ICH releases Q3E guideline on controlling extractables and leachables in drugs
The International Council for Harmonization (ICH) has released a draft Q3E guideline that offers a harmonized framework for assessing and controlling extractables and leachables (E&L) in pharmaceuticals and biological products.The guideline addresses chemical and biological products, including drug-device combination products. It also considers all dosage forms, factoring in extracting or leaching conditions, the route of administration, the drug's indication, and patient exposure.
Plans to develop guidelines date back to 2019, when ICH announced its intention to form a working group aimed at creating guidance on extractables and leachables. (RELATED:ICH Updates After Singapore Assembly Meeting, Regulatory Focus 27 November 2019)
The guideline aims to address a gap in the treatment of E&L issues, which are not covered by ICH, as noted in a concept paper from June 2020. This gap “generates uncertainty for industry and regulators due to lack of clarity regarding E&L to meet regulatory expectations. The uncertainty creates potential delays in the approval of regulatory applications, and it can lead to variable interpretation.”
The guideline defines leachables as “chemical entities that migrate from manufacturing components/systems, packaging, or delivery device components into a drug product under the established manufacturing and labelled storage conditions” and extractables as “chemical entities that are intentionally extracted from manufacturing components/systems, packaging or delivery device components under specified laboratory test conditions and thus are potential leachables.”
ICH said that guideline provides a “holistic framework” for assessing and controlling leachable impurities and expands the existing ICH guidelines on impurities, including impurities in new drug substances (ICH Q3A), new drug products (ICH Q3B), residual solvents (ICH Q3C), and elemental impurities (ICH Q3D), as well as DNA reactive impurities (ICH M7).
The guideline proposes a set of risk management principles for assessing the presence of E&L in pharmaceuticals, and outlines a core set of chemical testing and assessment principles for E&L.
“Any changes occurring during the product life-cycle significantly altering the extractable/leachable profiles should prompt re-evaluation of the extractable/leachable profiles and their correlation. If a specific leachable is observed in the drug product during stability studies at a level significantly greater than anticipated from the calculated potential maximum level of the leachable as established with the extraction study conducted on the same component/system lots as were used for the drug product stability batches, it can indicate that the extraction study was incomplete and it may not be possible to establish a meaningful leachables to extractables correlation for that particular leachable,” the guideline states.
It adds that “prior knowledge may comprise information useful to obtain before performing chemical testing, including information available from a supplier and any relevant information with regard to other drug products and processes.”
The guideline also discusses an analytical evaluation threshold for leachable studies, and addresses safety assessments. The guideline states that “a risk-based scientific evaluation is needed to provide confidence that any potential leachables in the drug product are at levels where they pose negligible risk to the patient. Within this overall risk-based evaluation, the focus of the safety assessment is the toxicological evaluation of leachables in the drug product exceeding a predefined SCT [safety control threshold] for that drug product.”
In their applications, sponsors should justify why the extractable and leachable studies were conducted.
The guideline includes six appendices. Appendix 1 outlines typical workflows for extraction and leachables (E&L) assessment. Appendix 2 describes the various types of studies. Appendix 3 explains the calculations for acceptable exposure thresholds (AET). Appendix 4 categorizes potency classes for leachables. Appendix 5 details methods for establishing exposure limits, and Appendix 6 provides monographs for Class I leachables.
Along with the guideline, ICH published supporting documentation that should accompany Class III leachable monographs.
ICH Q3E guideline
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