March 13, 2023 by Owen Green

Coronavirus medical equipment element set vector

Extractables are individual chemical entities that can be extracted from individual component types of any form of a medical device under laboratory conditions, using appropriate solvents or solvent systems. Extractables can, therefore, be considered as potential leachables from such devices. Leachables are compounds which are present in the drug product due to leaching from the container/closure system or other components of the device which the drug may come into contact with. The presence of leachable substances in the drug product requires specific hazard evaluation assessments that may be different to those for contaminants which could be present as a result of the pharmaceutical manufacturing process.

Regulatory guidelines exist for the protection of individuals and populations from accidental exposures to chemicals and agents from many different sources. However, there is no internationally harmonised guidance on the assessment and control of extractables and leachables (E&L). In the manufacture and use of medical devices there exists the risk of exposure to E&Ls from device components, and also to process based chemicals used in the cleaning and maintenance of the device components. Consequently, the end user of the device can be exposed to minute quantities of such chemicals during normal use of the device, owing to potential contamination of the therapeutic formulation. Currently, the assessment and control of such E&Ls is governed by a series of ICH guidelines covering many aspects of impurities. These include process and product-related substances (ICH Q3A and Q3B), residual solvents (ICH Q3C) and guidelines covering elemental (ICH Q3D) and mutagenic (ICH M7) impurities. These documents are either directly or indirectly related to E&L issues and carry limitations, either in the geographical region of acceptance or in specific drug or manufacturing applications. Some groups have produced recommendations for specific dosage forms e.g. Product Quality Research Institute (PQRI) for inhalatory forms. In addition, other recommendations, such as pharmacopoeial standards, exist. Furthermore, indirect reference is made to leachables within ICH M7 in which the outlined risk assessment principles involving application of the threshold of toxicological concern (TTC) may apply. ICH Q3D also covers elemental impurities from processing equipment and container closure systems.

Derivation of PDEs for E&Ls

Permissible daily exposure levels (PDEs) are calculated for substances based on the toxicological information available. PDEs are derived for substances based on the effect levels determined in the most relevant animal study(ies), known as the point of departure (PoD).

Often, by their very nature as biproducts of manufacturing and/or packaging processes or chemical contaminants, E&Ls are present at widely varying concentrations and quite frequently have not been subjected to detailed safety assessment programs under more general chemical regulations. Consequently, finding sufficient relevant and reliable data upon which to base a PDE derivation can be challenging.

Toxicological data may be identified through extensive literature and regulatory searches, following on to reliability assessments of any data considered to be relevant. If no relevant, reliable experimental data are available, read across substances can also be considered to identify a PoD. QSAR assessments are also a useful tool which can provide links to related chemicals or chemical groups for which toxicological data may exist or may directly provide some predictive information on potential hazards of interest. Therefore, in most cases it is likely that some data can be identified from which a PoD can be determined, allowing the PDE derivation process to be carried out;  although data may not exist for all the endpoints covered by the relevant guidance documents.

New legislation development

In mid-2020, ICH published a Final Concept Paper to harmonise the assessment and control of extractables and leachables (ICH Q3E). The principal objectives were to include alignment of the current guidance framework existing in various ICH guidelines, pharmacopoeias and other standards, as well as to provide guidance on the conduct of studies with extractables and leachables, the development of harmonised thresholds and the establishment of safety limits in accordance with human exposure scenarios. The timeline for the completion of this new guidance document included a sign-off at Step 1 in April/May 2023 which would then be followed by a Public Consultation period to be completed by the end of 2023. Final sign-off on Step 4 is scheduled for November 2024. The possible impact that the new guidance may have on the detailed process of establishing PDEs for E&Ls is difficult to predict, however, a harmonised guideline addressing gaps and inconsistencies would provide focus on critical aspects and improve transparency in requirements for medicinal products including drug delivery device components.

How we can help

Comprehensive hazard data assessments and robust PoD identification are critical in the risk assessment of extractables and leachables from medical devices. The human health and mammalian toxicology team at wca possess many years experience in the overview of regulatory hazard assessment programs, and the detailed review of toxicology studies. We also have considerable expertise in identifying appropriate toxicological data for a wide range of substances, as well as the application of read-across and modelling approaches where relevant experimental data are not available for a substance. In particular, the team have developed a specialty in the identification of points of departure for the derivation of relevant health-based exposure levels under the most complex exposure scenarios.

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