The risks have already been determined based on the classification of each solvent used and the PDEs, notes Kolbert. The accurate and robust data generated by a trusted CRO/CDMO can help pharmaceutical manufacturers make appropriate risk assessments for finished drug products. “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.
Kolbert stresses the necessity of method validation in addition to a robust quality system. “The compendial methods (such as USP ) 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. 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. 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. Pharmaceutical companies often rely on the scientific and regulatory expertise and resources of CROs and CDMOs, including Element. Outsourcing residual solvent testing of pharmaceuticals
“Ensuring that the concentrations of any residual solvents left over from processing is necessary to protect patient health,” he notes. “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 Santa Fe Springs. 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. “Residual solvent testing is important because solvents are used in drug substance and excipient manufacturing and it is not possible to completely remove them. The importance of testing for residual solvents In this article, Element’s experts explore the updated ICH guidance, key considerations for residual solvent analysis, and share their thoughts as to whether additional updates to regulatory guidance for residual solvents may be on the horizon. 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 cyclopentyl methyl ether is 15 mg/day, 2-methyltetrahydrofuran is 50 mg/day, and the permitted daily exposure limit for tertiary butyl alcohol is 35 mg/day.
Ich guidance update#
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. 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. An overview of the updated ICH Q3C guidelines
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