Pharmacopeial updates

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.

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.

Industry feedback

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 scientific developments.