Profiling Metal Content in Parenteral Grade Protein Stabilizers

By: Jason Forbes, Larry Lonski, and Christopher Wilcox

Sucrose, Trehalose, Mannitol, and Maltose are four of the most commonly utilized carbohydrates for protein stabilization in drug formulations. As the demand for parenteral excipients continues to rise, the biopharma industry is considering guidance that would require more extensive analysis of a variety of minor constituents, including metals. Despite the high purity of many of these excipients, it is important for manufacturers to have an understanding of non-sugar moiety profiles and how they may vary with raw materials and processing.

Specifically, we have analyzed multiple lots each of our trehalose, sucrose, mannitol, and maltose for levels of V, Cr, Mn, Fe, Ni, Cu, Zn, As, Mo, Ru, Rh, Pd, Cd, Os, Ir, Pt, Hg, and Pb. Results of the metal analysis performed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) on Pfanstiehl’s injectable grade platform excipients can be found at http://www.pfanstiehl.com/home/resource-center/profiling-metal-content/. Further details about the methods and their validation can be obtained by following the link as well. Upper limits described in the expanded article were set as harmonized limits based on the lower of the two levels suggested by the USP and/or EP. The data in each of the 4 tables illustrate that in all cases, these particular parenteral excipients have exceptionally low levels of the metals tested. In fact, there was only one instance in which a result was above the limit of quantitation. In that case, one lot of trehalose had a cadmium (Cd) level of 0.11ppm against a limit of quantitation of 0.05ppm and harmonized limit of 0.25ppm.

Given the very low levels of metals detected by these fully validated test methods, the takeaway is that the materials assayed are unlikely to cause any safety concerns with respect to metal contribution. There is also virtually no risk of these particular excipients failing to pass metal limits proposed by USP/EP/ICH in the future. This should provide a level of confidence for manufacturers and formulators using these excipients in existing processes and in pipeline development programs. The next step will be to try to correlate application data with these and other impurity profiles, and to map their impacts on formulation robustness and stability. At the very least, availability of such data should enable better decisions with respect to sourcing of critical raw materials for a variety of formulation applications, including media optimization, protein stabilization for liquid and lyophilized platforms, vaccine stabilization, and cell therapy.

For more information, visit www.pfanstiehl.com.