October 9, 2009
To Manufacturers and Initial Distributors of Medical Devices Containing or Coated with Heparin or that Use Heparin in their Manufacturing Processes, and Devices that are Used for Monitoring Heparin
The Center for Devices and Radiological Health (CDRH), Food and Drug Administration, wants to inform you of important information relating to heparin and to seek your immediate action, if indicated.
As part of the Heparin Sodium monograph revisions effective October 1, 2009, the United States Pharmacopeia (USP) has adopted a new potency assay for heparin, the chromogenic anti-Factor IIa test, and a new potency reference standard harmonized to the International Standard (IS) issued by the World Health Organization. The revised USP reference standard and unit definition for heparin will result in approximately a 10% reduction in the potency of the heparin marketed in the United States and in Canada. This change may have clinical significance and may mean that larger doses of heparin are required to achieve the desired effect.
This change was made largely in response to the 2007-2008 heparin contamination problem. The monograph was changed to include a test for the contaminant Oversulfated Chondroitin Sulfate.
Actions To Be Taken by Medical Device Manufacturers and Initial Distributors To Ensure that Any Heparin They Use or Distribute with Decreased Potency Will Not Affect Safety and Effectiveness of Their Devices
CDRH is concerned that the change in the potency reference standard and the resulting decreased potency of heparin products may affect the safety and effectiveness of devices containing or coated with heparin, devices utilizing heparin in their manufacturing processes, and devices used for monitoring heparin. We are writing to alert you of this risk and to remind you that it is your responsibility to have in place a quality system under 21 CFR Part 820 that provides reasonable assurance of device safety and effectiveness. This quality system includes proper design controls (21 CFR § 820.30), purchasing controls (21 CFR § 820.50), production and process controls (21 CFR § 820.70), and acceptance activities (21 CFR § 820.80). We ask that you assure that your product is safe and effective in light of the new potency reference standard and resulting decreased potency of heparin products.
The new USP heparin reference standard may require modification of procedures, specifications, formulations, in-process tests, quality control criteria, or other critical aspects of the manufacturing process for your device, or modification of the device itself.
You are required by 21 CFR §§ 820.30(i) and/or 820.70(b) to document the assessment of the impact on your products or processes of the new USP heparin reference standard and any resulting changes that may be necessary. For manufacturers that use heparin in medical devices, the impact of the monograph change must be assessed as it relates to the specific device submission. For devices subject to Pre-Market Approvals (PMA), the results of these activities should be reported in an annual report unless any change affects safety or effectiveness, in which case a PMA supplement or 30-day notice must be submitted before implementing the change, in accordance with 21 CFR § 814.39. For devices cleared under section 510(k) of the Federal Food, Drug, and Cosmetic Act, a new 510(k) must be submitted in those circumstances where the modification could significantly affect the safety or effectiveness of the device, in accordance with 21 CFR § 807.81(a)(3).
If your device contains heparin, is coated with heparin, or is used for monitoring heparin, FDA asks that you add to your product labeling an “N” next to the identified heparin to indicate if the device uses, or is to be used with, heparin made according to the new USP reference standard. This will help healthcare providers identify when heparin subject to the new reference standard has been or is to be used with the device.
Actions to Be Taken by Medical Device Manufacturers and Initial Distributors to Ensure that Their Devices Containing or Utilizing Heparin are Contaminant-Free
The new USP monograph, unlike the prior monograph, includes testing for the contaminant Oversulfated Chondroitin Sulfate. Therefore, the previous USP test method is no longer valid in assuring that the heparin is contaminant-free.
You should ensure that your products are contaminant-free. Ensuring compliance with the manufacturing and testing requirements under the new USP monograph will lessen the potential for contamination of heparin. Such assurance can be achieved through purchasing controls (21 CFR § 820.50) and acceptance activities (21 CFR § 820.80).
If you have any questions concerning the content of this notification, please contact the CDRH Heparin Hotline at 301-796-7436.
The following link provides additional information on the heparin monograph change: www.usp.org.