ABSTRACT
The critical question addressed in this paper regards how industry and regulatory agencies should manage the risk of adverse events to patients posed by product quality attributes for which a preponderance of evidence from clinical and/or non-clinical studies supports it as a risk, but for which the probability of clinical adverse events arising from the attribute is uncertain. We here provide our perspective on the principles that can be applied to determine the need for and the manner in which to control quality attributes when their impact on safety and/or efficacy is suspected, but uncertain. As an example, we use the risk of immune responses to protein therapeutics posed by sub-visible protein particulates in therapeutic proteins.
Subject(s)
Biological Products/adverse effects , Biological Products/immunology , Proteins/adverse effects , Proteins/immunology , Vaccines, Synthetic/adverse effects , Animals , Antibody Formation/immunology , Biological Products/pharmacology , Biological Products/therapeutic use , Humans , Probability , Proteins/pharmacology , Proteins/therapeutic use , Quality Control , Risk , Uncertainty , Vaccines, Synthetic/immunology , Vaccines, Synthetic/pharmacology , Vaccines, Synthetic/therapeutic useABSTRACT
Under the Abbreviated New Drug Application pathway, a proposed generic salmon calcitonin nasal spray is required to demonstrate pharmaceutical equivalence and bioequivalence to the brand-name counterpart or the reference listed drug. This review discusses two important aspects of pharmaceutical equivalence for this synthetic peptide nasal spray product. The first aspect is drug substance sameness, in which a proposed generic salmon calcitonin product is required to demonstrate that it contains the same active ingredient as that in the brand-name counterpart. The second aspect is comparability in product- and process-related factors that may influence immunogenicity (i.e., peptide-related impurities, aggregates, formulation, and leachates from the container/closure system). The comparability of these factors helps to ensure the product safety, particularly with respect to immunogenicity. This review also highlights the key features of in vitro and/or in vivo studies for establishing bioequivalence for a solution nasal spray containing a systemically acting salmon calcitonin.