Import Alert 55-03

Detention Without Physical Examination of Different Forms of Heparin and Heparin-
Related Products for CGMP Issues

Heparin is a widely used anti-coagulant and is commonly used during surgical procedures and for those undergoing dialysis. There are an estimated 12 million Americans that use heparin 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 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 active pharmaceutical ingredient (API), heparin products, and heparin-containing products.

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. One basis for detention without physical examination is that the firm's quality system is inadequate for the prevention of contamination or otherwise does not conform to CGMP. 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. (The USP has since revised in 2009 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. 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 per 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 attachment to this alert identifies firms for which we have information indicating that the different forms of heparin or heparin-related products appear to be adulterated for one of the reasons described above. It appears per 801(a) 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 in the attachment do not appear to conform to current good manufacturing practices within the meaning of Section 501(a)(2)(B); therefore such articles are subject to refusal of admission into the United States.

Districts may detain without physical examination all forms of heparin and heparin-related products from the firm(s) identified on the attachment to this import alert.

Since the article appears to be adulterated due to inadequate GMPs and is subject to Refusal of Admission per Section 801(a)(3) of the Act, FDA considers reconditioning or submission of analytical results to be insufficient to overcome the appearance of the violation. Drugs and other products offered for importation from the firm(s) listed on the attachment to this import alert are subject to detention without physical examination until FDA is satisfied that the appearance of a violation has been removed, either by inspection, reinspection, submission of documentation, and/or other actions requested by the FDA.

Firms may provide copies of inspection reports for inspections performed by third parties to assist FDA in prioritizing inspection requests. An establishment wishing to schedule an FDA inspection or to provide a copy of an inspection report conducted by a third party, should do so by submitting a request or documentation to the following address:

Food and Drug Administration
Division of Import Operations and Policy (HFC-170)
12420 Parklawn Drive, ELEM-3109
Rockville, MD 20857

Or via email: Importalerts2@fda.hhs.gov

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 listed below.

PROBLEM: Good Manufacturing Practices

"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