An Interview with Rhea Mahabir, Surendra Balekai and Mike Brewer from Thermo Scientific

• Thermo Fisher Scientific

Continuous manufacturing has be gaining acceptance in the pharmaceutical industry. What is its current level of acceptance in the industry and what are some roadblocks that are preventing widespread usage?

Rhea: Generally, the most significant roadblock hindering adoption is the upfront development costs needed to retrofit continuous processing capabilities into an existing biomanufacturing facility. From a media perspective, these costs are especially apparent in the intensive labour needed to support media preparation for continuous manufacturing. Additionally, continuous processing can demand a three to five fold increase in media volume to produce the same batch yield. Lot to lot media variability can affect cell culture performance, and nutrient requirements usually vary during growth phase versus steady state. Finally, commercially available media today may not be able to support the high cell densities needed to make continuous processing worthwhile.

Surendra: Continuous processing is not just about operations. This starts from selection of cell clones, robustness of cells to produce for 30 – 90 days and process development. To define a process for continuous manufacturing and go through regulatory process can take 3 to 8 years or more. So far questions around definition of the “batch” in downstream in continuous processing has been addressed to satisfy regulatory requirements and this is a significant boost. The bottleneck that continues is downstream processing. There have been efforts to address continuous chromatography at the lab scale and to transform this into a commercial process will take time.

Are there processes or applications that are better suited to continuous manufacturing technologies? If so, what are they, and what benefits can be realized by pharma companies that convert these processes to continuous manufacturing?

Rhea: Historically, continuous manufacturing has been preferred for labile recombinant proteins in order to achieve the highest product quality possible, and it makes sense for this trend to continue. Cell lines that generate toxic waste products can also reap benefits from continuous clearance. If a tightly controlled continuous process can be developed, pharmaceutical companies could certainly gain from fewer campaigns and a more consistent product quality for any biologic.

Surendra: Some of the processes that have been successfully proven for continuous biorpcessing are bioreactors with efficient cell separation systems in both ATF and TFF formats for over 30 days. With acceptance of “batch” definition for downstream processing, I see fewer hurdles for the rest of the process. A major benefit with continuous processing is enhanced capacity. Within same foot print one can produce anywhere between 10 to 20 times higher capacity. This makes it more efficient and drives lower cost of drugs.

If a pharma company is considering converting some of it processes to a continuous mode, what are some important factors they need to consider, and where should they start?

Rhea: Process development scientists should determine specific nutrient requirements under perfusion conditions, when making the shift from traditional fed-batch culture. Cell culture sensitivity to mixed media lots would need to be evaluated as well. Finally, if the fed batch product profile is influenced by an added feed, then the perfusion medium and conditions would need to be designed to produce a similar profile.

Surendra: First point in the direction of continuous processing is the selection of right cell clones and developing process. Once proof of continuous expression of proteins has been established, we need to define downstream processing. We need to touch on process analytics and product quality aspects that will be critical before process is scaled up. Selection of cell culture media for continuous processing plays major role in making continuous processing a success.

Mike: As the cell culture in a continuous process is maintained over an extended period as compared to fed batch processes, with continuous harvest of product, routine monitoring for the presence of difficult to detect contaminants, especially the most common CHO threats, Mycoplasma and Mouse Minute Virus (MMV) should be considered. This can be accomplished using sensitive, accurate and specific real-time qPCR tests. Use of these tests can enable early detection of a contamination event, which greatly reduces the risk of an undetected contamination event impacting multiple purification Lots. As the traditional tests for Mycoplasma and Adventitious agents requires 28 days, these tests, although required for Lot Release, are not practical for use in routine monitoring. And due to the extended time to result, a contamination can impact product for weeks to months in a continuous process if not detected and eliminated. Implementation of in-process monitoring for contaminants can be a very powerful risk mitigation tool.

How can a company like Thermo Fisher Scientific help a pharmaceutical company move towards a more continuous processing system? What continuous processing products/ technologies do you offer that can help a pharm company meet its quality, efficiency and market goals?

Rhea: Thermo Fisher offers a diverse CHO media portfolio that has been tested and used in perfusion processes by several of our customers. Gibco Media Express™ and Gibco BioProduction Services provide media prototyping capabilities and technical development expertise. Thermo Fisher also offers large scale cGMP manufacturing for customer developed formulations.

Surendra: Thermo Fisher being a leader in the industry offers cell culture media, feed supplements, process development support for cell culture process. Proven HyPerforma Single Use Bioreactors, Mixers, Storage and Transport solutions across upstream and downstream processes are core technologies offered by Thermo Fisher. Chromatography Capture Select resins for capturing, Poros resin platform for ion exchange and polishing steps and PCR/qPCR based analytical technologies from Thermo Fisher are integral part of most of the current molecules under development. Thermo has partnered with companies offering cell separation systems in ATF or TFF mode of operation and thus has become a preferred partner for many biological molecules under development.

Mike: We offer fully integrated systems that address a number of quality and safety tests, including qPCR based tests for Mycoplasma, MMV and Vesivirus. These solutions, when combined with training by specialized Field Application Scientists can be qualified and validated on relatively short timelines, to enable rapid implementation for routine use.

Do you offer additional services, such as compliance and validation tools, to help pharma companies meet continuous processing regulatory requirements? Can you elaborate?

Rhea: Thermo Fisher’s media manufacturing sites in Grand Island, New York and Inchinnan, Scotland are both certified ISO 13485:2003, EN ISO 13485:2012, and manufacture products according to 21 CFR Part 820 cGMP. Thermo Fisher also supports customers in their regulatory filings by providing a Drug Master File to the FDA for any processes that use Gibco media.

Surendra: We support pharma companies in qualification of the film used in various applications across processes, qualification of equipment like SUB, SUM, onsite Integrity testing, Freeze/thaw systems that meet cGMP standards.

What do you see as the future for continuous processing in the pharmaceutical industry, and how do you see Thermo Fisher Scientific being an integral part of this growing trend?

Rhea: We expect to see continued adoption in processes with unstable proteins, and growth from new biomanufacturing facilities now being built with modular designs and geared towards continuous manufacturing. Thermo Fisher aims to provide a total workflow solution from upstream processing, through media and equipment, to downstream harvest and analytics. As we continue to evolve our media offerings to meet the industry need, we will explore advanced media formulations that are optimised for perfusion.

Surendra: In the next 3 – 5 years, we see many molecules being developed and migrated to continuous processing. It is a buzzword today and will be a reality tomorrow. As the pressure on reducing cost/dose of treatment increases, the need for efficient processes and higher grams of drug produced per unit foot print area become inevitable. Having most of the core technologies from the process side, the ability to work with A&E companies to optimize and build required facilities in a short time, being a leader in the industry to provide laboratory products, consumables and analytical technologies Thermo Fisher is an undisputed leader to partner on developing molecules and commercializing the same with time.