Biologics’ share in the industry’s pipeline and in the global pharmaceutical market is increasing, so what are the key issues shaping the current and future direction of biomanufacturing? Industry experts share their perspectives.

Gaining an industry view

From wider adoption of single-use technology, to more flexible and potentially modular biomanufacturing facilities, to process-intensification strategies up to and including the potential for fully continuous processing, industry experts share their views. Participating in this industry roundtable are:

• Dr. Barbara Esch, Head of Business Development Strategy and Marketing, Biopharmaceuticals, Contract Manufacturing Business, Boehringer Ingelheim Biopharmaceuticals GmbH;
• Andrew Bulpin, Head of Process Solutions, MilliporeSigma;
• William Downey, President, HighTech Business Decisions, a consultancy;
• David Downey, Chief Commercial Officer, APC Ltd, a process research consultancy;
• Brian Glennon, Chief Technology Officer and Co-Founder, APC Ltd;
• John Milne, Director of Training, the National Institute for Bioprocessing Research and Training (NIBRT), a Dublin, Ireland-based global center of excellence for training and research in bioprocessing;
• Thomas Theelen, Business Development Manager, Univercells, a technology company specializing in bioprocessing; and
• Tania Periera-Chilima, Product Manager, Univercells.

Top trends impacting biomanufacturing

What would you identify as the three most significant trends impacting biomanufacturing from either a technology and/or business perspective?

Esch (Boehringer Ingelheim):  First, we see a growing diversity with regard to molecule formats. The dominant molecule formats of a standard monoclonal antibody (mAb) will still exist; for example, 15 out of the top 20 commercial biopharmaceutical products in 2025 [are projected] to be standard mAbs, based on data from Evaluate Pharma (2018). However, we expect new and more complex molecule formats, such as multi-specifics, but also advanced therapy medicinal products (ATMPs), such as gene-therapies and cell-therapies, to become commercial in the long term.

Secondly, there is a clear trend in our industry to develop and launch first-in-class medicines for unmet medical needs along with optimized cost of goods sold (COGS). This trend will require speed-approaches in biomanufacturing in order to support being first to market.

The third trend we foresee in our industry is toward precision medicine, resulting in more fragmented patient groups and markets. This might result in smaller scales, respectively, volumes regarding biomanufacturing solutions.

Bulpin (MilliporeSigma): In my opinion, single-use and continuous processing, the diversification of different modalities, and industry consolidation for both vendors and pharmaceutical companies will have significant impact on the future of biomanufacturing.

William Downey (HighTech Business Decisions): From a business perspective, a significant trend has been contract manufacturing organization (CMO) consolidations and mergers. We have also witnessed companies exit the contract manufacturing market. Overall, these changes brought a better balance between supply and demand. From a technology perspective, there’s now widespread acceptance of single-use technologies. Also, with improving productivity, we see the transition to smaller bioreactor tank sizes. Finally, many manufacturers are adopting next-generation production technologies. These include in-line media and buffer preparation, single-pass tangential flow filtration, and continuous multi-column chromatography technologies.

Glennon (APC): For mAbs, the focus continues to be on improving productivity and yield. For newer modalities in cell and gene therapy, aligning process needs with GMP-ready technology capability is an ongoing challenge, especially in downstream processing of viral processes.

Milne (NIBRT): Key trends emerging are the drive to develop process intensification strategies with the aim of designing smaller volume processes that will reduce facility complexity and cost of goods that can improve access for patients to therapies. Regulatory preference for greater control of unit operations using quality-by-design strategies and quality risk management tools is resulting in new and innovative solutions from vendors, including process analytical technologies that will enable greater process control, resulting in more robust performance and concomitant reproducible product quality.

Periera-Chilima (Univercells): From a technology perspective, companies are more and more moving toward flexible low-footprint single-use and continuous facility concepts to reduce capital investment, reduce time to market and ease changeover between products. From a business perspective, there has certainly been an increase in interest in developing cell and gene therapies.

