Avoiding the Regulatory Catch 22

Taking on a new process technology, such as an expression system, involves regulatory uncertainty. How will the FDA and other regulatory authorities react to the new technology? Will adopting new technologies cause unacceptable delays in obtaining approvals? Further uncertainty comes from deciding who should do, and pay for, the pioneering regulatory work: the technology developer or licensor, the early product developer, or both?

Eric S. Langer

"If the regulatory submission is for a known process or expression system, the regulatory agencies can review it quickly," says Jim Bingham, PhD, senior director of Development at Amplimmune, Inc. (Rockville, MD). "If it's for a novel technology with no history, such as an untested expression system, it may require a significant evaluation to manage risk and safety. Coming into it, [the regulators'] perception of the innovators can be, 'These guys are cowboys.'"

Indeed, the first companies pioneering adoption of a new manufacturing technology will almost certainly deal with some delays in approvals by the FDA, the EMEA, and others.³ Even if the product produced in a new system may be better (e.g., by having greater consistency, purity, potency, or safety), caution on the part of regulators about new developments is a necessary part of the regulatory system. At the moment, there are insufficient precedents to enable calculation of likely approval delays caused by adopting new manufacturing technologies.

Thus, pioneering the regulatory approval of a biological product manufactured using a novel expression system can be daunting, even for the most experienced regulatory manager.¹ Many in the industry feel that the regulatory challenges involved do not warrant the benefits of modifying old manufacturing processes. After all, the standard expression systems, E. coli, Chinese hamster ovary (CHO) cells, and Saccharomyces cerevisiae, which are used for about 90% of currently marketed recombinant protein and monoclonal antibody products, perform adequately. So why change?²

This thinking leads to a logical pack instinct, in which companies wait for a critical mass before adopting new technologies for commercial production. But if no one is willing to take the risk, that critical mass will never be reached. This catch 22 faces those who consider adopting almost any new biopharmaceutical manufacturing technology. As a result of such concerns, many new expression systems now commonly used in research have yet to make it to large-scale manufacture.

IN A MATURING INDUSTRY, INNOVATION IS NOT AN OPTION

Nonetheless, no high-tech industry can afford to ignore new and better technologies, and biotech is no exception. There are hundreds of new and long-ignored expression systems using novel host organisms and technologies in various states of development and industry adoption.¹ These platforms can offer many advantages, such as lower costs, higher yields, quicker turnaround or continuous manufacture, increased simplicity of expression and purification, less expensive equipment and infrastructure, and simpler and more rapid scale-up.¹

REGULATORY TRAIL BLAZERS

Because of these advantages, a few companies are finding the organizational fortitude to be regulatory trailblazers. For example, the first product manufactured using transgenic animals, recombinant human antithrombin (Atryn, from GTC Biotherapeutics) received FDA approval in early 2009; and a recombinant human papillomavirus (HPV) vaccine expressed in insect cells using baculovirus vectors (Cervarix, from GlaxoSmithKline), is pending at the FDA and already approved in the European Union. Many other recombinant proteins using novel expression systems are in development, mostly at early stages. This includes products being developed by expression systems' developers and their partners who intend to prove commercial feasibility of their technologies through actual product manufacture.

In addition, many contract manufacturing organizations (CMOs) are starting to adopt and offer new expression technologies, at least in early-stage R&D. This will likely expand as products progress in development pipelines and their manufacture is further scaled-up.

IMPACT OF BIOSIMILARS

Many of the products expected to enter the market using new expression systems are biosimilars and follow-on proteins. Biosimilar developers are motivated by manufacturing costs, so they may be a little more willing to adopt state-of-the-art technologies, which often make production cheaper and faster. In addition, new expression technologies may make it possible to produce drugs that are of higher quality than the innovator products. Many of these biosimilars companies want to be able to claim that their products are not just cheaper, but also better—more consistent, purer, more potent—than their reference products.

CURRENT REGULATORY STATUS OF NEW SYSTEMS

The regulatory status of various new expression systems and their familiarity in regulatory agencies varies greatly. In terms of ongoing adoption and regulatory filings, or quasi-approvals such as a biological master files (BMFs) accepted by the FDA, some leading technologies include the PER.C6 human host cell line being developed by Percivia, a joint venture of DSM Biologics and Crucell BV; and Dow Pharm's Pfenex, a Pseudomonas fluorescens bacterial platform. However, even a BMF and agency familiarity do not mean the FDA or other regulators will not delay and question the chemistry, manufacturing, and controls (CMC) aspects of product applications.

