managing waste in media, as well as in plastics.
What do you see as the future for continuous processing in the biopharmaceutical industry, and how do you see Pall Life Sciences being an integral part of this growing trend?
The future for continuous bioprocessing is already upon us. Much like the evolution we have seen with single use technologies, we are at the outset, and it will just be a matter of time before benefits are fully realized. In three years we expect to see semi-continuous processes at production scale; in five years, at full scale. By 10 years, these technologies should no longer be viewed as a novelty.
As a key supplier to this industry, moving towards fully continuous bioprocessing is a personal mission for our team. We have already made core investments of time and money to get to where we are today, and plan to continue building on this progress. We are committed to being there with customers every step of the way as they make the transition to continuous bioprocessing for the future.