The following is a report from a workshop on innovation in biopharmaceutical manufacturing held at the Annual bioProcessUK Conference in Bristol on 29 November 2012. The aim of the workshop was to access the experience of practitioners in the United Kingdom so as to understand better the challenges and opportunities for innovation in this sector. The workshop addressed the drivers that influence the implementation of process improvements and novel technologies in biopharmaceutical manufacture from the perspective of both manufacturers and vendors.
Biopharmaceutical companies must continuously improve and innovate to remain competitive and respond effectively to future challenges. However, the desire for modern manufacturing processes must be balanced against potential benefits, regulatory constraints, and risks. The Engineering and Physical Research Council (EPSRC) created the EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies in 2011 with remit to create biomanufacturing innovations that deliver affordable, next-generation advanced therapies to the UK healthcare system.
The center is hosted by the Department of Biochemical Engineering at University College London in collaboration with Imperial College London, a growing network of academic collaborators, and a consortium of more than 25 industrial and government users. The center’s remit is also closely aligned to the key issues underpinning the consultation document launched by the Technology Strategy Board at the Annual bioProcessUK Conference in November 2012: The Future UK Life Sciences Manufacturing Landscape Opportunities and Challenges for High Value Manufacturing in the Pharmaceutical and Biopharmaceutical Sector. To encourage a debate on innovation in biopharmaceutical manufacturing, bioProcessUK invited Dr. Suzanne Farid, codirector of the EPSRC Centre for Innovative Manufacturing, to organize a 90-minute workshop at its annual conference on the topic. Here we summarize the presentations and discussion arising from that workshop.
The interactive workshop explored three core themes, each introduced by a leading industrial practitioner and member of the center’s industrial user group. Questions for each were as follows:
Is innovation still required in biopharmaceutical manufacture, and if so, what kind?
How do you balance risk and benefits when implementing new technologies?
Is new technology research and development (R&D) investment directed toward the most pressing issues?
Following a theme introduction, each topic was discussed by the audience in groups. Comments and questions from those groups were then reviewed with the whole audience. More than 70 delegates attended the workshop, including researchers and process development experts from companies and academia in roughly equal proportions. The topic of this workshop was similar to one cochaired by Dr. Suzanne Farid at ECI’s Cell Culture Engineering XIII Conference in Scottsdale, Arizona, in April 2012.Is Innovation Still Required? If So, What Kind?
Andy Hooker (head of CMC and quality management at Syntaxin) began by reviewing some recent trends in biopharmaceuticals, starting with the scale of the recent shift to biopharmaceuticals in the market. Quoting from a 2012 BioPlan Associates survey report (1), he highlighted that an estimated 40% of therapeutics in R&D (4,000–5,000 candidates) are biopharmaceuticals, which represents a significant increase from five years ago. Furthermore, the world market for biopharmaceuticals is ~$145 billion, growing at >15% annually. Those trends reflect the industry’s increasing dependence on investments in innovative biopharmaceuticals for growth and profit generation.
In addition to the shift in portfolios from new chemical entities (NCEs) to new biological entities (NBEs), the biopharmaceutical industry is preparing for increased commercialization of biosimilars as early biopharmaceutical products lose patent exclusivity. Many follow-on biologics will be produced by contract manufacturing organizations (CMOs). Some companies see a need to handle a larger number of pipeline products, thereby driving the evaluation of single-use or disposable technologies. The industry continues its trend toward significant downsizing and streamlining as organizations seek efficiency gains. Economic challenges have forced companies to decide whether they will innovate or stagnate.
Success of the monoclonal antibody (MAb) market segment, which accounts for a third of biopharmaceutical market revenues, has encouraged several players to join that sector. This has meant greater competitive pressures in an increasingly crowded market place.
