Reference standard program
Compendial.
The use of compendial reference standards is preferred for a reference-standard program. Regulatory agencies will accept
reference-standard materials from a pharmacopeial source and NIST without further qualification (1). NIST provides a certificate
of analysis (CoA) that includes purity information and an expiration date. USP, however, labels its reference standards (assay
reference standards to the nearest 0.1% and impurity reference standards to the nearest percent). In addition, USP reference
standards are considered suitable for use up to one year after a new lot is released.
Wherever possible, therefore, compendial methods should be used to qualify reference standards. If the reference-standard
program requires tests that are not captured in compendial methods (as is the case with organic impurities), then analytical
test procedures must be developed and qualified. This can be an expensive process and may delay the process of stability or
clinical programs.
Noncompendial.
Applicants that use proprietary materials will find that primary standards are not typically available through compendial
sources. As a result, noncompendial (secondary) reference standards require characterization and, thus, reference-standard
development and qualification programs need to be implemented. Materials can be developed or purchased from chemical-supply
companies for use as in-house secondary reference standards even when compendial reference standards are available. In such
instances, the secondary reference standard should be qualified against the compendial reference standard.
Identification of impurities.
Actual and potential degradation products should be isolated and identified during development of the reference standard.
Typically, organic impurities are identified and confirmed using liquid chromatography–mass spectrometry (LG–MS); nuclear
magnetic resonance (NMR) and inductively coupled plasma/mass spectrometry (ICP–MS) are used for inorganic impurities; and
gas chromatography/mass spectrometry (LC–MS) is used for residual solvents.
It should also be determined whether enantiomeric or polymorphic forms exist. Each of these factors must be considered in
the development of a comprehensive reference-standard material program. Qualification of a secondary source reference-standard
material begins with obtaining a CoA, the synthesis pathway (if available), and a list of methods used in product manufacturing.
This information can help analysts determine essential parameters for qualification. The identity of the material should be
confirmed with a "fingerprinting" technique such as fourier transform infrared spectroscopy (FTIR) to a library source or
by elemental analysis to confirm the molecular formula. Once identity has been established and confirmed, the quality of the
material must be ascertained. Elemental analysis, titration, GC, or LC can be used for purity determination. Based on the
results, the material may require further purification by distillation or recrystallization. Additional testing may be required
to identify and quantify known or potential impurities that may have been overlooked during the manufacturer's assessment
of the material.
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