25 Years of BioPharma Industry Growth

The biopharma industry remains a vibrant and exciting segment, partly because of the promise it holds for a better future for each of us. Much of the energy comes from the dedication of this industry's participants: from its inventors, to its managers, to its innovative suppliers.

Twenty-five years may seem like a long time, but many of the 275 industry experts represented in BioPlan's Biotechnology Industry Council have been in the field for that time span, and have dedicated their careers to meeting the challenge of helping to bring innovative products to market. Here, the experts share their opinions about what's changed over that time, and where they see the promise and opportunity for the future. These perspectives from the industry experts, are tied to trend data from BioPlan's recently released 9th Annual Report and Survey of Biopharmaceutical Manufacturing (1).

LANDMARK ADVANCES

BioPlan asked the industry, represented by 275 Biotechnology Industry Council participants, to define the evolutionary changes that have occurred over the past 25 years. Although great depth and diversity of answers were obtained from this industry's senior subject matter experts, they all generally focused on the dramatic increases in productivity resulting from improved processes, higher titers, and in particular, the enabling changes that have resulted from the introduction of single-use devices.

THE PAST 25 YEARS

The comments on this page are representative of survey participants regarding thoughts on the past 25 years of change in biomanufacturing.

“The transition from highly specialized processes performed within a small number of specialist companies in equally specialized facilities, to those performed on a world-wide basis in all continents, with major growth areas outside the US and EU. From a processing perspective, the significant increases in process productivities for mono-clonal antibody systems.Additionally, the adoption of single-use technologies over the past 10 years has reduced the cost and time of getting products into clinical trials."—Tony Hitchcock, head of manufacturing technologies, Cobra Biologics

“Single use equipment.”—Dr. Fausto Vellani, COO, Cerbios-Pharma SA

“The explosive increase in cell culture productivity.”—Sourav Kundu, Director, Process Development, Amgen

“The change from lack of bioreac-tor capacity to a glut of bioreactor capacity and idle facilities, due to the dramatic increase in cell cul-ture titers.” — Jeffrey C. Johnson, engineering director, BioVaccine Process Engineering, Merck

“Single use and disposable tech-nologies have allowed process economics to play a major role in system design.”—Michael LaBreck, global product man-ager, TangenX TFF Products, Novasep

“The emergence of single-use technologies.”—Bruce Rawlings, senior mar-keting manager, Allegro SUS, Pall

“The rise and fall of reusable hardware in upstream bio-processing and the takeover by disposables (both upstream and downstream). The effects on the industry have been truly profound.”—Dr. John Morrow, Jr., Newport Biotech Consultants

“Without question, it is the change in expression systems and cell substrate diver-sity….engineering, design, clonal selection, and metabolic engineering. We have witnessed multi-fold improvements in product titers, yields, and productivities, across a wide range of products (therapeutic proteins and vaccines). It was the engineering inside the cell that has been the driver in bioprocess innovation.”—Jose Manuel Otero, manager/group leader, Upstream Process Development, Merck

“The phenomenal increase in titers (mainly antibodies) with mamma-lian cell cultures.”—Dr. Ajish Potty, development engineer III, Process Solutions, EMD Millipore

“Emergence and maturation of mammalian cell culture as a product supply option. It has gone from struggling with low titers in the early days to stable cell lines producing several grams/L out of the gate!”—Anonymous, director, global bio/pharma

“Strain optimization and advances in genomics and pro-teomics made hard to produce proteins available for human use. Use of disposables reduced capital invest-ments in hard-steel.”—Semsi Ensari, associate director, Process Development, Upstream, Ambrx

“Better understanding of bioprocess requirements [result-ing from] dedicated facilities, to product dedicated process trains, to (truly) multipurpose facilities, as well as quan-tum leaps in product titers.”—Hans Engels, president and CEO, DSM Pharmaceuticals

“Increased standardization of bioassays. Validation param-eters have become more stringent. There has been movement for harmonization when the same assay is performed at multiple sites.”—Janet Lathey, director, Immunology and Assay Validation, Emergent BioSolutions

“Removal of animal-derived components from all aspects of production of biologics.”—Dr. Denny Kraichely, associate director and CMC team leader, Portfolio Management, Janssen

“Automation of manufacturing and formulation processes have completely changed the biomanufacturing arena and contributed to reducing cost and increasing yield.”—Eric Halioua, CEO, Promethera Biosciences

THE NEXT 25 YEARS

It was perhaps more important to understand how these global experts felt about how biomanufacturing will change the industry over the next 25 years. Many see the improvements in biomanufacturing today as having a profound effect on global healthcare. Improved manufacturing will permit greater global accessibility to drugs, will dramatically reduce manufacturing costs, and will ultimately increase the overall number of biological products going into clinical trials. Thus, the changes and improvements in manufacturing operations today are being directly translated into improvements in how patients will be treated over the next quarter century.

This page and the previous page include quotes that are representative of how current trends will affect the industry during the next 25 years, according to experts.