CMC Scrutiny

Fears about regulatory delays that companies may face when adopting new expression systems are compounded by recent regulatory problems companies have experienced even when not using novel technologies. For example, biosimilar developers using venerable E. coli technology have experienced problems. The EU refused to approve a biosimilar interferon alfa from BioPartners GmbH, primarily because of manufacturing issues and related insufficient similarity to its reference product.

And even in the same company, using the same technologies, cell lines, processes, to manufacture the same already-approved product, but at larger scale and different location, regulators have delayed approvals. Genzyme, for example, recently encountered significant delays in obtaining FDA approval for one of its CHO-cell–expressed glycoprotein enzymes, alpha glucosidase (Lumizyme), at a new facility. The company set manufacturing at a 2,000-L scale, while the same product (according to Genzyme, and approved as Myozyme by the EU) has long been manufactured at the 160-L scale at a different facility. The FDA, citing a detectably different glycosylation pattern in the products made at different scales, has required Genzyme to file a new full biologic license application (BLA), rather than approving the supplemental BLA originally filed.

With the biological activity of biologics traditionally defined at their most basic level by their sources and methods of manufacture ("process = product"), these and other examples suggest that regulatory agencies are closely evaluating the CMC aspects of all filings. Furthermore, different expression systems impart their own unique characteristics to recombinant proteins and, particularly, glycoproteins, so those adopting truly novel expression systems may face considerable regulatory scrutiny.

"We all need to be cognizant of the sensitivity of regulatory bodies to heterogeneous glycosylation (most recently the Myozyme situation), as well as the risks with using animal-derived products and antibiotics," commented Bert Liang, MD, managing director of Pfenex, Inc. "Using expression technology platforms that avoid such challenges facilitate moving product programs through the development value chain."

SO, HOW TO DO IT?

Some expression system developers partner with early adopters to generate the needed regulatory documentation. For example, the BMF for the PER.C6 human cell line is updated on an annual basis by Percivia, its commercial developer, in collaboration with Merck & Co. Such early adopter collaborations can provide significant cost savings, whether through shared R&D or regulatory expenses, or reduced licensing royalties. This may compensate for the added expenses, time, and risks involved in adopting any novel system.

CONCLUSIONS

Adopting newer manufacturing technologies will likely result in regulatory delays. However, as the FDA encounters more products using novel technologies, approval processes will become more consistent. To minimize regulatory concerns, a new manufacturing technology is best adopted as early as possible in development. This approach, combined with meeting and corresponding with the FDA regarding manufacturing concerns at all stages, should smooth the way, particularly as reviewers gain familiarity and trust in these technologies.

As Amplimmune's Bingham states, "Innovation is critical for our industry but you must have a long-term plan and strategic partnerships to implement new technology effectively." Companies need to fully consider the benefits and hazards of not adopting the best and often most cost-effective manufacturing technology, compared to using old technology that may gain slightly quicker market entry but likely spending more, and getting less, in the long run. Further, using patented or otherwise proprietary new manufacturing technologies can provide a good defense against eventual biosimilar competition.

Eric S. Langer is president and managing partner at BioPlan Associates, Inc., Rockville, MD. He is the publisher of Biopharmaceutical Expression Systems: Current and Future Manufacturing Platforms, 301.921.5979, elanger@bioplanassociates.com He is also a member of BioPharm International's Editorial Advisory Board.

REFERENCES

1. Rader RA. Biopharmaceutical expression systems and genetic engineering technologies: current and future manufacturing platforms. BioPlan Associates, Rockville, MD, 2008 Oct. Avaliable from: http://www.bioplanassociates.com/es/index.htm.

2. BIOPHARMA: Biopharmaceuticals in the US and European Markets (online database), BioPlan Associates, Inc. Available from: http://www.bioplanassociates.com/publications/pub_bpuseu.htm.

3. Langer E. Manufacturers must cooperate to compete: the biomanufacturing industry faces a catch-22. Contract Pharma. 2002 Oct. Available from: http://www.bioplanassociates.com/publications/ContractPharma_manufacturers.pdf.