Dr. Barbara Esch Head of Business Development Strategy and Marketing, Biopharmaceuticals, Contract Manufacturing Business, Boehringer Ingelheim Biopharmaceuticals GmbH	Andrew Bulpin Head of Process Solutions MilliporeSigma	William Downey President HighTech Business Decisions	David Downey Chief Commercial Officer APC Ltd.

Issues shaping capacity and scale

What do you see as the key issues shaping biomanufacturing in terms of capacity and scale now and in the future? How may facilities of the future differ compared to today?

Esch (Boehringer Ingelheim): Higher manufacturing flexibility and agility in a facility could be required to meet upcoming manufacturing demands for a more diverse molecule portfolio. The future biomanufacturing facility may provide such increased flexibility and agility by use of stainless steel, single-use bioreactors (SUBs), and continuous manufacturing solutions at the same time.

Bulpin (MilliporeSigma): It always seems to be feast or famine in terms of capacity in the biologics world. Monoclonal antibody capacity currently exceeds demand contrasted against newer modalities, such as antibody drug conjugates, viral and gene therapies, and cellular gene therapies, whose demand outstrips capacity.

Improvements in the manufacturing template and expression levels allow production on a much smaller scale while delivering higher yields and more potent drugs. The manufacturing facility of the future will be highly digitalized (cybernation), multi-product, or multi-modality facilities. Artificial intelligence and algorithms will not only control production but run better processes.

Globalization is increasing the industry’s geographic scale, and clearly the pharmaceutical market is continuing to expand its reach globally.

William Downey (HighTech Business Decisions): There is a trend toward smaller-scale bioreactors. This is occurring because product volumes are getting smaller as biopharmaceutical drugs target smaller patient populations and cell-line expression is improving. Also, adoption of continuous manufacturing technologies is another significant trend. The combination of smaller bioreactor size and continuous manufacturing has increased use of disposable technologies. Disposable technologies also enable new facility designs such as modular manufacturing units that can be placed near patient populations or linked, multi-pack bioreactors that can provide adjustable capacity.

This is consistent from what executives at pharmaceutical and biotechnology companies have told us. They expect greater use of single-use bioreactors and disposables. These executives also noted the trend to maximize the size of single-use bioreactors, and they suggested that disposable technology may advance enough to enable its use for microbial fermentation.

David Downey (APC): The contract biopharmaceutical market continues to be capacity constrained. Often processes are designed solely for the fixed assets available, which produces suboptimal processes and decreases flexibility. Increasing cell-culture productivity and decreasing product and process variability through better understood and designed development processes will better utilize capacity and produce a better product. Large, fixed-asset facilities will need to remodel themselves to provide smaller, more flexible, innovative solutions.

Milne (NIBRT): As cell titers continue to improve due to better cell-line development strategies and improved cell-culture media optimization, dependence on larger-scale stainless steel bioreactors will decrease with many product demands being achieved using a smaller bioreactor footprint. If volumes continue to reduce, the impact of single-use bioreactors will be noticeable. In fact, many companies are already deploying single-use bioreactors in their seed trains even if their production vessel is operated in a traditional stainless-steel configuration.

There is no doubt that facilities of the future will combine deployment of single-use technologies with modular construction. Facilities will seek leverage by employing platform manufacturing technologies resulting in overall facility designs that will offer increased flexibility to respond to manufacturing needs and to embrace multiproduct production scenarios.

Theelen (Univercells): Existing manufacturing facilities are often over- or under-sized. The facility of the future will therefore be more flexible and modular. This allows companies to grow with the market demand. Hence, the risk of immense capital expenditure without knowing the true market potential is mitigated. Additionally, the flexibility of modular manufacturing facilities would allow multi-product manufacturing. The possibility for multi-product manufacturing is especially interesting for biotech companies starting as a one product company and which may later diversify.

Brian Glennon Chief Technology Officer and Co-Founder APC Ltd.	John Milne Director of Training National Institute for Bioprocessing Research and Training	Thomas Theelen Business Development Manager Univercells	Tania Periera-Chilima Product Manager Univercells

In-sourcing versus outsourcing

A key decision for biopharmaceutical companies is whether to internalize manufacturing capabilities or use external partners. From an industry view, how do you see that decision criteria evolving in light of changing product mix, technologies, and capabilities’ needs? How are partnership models in biomanufacturing evolving?

