The examination of extractable and leachable substances (such as plasticizers, antioxidants, stabilizers and dyes) is extremely important for the protection of patients and for regulatory documentation destined for authorities such as the FDA and EMA.
In recent years, the pharmaceutical industry has developed a better understanding of the impact of extractables and leachables on patient safety and drug product interaction, leading to increased scrutiny by the regulators. When there is a change in a drug product’s immediate packaging materials, there is a regulatory requirement to assess the impact of the change.
Testing is conducted to ensure that the materials are not leaching into a pharmaceutical or from a medical device to a patient. Typically, the testing is done on rubber and polymer materials or components used in medical device and pharmaceutical packaging.
Analytical Testing Service providers offers a number of services for Extractables and Leachables such as: Test strategy planning and data evaluation based on the available information; Supporting of risk analysis procedures; Development of a tailored study design for extractables and leachables or chemical characterization, according pharmaceutical standards and ISO 10993 part 12/18; Extractables profiling (inorganic and organic extractables); Sequential extractions and alternative extraction techniques for isolating extractables in materials made from polymers, metals and ceramics; Characterization of extractables by chromatographic and spectroscopic investigations; Identification of a material and the identification and quantitation of the chemicals present in materials by chemical characterization; Identification and evaluation of the physico-chemical, mechanical, morphological and topographical properties of materials; Chemical and structural changes (e.g. by DSC) on polymeric materials after stressing by temperature or irradiation; Determination of the Analytical Evaluation Threshold (AET); Calculation of the AET based on Safety Concern Threshold (SCT) or Threshold of Toxicological Concern (TTC) and ICH M7 guideline; Biocompatibility: USP<87> and USP <88>; Toxicological assessments and method development and validation of potential leachables in pharmaceutical products and from medical devices; Performing leachables studies or simulated use studies on pharmaceutical products and medical devices; Reporting and evaluation of results within the current guidelines.
Since leachables may affect drug product safety, efficacy and quality, regulatory guidances have provided recommendations regarding their analysis and toxicological safety assessment, i.e., qualification. Extractables studies are necessary to facilitate the leachables’ analysis, providing predictive information of potential leachables and in certain cases controlling leachable amounts in the final drug products through the control of extractable amounts of the container/closure components.
The extractables profile of the container/closure components from the controlled extraction study and leachables profile from the forced migration study or aged drug product screening analysis should go through a careful toxicological and physical/chemical assessment. The toxicological assessment includes an evaluation if any of the extractables and leachables present a structure activity alert, which may indicate a safety concern for the drug product and the physical/chemical assessment includes an evaluation of how likely the extractables from the container/closure components are to leach into the drug product formulation (including an evaluation of the leachables detected in the aged product screening analysis or forced migration study). Some of the factors that should be considered in this assessment include: extractable compound solubility; direct/indirect contact with the drug product; duration of contact; and any physical barrier for the migration of the compounds to the drug product.
Contract Pharma Analytical service providers perform analytical and toxicology assessment for extractables and leachables, reinforced by their knowledge of polymer, plastic and packaging materials, allowing to identify components from the most complex polymer formulation including adhesives, additives and stabilizer ingredients and their degradation products. They also provide a first-class evaluation and assessment of existing E/L data gaps, and through strategic screening or quantitative studies.