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.
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.
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, firstname.lastname@example.org
He is also a member of BioPharm International's Editorial Advisory Board.
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