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Tina S. Morris, PhD, is vice president of Biologics & Biotechnology at United States Pharmacopeia (USP)
USP workshop participants support new methods to safeguard heparin products but desire international harmonization. This article contains bonus online-exclusive material.
Continuing to help ensure the identity, purity, and quality of heparin, the US Pharmacopeial Convention (USP) has revised written and physical standards for the widely used blood thinner. In February 2009, USP released updated heparin standards at the request of the US Food and Drug Administration in response to the 2008 public health crisis in which many patients died as a result of adulterated heparin. A second phase of heparin monograph revisions is reflected in the newly posted standards (1). These developments and new analytical characterization tools for heparin were discussed by scientists and regulators at the Third International Heparin Workshop held at USP headquarters in Rockville, Maryland, July 27–28, 2009 (2).
The workshop, cosponsored by USP, the British National Institute of Biological Standards and Control (NIBSC), and the European Directorate for the Quality of Medicines (EDQM), reflected the global nature of both the problem of adulteration and the resources available to combat it. Attendees came from more than 17 countries. Workshop deliberations focused on safeguarding heparin supply, pharmacopeial updates, and progress on biosimilar low-molecular-weight heparins (LMWHs).
In early 2008, FDA confirmed reports of adverse health events associated with the use of heparin that had been contaminated with oversulfated chondroitin sulfate (OSCS) originating in China (3, 4). In June 2008, USP responded to the heparin crisis by revising its heparin sodium and heparin calcium monographs. Stage-1 monograph revision incorporated FDA's analytical methods for the identification of OSCS in heparin: proton nuclear magnetic resonance spectroscopy (1H NMR) and capillary electrophoresis (CE). Other pharmacopeias followed suit.
Although this short-term measure prevented contaminated heparin from entering the supply chain, USP and stakeholders realized that a thorough modernization of the existing monographs would be needed to ensure the continuing quality of heparin. USP has since undertaken a second stage of revisions to the heparin sodium monograph, adding new identification, potency, and impurity tests that better control the quality of heparin active pharmaceutical ingredient (API). The European Pharmacopoeia (EP) and Japanese Pharmacopoeia (JP) also are taking a stepwise approach to revising their heparin monographs.
LMWHs are defined as heparin salts that have an average molecular weight of < 8000 Da and for which at least 60% of all chains have a molecular weight of < 8000 Da. LMWHs are prepared from unfractionated heparin (UFH) by various chemical or enzymatic depolymerization processes. Thus, the starting material of LMWHs is of biological origin, and the manufacturing process defines the characteristics of the drug substance. Because the manufacturing process does not necessarily remove all impurities present in UFH, manufacturers should ensure that the starting material complies with the latest regulatory requirements.
Table I: Stage-2 revisions of heparin monographs from world pharmacopeias.
Several licensed LMWHs differ in their source material, manufacturing process, pharmacokinetic/pharmacodynamic properties, and therapeutic indications. The development of biosimilar LMWH products has increased globally during the past decade. In anticipation of the arrival of more biosimilar LMWHs in the near future, workshop participants discussed the regulatory framework for follow-on biologic products. Additional topics included regulatory issues (e.g., immunogenicity) and analytical tools aimed at demonstrating comparability to licensed products.
Challenges of heparin characterization
Heparin is structurally the most complex member of the glycosaminoglycan (GAG) family of polysaccharides, which also includes chondroitin sulfate, dermatan sulfate, and keratin sulfate. Commercially available heparin in the US is derived mostly from porcine intestinal mucosa. Selectivity and yield emphasis in the purification steps affect the impurity profile of the resulting API with regard to common impurities such as dermatan sulfate and residual solvents. Because the different GAGs coexist in their natural sources, it is not uncommon to obtain GAG preparations contaminated with a structurally similar polysaccharide.
Because of this complex milieu, the challenges are to sufficiently quantify process impurities and naturally occurring impurities that are not cleared by the purification steps and to concurrently detect any potential contaminants intentionally added to heparin. Workshop partcipants agreed that the quality of crude heparin can only be achieved by complete traceability and good manufacturing practices (GMPs) throughout the manufacturing life cycle and by supplier qualification.
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 scientific developments.
Regulatory expectations regarding the quality of UFH have increased since the global heparin crisis of 2008. Industry has witnessed modernization of pharmacopeial methods that demand higher criteria for all quality attributes. Orthogonal tests have been implemented to identify heparin and to demonstrate lack of contaminants. At the workshop, USP and FDA jointly announced their intent to further revise heparin monographs to ensure the continued supply of safe and effectve heparin for patients. USP will update heparin stakeholders about the status of the monograph revisions and will ensure sufficient time for a public evaluation of the procedures, specifications, and implementation date.
Anita Y. Szajek, PhD, is a senior scientific liaison, Tina S. Morris, PhD, is vice-president of biologics & biotechnology, both at the US Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, tel. 301.816.8325, firstname.lastname@example.org
1. USP Heparin Hot Topics Page, www.usp.org/hottopics/heparin.html, accessed Aug. 27, 2009.
2. USP Heparin Workshop Page, www.usp.org/meetings/workshops/heparinWorkshop2009.html, accessed Aug. 27, 2009.
3. FDA, Information on Heparin (2009), www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM112597, accessed Aug. 27, 2009.
4. M. Guerrini et al., "Oversulfated Chondroitin Sulfate Is a Contaminant in Heparin Associated with Adverse Clinical Events," Nature Biotechnol. 26 (6), 669–675 (2008).
5. EMEA, Guideline on Similar Biological Medicinal Products Containing Low-Molecular-Weight-Heparins (London, March 2009).