Heparin Sodium monograph Stage 3—specifics
Immediately after the implementation of the Stage 2-revised Heparin Sodium monograph, USP collaborated with stakeholders and
FDA to further strengthen the standard and help ensure continued access to heparin of good and acceptable quality. USP's third
stage of revisions aimed to optimize and reinforce the Heparin Sodium monograph against OSCS and process impurities.
The USP Unfractionated Heparin Expert Panel played a crucial role in modernizing the Heparin Sodium monograph and updating
the associated specifications. The panel consists of industry, academic, and regulatory experts from around the world and
is advisory to USP's Monographs—Biologics & Biotechnology 1 Expert Committee (Monographs-BB1 EC), which is responsible for
establishing and updating heparin standards and is part of USP's Council of Experts. With FDA input, panel members reviewed
submissions regarding new and improved analytical procedures for the characterization of heparin. These procedures first were
evaluated for suitability as compendial methods; when needed, further validation work was carried out.
Identification.
Public feedback on the Stage 2 1H NMR procedure generally was positive, but commenters did recommend minor modifications to the experimental procedure. These
include the option of adding ethylenediaminetetraacetic acid (EDTA), reduced trimethylsilylpropionic acid sodium salt (TSP)
concentration in a sample solution, as well as adjustments to the temperature range, acquisition time, and longer delay time.
The major change was the reduced percentage—0.3% (w/w) instead of 1% (w/w)—of OSCS in system suitability solution to ensure
a higher sensitivity of the method for OSCS.
Also based on public comments, the expert panel optimized and validated an improved anion-exchange high-performance liquid
chromatography (HPLC) procedure that provides a shorter run time, higher resolution between heparin and dermatan sulfate,
and improved sensitivity for impurities.
The third identification test that has been introduced is molecular weight determinations. The molecular weight profile of
heparin is an intrinsic property that depends on the starting material and the manufacturing process. The resulting molecular
weight distribution of finished heparin API in turn influences its potency, its ease of neutralization by protamine sulfate,
and its propensity to interact with plasma proteins (e.g., platelet factor 4, leading to heparin-induced thrombocytopenia
[HIT]). Therefore, the molecular weight distribution of heparin API could be used to ensure manufacturing process consistency
as well as the safety of heparin API.
Nucleotidic impurities and protein impurities.
A new quantitative HPLC-based method has been added to control residual DNA in heparin. A quantitative Lowry method replaced
the old turbidity test for protein impurities during Stage 2 revision. The improved procedure proposed in Stage 3 incorporates
an additional step for removing interfering substances from heparin sample solution. A lower acceptance limit is proposed
for both impurities procedures based on the batch data received during the round-robin studies.
The proposed revisions to the Heparin Sodium monograph—which include the two optimized identification procedures, the new
molecular weight determinations procedure, the optimized method for protein impurities, and the new method for nucleotidic
impurities—will be published in Pharmacopeial Forum 38(6) (November–December 2012). Comments will be accepted until Jan. 31, 2013. After review of the comments and further consideration
by the monographs-BB1 EC, the Heparin Sodium Monograph is expected to be approved and become official in USP 37–NF 32. Comments on the standards should be sent to aey@usp.org
.
Conclusions
In light of the significant changes introduced in the Stage 3 revisions, USP will continue to update stakeholders in a timely
manner about the current status of the monograph revisions and ensure that sufficient time is provided for a public evaluation
of the procedures, specifications, and implementation date. Working in close partnership with FDA, industry, and other stakeholders,
USP will work to ensure that revisions to the monographs are suitable and will support the overall framework for delivering
a safe and effective supply of medicines for patients.
Anita Y. Szajek, PhD, is principal scientific liaison, and Tina S. Morris, PhD, is vice-president of biologics & biotechnology, both at the US Pharmacopeial Convention (USP), aey@usp.org
.
References
1. FDA, Information on Heparin (2009),
http://www.fda.gov/cder/drug/infopage/heparin/default.htm, accessed Jan. 29, 2009.
2. M. Guerrini et al., Nat. Biotech., 26 (6), 669–675 (2008).
3. USP, USP 35–NF 30, Heparin Sodium monograph, pp. 3403–3406 (USP, Rockville, MD).
4. A. Szajek et al., Pharm. Tech., 33 (3), 136–137 (2009).
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