Reference standards assigned purity

As discussed earlier, the assignment of purity is ideally done by a relative method, comparing analyte peaks in chromatograms of sample solutions with analyte peaks in chromatograms of a reference standard of assigned purity. The difficulty that arises when no suitable reference standard exists has already been alluded to. Purity then has to be assigned on a 100% detected impurities basis. The nature of the difficulties that arise in assigning purity in this way is discussed in the next section. 

The critical parameter in the discussion of reference standards is the process of qualification. FDA guidance on this topic states that A non-compendial standard should be thoroughly characterized to assure its identity, strength, quality and purity. 3 It is therefore left to the pharmaceutical firm to establish thorough characterization for the ARS of each NCE. The overall qualification process for an ARS includes characterization of the material, proper form selection, and assignment of purity. Some general considerations in this process include... 

Once a thorough characterization of the reference standard has been completed, purity and assay values are assigned to the ARS. The purity, also known as potency or activity, is expressed on a theoretical and experimental basis. The theoretical purity (puritytheory) is the calculated amount (weight percent) of the API present in the DS based on the chemical structure. The puritytheory is used to calculate the assay value. 

In most cases, the purity of a pharmaceutical substance is determined by comparison of the reference standard with the known purity assigned. On the other hand, when no reference standard sample is available, the purity is determined by an absolute method in which the calculated result is based on theory and not by a comparative method. Purity established by analytical methods such as phase-solubility analysis or differential scanning calorimetry (DSC) is known as absolute purity (Figs. 3 and 4). 

Characterization data—Full characterization data should be supplied for the primary reference standard, including the results from analytical testing and spectral characterization. The assigned purity of the reference standard should be clearly designated. 

Documentation of preparation of stock and sub-stock solutions must start with receipt of the reference standard, its Certificate of Analysis, assigned purity (and possibly chiral purity) and its history of storage and use after receipt (Section 9.4.4). Procedures for preparation and subsequent dilution of stock solutions are described in Section 9.5.4 and stability testing for these solutions in Section 10.4.Ih. Some of the relevant documentation might be included in general laboratory SOPs but full documentation of all study-specific procedures and data regarding preparation, storage and validation of stock solutions is required. 

Related compound standard These standards are typically characterized fully, but not to the same extent as the primary reference standard of the active drug substance. Because quantities of these standards are typically limited, response factors for these standards can be assigned to eliminate routine use in FIPLC purity determination. 

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