Workshop participants strongly agreed that modernization of heparin monographs was necessary but grappled with the questions
of methods, specifications, and speed of implementation. USP announced that its Stage-2 revision of heparin monographs will
become official on Oct. 1, 2009. To support these extensive revisions, USP released five new reference standards (RS): USP
galatosamine hydrochloride RS, USP glucosamine hydrochloride RS, USP oversulfated chondroitin sulfate RS, USP dermatan sulfate
RS, and USP heparin sodium for assays RS.
As part of the secondary revisions to the heparin sodium monograph, USP has adopted a new potency assay for heparin, the chromogenic
antifactor IIa test. The high specificity of this assay provides an additional safeguard against potential adulterants that
may display heparin-like activity in the current USP plasma-based assay.
EP also plans to refine its 1H NMR test to detect potential contaminants, including OSCS. One possibility under consideration is a 2-D NMR procedure. Like
USP, EP recommends adopting the antifactor IIa assay and increasing the potency specification to not less than (NLT) 180 IU/mg.
For related substances, EP is evaluating eight procedures submitted by industry and academic laboratories. A crucial criterion
for the selection of a related-substance procedure is the ability to differentiate between natural impurities and chemically
modified contaminants, but it is not deemed necessary to differentiate naturally occurring impurities. EP plans to set the
limit for dermatan sulfate, a heparin-related substance, at not more than (NMT) 2.0%.
For JP's heparin sodium monograph, planned revisions include two new identification tests, weak anion–exchange highperformance
liquid chromatography (HPLC) and 1H NMR, and two new impurity tests, a test for galactosamine and an updated 1H NMR test for the absence of OSCS. Additional revisions for protein impurities and nucleotidic impurities are planned as
well. For the heparin calcium monograph, JP plans to incorporate the 1H NMR identification test and the galactosamine impurity at a later stage. Note that the potency assay in JP heparin monographs
is an antifactor Xa-based assay.
At the workshop, industry stakeholders were invited to present their experiences with the proposed USP Stage-2 revised heparin
monographs. In general, industry concurred with and supported the modernization efforts, but manufacturers are concerned about
the lack of harmonization between pharmacopeias. Several recommendations were raised, including further optimization of protein
impurities and chromatographic identity tests to improve protocols and resolution requirements. An improved CE procedure was
presented as an alternative to the proposed anion-exchange HPLC procedure. Several manufacturers expressed concerns regarding
the implementation timeline for these revisions. Industry noted that the lack of a new potency RS, USP heparin sodium for
assays RS, during the public comment period contributed to its inability to evaluate USP's new potency requirement (NLT 180
USP heparin units/mg). (USP released the new potency RS in late July.) In addition, many comments made at the workshop and
during the public comment period were incorporated in the final USP Stage-2 revised monographs. USP Stage-3 revisions of heparin
monographs will include further optimization of procedures as suggested by the workshop participants.
Progress update—biosimilar LMWHs
The workshop reviewed the European Medicines Agency (EMEA) guidance document for biosimilar LMWHs, which establishes the nonclinical
and clinical requirements for LMWH-containing medicinal products that claim to be similar to another one already marketed
(5). EMEA's current recommendation is that the major burden of demonstrating that two LMWHs have similar biological medicinal
properties is by means of a clinical trial. Clinical trials are preferred because the product's mode of action is not completely
understood, and it is uncertain whether the pharmacodynamic markers are representative for the clinical outcome.
In contrast, the US has not yet finalized a regulatory pathway for approval of follow-on biologics. Workshop participants
advocated that FDA be granted the authority to approve biologics that reference a previously approved Public Health Service
Act biologic and that the burden remain on sponsors to demonstrate safety, purity, and potency. This pathway should be immediately
available, apply consistent regulatory standards, allow an interchangeability designation, and be flexible enough to incorporate