Historically, serious injuries and deaths have been associated with the use of contaminated heparin. FDA expects all imported heparin sodium lots to be compliant with the latest US Pharmacopeia (USP) specifications and FDA’s regulatory standards to ensure the safety of heparin products.

The agency also conducts testing on a case-by-case basis on all forms of heparin (crude, active pharmaceutical ingredients (API), low molecular weight heparin (LMWH) and finished dosage forms) to help protect patients from unsafe heparin.

Expected documentation for importing crude heparin

Importers are expected to submit the following analytical data with each shipment, which will help facilitate FDA’s review of the entry:

  • SAX-HPLC chromatograms.
  • The 500 MHz 1D-1H-NMR spectrum, which includes an expansion plot of the 1.8 to 2.3 ppm region along with the full spectrum, and (1)H-NMR of the USP Reference Standard and the USP System Suitability Solutions.

Test method that complies with USP and the National Formulary monograph: Analysis of crude heparin by (1)H NMR, capillary electrophoresis, and strong-anion-exchange-HPLC for contamination by over sulfated chondroitin sulfate.

Expected documentation for importing heparin sodium API and finished dosage forms

All heparin sodium API and finished dosage form heparin sodium importers are expected to submit the following analytical data with each shipment, which will help facilitate FDA’s review of the entry:

  • Certificate of Analysis for the batch.
  • (1)H-NMR spectrum (testing conducted per current USP method), with expanded 1.8 to 3.0 ppm region shown, and (1)H-NMR of the USP Reference Standard and the USP System Suitability Solutions.
  • HPLC-SAX chromatogram (testing conducted per USP method ).

If testing is not conducted per USP specifications, submitting one additional standard chromatogram spiked with oversulfated chondroitin sulfate (OSCS), that is analyzed at the same time, serves as demonstration of the suitability of the test method. Therefore, submitting this result facilitates FDA’s review of the entry. This will help the agency assess whether the submitted test results were conducted with validated methods.  

Expected documentation for importing LMWH products

The analytical file is expected to include data for the heparin sodium API used to make the low molecular weight heparin API, which will help facilitate FDA’s review of the entry. If possible, data should be submitted in one electronic file. Importers are expected to submit the following analytical data with each shipment, which also will help facilitate FDA’s review of the entry:

  • Certificate of Analysis for the LMWH API batch. This document should include certification that no OSCS is present in the drug.
  • (1)H-NMR spectrum (testing conducted per current USP method) expanded 1.8 to 3.0 ppm region shown, and (1)H-NMR of the USP Reference Standard and the USP System Suitability Solutions.
  • HPLC-SAX chromatogram (testing conducted per USP method).

If testing is not conducted per USP specifications, submitting one additional standard chromatogram spiked with OSCS, that is analyzed at the same time, serves as demonstration of the suitability of the test method. Therefore, submitting this result facilitates FDA’s review of the entry. This will help the agency assess whether the submitted test results were conducted with validated methods. 

Visit Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality for more information.