Note: The revision of this Import Alert (IA) dated 08/2/2024 updates the reason for alert, guidance, agency contacts, product description section, charge code section, PAF, PAC. Changes to the import alert are bracketed by asterisks (***). ***On July 21, 2014 the charge code was revised within the Alert to include authority set forth in section 501(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) making a drug adulterated if it has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection. Articles of drug falling within this new section are subject to refusal under 801(a)(3) of the FD&C Act. To date firms in violation of 501(j) are now placed on Import Alert 66-79,"Detention Without Physical Examination of Drugs From Foreign Establishments Refusing FDA Inspection.�*** Heparin is a widely used anti-coagulant and is commonly used during surgical procedures and for those undergoing dialysis. ***Since 2018, approximately 265 million doses of heparin products have been used in the United States each year.*** In 2008, a number of deaths in the United States were associated with either contaminated or adulterated heparin. The adverse events have included allergic or hypersensitivity-type reactions, with symptoms such as low blood pressure, angioedema, shortness of breath, nausea, diarrhea, and abdominal pain. The vast majority of crude heparin, heparin intermediates, and heparin active pharmaceutical ingredient (API) used in finished drug product in the United States is imported from other countries. The phrase "different forms of heparin and heparin-related products" is used for brevity to refer to articles such as crude heparin, heparin intermediates, heparin API, heparin products, and heparin-containing products. ***The phrase also includes low molecular weight heparin (LMWH) products (e.g., dalteparin, enoxaparin, etc.).*** As part of FDA's activities intended to protect the health and safety of U.S. consumers, FDA often conducts inspections of foreign establishments that produce FDA-regulated articles intended for use in the United States. The basis for detention without physical examination under this Import Alert is that the firm's quality system is inadequate for the prevention of contamination or otherwise does not conform to current good manufacturing practice (CGMP) requirements. Heparin contaminated with oversulfated chondroitin sulfate (OSCS) clearly indicates that the "methods used in" or the "controls used for" the "manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity" with CGMP. OSCS is not part of the manufacturing process for heparin and its presence suggests that somewhere in the supply chain OSCS has been added intentionally to heparin for financial reasons because it is a very cheap material prepared by a simple synthetic process. In addition, it mimics certain heparin properties so that it would pass then-current United States Pharmacopeia (USP) specifications for Heparin Sodium USP. ***In 2009, the USP revised its monograph for Heparin Sodium USP to incorporate tests that can detect the presence of OSCS.*** Manufacturers must have adequate traceability, qualification, and testing systems in place in order to satisfy applicable CGMP requirements. ***When inspections are performed that are unable to adequately demonstrate that a firm meets the applicable CGMP requirements or the firm appears to have been responsible for introducing contaminated forms of heparin or heparin-related products into the supply chain then the firm's drug(s) or other products are subject to imports refusal under 801(a)(3) of the FD&C Act for the appearance of adulteration, and the firm's quality system is inadequate or otherwise does not conform to CGMP requirements. Where there is an inspection that identifies an inadequate system in this regard, the firm's drug(s) or other products appear to be adulterated and are subject to imports refusal 801(a)(3).*** Furthermore, if the firm appears to have been responsible for introducing contaminated forms of heparin or heparin-related products into the supply chain, then there is an appearance that the firm's quality system is inadequate or otherwise does not conform to CGMP. If the firm demonstrates that they have appropriate controls in place, the firm's drugs or other products may no longer appear to be adulterated. ***The Red List of this alert identifies firms for which we have information indicating that the different forms of heparin or heparin-related products appear to be adulterated as described above. It appears under section 801(a) of the FD&C Act that the methods used in and controls used for the manufacture, processing, packing, or holding of the drugs or other products from the firms listed on the Red List do not appear to conform to current good manufacturing practices within the meaning of section 501(a)(2)(B) of the FD&C Act; therefore, such articles are subject to refusal of admission into the United States.***
Different Forms of Heparin and Heparin-Related Products (e.g., Crude Heparin, Heparin Intermediates, Heparin Active Pharmaceutical Ingredient (API), Heparin Products, and Heparin-Containing Products) from the firms ***on the Red List.*** ***61L[][]45 Crude Heparin 61L[][][] Heparin Sodium, Heparin Calcium, and Heparin-Containing Product, including Ardeparin Sodium, Calciparine, Dalteparin Sodium, Enoxaparin Sodium, and Tinzaparin Sodium***
***"The article is subject to refusal of admission pursuant to Section 801(a)(3) in that the methods used in and controls used for the manufacture, processing, packing, or holding of drugs and other products do not appear to conform to current good manufacturing practices within the meaning of Section 501(a)(2)(B)." OASIS Charge Code: DRUG GMPs***
***Divisions may detain, without physical examination, all forms of heparin and heparin-related products from the firm(s) identified on the Red List of this Import Alert. Since the article appears to be adulterated due to inadequate CGMPs, and is subject to refusal of admission under section 801(a)(3) of the FD&C Act, FDA considers reconditioning or submission of analytical results to be insufficient to overcome the appearance of the violation. Recommendations for additions to the Red List of this import alert, should be forwarded to the Division of Import Operations (DIO) and FDA's Center for Drug Evaluation and Research (CDER) will evaluate regulatory packages on a case-by-case basis. Removal from Detention without Physical Examination (REMOVE FROM RED LIST): In order to remove a firm's product from the Red List, information should be provided to the Agency to adequately demonstrate that the firm