PQRI Best Practice Recommendations (with comments) for Controlled Extraction Studies (CES)

Best Practice RecommendationComments
CESs should employ vigorous extraction with multiple solvents of varying solvating power.• A due diligence criterion. The term “vigorous” does not imply deformulation, but rather a “rigorous” study design. Solvents should be chosen with the drug product formulation in mind.
CESs may incorporate multiple extraction techniques.• A due diligence criterion. “Multiple extraction techniques” can include Soxhlet, reflux, sonication, headspace, automated solvent extraction, microwave, etc.
CESs should include careful sample preparation based on knowledge of analytical techniques to be used.• This is simply good practice of trace organic analysis.
CESs should employ multiple analytical techniques.• A due diligence criterion. In general, gas and liquid chromatography in combination are adequate.
CESs should include a defined and systematic process for identification of individual extractables.• This is simply good practice of trace organic analysis.
CES “definitive” extraction techniques/methods should be optimized.• A due diligence criterion. This implies the so-called “asymptotic levels” (i.e., equilibrium levels).
During the CES process, sponsors should revisit supplier information describing component formulation.• A due diligence criterion.
CESs should be guided by an AET that is based on an accepted SCT.• A due diligence criterion which takes the safety-based leachables thresholds into account.
Special case compounds such as PAHs (or PNAs), N-nitrosamines, and 2-MBT require evaluation by specific analytical techniques and technology-defined thresholds.• Compounds of particular potency as recognized by the TTC concept.
Qualitative and quantitative extractables profiles should be discussed with and reviewed by pharmaceutical development team toxicologists so that any potential safety concerns regarding individual extractables, that is, potential leachables, are identified early in the pharmaceutical development process.• A due diligence criterion. Safety assessment should be an integral part of every phase of an extractables/leachables assessment.