ICH proposal for Guidelines for Extractables and Leachables
The ICH proposal for Guidelines for Extractables and Leachables has been published on the European Medicines Agency (EMA) website. The purpose of the draft Guideline is to provide a global framework for managing leachables in pharmaceutical products.
This draft Guideline presents a holistic framework and process for the assessment and control of leachable impurities to further expand the existing ICH guidelines on impurities, including impurities in new drug substances (ICH Q3A) and new drug products (ICH Q3B), residual solvents (ICH Q3C), and elemental impurities (ICH Q3D), as well as DNA reactive (mutagenic) impurities (ICH M7).
The framework of this draft Guideline follows the principles of risk management as described in ICH Q9. While the draft Guideline includes materials characterization and process understanding, its primary purpose is to protect patient safety and product quality through assessment and control of leachables in the drug product. Due to rapid advances in materials engineering, device innovations, new manufacturing paradigms and novel therapeutic modalities, the aim is to provide principles and concepts that are forward looking within the scientific and regulatory landscape.
The draft Guideline expands existing ICH impurity guidelines and includes an multifactional risk matrix. The overall risk management process includes hazard identification, risk analysis and an integrated risk evaluation. The draft Guideline applies to the risk assessment and control of leachables in new drug products, including cell and gene therapy products. Drug-device combination products that require marketing authorizations and meet the definition of pharmaceutical or biological products also fall within the scope of the draft Guideline.
Organic leachables are the primary focus of this draft Guideline. Though recommended methodologies for elemental analysis are within the scope of the draft Guideline, the safety assessment of elemental leachables are addressed by ICH Q3D and thus out of scope for this draft. Products excluded from the scope of the draft Guideline include herbal medicinal products and crude non-processed products of animal or plant origin and products used during clinical research stages of development.
The draft Guideline recalls that leachables generally represent a subset of extractables. The concentration of each leachable is typically below that of the corresponding extractable from a well conducted extractables study. Once the extractable and leachable are established the draft Guideline recommends that a qualitative and quantitative correlation between the two be evaluated. Related purposes and procedures are discussed. The draft Guideline recommends incorporation of a Safety Concern Threshold to first establish a study-specific Analytical Evaluation Threshold (AET). This is the threshold at or below which a leachable would have a dose so low as to present negligible safety concerns from mutagenic and non-mutagenic toxic effects unless the leachable is identified as being a leachable of high concern.