Esch (Boehringer Ingelheim): As a CMO, we have been and we are very often closely involved when our customers/partners go for make vs. buy decisions. In the past (15-20 years ago), the outsourcing of our customers was very often driven by a lack of in-house capabilities and capacities. Today, a clear trigger for such decisions are growing product pipelines, diversity in molecule formats, and a clear focus on R&D activities. In biomanufacturing outsourcing, we have now reached a similar stage as we had in small-molecule outsourcing 20 years ago, meaning that outsourcing has become a standard approach. Therefore, network and portfolio management are key drivers for biopharmaceuticals outsourcing.

Outsourcing strategies are clearly evolving toward partnerships in a sense that the CMO is considered as an integral part of the customer’s supply network. That requires a more holistic long-term view and collaborative approach of both parties as the approach is not transactional anymore. In such partnerships, critical success factors besides quality, strong track-record, and supply reliability include continuity, transparency, commitment to customer products and patients, and in the end, trust, cultural fit, and shared values of both parties. In such currently evolving partnerships, the clear benefit for the customer is in the increased engagement of the CMO, simplifying the supply chain with less complexity and oversight activities.

Bulpin (MilliporeSigma): In general, product lifecycle determines the decision to outsource or insource manufacturing. In early product development and early commercial stages, speed to market is critical, and therefore, pharmaceutical companies may outsource production to keep their focus on in-house drug development and clinical trials. During the ramp-up and major commercialization stages, a company may want complete control over the supply and therefore may lean toward insource manufacturing. During the sunset period, it may make more sense to outsource production again.

Pharmaceutical companies generally are heavily involved in the drug discovery and development phase and look to partner with vendor companies for manufacturing innovation. Overall, pharmaceutical companies are looking for three things. Their ability to manage supply and guarantee supply from a capacity standpoint is very important. Risk mitigation and business continuity are another factor. Lastly is successfully managing logistics and supply on a global level.

William Downey (HighTech Business Decisions): Small biotechnology companies continue to use CMOs because of their product-focused investment strategy. This is a smart strategy given that financial markets place a higher value on a drug-product portfolio than on a fixed-asset portfolio. This drives the demand for outsource services; thus, few small companies invest in new facilities.

For large biopharmaceutical companies, the outsource decision is complex. Over the past decade, large biopharmaceutical companies increasingly shifted more of their manufacturing spending to outsourced services. This reduced supply-chain risks and potentially took advantage of capabilities they did not have. Additionally, using a CMO reduced their capital asset needs, which increased short-term cash flows and improved financial returns. Now, however, we see an inflection point in this trend. The mix between in-house and outsource spending is stabilizing.

Technologies on the horizon: opportunities and challenges

What new or disruptive technologies are emerging in biomanufacturing? For example, where do you think the industry stands in terms of continuous manufacturing (i.e., upstream perfusion and downstream continuous purification processing)? What are the drivers and challenges for potential adoption of these and/or other technologies?

Esch (Boehringer Ingelheim): The fully continuous manufacturing processes as well as automation will play an important role in our biopharmaceutical industry in the upcoming years. We see this trend evolving from already established continuous unit operations toward fully continuous processes.

Drivers, for sure, are the need to optimize efficiency, time, and costs of biomanufacturing to meet the requirements that come, for example, with new low-titer complex biologics but also from speed-to-market approaches and pricing requirements of payers. A fully continuous facility will also come with reduced capital expenditures due to smaller size and potential implementation of single-use equipment.

Along with this new trend, where we are also active in, there are still challenges that our biomanufacturing industry will face, for example, development of standard manufacturing platforms suitable for continuous processes, such as the fed-batch platform established for monoclonal antibodies. In order to further benefit from this new technology, the technology-transfer conditions from continuous to fed-batch processes and vice versa need to be under control and fully understood. Hence, it will be very important to have access to predictive models that will help our whole industry to better understand influencing factors in biomanufacturing.

