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HEPARIN - NEW USP STANDARDS FOR UNFRACTIONATED HEPARIN

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August 5, 2010

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October 13, 2009

Questions & Answers:

Clinical Considerations Unfractionated Heparin (UFH) USP Standard Change

Pharmaceutical Partners of Canada’s Unfractionated Heparin (UFH) Products

Clinical Considerations Unfractionated Heparin (UFH) USP Standard Change (Effective October 1, 2009)

  1. Question: In simplest possible terms, what has changed in the Unfractionated Heparin (UFH) products � what caused this change � how does this change help in ensuring purity and safety?
    1. Answer: With the objective of ensuring purity of Unfractionated Heparin and patient safety in response to the 2008 adulteration problem (involving another manufacturer�s heparin products), USP has implemented several changes to the current standard, effective October 1, 2009. These changes essentially update test methods used to identify the contents of UFH and to characterize the potency and purity of the Active Pharmaceutical Ingredient (API) and resultant Finished Product. In addition, USP is harmonizing their reference standard with the International Standard. This is creating a shift in apparent potency by approximately 10%1.
    2. These changes are required of all manufacturers of heparin marketed as USP standard.
  2. Question: Please clarify the USP statement that there has been an estimated drift of 10% between the USP unit and the International Unit (IU) for Unfractionated Heparin (UFH) over the past 30 years. In which direction has the 10% potency change been?
    1. Answer: The USP has noted that UFH finished product prepared with current USP standards has averaged 10% higher potency (a range of 7% to 13%) than drug prepared with the International standards (International Units).1
    2. The new heparin standard now aligns the USP potency unit with the International Unit.
  3. Question: How will UFH prepared with the new USP standard differ in potency from heparin prepared under the previous USP standard?
    1. Answer: The USP has noted that UFH finished product prepared with the new International Standard has averaged an approximately 10% decrease in potency (range 7% to 13%) in comparison with UFH prepared with the previous USP standard1.
  4. Question: Do we need to use a conversion factor when considering dose modifications between UFH prepared with the old USP standard in comparison with UFH prepared with the new USP standard?
    1. Answer: A specific conversion factor cannot be recommended due to the inherent bioavailability of heparin, in addition there continues to be variability from lot to lot of UFH. As with all UFH use, careful clinical and laboratory monitoring of the patient�s response, with dose adjustment as appropriate continues to be recommended.
  5. Question: Do you expect heparin prepared with the new standard to result in a higher or lower activated partial thromboplastin time (aPTT) or activated clotting time (ACT) than heparin prepared with the previous standard?
    1. Answer: Heparin prepared according to the new International Standard has been successfully used in Europe, Canada, and other countries for many years. A few studies suggest that in comparison with heparin prepared in accordance with the previous USP standard, use of heparin prepared with the new International Standard may result in decreased activated clotting times (ACT) in some patients and a resultant decrease in clinical effect 2, 3. Therefore, PPC is committed to communicating the changes to health care practitioners to allow them to make informed decisions regarding dosing.
  6. Question: How can health care providers prepare for the changes?
    1. Answer: The following is a suggested UFH readiness checklist:
      1. Plan for transition
      2. Consider USP changes and potential effects
      3. Use as an opportunity to review all potentially affected protocols
      4. Reevaluate aPTT and ACT targets for Stage 2 UFH lots
      5. Monitor for changes
      6. Provide ongoing support4

References:

  1. www.usp.org/hottopics/heparin.html
  2. Dyck L and Friesen RM. Do Different Heparin Brands Influence Activated Clotting Times? J Extra Corpor Technol. 1998; 30:73-6.
  3. Hamilton M, MacDonald W, Levely A, et al. A rose is a rose - or is it? The 1993 Compendium of the Canadian Society of Clinical Perfusion, Scientific Sessions, October 1993
  4. Nutescue E.Readiness for the New USP Standards for Unfractionated Heparin (UFH). Webinar [archived, available at]: www.appdrugs.com/usp.aspx , September 23, 2009

Pharmaceutical Partners of Canada�s Unfractionated Heparin (UFH) Products

  1. Question: Will PPC�s Unfractionated Heparin (UFH) be compliant with the new USP standard required for October 1, 2009?
    1. Answer: Yes. PPC was on time in implementing new heparin raw material purity standards that were required by the USP in 2008 (stage 1). In addition, PPC�s UFH products shall be in compliance with the new USP changes required for October 1, 2009 (stage 2), which include harmonization with the International Standard among other changes (see above).
  2. Question: How can one distinguish between vials of PPC UFH prepared with the previous USP standard and vials of UFH prepared with the new USP standard?
    1. Answer: PPC�s vials of UFH prepared with the new USP standard will be marked with the letter �N� (for �new�) after the lot number on every vial, pack and case.
    2. PPC's vials of UFH prepared with the new USP standard will be marked with the letter "N" (for "new") after the lot number on every vial
    3. PPC's vials of UFH prepared with the new USP standard will be marked with the letter "N" (for "new") after the lot number on every vial
    4. Heparin Label
    5. Heparin Label
  3. Question: When will PPC begin supplying the market with the Heparin products prepared with the new USP standard?
    1. Answer: PPC has several months of inventory of UFH product prepared with the previous USP standard. We do not expect to begin shipping UFH product prepared with the new USP standard until early 2010. PPC will provide a communication to all our customers reiterating this USP change one month before any UFH product prepared with the new USP standard is shipped to hospitals in Canada.
  4. Question: What is the shelf life of PPC UFH products, and how long will there be product of both types on the market?
    1. Answer: The shelf lives of PPC Heparin Sodium Injection, USP products range from 24 to 36 months.
    2. Inventory levels vary by code at the individual wholesaler distribution center. In order for customers to clearly differentiate product tested using the new USP standards, PPC will be incorporating an �N� (for �new�) after the lot number on every vial. It is possible that once PPC begins shipping, product meeting the two different standards will be in circulation together for up to three years.
  5. Question: Should we return PPC UFH product manufactured using the previous USP standard and exchange it for PPC UFH product manufactured using the new USP standard?
    1. Answer: No. PPC has tested all of its heparin raw material dating back to 2006 (which was used for finished UFH within expiry in circulation) and all PPC heparin was found to be contaminant-free.
  6. Question: Will the Stage-2 product be available in all sizes?
    1. Answer: This USP Stage-2 monograph change will be made to all current PPC Heparin Sodium Injection sizes and codes.
  7. Question: When will the webcast be available for on-demand listening?
    1. Answer: The archived version of the first webinar in the series, “Readiness for New USP Standard for Unfractionated Heparin” is now available at www.APPpharma.com. Click here to register to view the archived webinar and to download takeaway materials from the event.
  8. Question: How can I obtain more information about this change?
    1. Answer: PPC has the following resources available for further information:
      1. PPC Website: www.ppcdrugs.com
      2. APP Website: www.apppharma.com
      3. PPC Customer Service at 1-877-821-7724 between 8am and 5pm ET
      4. For clinical and technical questions call PPC Medical Information at 1-877-779-7760 between 8am and 4:30 pm ET, or send e-mail through our website.
      5. USP: www.usp.org
      6. FDA Drug Safety Information for Patients and Providers:
        http://www.fda.gov

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