The original US-approved heparin drugs from the 1930s were from a bovine source (cow lung). Notably, bovine mucosa heparin drug product is currently available and manufactured in South America (e.g., Brazil and Argentina). There have been about 60 years of safe and effective use of bovine lung heparin in patients in the US, and bovine mucosal heparin has been used safely in South America. However, due to concerns of possible introduction of transmissible spongiform encephalopathy agents (TSE or “Mad Cow” disease agents), bovine lung heparin was voluntarily removed from the US market by manufacturers in the late 1990s and replaced by porcine heparin. In 2008, some samples of porcine heparin were found contaminated with Over-Sulfated Chondroitin Sulfate (OSCS). Since then, FDA has worked continuously to safeguard heparin products and related heparin supply chains. CDER remains interested in alternative sources to porcine heparin to diversify sources and enable a proactive approach to address possible shortages or contamination of the global porcine heparin supply.
FDA encourages all prospective manufactures and suppliers of bovine heparin and other animal-sourced products to develop good manufacturing process capability and related quality controls for their products. FDA welcomes engagement with sponsors considering use of such animal-sourced products through the pre-IND process. FDA will consider meeting requests, as appropriate, to discuss prospective applications with respect to demonstrating safety, efficacy, quality, and purity.
We recommend that sponsors interested in meeting with FDA prepare a comprehensive pre-IND meeting package with the appropriate regulatory and scientific data to support the current stage of drug development.1 The meeting package should include, but is not limited to, the following information:
- Name and address of the manufacturer(s) (if different from the sponsor)
- Description of the candidate product, including physical, chemical, and/or biological characteristics, as well as its source
- Description of the dosage form and information related to the dosage form
- Quantitative composition of the product
- A brief description of the Chemistry, Manufacturing, and Controls Information. The regulations at 21 CFR 312.23(a)(7)(i) emphasize how the extent of chemistry, manufacturing, and controls (CMC) information should be commensurate with the stage of development as an IND application progresses
- A brief description of adequate test methods used to ensure the identity, strength, quality, purity, and potency accompanied by the test results, or a certificate of analysis, of the candidate product lots used in toxicological studies and intended for the proposed human study.
- The grade and quality (e.g., USP, NF, ACS) of excipients used in the manufacture of the investigational candidate product.
- The method of preparation of the candidate product lots used in preclinical studies and intended for the proposed human study, including a brief description of the method of manufacture and the packaging procedure, as appropriate, with a description of the container and closure system including any available stability data.
Assuring that quality and safe medicines are available to the American public is of paramount importance to FDA. FDA remains committed to safeguarding heparin and other animal-sourced products by controlling the source of materials and processes used to manufacture these products, ensuring that manufacturers implement and comply with CGMPs for monitoring quality and production processes, and ensuring the quality and traceability of product and raw materials. Although FDA cannot eliminate all possible risk, it can enforce appropriate requirements, controls, and best practices allowing the early detection of problems and ensuring the availability of safe and quality medicines to the American people.
Additional guidance regarding heparin and background information on the bovine heparin initiative can be found below.
Guidances and references related to heparin:
- Guidance for Industry Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality, June 2013
- Heparin-Containing Medical Devices and Combination Products: Recommendations for Labeling and Safety Testing Draft Guidance for Industry and Food and Drug Administration Staff, July 2015
- Immunogenicity - Related Considerations for Low Molecular Weight Heparin Guidance for Industry, February 2016
- Information on Heparin
- November 2016 Public Science Board Meeting
- June 2014 Public Science Board Meeting
- Diversifying Global Heparin Supply Chain; Reintroduction of Bovine Heparin in the United States. Pharmaceutical Technology, November 2016.
1 For more information, see the draft guidance Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products. When final, this guidance will represent FDA’s current thinking on this topic.