So where will the next drug successes come from? Future success will depend on being able to differentiate your product to stand out. Syntaxin, which was spun out of the UK Health Protection Agency in 2005, is one company that has identified attractive opportunities in other emerging biopharmaceutical platforms. Its own technology is based on Botulinum toxin, and the company anticipates compound market growth of 10% for its family of products. Syntaxin is developing new markets and new applications for its products based on low-cost good manufacturing practice (GMP) microbial production. During the workshop, Andy Hooker summarized Syntaxin’s approach to innovation with a quotation from Peter Drucker: “The best way to predict the future is to create it.”
Derek Ellison (chief operating officer at Eden Biodesign) drew on his experience to discuss the challenges of balancing a culture of innovation with that of disciplined control. Eden Biodesign started as a small consultancy before becoming a mid-sized CMO and then the global center of excellence for biopharmaceuticals within generics manufacturer Actavis. As a consultancy and cash-constrained CMO, the company was heavily involved in process development and early stage manufacture for a wide variety of innovative “hard to make” biopharmaceuticals. So there was a natural business pressure toward innovation and finding creative solutions to problems. The focus shifted to taking on fewer projects but doing them well. Actavis is currently developing and marketing “biosimilar” products in women’s health, oncology, and other therapeutic categories, especially for late-stage development and commercial production.
Refocusing the business has required a shift in approach to innovation as the company seeks to
create and maintain a culture of innovation within a heavily regulated and controlled environment. Eden Biodesign looks at innovation through a matrix of quality, cost, volume, and time. For biosimilars, quality attributes are set by the originator company, and volume is set by market demand. Consequently, innovation in the biosimilar space is focused primarily on time and cost to gain competitive advantage.
The company recognizes that an important source of innovation is gained from viewing a situation through a “fresh pair of eyes.” People from different disciplines and backgrounds may have quite different perspectives on any particular problem. So the company has worked hard to encourage people to move between functions to ensure that a number of perspectives can be brought to bear on each problem and to encourage innovation without detriment to compliance and control.
Discussion: The audience supported the proposition that innovation in a process development or manufacturing environment is needed to retain competitiveness. It was recognized, however, that in practice there still appears to be a culture of conservatism. Once a production process has been established, it is very hard to justify change, and the emergence of established platform technologies makes it very challenging to consider alternatives. The resources required to evaluate radical alternatives are not always available.
Some workshop attendees had strong and diverse views concerning disruptive technologies. It was clear that there is no widely shared agreement of what constitutes a disruptive technology. One debate focused on whether advancements in the industry such as higher titers, single-use technologies, and membrane chromatography were incremental or disruptive. Few examples were quoted of truly disruptive technologies — although the development of recombinant DNA technologies was cited as was the invention of the printing press from another industry. The audience was clear that new technologies require careful risk management and that innovation should lead to a step change with potential benefits that can justify and outweigh the costs and risks involved.
In addition to process innovation, it was noted that innovation in the way a new process is developed could yield even more benefits given the efforts and time invested in process development. The role of high-throughput scale-down experimentation and quality by design (QbD) were mentioned in this context.
The audience discussed the role of innovation to respond to challenges in emerging areas such as stratified medicines and cell therapies. For example, technology gaps exist when considering the large-scale production of cell therapies, which opens the way for new entrants with novel approaches.Balancing Risk and Benefits to Implement New Technologies
To introduce this theme, Richard Francis (Francis Biopharma) showed how the risk of introducing new product process technologies in the biopharmaceutical industry could be better managed by adopting QbD. He set the scene by stressing the importance of product and process knowledge and understanding and the imperative for developing them very early in a product development life cycle. Before the advent of QbD, that had often been left to run in parallel with phase 3 clinical development. In practice, however, this seriously limits the scope to modify the process because it is effectively locked before phase 3 and thus could be a pathway to commercial failure.
Francis discussed Genzyme as one example of the effects that inadequate process and product understanding can have on a company. Following manufacturing violations at its Allston facility, the company signed a consent decree with the US Food and Drug Administration (FDA) in May 2010. That included an up-front “disgorgement” of US$175 million of unlawful profits. But the total potential costs of fines and remediation have been estimated to exceed $1 billion over the life of the work plan agreed with the FDA (which is likely to take four years).
