Let us solve your solvent challenges- A <467> and <1467> overview

by Erika Guerrero, Raw Materials Principal Scientist Group Leader; Harley Wilcox, Senior Scientific Advisor, EBPT Columbia

Compendia products may be subject to the requirements within USP <467> Residual Solvents. This general chapter outlines methodology, solvent classifications, and tolerable daily intake (TDI) to be used for establishing limits of class 1, 2, and 3 solvents. USP <467> covers drug substances, excipients, and drug products; solvents may be measured either quantitatively or by a limit test. The methodology in USP <467> is readily applicable for Class 1, Class 2 (Mix A and B) solvents by headspace gas chromatography. Class 2, Mix C and Class 3 solvents may not be readily detected by this technique and an alternative method must be appropriately validated prior to use.

Prior to USP <1467>, verification parameters for USP <467> relied upon USP <1226> “Verification of Compendial Procedures.” This chapter references Table 2 in USP <1225>. To accomplish establishment, a subset of validation parameters was subjectively chosen from the USP guidelines to Let us solve your solvent challenges- A <467> and <1467> overview verify the residual solvent method. Upon the implementation of USP <1467>, USP now offers clearly defined verification and validation requirements for test articles subject to compendial analysis as noted in the guidance’s Table 1; this includes limit and quantitative approaches. In the event the USP <467> method requires modifications, the new chapter provides validation requirements for alternative procedures, which closely resembles the ICH validation guidance. The USP improvements with this implementation include a list of required verification parameters, a welcomed addition which eliminates subjectivity. In addition, outlining validation parameters for alternate procedures simplifies method suitability for special situations.

Eurofins BioPharma Product Testing performs significant residual solvent testing for raw materials, drug products, and drug substances at four US GMP sites, each capable of residual solvent method development. Eurofins BPT’s technical experts provide insights into establishing a method for clients’ test articles, including an understanding of the implication of synthesis process, drug product formulations, identification of unknowns, solvent screening as well a life cycle management.

Eurofins offers a number of solutions to clients to suit their individual regulatory needs. The following options, developed by Eurofins based on the USP, are available:

• Limit tests: Method verification is accomplished concurrently with routine testing and evaluated for every sample submission.
• Quantitative testing: Formal method verification, directed by Eurofins Lancaster Laboratories’ platform protocol, is performed prior to routine testing. Upon successful completion of verification, routine testing is performed to meet USP <467> requirements. Self-Validating Method for Class 2, Mix C and Class 3 solvents: This method has been widely used by Eurofins Lancaster Laboratories since 2012 for excipient evaluation. Each lot of material is subjected to a scaled-down method validation study targeting the key elements of interest.
• Development and Validation for Drug Products: Eurofins BPT Columbia and Eurofins Lancaster Laboratories have subject matter experts ready to discuss studies and the technical approach for development and validation.

Eurofins continues to adapt to regulatory changes while considering the most time-sensitive and cost-effective solutions for residual solvents needs. For more information about the USP <467> and <1467> changes and the impact on unique programs, join EBPT’s webinar hosted in conjunction with University of Wisconsin-Madison on July 24, 2019.