Survey of heparin products

Between November 2024 and April 2025, the Therapeutic Goods Administration (TGA), Laboratories Branch tested various Heparin products including low molecular weight heparin and unfractionated heparin - with a focus on Heparin Sodium, Clexane, Fragmin, and Exarane. 

Why this testing matters:

• High usage of heparin products in Australia, with hundreds of thousands of units distributed annually
• Verification of anticoagulant activity in compliance with pharmacopoeial standards
• Screening for impurities that could pose safety risks
• Routine monitoring is carried out to ensure the ongoing quality of pharmaceutical products

Heparin is a critical anticoagulant medication used to both treat existing blood clots and prevent the formation of new ones. Its therapeutic application significantly reduces the risk of serious thromboembolic events, including stroke and myocardial infarction (1). Heparin is included in the Pharmaceutical Benefits Scheme and is widely used in various health care settings across the country. 

For Treatment:

• Heparin is employed in the management of conditions such as deep vein thrombosis, pulmonary embolism, and acute coronary syndromes (e.g. myocardial infarction). It is also routinely used during cardiac and vascular surgical procedures to inhibit clot propagation.

  For Prophylaxis: 

• In patients at elevated risk of thromboembolism—such as those undergoing major surgery (particularly orthopaedic procedures) or those with atrial fibrillation—heparin is administered in low-dose regimens or as low molecular weight heparins (LMWH) to prevent clot formation.

Heparin helps prevent harmful blood clots by enhancing the action of a natural protein in the body called antithrombin (2,3). This protein helps slow down the clotting process by blocking two important clotting factors: Factor Xa and Factor IIa. To ensure that heparin products are effective, we investigate their ability to block these clotting factors in accordance with international pharmacopoeial monographs. 

These two clotting factors are critical for the coagulation cascade – a finely tuned biological process that helps the body stop bleeding after an injury to a blood vessel. 

Here’s how heparin works:

• When a blood vessel is damaged, platelets quickly gather at the site and form a temporary plug to reduce blood loss.
• Simultaneously, a series of clotting factors are activated. These are specialised proteins in the blood that trigger one another in a cascade-like sequence.
• This cascade leads to the production of fibrin, which forms a stable, insoluble network that reinforces the platelet plug and seals the wound (4).

When this system malfunctions:

• Insufficient clotting leads to excessive bleeding (e.g. haemophilia) and is managed with therapies that replace missing clotting factors.
• Excessive clotting (thrombosis) can block blood flow. In such cases, medications like heparin help by disrupting the clotting process to prevent dangerous clot formation.

The aim of this  survey was to assess the quality of heparin products on the Australian market.

The objectives of this testing were to:

• Perform laboratory testing in accordance with International Pharmacopoeias to determine anticoagulant activity (via anti-Xa and anti-IIa assays), and the absence of related substances.
• Evaluating labelling to ensure compliance with Therapeutic Goods Order (TGO) 91
• Reviewing documentation, including analysis of shipping records and manufacturer certificates of analysis, to verify compliance with required specifications.

Methods

Samples

The following samples were included in the survey: 

Compliance assessment summary

Following comprehensive testing and documentation review, each heparin product was evaluated for regulatory compliance and classified into one of the following categories: 

• Compliant: The sample meets all applicable quality and regulatory standards.
• Non-Compliant: The sample fails to meet one or more critical quality requirements, rendering it unsuitable for use.
• Minor Non-Compliance: The sample exhibits minor deviations from standards that are potentially correctable and do not pose immediate safety concerns.

Test methods

The following monographs were used:

• Ph. Eur. Monograph 11.2 - 07/2023:0828 Heparins, low-molecular-mass
• Ph. Eur. Monograph 11.0 - 01/2008:1195 Dalteparin sodium
• Ph. Eur. Monograph 11.0 - 04/2014:1097 Enoxaparin sodium
• Ph. Eur. Monograph 11.5 - 07/2024:0333 Heparin sodium
• Ph. Eur. Monograph 11.5 - 07/2024:20705 Assay of Heparin
• BP Monograph - Heparin Injection

Labelling of all drug products were visually examined, photographed and analysed according to the TGO91 for medicine labelling.

Results

* Sponsor directed to either (a) correct labelling non-compliance, or (b) submit a Section 14 exemption.

Conclusion

All 13 tested products met required specifications for quality attributes. Minor labelling non-conformances were identified, with follow-up actions issued to sponsors. 

References

1. Hull RD, Raskob GE, Rosenbloom D, Panju AA, Brill-Edwards P, Ginsberg JS, et al. Heparin for 5 Days as Compared with 10 Days in the Initial Treatment of Proximal Venous Thrombosis. New England Journal of Medicine. 1990;322(18):1260-4.

2.  Gray E, Hogwood J, Mulloy B. The Anticoagulant and Antithrombotic Mechanisms of Heparin. In: Lever R, Mulloy B, Page CP, editors. Heparin - A Century of Progress. Berlin, Heidelberg: Springer Berlin Heidelberg; 2012. p. 43-61.

3.  Oduah EI, Linhardt RJ, Sharfstein ST. Heparin: Past, Present, and Future. Pharmaceuticals. 2016;9(3):38.

4.  Hirsh J, Raschke CR, Warkentin TE, Dalen JE, Deykin D, Poller L. Heparin: Mechanism of Action, Pharmacokinetics, Dosing Considerations, Monitoring, Efficacy, and Safety. CHEST. 1995;108(4):258S-75S.