The lack of product and process understanding is affecting commercial success. At an FDA drug shortage workshop in 2011, presenters provided figures showing 178 shortages in 2010, with 54% of real and potential shortages related to product quality and significant manufacturing problems.
Francis reviewed how QbD can provide a better approach to biopharmacuetical development. He stressed reliance on an extensive knowledge of structure–function relationships and a deep understanding of products and processes through development life cycles. He also emphasized that knowledge is the essential component and that it should not be driven by regulatory agencies, but rather an industry desire to apply the best science for product development. Benefits of greater understanding include a higher probability of generating the best-quality product to suit patient needs and being able to maintain market supply.
Extensive process and product studies undertaken early in a product’s life cycle allow a manufacturer to define and understand that product’s design space. In the case of Protherics (a small biotech company that licensed a septic shock treatment to Astra Zeneca in 2005), extensive and detailed early stage process investigations involving small-scale (1–5 mL) experimentation defined the proposed purification process. The small-scale process data were important to the due diligence exercise that underpinned the initial deal. The purification process defined at milliliter scale was scaled up successfully to a 500-L scale after licensing and triggered the first milestone payment of £10 million.
The quality risk management process that is implemented with QbD provides a data-driven basis for setting specifications for critical quality attributes. It identifies critical process parameters and establishes appropriate manufacturing controls. Successfully applied, that will lead to reduced product and process variability and hence fewer product and manufacturing defects. This approach allows process changes to be made within a registered process design space. That results in minimized regulatory agency oversight in terms of approval for process modification.
QbD is still in its early stages of development and adoption. A review by McKinsey on behalf of the FDA (2)claimed that QbD could deliver annual savings of between $20 and 30 billion per year across the pharmaceutical industry. Two thirds of those savings arise from a reduction in the cost of goods and capital expense. The other third comes from improved productivity of product and process development, reduced risk of regulatory citation, and potential revenue growth through better product launches and improved product design.
Using QbD, processes will be developed in a manner that facilitates understanding. Understanding enables control, and control of processes means maintenance of commercial product supplies by intelligence-driven manufacturing. According to Gerry Migliaccio, senior vice president of Pfizer Global Supply, “You can’t get to intelligence-based manufacturing without QbD.”
QbD makes sense because it is based on process knowledge and understanding. That is a benefit to industry, regulators, and — most important — patients.
Discussion: The audience generally agreed that changes to new technologies offering potential benefits should be implemented either very early in a development cycle or postlicensure (to avoid the risk of affecting a reliable supply to the market). Discussions included real examples of each case, such as postlicensure change applications in which manufacturing site changes were combined with equipment changes and introduction of process improvements.
Technology vendors can find it difficult to introduce new technologies to biotech companies because many have limited resources to evaluate and investigate new technologies. That often changes only when a serious problem is encountered
with the existing technology solutions. In turn, that can lead to a fire-fighting response to find a stop-gap solution rather than a long-term solution.
On criteria used to evaluate new technologies, cost of goods (CoG) and development time savings were generally considered important but secondary to impact on quality and process robustness. However, criteria ranking will change depending on a product’s stage of development.Does New Technology R&D Investment Go to the Most Pressing Issues?
“How can we manage new technology R&D better between vendors and manufacturers?” was the subtitle to the third theme introduced by Peter Levison (senior director of technical development at Pall Life Sciences). His presentation described new technology development for the biopharmaceutical industry from a vendor perspective.
For a company such as Pall Life Sciences, which introduces 10–20 new products annually, it is important to know how to decide what to develop. New products must have strategic fit and relevance to a company’s business. Incorporating “the voice of customers” and leveraging core competencies are two key elements in deciding what products to develop. In a highly competitive environment, companies are bound to want to exploit core intellectual property (IP) and, where possible, underpin future business by expanding their IP portfolios.