“Disposables will continue to improve and infiltrate the market. They will become cheaper and easier to operatewith posit ive ramif icat ions for the cost of a developmental program, meaning that drug development willbecome faster and more efficient.”—Dr. John Morrow, Jr., Newport Biotech Consultants

“Higher titers are transforming the way we do and think about downstream purif ication and will continue to drive innovation in this area.”—Dr. Ajish Pot ty, development eng ineer I I I, Process Solutions, EMD Millipore

“Biotech products [will become] more affordable. Addressing the needs of the patients by producing (affordable) products for smaller segments and further optimizing and standardizing the unit operations.”—Hans Engels, president and CEO, DSM Pharmaceuticals

“The focus [will continue to be] on consolidation, and a renewed focus on designing robustness (e.g., QbD, PAT) and being able to deploy processes to all parts of the globe. This means bioprocesses will be simpler, smaller, disposable, requiring minimal utility and energy inputs, while capable of standing up to increased regulatory and quality requirements.”—Jose Manuel Otero, manager/group leader, Upstream Process Development, Merck

“The standardization and harmonization of vaccines will allow us to better evaluate the effectiveness of one product compared with a similar product produced by a different institution or a different process, allowing better choices to be made for continued production. The product produced, released, and marketed will be of a higher quality.”—Janet Lathey, director, Immunology and Assay Validation, Emergent BioSolutions

“Big changes are already happening. Now I’m looking forward to the new different, big changes! Which ones? No idea!”—Dr. Fausto Vellani, COO, Cerbios-Pharma SA

“Industrialization of antibody-drug conjugate products. I expect to see many more products in this class on the market in the next25 years – with indication expanding well beyond traditional oncology applications.”—Anonymous, director, global bio/pharma

“The cost of human health care will decrease with increased productivities and highly efficacious products coming out of these advances. Green manufacturing will be part of new human health care with the expansion of eco-friendly disposable use.” — Semsi Ensari, associate director, Process Development, Upstream, Ambrx

“Automation and miniaturization will increase in the future.”—Eric Halioua, CEO, Promethera Biosciences

“Making smaller manufacturing facilities, fewer and platformed unit operations, and making biopharmaceutical manufacturing more portable and clonable at any part of the world.”—Sourav Kundu, director, Process Development, Amgen

“More products on the market much more quickly. Hopefully, we will address the waste management of all of these “disposable” it ems. The re are opportunities for advances to be made in recycling technology as we address this issue.”—Michael Larson, downstream process development, CMC Biologics

“Better controlled commercial manufacturing processes providing more reliable and sustainable delivery of new biopharmaceuticals for the treatment of life-threatening diseases to improve patients’ lives.”—Dr. Denny Kraichely, associate director and CMC Team Leader, Port folio Management, Janssen

“Increased product titers and the worldwide adoption of process will lead to price reductions and increased access of [drug] products to the worldwide community. The changes will also lead to a wider range of products being taken forward to clinical trials.“—Tony Hitchcock, head of manufacturing technologies, Cobra Biologics

“Over the next 25 years, improved [production] economics will allow or the development of therapeutics and vaccines designed to treat more targeted and specific diseases.”— Michael LaBreck, global product manager, TangenX TFF Products, Novasep

“The higher titers are driving twofundamental changes: To smaller bioreactors and the possible use of 2000-L single-use bioreactors for full-scale production, and to transfer of the process bottleneck from upst ream to downst ream, which is driving a need for improved or new downst ream processing technologies.”— Jeffrey C. Johnson, engineering director, BioVaccine Process Engineering, Merck

MARKET TRENDS

Reviewing the past 25 years, it is clear that the biopharmaceutical industry has more than survived the recent economic downturn, and 2012 is looking to be a good year again. This year, BioPlan's annual survey results show that both biopharma companies and their vendors are spending and investing more in improving R&D and bioprocessing productivity, staff, and other infrastructure. A summary of recent trends includes the following:

