Abstract
Many specified impurities in vildagliptin’s finished product have been disclosed in the literature that are above their qualification threshold. We used the impurity B (amide impurity) as a case example to explore whether existing literature can be leveraged to determine the safe level of impurity and thereby develop a patient-centric specification (PCS) for impurities. No-observed-adverse-effect level (NOAEL) was derived from rate metabolism information and converted to human equivalent dose (HED). The HED was estimated as 6.5 mg/day. The high qualification levels are supported by repeat dose toxicity studies performed in rats, mice and dogs. Maximum theoretical amount (MTA) was correlated with the maximum observed amount (MOA) to verify whether the exposure was due to impurity and/or metabolite. MOA/MTA was found ≥1 suggesting that metabolism contributed to the amount excreted in feces and therefore could be used to further justify a higher specification limit than the usual one of ≤0.5%. Quite often the drug metabolism and degradation pathways overlap, resulting in the formation of identical constituents. Therefore, metabolism data can be leveraged for deriving safe levels of degradation impurities and develop PCS for impurities.
Highlights
Three types of impurities may arise in drug substances
Using the impurity B as a case example, we explore how existing literature can be leveraged to determine the safe level of impurity and thereby, develop a patient-centric specification (PCS) for impurities
The maximum theoretical concentration (MTC) and the maximum observed concentration (MOC) were estimated by using a method proposed by Weidolf and co-workers [3]
Summary
Three types of impurities may arise in drug substances. These are organic impurities, inorganic impurities and residual solvents. The presence of organic impurities in drug substances is attributed to the manufacturing process and/or to the degradation during shelf life These impurities include starting materials, by products, intermediates, degradation products, reagents, ligands and catalysts. Inorganic impurities are generally known and identified, and produced directly from the manufacturing process Examples of these impurities are reagents, ligands, catalysts, heavy metals or other residual metals, inorganic salts and other materials such as filter aids, charcoal, etc. Organic or inorganic solvents which are required during the synthesis of a new drug substance may be present in the drug substance as residual impurities Based on their potential risk to human health, they are divided into three categories, i.e., Class I (solvents to be avoided), II (solvents to be limited) and III (solvents with low toxicity potential). Apart from these impurities, polymorphic forms and enantiomeric impurities impact the safety and efficacy of the drug substance, these should be controlled in the specifications [1,2]
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