Evaluating your product beyond standard characterization can provide a comprehensive understanding of a molecule in early phase development. Allan Watkinson, PhD, Director of Biopharmaceutical Development CMC at Covance, recently discussed a few of the assays that can help drug development sponsors gain new insights about their product and making earlier go/no-go decisions.
“Sponsors may want to take a minimalist approach to get to First in Human, but we’re seeing more interest in applying a Quality by Design (QbD) approach, which is outlined in ICH Q8 and will be part of the ICH Q14 analytical development guidelines, expected to be released next year,” explained Allan.
“With QbD, regulators are increasingly looking for characterization work done early on. Sponsors will gain much more understanding of their molecule and, therefore, will improve their chances of getting their product through to the later stages of development,” he added. “If the product is not robust enough to get through to commercialization, it’s much cheaper to fail early than it is to fail in Phase III. Early characterization is ultimately cost-saving in the long run.”
Comparability studies and references standards
“Characterization is meant to cover all aspect of the primary, secondary, tertiary structure and aggregation, providing a comprehensive understanding of the biopharmaceutical,” said Allan. In addition to providing basic product understanding, the range of characterization assays can support comparability studies. If there is a change in a process or formulation that can potentially effect product safety and/or efficacy, there is a regulatory requirement to demonstrate that the changes have not adversely affected the product. Here the characterization assays provide a platform, in addition to QC release testing, to demonstrate product comparability, of materials before and after the process/formulation modification.
“Comparability is another of the major uses. If a process is changing as a molecule progresses to the next development phase, it is necessary to ensure the reference standard doesn’t change, or has very minimal changes. Having a well-characterized reference standard is very helpful.”
During product development, a reference standard will be required for various analytical methods, and definitely for a relative potency assay. Such reference standards need to be ‘well characterized’ using the range of characterization selected. Initially the reference standard could be a laboratory scale batch or a batch from the engineering run, but later on in development this will need to be GMP material. As with comparability studies for process modifications, any change of reference standards will need similar comparability studies to bridge to the new reference standard, to demonstrate no significant changes.
Stability testing and manufacturing support
Development of an early characterization profile can also have implications for subsequent stability studies. Characterization assays, particularly if linked to forced degradation, can identify stability-indicating methods, which can then be incorporated into a stability study. Initially at least, these can be ‘for information only’ (FIO), and later validated for inclusion in the formal stability studies. “As the product develops into later phase and commercialization, sponsors need to be open to the availability of new techniques and potentially perform additional characterization. Indeed, during manufacturing runs: we can store a few retain vials that can be used to recheck characterization if new assays are being used.”
Providing guidance on assays
To support emerging biotech sponsors, Allan often helps extend the expertise of teams, acting in a consultancy role.
“I can provide advice and make suggestions about the types of assays that sponsors may need. Many of the emerging biotechs will have their own assays in R&D in their lab and we can help transfer, develop and validate them specifically for GMP use, if needed. Alternatively, assays can be developed based on a particular client need and the analytical target profile.
Given that characterization and QC release go hand-in-hand to address critical quality attributes and provide comprehensive product knowledge, we recognize that other assays can support informational characterization. We do not want to overload a QC release specification with too many complex assays, as that can lead to higher risks if the assay fails. We work to help sponsors find the optimal number of assays for characterization and QC release.”
Looking ahead toward changes
Going forward, Allan assumes that regulators will still expect the so-called traditional assays for characterization, but he also is part of implementing new improvements in the field.
“As a contract research organization, we are always updating our technologies and methods. Multiple attribute monitoring using mass spectrometry is going to be one of the major changes,” explained Allan. “You can get most of the primary structural information from your protein from one assay rather than performing several assays with the more classic liquid chromatography or electrophoretic assays. Assays for high order structure methods will also improve to become more sensitive to provide more detail about molecular structure.”
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