Regulators are highlighting a better understanding of protein glycosylation – its linkage to product safety and efficacy and what constitutes appropriate characterization – as an important element in developing a more internationally-aligned approach to regulating biotech products.
A large number of the proteins in nature are glycosylated – modified with sugar chains – which affects not only their physical properties such as solubility and thermostability, but also their biological properties, including serum half-life and functional protein-protein interactions. Although more knowledge is being gained about the glycan moieties that have been found to be critical to product quality, the biological impact of other glycan structures is still not well-understood, regulators point out.
How glycan modifications to therapeutic proteins and antibodies may impact biological action was a central focus at a session of a CASSS CMC Strategy Forum held in Tokyo in December. At the forum, regulatory, industry and academic experts from across Asia, North America and Europe provided their insights on the issues involved.
Center for Drug Evaluation and Research (CDER) Division of Monoclonal Antibodies (DMA) Deputy Director Patrick Swann commented that “absent that knowledge, all we know is that there are a lot of glycoforms for a product. But we don’t know the linkage, so we have to be conservative. I think that provides some motivation for all of us to better understand that linkage.”
Amgen Global Analytical Sciences Executive Director Drew Kellner added that “in the absence of this knowledge, there are some risks. Sometimes you can be surprised.” In the context of a process change in the manufacture of a glycoslylated protein that seems minor, the follow-up bioequivalence (BE) studies can indicate a major change in how the molecule interacts with the patient – something that has happened to Amgen, he said.
Biogen Idec Biopharmaceutical Development VP Rohin Mhatre, one of the session moderators, commented that “when you have process changes, you will have changes in glycosylation, particularly for more complex molecules, and even for monoclonal antibodies.” The challenge is determining what they mean.
The characterization and control of protein glycosylation was one of five topic areas addressed at the CASSS international CMC forum in Japan.
The four other sessions focused on: ● recent trends in the regulation of biopharmaceutical products and practices ● the development of biosimilars ● new technology for the development of monoclonal antibody therapeutics, and ● challenges and opportunities in biologics quality by design (QbD). [Editor’s Note: A detailed summary of the forum, presented at its conclusion by Biologics Consulting Group’s Nadine Ritter, is included below.]
Presentations were given covering various aspects of each topic, followed by panel discussions during which the presenters and other regulator and industry experts addressed prepared questions and those posed by attendees.
The Japan meeting represented the first of CASSS’ CMC Strategy Forums to be held in Asia. The separation science society is anticipating that the Asia meetings will be held on a yearly basis.
The next Asian forum will again be held in Tokyo in December 2013. The Japanese Pharmaceutical Manufacturers Association (JPMA) will again be assisting in the coordination of the meeting.
The Asian meetings are being structured similarly to those now being held on a yearly basis in Europe, which pull together industry and regulators to focus on a handful of biotech topics of international import.
In the US, CMC Strategy Forums are held both in January, in conjunction with CASSS’ annual Well-Characterized Biotechnology Product (WCBP) conference, as well as in mid-summer. Each of the US forums drills deeply into one topic area on the regulatory front burner. In conjunction with the January 2013 WCBP conference, parallel one-day forums will focus on the use of expanded change protocols and new paradigms for process validation, respectively. The two-day summer 2012 forum held in Bethesda, Maryland in July, focused on biotech/device combination products.