The country of origin of Stalevo®

N286904 June 30, 2017 CLA-2-30:OT:RR:NC:N2:238 CATEGORY: Country of Origin Ms. Jennifer L. Plitsch Covington and Burling LLP One City Center 850 Tenth Street, NW Washington, DC 20001-4956 RE: The country of origin of Stalevo® Dear Ms. Plitsch: In your letter dated May 30, 2017, on behalf of Orion Corporation, you requested a country of origin ruling. Stalevo is a combination of three active pharmaceutical ingredients (API) carbidopa, levodopa and entacapone. Stalevo is used for the treatment of Parkinson’s disease. It will be imported in tablet form of various dosages. Levodopa, which is a white crystalline powder, is synthesized in the brain into dopamine. It is used in the treatment of Parkinson's disease. Levodopa is almost always given in combination with the drug Carbidopa, which prevents the nausea that can be caused by levodopa alone. Carbidopa is also a levodopa enhancer. When added, carbidopa enables a much lower dose of levodopa and helps reduce the side effects of nausea and vomiting. Pills containing both drugs are often labeled “carbidopa-levodopa,” with the active components listed in alphabetical order. Entacapone is a medication commonly used in combination with other medications for the treatment of Parkinson's disease. Entacapone together with levodopa and carbidopa allows levodopa to have a longer effect in the brain and reduces Parkinson’s disease signs and symptoms for a greater length of time than levodopa and carbidopa therapy alone. Entacapone is a selective and reversible inhibitor of the enzyme catechol-O-methyltransferase (COMT). When taken together with levodopa and carbidopa, entacapone stops catechol-O-methyltransferase from breaking down and metabolizing levodopa, resulting in an overall increase of levodopa remaining in the brain and body. You claim that patients receiving Stalevo experience greater benefits from the integrated presence of entacapone compared to those patients taking levodopa/carbidopa tablets together with a separate entacapone tablet. The three API’s are sourced from various countries. The carbidopa is currently sourced from Italy, although it might later be sourced from elsewhere. The levodopa is sourced from Japan. The entacapone is sourced from Finland. These three API’s are combined in Finland, and together with additional inactive ingredients they are manufactured into the finished product, Stalevo in tablet form. You have asked for a country of origin determination. You claim that a substantial transformation has taken place in Finland, and therefore the country of origin should be considered Finland. As a first step in the manufacturing process, levodopa and entacapone are mixed with inactive ingredients and then granulated in a vertical wet high-shear granulator. The granules are then dried in a fluid-bed granulator and screened in preparation for mixing with other ingredients. In a separate process, carbidopa is mixed with other inactive ingredients, and then granulated, screened, and dried to produce carbidopa granules intermediate product. Before the carbidopa granules intermediate are mixed with the levodopa entacapone granules and other inactive ingredients, the yield of levodopa-entacapone granules is weighed and adjusted accordingly. The final mass is pressed into tablets and coated with coating suspension using a perforated coating pan. In determining whether a substantial transformation occurs in the manufacture of chemical products such as pharmaceuticals, CBP has consistently examined the complexity of the processing, and whether the final article retains the essential identity and character of the raw materials. To that end, CBP has generally held that the processing of pharmaceutical products from bulk form into measured doses, filtering and packaging does not result in a substantial transformation. In this instance, we find the combining of the three API’s carbidopa, levodopa and entacapone results in a new product, Stalevo tablets, which have undergone a substantial transformation in Finland, and the country of origin of the Stalevo tablets is Finland. Finally, you stated that in the future Orin may also source the carbidopa API for Stalevo from Fermion in Finland. You claim that Fermion creates the carbidopa API from crude carbidopa from China and believe that the crude carbidopa is substantially transformed into carbidopa API as a result of the manufacturing process in Finland. If you wish to obtain a country of origin ruling for crude carbidopa into carbidopa API, we need additional information to make this determination. Please provide a complete component breakdown by weight of all ingredients including the CAS numbers as well as all starting materials to make Carbidopa API. Include a detailed step by step manufacturing process and a flow chart. This merchandise may be subject to the Federal Food, Drug, and Cosmetic Act and/or The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (The Bioterrorism Act), which are administered by the U.S. Food and Drug Administration (FDA). Information on the Federal Food, Drug, and Cosmetic Act, as well as The Bioterrorism Act, can be obtained by calling the FDA at 1-888-463-6332, or by visiting their website at www.fda.gov. This ruling is being issued under the provisions of Part 177 of the Customs Regulations (19 C.F.R. 177). A copy of the ruling or the control number indicated above should be provided with the entry documents filed at the time this merchandise is imported. If you have any questions regarding the ruling, contact National Import Specialist Judy Lee at judy.h.lee@cbp.dhs.gov. Sincerely, Steven A. Mack Director National Commodity Specialist Division