• Industry status is improving: The world market for biopharmaceuticals is now about $145 billion, growing at 15–18% annually. Much of this growth is due to an increasing number and sales of recombinant monoclonal antibodies, now a $45 billion market. New products and new markets, particularly internationally, continue to support market growth, driving more investment in the industry.
• Industry spending and investment are up: Survey results indicate that companies are investing more in biopharmaceutical R&D, including hiring staff and expanding manufacturing capacity. Increased spending is occurring in new technology, capital equipment, process development, and personnel training and development. Vendors are also investing more in product development and new and better technology.
• Outsourcing trends remain but are slowing: Outsourcing, including contract manufacturing, continues as a major trend, with our data showing 70% of biopharmaceutical companies outsourcing at least some activity. Survey results also indicate the rate of outsourcing is slowing, probably as outsourcing approaches its inherent limits. Companies are taking a much more rational and sophisticated approach to outsourcing, looking at options from a longer-term perspective.
• Mergers, acquisitions and partnering are becoming more strategic: Corporate mergers and acquisitions are being directed to improving R&D pipelines. Many large companies are now focusing more on acquiring smaller companies and licensing-in candidate products.
• New and small company financing is tight: Financing available for new startup and smaller non-public companies continues to be tight, despite an improving environment. Much smaller company financing and expansion is being accomplished through partnerships and collaborations with larger biopharmaceutical companies.
• China, India, and the rest of the world as biopharmaceutical manufacturers: Biopharmaceutical companies in many developing countries serving their domestic, regional, or lesser-regulated international markets are experiencing rapid growth, but have yet to pose a threat to US and European dominance of the innovative biopharmaceutical industry, particularly related to product development and manufacturing.
• Pipeline shrinkage? The biopharmaceutical pipeline of products in development appears to no longer be significantly expanding, perhaps due to streamlined or leaner staff and delayed investments in recent years.
• Single-use equipment: The trend towards adoption of single-use equipment continues, with rapid growth in this market projected. As confirmed by survey data, single-use equipment, particularly for upstream manufacture (e.g., bioreactors), now thoroughly dominates precommercial, although fixed stainless-steel equipment still dominates commercial-scale manufacturing.
• Bioprocessing continues to improve: The gradual increase in expression yields continues, with incremental improvements in host cell lines, cell line engineering, expression systems, vectors, promoters, etc. But other improvements are also nearing industry adoption, including large-scale single-use systems and new downstream technologies such as highly-flexible simulated moving bed purification systems. More and better sensors and control equipment are also becoming available, but improvements are needed.
• Biopharmaceutical R&D outpacing small molecule R&D: Biopharmaceutical R&D investment is growing, at the expense of small molecule R&D. It is widely accepted that 40% or more of pharmaceutical industry R&D funding is now going for biopharmaceutical versus small molecule development, and this could grow to 50% or more within a matter of years.
• Downstream is becoming less of a problem: Survey results indicate that problems are lessening and the industry is finding ways to increase downstream productivity. Downstream processing today remains more of a challenge than upstream.
• Mammalian-cell manufacturing is crowding out other platforms: More companies, particularly larger ones, are now standardizing their in-house bioprocessing to be solely mammalian-cell based, as higher cell-culture yields and improved technology have made mammalian manufacture more cost-effective and easier than microbial manufacture.
• Modular bioprocessing facilities are coming: Multiple bioprocessing equipment and technology developers and vendors are developing modular approaches to bioprocessing. Companies will be able to assemble bioprocessing systems using off-the-shelf or customized modules ready for plug-and-play with other modules (from the same company).
• Biosimilars are finally coming to the US: Well over 400 biosimilars and over 350 biobetters are in development targeted for the US, EU and other major markets. With private sector insurers expected to rapidly require use of biosimilars wherever possible, the market for biosimilars will likely grow rapidly over the next five years.
• FDA and industry are getting ready for biosimilars: In later 2011 FDA finally issued its first installment of biosimilars filings guidance documents, which contained few surprises are unlikely to disrupt ongoing development activities. In many respects, developing a biosimilar is harder than developing an innovative product involving full approval, since it will likely be harder to closely match many aspects of analytical,clinical, and safety data.
• Cost-containment and controls: Since most biopharmaceuticals are used for indications for which there are few alternatives, the overall market is rather protected from widespread cost-containment and controls. But in other countries, cost containment and government-directed cost controls continue to adversely affect biopharmaceuticals.
• Internationalization of biopharmaceuticals: Perhaps indicative of a trend, FDA granted the first approval in 2011 for a biologic manufactured in Latin America. With the US by far the largest and most receptive market for biopharmaceuticals, we can expect other companies in developing countries to launch products in the US, EU, and other major markets.
• Manufacturing in developing countries is increasing: Biopharmaceutical manufacturing outside of the major market countries is increasing, as indicated by BioPlan's Top 1000 (2).
• Worldwide standardization of manufacturing: As more biopharmaceutical manufacturing is performed worldwide, companies, particularly large ones, are working to standardize products and manufacturing processes on a worldwide basis. For many, this includes having second or even third source facilities actively manufacturing or serving as backups, having received approvals for manufacture for the US and other major markets.

SUMMARY

• The past 25 years have seen a maturation of the biopharma industry, and it has transformed from a technology-focused industry, to a process-based, outcomes- and patient-focused segment. Industry participants envision the next 25 years as the time when strategic manufacturing becomes closely aligned with global patient care.

ERIC S. LANGER is president and managing partner at BioPlan Associates, and a member of BioPharm International's Editorial Advisory Board, langer@bioplanassociates.com, www.bioplanassociates.com

REFERENCES

• 1. 9th Annual Report and Survey of Biopharmaceutical Manufacturing, BioPlan Associates, Inc, April 2012, www.bioplanassociates.com.

2. Top 1000 Global Biopharmaceutical Facilities Index, BioPlan Associates, www.top1000bio.com .