Bulpin (MilliporeSigma): It seems not that long ago that monoclonal antibodies were considered novel and using gene therapies to cure rare diseases was just a dream – however, the mAb process is about 30 years old.

With this enthusiasm and drive comes process challenges. Manufacturers are looking to suppliers for integrated solutions as they think holistically about their process and visualize future scale-up. The industry is buzzing about continuous processing because it will have a significant impact on how companies bring therapies to market by delivering them to patients faster and more cost-effectively than ever before. The industry is moving toward intensified, connected and continuous bioprocessing. MilliporeSigma’s vision goes beyond continuous manufacturing to deliver what we term as ‘contiGuous’ bioprocessing, a seamless confluence of digital and intensified bioprocessing building blocks. “ContiGuous” manufacturing goes beyond just connecting the individual unit operations; it will include the orchestration and management of all the processing steps (materials, production, testing and analytics) with a streamlined and optimized approach.

Gene-therapy manufacturers are eager to develop a mAb-like process template that will help them increase upstream and downstream productivity while avoiding bottlenecks during process scale-up.

This industry paradigm shift, fueled by novel modalities and forward-looking bioprocessing applications, has reinforced the need for better integration, collaboration and education. High-growth regions, such as China, are moving at the speed of light, and the entire Asia Pacific region is thirsty to train its workforce in biologics GMP best practices to meet the demand for skilled labor. Emerging regions, such as Africa, the Middle East, Eastern Europe, and Latin America are all in the race to get affordable medication to local patients.

One of the major challenges is precedence from a regulatory standpoint. Nobody wants to be the first company to put in a new manufacturing process and get that through the regulatory agencies; hence, there is a natural inertia to bring innovation into manufacturing.

Future innovation lies with analytics and process monitoring. Initially, that will evolve to be at-line, but progressively as more technologies advance and the industry moves towards continuous manufacturing, analytics will evolve to be included in-line.

William Downey (HighTech Business Decisions): As mentioned previously, new process technologies that biomanufacturers have or will adopt include in-line media and buffer preparation, single-pass tangential flow filtration, and continuous multi-column chromatography technologies.

Glennon (APC): If not continuous, then greater levels of process intensification to deliver much improved productivity. No doubt, there will continue to be technological innovations to allow greater automation and control of processes, especially in the areas of cell and gene therapy.

Milne (NIBRT): There is a real trend and interest in the development of process-intensification strategies up to and including the potential for fully continuous processing. From an upstream cell-culture perspective, continuous cell cultures that can result in high-density cultures to maximize productivity have been established for many years. Downstream processing in continuous mode is not well established due to the complexity of individual downstream operations and the difficulty in conditioning key product fractions between successive operations operating in a continuous configuration. One tangible difficulty is integrating hardware and software systems perhaps from multiple vendors in a continuous process. A solution to this conundrum where systems could communicate in a plug-and-play scenario is the focus of much conversation within the automation industry.

Theelen (Univercells): There is a strong trend towards turnkey manufacturing solutions, which allow an increase of volumetric productivity. The reduction in footprint results in significantly lower capital expenditure and allows to potentially fit multiple modules in one shell. Turnkey solutions are rapidly deployable, which enhances speed to market. Continuous and intensified processes are the enabler of smaller footprint solutions. Thus, handling a large biomass on a small surface, continuously feeding the purification train with relatively small amounts of volume. To reduce process times, innovation in downstream purification is needed: small purification equipment with high volumetric throughput.

Periera-Chilima (Univercells): There is certainly a strong trend toward intensified continuous systems due to the enhanced productivity of these technologies. Through continuous bioprocessing, large amounts of product may be manufactured with smaller equipment, decreasing the overall capital investment. Moreover, the reduction in footprint eases multi-product manufacture, as multiple manufacturing modules can be run in parallel within the same shell. Challenges associated with developing fully continuous processes include process integration and harmonization of different unit operations, to minimize holding times and maximize productivity. Moreover, the current technologies available for certain process steps is also a challenge.