Vendor–manufacturer interactions and real understanding of customer requirements need careful management. The choice between a standardized or customized product is significant. High customization can be associated with great risk, and to achieve openness from customers requires providing some benefit to customers in the form of preferential access to technologies.
The relationship between vendors and customers is likely to evolve. It can be managed with rolling collaboration agreements that set out a project’s scope and terms for materials transfer. A collaboration agreement, although necessary, is not sufficient to generate a good partnership. That depends on trust and good working relationships between partners — the so-called soft issues.
Levison included two examples of products that were developed collaboratively with customers: a chromatography absorbent and a sterilizing filter. In both cases, Pall used structured development programs with key milestones and had in place agreed target performance requirements as well as quality testing and release parameters. Both projects relied on regular interorganizational project team meetings to manage and monitor progress. Those projects generated ongoing commercial relationships and identified further development programs while expanding the technology available to ongoing development activities.
Discussion: During the discussion, it was evident that the audience accepted the proposition that the “voice of the customer” should be driving changes for vendors. However, for some vendors it is difficult to predict the market size for new technologies and get sufficient feedback from customers. Richard Francis reminded the audience of a historical example in which the market success of antibodies was not yet known. That led Pharmacia to initially resist developing protein A resins for antibody purification.
In emerging markets such as cell therapy, market demand is not sufficient to drive innovation by vendors. However, there remains a desperate need to provide technologies to allow cell therapies to progress through clinical trials and to market.
Use of decisional tools and simulations of current technologies can help vendors predict where technology gaps exist or when more efficient technologies will be needed. A growing information and technology base will underpin those tools.
The role of universities in new technology development R&D needs to be recognized. Longer term, they will continue to need funding support from research councils if they are to deliver new technology innovations to underpin the future prosperity of the sector. Taking ideas from existing industries can also help to fill gaps in technology (e.g., dairy industry and mammalian cell processing).
The audience also endorsed the importance of a trust relationship between vendors and manufacturers to share useful data. The UK’s Technology Strategy Board High Value Manufacturing program was highlighted as one of the mechanisms designed to help bring vendors, manufacturers, and academics together.Key Points and Discussion
Belief is widespread in the need for and importance of innovation in biopharmaceutical manufacturing. The focus of many organizations is on developing new products using existing technology platforms, defending and building on established technology positions, and on incrementally improving processes for licensed products. In a highly regulated industry with scarce resources for process development in many companies, significant barriers must be overcome to implement radical new technologies.
Nevertheless, with antibody production technology maturing and intense competition in that market segment, some companies are looking at new targets and potentially new technology platforms. At the workshop, there was no clear view about the importance of disruptive innovation, and indeed it was not evident that there was a shared understanding of what it is. Perhaps the disruptive nature of innovations cannot be judged until some time after their introduction. However, requirements for new products for stratified medicine and cell therapies may not necessarily be readily addressed with existing technologies. The conservative nature of many biopharmaceutical companies suggests that the next disruptive technologies may well arise from outside the existing industry.
QbD could be more of an opportunity than a threat. Its approach provides a stronger basis for developing and introducing innovative products to the market and addresses the inherent technology risk. QbD is still in the early stages of adoption, and it has been more challenging to apply to biopharmaceuticals than to small molecules. However, the biopharmaceutical industry has seen strong indications that QbD will deliver widespread benefits to the industry, regulators, and ultimately to patients.
Innovation by technology vendors is an important feature of the sector innovation landscape. There are good examples of established and successful collaborative developments involving vendors and biopharmaceutical companies with effective mechanisms for capturing the “voice of customers.” However, plenty of opportunity remains for the number of such collaborations to increase and the approach to become more widespread. University research is an important source of new technology innovations feeding the pipeline of new processes. Those can be delivered only by high-quality research, which requires ongoing funding from research councils.
Andrew Davidson is national outreach manager of EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies hosted by the Department of Biochemical Engineering at University College London;
hallengesPresented at the CDER Committee for Pharmaceutical Science and Clinical Pharmacology.