The developers of biotherapeutics are intensifying their efforts to understand the complex relationships between the structure of their molecules and immunogenicity and to expand the predictive power of their CMC toolbox. However, there is also a growing recognition of the long-term nature of the project and the difficulties in validating the quality analytical tools against the less than solid ground of immunogenicity assessments in the clinic.
The connection between the quality attributes of biotech products and their clinical impact is center stage in the industry/regulator dialogue, with implications that extend across the discussions on quality by design, investigational and marketing application filings, manufacturing changes, post-marketing surveillance, and biosimilars (IPQ, December 17, 2013).
Tightening the quality/clinical connection is proving to be a particularly daunting challenge in the immunogenicity arena, given the limitations in the clinical assessment capabilities and the lack of a firm foundation against which to validate the CMC methodologies.
The major players in the biotech arena are putting valuable resources into expanding the ability of their quality analytical techniques to assess and predict the structure/immunogenicity relationships and help make better choices in candidate selection and molecule design, while recognizing the limitations and gaps in the overall immunogenicity knowledge base and the long-term challenges involved in filling them.
In Basel, Switzerland in September, PDA held a workshop to review the current regulatory expectations in Europe and benchmark best practices on immunogenicity assessments for monoclonal antibodies (MAbs) and what role the CMC analytical toolbox can play in making them.
Included in the opening session on the current regulatory situation in Europe were presentations by two experts that have been heavily involved in framing the relevant EMA guidance – Austria Agency for Health and Food Safety (AGES) Biologics Preclinical Assessment Group Head Gunter Waxenecker and National Institute for Biological Standards and Control (NIBSC) Biotherapeutics Group Head Robin Thorpe.
The two regulators provided valuable insight into the challenges of immunogenicity assessments in the MAb context and stressed the need to have a carefully crafted clinical strategy to facilitate the approval process for new monoclonals, changes to processes, and for biosimilars (IPQ, December 30, 2013).
Thorpe, in particular, cautioned on the danger of relying on immunogenicity predictions and generalizations short of this well-thought-out clinical evaluation, as he explored the lessons he has learned from his involvement at NIBSC in biotherapeutic research, application review, and guidance development.
In the second session, industry experts discussed the work their companies are now doing to try to understand better the linkages between quality attributes and unwanted immunogenicity and increase the power of their in-vitro and in-silico analytical toolbox in molecular engineering and immunogenicity risk mitigation.
Two additional sessions followed on day two of the MAb workshop focused on: ● the analytical challenges of two critical quality attributes with immunogenic potential – protein aggregates and host cell proteins (HCPs), and ● how the immunogenicity issues play out in the development of biosimilars.
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