August 22, 2022
Sponsored by Yposkesi
Brian Mullan joined Yposkesi, an SK pharmteco company, as its chief technical officer in 2020. With over 20 years of experience, he has held leadership roles in late-phase process development, product launch, and commercial supply for large pharmaceutical companies making therapeutic monoclonal antibodies (MAbs). In eight years at Novartis, Mullan held posts as head of manufacturing science and technology and as a global technical project leader. From 2008 to 2012, he was process technology-transfer lead at Eli Lilly and Company. Before that, he worked at Centocor Biologics and Sanofi-Aventis. Mullan holds a 2001 PhD in viral genetics from University College Cork in Ireland and a 2011 MBA from the Open University Business School in Milton Keynes, UK. He conducted industrial postdoctoral work in adenoviral and adenoassociated virus gene-therapy vectors at Sanofi-Aventis. Below are his personal and professional reflections on the past 20 years in the biopharmaceutical industry.
Company and Industry Reflections
What has been the most important scientific or technological innovation in the past 20 years of bioprocessing? There have been many, but I would highlight improved on-line process monitoring, most notably with Raman spectroscopic probes in bioreactors. Combined with other advances such as multivariate data analysis (MVDA) and predictive process modeling, such approaches have helped provide insights into process performance that have enabled the industry to implement digital twins and other such engineering concepts. All this increases our understanding of manufacturing processes, leading to more robust and predictable outcomes. These digital developments also add much more power to process analytical technology (PAT) platforms such as SIMCA and Discoverant software.
What scientific and technical developments have surprised you the most over the past 20 years? There have been many, but single-use technology (SUT) stands out to me. It was quite a surprise initially and seen as “making biologics in a plastic bag,” but SUT has become a well-developed and well-established option for bioprocessing. It has added a great deal of choice and flexibility in manufacturing platforms over what comes with stainless steel as the principal option. Although SUT will remain a choice for bioprocessing in general (depending on the needs of each process, its desired scale, and flexibility requirements), the impact of disposables is most obvious for cell and gene therapies (CGTs). For those, SUT has enabled rapid creation of manufacturing capacity and straightforward management of product segregation in multiproduct facilities.
What has been the most significant regulatory development in the past 20 years? I think the regulatory sector still has a long way to go, most notably toward standardization across different regulatory regions (global harmonization) for postapproval change management. Two regulatory aspects have improved in recent decades, however: One is standardization within certain regulatory regions (e.g., Europe) for change management of process transfers between sites or during site-capacity expansions, and the other relates to the arrival and growing acceptance of quality by design (QbD) and related approaches. The latter has encouraged improving process understanding and prioritizing science over risk-based approaches. Those advances have provided clarity in how to approach certain changes within certain regulatory regions — e.g., process changes and intersite process transfers — so that our evaluation of such changes is more aligned with regulatory expectations. That allows for less “to and fro” with the agencies toward approval of our change-management protocols, with a higher incidence of “right first time” approvals.
What has been the most notable development in bioprocess business strategy? The contract development and manufacturing (CDMO) sector has become well established, providing a broad range of choices for product developers through expanded chemistry, manufacturing, and controls (CMC) capacity, and access to expertise for certain processing technologies. All that enables biopharmaceutical companies to delay expensive investments in physical development and manufacturing capacity until their product pipelines reach more advanced stages.
What expected regulatory, technical, and scientific advances didn’t happen? Alignment still is lacking among different regulatory regions globally for common technical document (CTD) content and postapproval change management. The central tenets in ICH Q12 are not yet broadly accepted. For example, the use of “established conditions” to discriminate between what CMC regulatory aspects can be managed by a company’s quality management system and those that must be agreed upon with regulatory authorities. Maybe we are lost in the details or the legal aspects and are struggling to focus on the bigger picture, which should be improving manufacturing flexibility (with a focus on quality) for speedy supply of medicines to patients who need them.
How might the industry appear five, 10, or even 20 years from now? In general, the CGT sector needs to catch up with where the MAbs industry is today: with a mature product understanding, a wide range of technology offerings, and well-understood manufacturing processes. Given the interest and investment in the CGT sector, it is clear that this will happen — most notably with the increasing number of products moving through approval and out to market. But more technology offerings are needed now (e.g., new chromatography resins for viral vector purification) because the overall solution set remains quite limited.
What opportunities are ahead? Improved automation (requiring less human intervention in manufacturing processes) would have a major impact on many product categories, including MAbs and CGTs. This has not developed significantly over the past 10–15 years toward real-time control or reliable automated transitions between manufacturing unit operations. Automated samplers are another opportunity for technology improvement. We need more options to encourage their widespread uptake and implementation.
What dangers and difficulties must be faced? The industry needs better ways (or different strategies) to beta-test new and promising technologies. Such activities are important if bioprocessing is going to evolve and embrace new technologies, but they can be time consuming for end users. Usually, few “ready-to-go” options are available for trying out a given technology, which often requires end users to partner with technology developers and codevelop solutions.
Personal Reflections
How has the COVID-19 pandemic influenced your thinking about industry conferencing and networking? After a long period of largely virtual interactions, it has made people appreciate the importance of face-to-face interactions. The pandemic also has highlighted the fragility of our supply chains. Two years on, the supply side of things needs to sort itself out and become more reliable. Lead times are too long for a wide range of items, and there is little confidence in agreed-upon delivery dates. The market and industry have undergone a step change in activity, and the supply industry needs to stop holding back (trying to meet increased demands with existing approaches and capacity), embrace that step change, and bring online more capacity and/or different practices now.
What advice do you have for upcoming life-science professionals? Get experience where you can, preferably multidisciplinary, from which you can learn the most. Identify roles that can offer learning opportunities in companies that are in a growth/transformation phase or at a key milestone (e.g., the year or two before a first regulatory submission for market approval). Such positions generally provide richer experiences than would come from a similar period spent in more routine operations or with companies that are at a more stable phase.
What lies ahead for you and your company? Yposkesi still is quite a young company. Although we have gained significant experience in gene-therapy vector development and production over recent years, our future will focus on transforming (becoming more industrialized), stabilizing (further building our reliability), and continuing to develop our technology offerings. That way, we always will be a reliable partner of choice for our clients.
Brian Mullan, PhD, is chief technical officer at Yposkesi, an SK pharmteco company; 26 Rue Henri Auguste-Desbruères, F-91100 Corbeil-Essonnes, France; 33-1-61617174; [email protected]; https://www.yposkesi.com.
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