Organic solvents are used in the creation or manufacture of most drugs and/or pharmaceutical additives, and solvents that are not completely removed after processing by practical manufacturing techniques are classified as residual solvents. In May 2021, the International Council for Harmonization (ICH) announced an update to its residual solvents guidelines, establishing new permitted daily exposures (PDEs) for three residual solvents in finished drug products. ICH Q3C now includes cyclopentyl methyl ether and t-butanol as Class 2 “solvents to be limited”, and 2-methyltetrahydrofuran as a Class 3 “solvents with low toxic potential”. The PDE for 2-methyltetrahydrofuran is 50 mg/day, cyclopentyl methyl ether is 15 mg/day, and the PDE for tertiary butyl alcohol is 35 mg/day.
We spoke with experts at Avomeen and Element about the updated ICH guidance, key considerations for residual solvent analysis, and their thoughts about whether additional updates to regulatory guidance for residual solvents may be on the horizon. With Element’s acquisition of Avomeen in 2021 and Analytical Lab Group (ALG) in 2020, Element has combined complementary capabilities to offer an even wider array of services and value to clients in the life sciences, with an unwavering commitment to scientific excellence and quality, as well as exceptional client service and partnership.
The Importance of Testing for Residual Solvents
“Residual solvent testing is important because solvents are used in drug substance and excipient manufacturing and it is not possible to completely remove them. They have no therapeutic effect, and their level in the drug product is the level at which they are effectively administered to the patient along with the drug, giving rise to toxicological concerns,” says Dr. Andrew Kolbert, President and Chief Technical Officer at Avomeen. “The ability to test leads to the ability to control, which is ultimately what a manufacturer wants to do.” At the core of residual solvent testing and control of residual solvents is protecting patients, asserts Mike Shelton, Technical Director at Element. “Ensuring the concentrations of any residual solvents left over from processing is necessary to protect patient health,” he notes.
Outsourcing Residual Solvent Testing of Pharmaceuticals
Pharmaceutical companies often rely on the scientific and regulatory expertise and resources of CROs and CDMOs, including Avomeen and Element. A thorough understanding of both the methodologies and the regulations is critical when choosing the right outsourcing partner lab, particularly when requirements need to be applied to new drug substances and drug products. Shelton points out that if an outsourcing lab does not fully understand the regulations, particularly how PDE limits were arrived at, their ability to perform the analysis will not be sufficient to meet the needs of pharmaceutical manufacturers. “The compendial methods (such as USP <467>) have built in certain assumptions when determining these limits, and having a lab that understands those processes can help guide manufacturers through the options in assessing their finished goods for compliance to those specifications,” Shelton explains.
Kolbert stresses the necessity of method validation in addition to a robust quality system. “One needs to be able to execute the methods capably to avoid out-of-spec results traced to laboratory error which results in investigations and delayed batch release,” he adds. The accurate and robust data generated by a trusted CRO/CDMO can help pharmaceutical manufacturers make appropriate risk assessments for finished drug products. The risks have already been determined based on the classification of each solvent used and the PDEs, notes Kolbert. “As long as the PDEs are not exceeded, there is no meaningful risk to human health due to the solvents.”
CRO/CDMO Expertise can Help to Inform Residual Solvent Testing Strategies
A consultative CRO/CDMO partner with expertise and an in-depth understanding of regulatory guidance for control of residual solvents can provide valuable insight to pharmaceutical manufacturers when determining their testing strategy. “There are options set forth in the compendial chapters (USP <467> and Ph. Eur. 2.4.24) for calculating whether a finished product will comply with the specification based on the residual solvent levels in the raw materials that were used in the manufacturing process,” notes Shelton.
“It is standard practice to measure residual solvents in the drug substance (DS) and all excipients and perform an algebraic calculation to determine the maximum levels in the drug product (DP),” agrees Kolbert. “If the maximum level found in this manner exceeds the PDE of the solvents, then one would be expected to measure in the DP itself.” He points out that ultimately, the PDE is for the drug product; however, if the drug product formulation uses no solvents, all residual solvents will come from the drug substance and excipients.
Expectations for Compliance and Revisions to Pharmacopeial Residual Solvents Guidance
While test results should be reviewed for products where the manufacturing process of a drug substance or excipients involve these specific solvents to ensure continued compliance, pharmacopeial guidance has yet to be updated to reflect the recently approved changes. “It is important to realize that ICH is only an advisory body, and the revision has now reached the point of being recommended for adoption to the regulatory bodies,” says Shelton. “It is those regulatory bodies in the US, Europe, and Japan which will make any decisions as to whether to actually adopt the changes.” Kolbert notes that ICH Q3C (R8) only establishes the PDE for two class II and one class III solvent, so the effect of the revision is minimal.
Revision of the United States Pharmacopeia (USP) is a lengthy process, and furthermore, the USP is not harmonized with the ICH automatically. Kolbert states, “If new toxicology data becomes available to support revision of PDEs, reclassification of any solvents, or new calculations of PDEs for solvents where same was not possible, a further revision is likely.” Shelton provides additional background, “For example, the last time compounds were added, in ICH Q3C (R6), it was proposed for adoption in November, 2016. Ph. Eur. (European Pharmacopoeia) did not publish the change until April 2020, and USP in December 2020.”
If you are ready to start the conversation about your residual solvents testing needs, connect with a scientist today to learn how a partnership with Avomeen can help you to ensure compliance to updated ICH regulatory recommendations and current regulatory guidance. Avomeen’s consultative team of industry and regulatory experts can help you stay ahead of the curve, devising a residual solvent testing strategy to ensure your entire portfolio of products complies with recommendations likely to be adopted by regulatory bodies before the changes are fully adopted, ensuring patient safety and product quality.
Andrew Kolbert, Ph.D., M.T.M., Avomeen’s President & Chief Technical Officer, is a featured expert. Andrew has 20 years of experience executing and managing analytical and product development programs, both internally and in external organizations. Avomeen clients regularly benefit from his expertise in analytical chemistry and product development, particularly in highly regulated areas, including pharmaceutical development and testing, food contact migration studies, extractables and leachables studies, food additive and food contact notification testing and registration, and pesticide and insecticide testing under FIFRA. With his sound perspective, Andrew has been sought out as an expert witness for industry litigation cases and has participated in FDA pre-notification conferences, FDA site audits, and trained FDA inspectors on analytical technology.
Mike Shelton, Technical Director at Element, is a featured expert. Mike has over 30 years of analytical laboratory experience, and Element’s clients benefit from his ability to apply his extensive experience and expertise to solving new analytical challenges. He specializes in hyphenated mass spectrometry techniques, including, but not limited to, GC-MS, LC-MS and LC-MS/MS, and has extensive experience and familiarity with GC, HPLC, IR, NMR, ICP-MS and wet chemistry techniques.