Improve the efficiency of your impurity testing

Nick Hauser, Product Manager Analytical Standards, nick.hauser@m​illliporesigma.com​

To ensure the safety of pharmaceutical products, active pharmaceutical ingredients (APIs) need to be tested thoroughly. The accurate detection and control of impurities in drug substances and products is an essential element of ICH and GMP requirements. Reference Materials for these impurities are often hard to find, very expensive, or time consuming to make and maintain consistency. In pharmaceutical quality control (QC) laboratories, APIs and related substances are weighed daily or weekly to make multi-analyte stock or working level solutions. This cumbersome approach introduces the potential for inconsistencies and error, especially with difficult to handle materials.

Our new product range of pharmaceutical impurity solutions saves both cost and labor by providing all regulated impurities in one mix. These impurity solutions are manufactured as Certified Reference Materials (CRMs) according to ISO 17034 and ISO/IEC 17025 double accreditation. Accelerated stability studies are conducted under sub-freezer, freezer, refrigerated, room temperature and 40⁰C conditions over several weeks to determine any degradation or interaction of the individual analytes. If necessary, individual impurities will be removed from the mixtures and manufactured as single component solutions using conditions that will fortify stability. These single component solutions are manufactured at convenient concentrations to be easily combined with the existing mixtures with minimal sample handling. Also, storage in ampoules under argon protects the materials from air, light and changes in concentration.

Another unique and valuable aspect of these solutions is that the individual neat materials that are used as starting materials are Secondary Pharmaceutical Reference Standards. These Secondary Standards are manufactured as Certified Reference Materials and made traceable to a corresponding Primary Compendial Standard. The products are designed to be used as stocks and/or working level solutions.

Table 1​ shows the composition of the combination of Acetaminophen impurity mix A-134, 4′-Acetoxyacetanilide (Acetaminophen RC A) solution A-135, 4-Aminophenol (Acetaminophen RC K) solution A-136, and 4-Chloroacetanilide (Acetaminophen RC J) solution C-166 comprising the components required for analysis according to the monograph methods. See compound structures in Figure 1​.

Figure 2​ shows an example chromatogram of the Acetaminophen and Related Compound solutions (structures of components shown) combined as one sample solution.

Ready access to consistent, accurate, and reliable ISO manufactured impurity solutions is a significant improvement for the efficiency of pharmaceutical product QC testing.

A complete overview of all our available reference materials for pharmaceutical impurities (neats and solutions) listed by API can be found at SigmaAldrich.com/pharma-impurity-mixture​.​

To see all our reference materials for Pharmacopoeias, please visit SigmaAldrich.com/standards-pharma​.​

Table 1.​ Acetaminophen Impurity portfolio (combining cat.nos. A-134, A-135, and A-136).

Figure 1.​ Chemical structures of the Acetaminophen impurities

Figure 2.​ HPLC-UV Analysis of the combined Acetaminophen Impurities (Cat. Nos. A134, A135, A136).

Conditions ​

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Pharmaceutical Impurity CRM Mixes and Solutions Currently Available​

The content of a mix (compound listing) and the CRM’s solvent can be seen on the product detail page on our website. ​