Editor’s Note: For full commentary on and coverage of the industry’s heparin crisis, please visit our Heparin Resource Center.
The U.S. Pharmacopeial Convention (USP) has released a second round of revisions to heparin standards, which went into effect this month, harmonizing dosage measurement units with those of WHO. USP and FDA are now working on a third revision. They will require that heparin be tested for the presence of oversulfonated chondroitin, using methods already approved.
The need for harmonization became clear during a USP Workshop on heparin in late July, at USP’s headquarters in Rockville, Md. There is still strong disagreement among scientists and companies as to the “necessary and sufficient” tests needed to prove heparin safe and potentially effective. In fact, the units used to measure the strength of heparin differ between the U.S. (via the USP) and the rest of the world (as IU’s). This was largely due to different “standardized” tests for the activity which, as one might guess, are not standard. The speakers referred to UFH (unfractionated heparin) and LMW (low molecular weight) heparin where exact definitions are slippery. The LMW heparins, for instance, are better among batches than UFH lots and have been supported by the World Health Organization as the International Standard (IS) since 1987.
The EP has a monograph, while the new USP monographs are in draft mode (at best); meanwhile, the first IS for LMW heparin is becoming depleted. (Japan apparently is not, so far, agreeing with any other agency and is holding out its standards as sufficient.) Numerous speakers suggested methods of analysis from simple blood and chemical tests, through capillary electrophoresis, followed by 2-D NMR. It is this last method that received the most comments, it seemed.
One reason is, quite simply, the cost of purchasing and maintaining a 300MHz NMR instrument. The purchase alone can run into the high six figures, quite beyond the operating budget of most small pharmaceutical houses and suppliers. Add to that the requirements of an isolated room (strong magnetic field) and liquid helium to cool the magnet with liquid nitrogen used to slow the liquid He evaporation.
The second would be the operation of the instrument. While it was second nature to Dr. Ian McEwen (Swedish Medical Products Agency or MPA) to operate the system and correlate it with a second NMR scan using a 1H-NMR, generating a two-dimensional graphic. This is an excellent method for characterizing heparin, but is far from routine or simple.
A poster by Health Canada workers (Regimbald-Krnel et al.) showed some interesting work. The poster, titled “Characterization of heparin products and contaminant glycosaminoglycans using optimized proton NMR, capillary electrophoresis, and ion-exchange HPLC,” showed that lesser methods (than 2D NMR) could be used to characterize heparin. This is key to universal acceptance of any method.
Other speakers at the conference covered the actual harvesting and treatment of “raw” heparin stock, how to assure quality, how to standardize treatment, and other operational techniques. The meeting was overall non-confrontational and there was a sincere air of cooperation and willingness to listen to all points of view. Most importantly, the USP is a key player in the updating of monographs of not only heparin, but any and all other biologics for which there may be outdated methodologies.
In light of the international nature of API and raw materials production and supply-chain, with newer players, it is becoming a necessity to have specific unified methodologies for materials. It is no longer sufficient to have the older, inferential tests (many originating 50-75 years ago) as guardians of our safety. This conference and more like it are important steps in healthcare safety and should be applauded.