has resolved the conditions that gave rise to the appearance of the violation, either by inspection, reinspection, submission of documentation, and/or other actions requested by the FDA. The purpose of this is so that the Agency will have confidence that future shipments/entries will be in compliance with the FD&C Act and applicable regulations. If a firm and/or a representative thereof would like to petition for removal from detention without physical examination under this Import Alert, a firm or representative thereof may schedule an inspection or reinspection or provide copies of inspection reports for inspections performed by third parties to assist FDA in prioritizing inspection requests. The request and all relevant documentation supporting the request should be sent to the following address: Food and Drug Administration Division of Import Operations 12420 Parklawn Drive, ELEM-3109 Rockville, MD 20857 Or via email: Importalerts2@fda.hhs.gov Questions or issues involving import operations should be addressed to ORA/DIO (301) 796-0356 or FDAImportsInquiry@fda.hhs.gov. Questions or issues involving science policy, analysis, preparation, or analytical methodology, should be addressed to FDAPRIVATELABIMPORTALERTS@fda.hhs.gov. Questions or issues on policy or any other additional questions not directly related to a detained entry, should be addressed to CDER/OC/ODSIR/DGDDP/Imports Compliance Branch at CDERImports@fda.hhs.gov. ***
This alert authorizes Detention Without Physical Examination (DWPE) for products matching this alert. Reason: Note: The revision of this Import Alert (IA) dated 08/2/2024 updates the reason for alert, guidance, agency contacts, product description section, charge code section, PAF, PAC. Changes to the import alert are bracketed by asterisks (***). ***On July 21, 2014 the charge code was revised within the Alert to include authority set forth in section 501(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) making a drug adulterated if it has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection. Articles of drug falling within this new section are subject to refusal under 801(a)(3) of the FD&C Act. To date firms in violation of 501(j) are now placed on Import Alert 66-79,"Detention Without Physical Examination of Drugs From Foreign Establishments Refusing FDA Inspection.�*** Heparin is a widely used anti-coagulant and is commonly used during surgical procedures and for those undergoing dialysis. ***Since 2018, approximately 265 million doses of heparin products have been used in the United States each year.*** In 2008, a number of deaths in the United States were associated with either contaminated or adulterated heparin. The adverse events have included allergic or hypersensitivity-type reactions, with symptoms such as low blood pressure, angioedema, shortness of breath, nausea, diarrhea, and abdominal pain. The vast majority of crude heparin, heparin intermediates, and heparin active pharmaceutical ingredient (API) used in finished drug product in the United States is imported from other countries. The phrase "different forms of heparin and heparin-related products" is used for brevity to refer to articles such as crude heparin, heparin intermediates, heparin API, heparin products, and heparin-containing products. ***The phrase also includes low molecular weight heparin (LMWH) products (e.g., dalteparin, enoxaparin, etc.).*** As part of FDA's activities intended to protect the health and safety of U.S. consumers, FDA often conducts inspections of foreign establishments that produce FDA-regulated articles intended for use in the United States. The basis for detention without physical examination under this Import Alert is that the firm's quality system is inadequate for the prevention of contamination or otherwise does not conform to current good manufacturing practice (CGMP) requirements. Heparin contaminated with oversulfated chondroitin sulfate (OSCS) clearly indicates that the "methods used in" or the "controls used for" the "manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity" with CGMP. OSCS is not part of the manufacturing process for heparin and its presence suggests that somewhere in the supply chain OSCS has been added intentionally to heparin for financial reasons because it is a very cheap material prepared by a simple synthetic process. In addition, it mimics certain heparin properties so that it would pass then-current United States Pharmacopeia (USP) specifications for Heparin Sodium USP. ***In 2009, the USP revised its monograph for Heparin Sodium USP to incorporate tests that can detect the presence of OSCS.*** Manufacturers must have adequate traceability, qualification, and testing systems in place in order to satisfy applicable CGMP requirements. ***When inspections are performed that are unable to adequately demonstrate that a firm meets the applicable CGMP requirements or the firm appears to have been responsible for introducing contaminated forms of heparin or heparin-related products into the supply chain then the firm's drug(s) or other products are subject to imports refusal under 801(a)(3) of the FD&C Act for the appearance of adulteration, and the firm's quality system is inadequate or otherwise does not conform to CGMP requirements. Where there is an inspection that identifies an inadequate system in this regard, the firm's drug(s) or other products appear to be adulterated and are subject to imports refusal 801(a)(3).*** Furthermore, if the firm appears to have been responsible for introducing contaminated forms of heparin or heparin-related products into the supply chain, then there is an appearance that the firm's quality system is inadequate or otherwise does not conform to CGMP. If the firm demonstrates that they have appropriate controls in place, the firm's drugs or other products may no longer appear to be adulterated. ***The Red List of this alert identifies firms for which we have information indicating that the different forms of heparin or heparin-related products appear to be adulterated as described above. It appears under section 801(a) of the FD&C Act that the methods used in and controls used for the manufacture, processing, packing, or holding of the drugs or other products from the firms listed on the Red List do not appear to conform to current good manufacturing practices within the meaning of section 501(a)(2)(B) of the FD&C Act; therefore, such articles are subject to refusal of admission into the United States.***
Country-specific information is available in the full alert detail on the FDA website.
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