4.13.2 Potency

Biosimilarity: The FDA Perspective

188 suitable measurement of both the originator and the biosimilar product. Other factors that can modulate the results include the level of the endogenous counterpart, the free versus total analyte, and the mechanisms of therapeutic protein’s absorption and disposition.

While establishing the PK assay development, the potency is de ned as the ability of a drug/analyte to bind with assay reagents (i.e., capture protein and detection protein). It is a measure of a drug’s immunoreactivity to the assay reagents. A reference standard such as from the WHO or another quali ed source may be used as reference calibrator. The potency of a biosimilar product is inevitably the statistical Level 1 comparison and comprises the quantitative measure of the biological activity. Two factors provide a wider range of potency assays—one is the actual variability, which is expected, and the other is the variability due to the testing methodology. As a result, the bioanalytical assays have a wider acceptance criterion (e.g., 50%–150%) than the ligand-binding assay (e.g., 80%–120%). It is always possible to see a higher level of similarity in the ligand-binding assay than in the potency assay. This requires establishing an acceptance criterion of potency based on multiple lots of the originator product. The biosimilar developer must also secure these originator lots with different expiry dates to enable the establishment of a wider range; if samples that were manufactured within a short period are used, the biosimilar developer may face a signi cant risk of failing the comparable potency test for its product. It is also worthwhile to consider that the FDA allows the use of only one value per sample, so within-lot variability is authorized to be made part of the establishment of acceptance criteria; however, replicate measures are allowed to ascertain the testing variability. Potency testing is often done using a parallel line analysis, wherein the dose–response curves from the biosimilar and the originator drug products are compared side by side. The two curves must be as close as possible to being superimposable. If not, then a root cause investigation is performed. The reasons may include that the originator and the biosimilar product do not have the same immunoreactivity toward the assay reagents (e.g., capture antibody, detection antibody). A more detailed analysis will include the evaluation if the epitopes on the biosimilar that react to the assay reagents are similar and then an alternative assay format may be developed. If an adequate cause is not established, this creates a level of residual uncertainty in the mind of the FDA that the ef cacy of the two products may not be the same. Some of the corrective steps will include revising manufacturing processes in some instances.