Avoiding the Regulatory Catch 22 - Companies often wait for a critical mass before adopting new technologies. But if no one takes the risk, critical mass will never be reached. - BioPharm

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Avoiding the Regulatory Catch 22
Companies often wait for a critical mass before adopting new technologies. But if no one takes the risk, critical mass will never be reached.


BioPharm International
Volume 22, Issue 8

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,
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.


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