Mixing Two Active Pharmaceutical Ingredients Is 'Substantial Transformation,' CBP Tells GlaxoSmithKline
The mixing of two active pharmaceutical ingredients in Canada creates a substantial transformation and determines the country of origin for government procurement purposes, CBP said in a July 2 final determination ruling. GlaxoSmithKline, represented by Nicolas Guzman at Drinker Biddle, asked CBP for a final determination on the country of origin of Malarone tablets. The tablets are used to treat and prevent malaria, the company said.
The tablets are a "fixed-dose combination of atovaquone and proguanil hydrochloride," according to the Food and Drug Administration's prescribing information. Atovaquone alone doesn't treat malaria, though proguanil hydrochloride by itself can be used for such treatment. "However, GSK cites to several academic studies that conclude that the combination of atovaquone and proguanil hydrochloride provides a more effective treatment compared to taking proguanil hydrochloride alone," CBP said. "GSK therefore states that atovaquone and proguanil are 'synergistic in their mechanisms of action,' resulting in the increased effectiveness of Malarone tablets compared to taking atovaquone or proguanil hydrochloride alone."
Both atovaquone and proguanil hydrochloride are made in India, the company said. The APIs are then imported into Canada to be combined together along with other inactive ingredients and pressed into tablets, CBP said. The tablets then go to North Carolina to be packaged and labeled for sale, it said. While "CBP has generally held that the processing of pharmaceutical products from bulk form into measured doses does not result in a substantial transformation," when such processing includes mixing APIs to offer additional medicinal benefits, "CBP has held that a substantial transformation occurred," the agency said.
Though one of the APIs can treat malaria alone, it is less effective than Malarone, CBP said. "This is because of the 'synergies in [the APIs'] method of action,' which result in a product that 'interfere[s] with 2 different pathways' to prevent and treat malaria," CBP said. As a result Canada is the country of origin for purposes of government procurement, CBP said.
(Federal Register 07/09/18)