Leachables and Extractables: From Regulatory Expectations to Laboratory Assessment

Abstract

During manufacturing, storage and administration, a pharmaceutical drug product (DP) formulation and its constituents are in contact with a multitude of polymeric materials. Every such contact leads to leaching of chemicals from the material into the formulation. Health authorities demand from the pharmaceutical manufacturer to control leaching within an extractables/leachables (E/L) assessment as a measure to prevent the patient from undue risk. Such an E/L assessment is structured into different parts. Initially, the manufacturing, storage and administration process is mapped; i.e. all contact materials are listed together with relevant process parameters that might influence leaching. A risk evaluation scores the materials according to their risk. High-risk materials are subjected to laboratory E/L testing. Test conditions, i.e. incubation of materials, should reflect the conditions encountered in the process—too exaggerated incubation conditions leading to excessive extractables profiles that do not correlate with leachables profiles encountered during real contact should be avoided. Analysis of the incubation solutions within screening studies should cover comprehensively the physical–chemical properties of E/L compounds; typical analytical methods are headspace-GC–MS, GC–MS and LC–UV–MS. Quantitative evaluation of analytical data should be performed against analytical evaluation thresholds derived from toxicological safety thresholds. Compounds encountered above the threshold need follow-up activities, e.g. structural identification and toxicological assessment. Special considerations have to be applied and are discussed within this chapter with regard to E/L assessment of drug substance manufacturing materials, the interaction of leachables with process constituents, glass delamination, leaching of silicon oil and leaching from secondary packaging materials, adhesives and printing. In summary, a proper E/L assessment should enable the pharmaceutical manufacturer to choose manufacturing, storage and administration materials that do not pose an undue risk for patients with regard to leaching.