AAPS White Paper Provides Guidance on Analytical Similarity Evaluations of Biosimilars

The American Association of Pharmaceutical Scientists (AAPS), a professional organization of 9000 scientists, has published a new white paper in The AAPS Journal that discusses the scientific and methodological considerations of the process of attribute and test method selection, criticality assessment, and assignment of analytical measures to the FDA’s 3 tiers of analytical similarity assessment for biosimilars.

“Biosimilar developers face the difficult task of designing analytical studies capable of detecting relevant differences in structure and function from a licensed reference product, without access to detailed product knowledge,” said noted coauthors Kristof Vandekerckhove and Henriette Kuehne, PhD, in a statement. “Generating compelling evidence of analytical similarity despite the paucity of available information requires a methodical approach to study design, in order to select the right analytical tools and data and decide the appropriate level of assessment rigor for each. In our paper, we lay out the emerging ‘gold standard’ approach and illustrate the concepts discussed with examples from successful applications.”

According to the white paper, the main purpose of an analytical similarity assessment is to identify and evaluate all aspects of similarity that could impact purity, potency, safety, and efficacy of the proposed drug. Quality attributes (QAs) may be identified with the help of publicly available reference product information; reported information from regulatory authorities, pharmacovigilance reports, standard-setting organizations, or health agency communications; literature on the reference or related products; or results of detailed analytical characterization of multiple lots of the reference biologic.

After defining QAs, appropriate ways to assess those QAs are selected, based on suitability of the analytical method to measure differences between the biosimilar and its reference, the ability of the method to yield quantitative data, and orthogonality.

Some common QAs and methods to query those attributes include primary structure (assessed by primary sequence, disulfide structure, intact mass, isoelectric point, and extinction coefficient), secondary and tertiary structure (assessed by low-resolution secondary structure or indirect tertiary structure measurements and high-resolution measurements of higher-order structure), glycosylation (assessed by exoglycosidase sequencing and glysosylation site mapping and site occupancy), dose (assessed by protein content and deliverable volume), particulates (assessed by subvisible particles), function (assessed by biological activity or other assays that may vary by proteins, and receptor and/or ligand binding), and product variants (assessed by high—molecular weight species, covalent dimers, purity and impurities, amino acid misincorporations, microsequence heterogeneity, and C- and N-terminal modifications).

Once a comprehensive list of QAs has been established, the next step of the process is to assess risk of each QA for potential patient impact. The relationship of each attribute to pharmacokinetics, pharmacodynamics, efficacy, and safety must be assessed, and useful prior knowledge can be obtained through knowledge of the specific mode of action, publicly available information on the reference drug, knowledge of similar products, and the developers’ own experimental data.

Finally, the FDA recommends assigning each analytical measure to 1 of 3 tiers. The tiers are based on a risk assessment that considers potential clinical impact and uncertainty. Tier 1 is used for the most critical test with direct impact on the mode of action, tier 2 is used for tests of moderate criticality, and tier 3 has the lowest rank of criticality. Each analytical measure used to demonstrate similarity must be assigned to an appropriate tier.

The authors encourage biosimilar product sponsors to expend careful attention on the design of their in vitro study programs and to work closely on their proposals with regulatory agencies prior to execution, as the structural and functional comparison of a proposed biosimilar with its reference continues to gain in importance.

Reference

Vandekerckhove K, Seidl A, Gutka H, et al. Rational selection, criticality assessments, and tiering of quality attributes and test methods for analytical similarity evaluation of biosimilars. AAPS J. 2018;20(68). doi: 10.1208/s12248-018-0230-9.