The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has in place a guideline, ICH Q3D, to assess the risk of excessive exposure to elemental impurities in pharmaceuticals. ICH Q3D covers 24 elements, including arsenic, cadmium, lead, and mercury, which are known to be toxic and can have adverse effects on human health. The guideline itself provides all the background safety information as well as a series of tables and calculation methods which can be used to determine if there is an excessive risk of overexposure to these toxic elements as a result of patients taking daily doses of our medicinal products.
This guideline is based on the principles of quality risk management, and it takes into account the potential exposure to elemental impurities, the toxicity of the impurity, and the sensitivity of the patient population.
By reviewing potential exposure, ICHQ3D assessments look at the likelihood that humans or animals may come into contact with these elements in drug products entering the body through injection, ingestion, inhalation or absorption through skin contact. In simplest terms, we determine this by assessing all potential exposure risks in the formulation and manufacturing process. We calculate the maximum potential exposure using control measures and limit specifications from all process water, equipment, constituent excipients and Active pharmaceutical ingredients to determine a calculated maximum potential daily intake. Where control limits may not be in place, there would be a requirement to test representative samples using an appropriate method such as ICP-MS to determine the actual levels present in either a constituent or in the final drug product. The result would be a calculated or measured maximum potential daily intake.
A review of the toxicity determines the ability of these elements where present to then cause harm when they enter the subject and this will consider factors such as genotoxicity, carcinogenicity, neurotoxicity and teratogenicity. ICH Q3D also considers the sensitivity of the patient population, and factors such as age and pre-existing conditions may be taken into account and lead to safety limiting factors used in the subsequent calculations. From this, we determine a maximum Permitted Daily Exposure (PDE) limit for each of the elements required using the tables in the guideline and based on the route of administration of the drug. We then compare the calculated or measured maximum potential daily intake of each element and determine if it exceeds the Permitted Daily Exposure limit.
ICH Q3D uses a control threshold which is defined as a level that is 30% of the established PDE in the drug product. This control threshold is typically used to determine whether additional risk mitigation controls may be required. If the calculated or measured maximum potential daily intake for a particular element is less than the 30% control threshold, we may conclude that no further control measures or mitigation is required. Where the calculated or measured maximum potential daily intake is less than the permitted daily exposure, but still greater than the control threshold, then we may need to consider additional controls. This may be in the form of periodic testing or a change of raw material to a grade or source with a lower risk of exposure to the element in question.
Where the calculated or measured maximum potential daily intake is in excess of the permitted daily exposure limit for an element, then we must consider steps to reduce this, such as multiple changes to the grades or sources of raw materials or even reformulation of the drug product.
The ICH Q3D guideline has become an essential part of regulatory compliance in the pharmaceutical industry and it provides a standardised approach for evaluating the presence of toxic elemental impurities in drug products, drug substances and excipients.
Pharmaceutical companies must comply with ICHQ3D during the drug development process and throughout the product lifecycle. This requires an investment in analytical testing, quality control and risk analysis measures to ensure that the product meets the standards set out in the guideline. Also, changes to manufacturing processes and alternate suppliers require continual reassessment of product ICH Q3D assessments to ensure that the levels of elemental impurities in the product remain safe for patients. From a patient perspective, ICHQ3D is a positive development, as it ensures that pharmaceutical products are safe and free from harmful impurities.
Orion GXP Consulting has a team of Risk Management and ICH Q3D subject matter experts ready to help you review your elemental impurity program and assist you in ensuring it is on track. If you are in any doubts, please contact us today to ensure your products are safe and that the risk of exposing patients to potentially harmful impurities are appropriately assessed and controlled.
Get in touch today by emailing info@oriongxp.com; or by calling us IRL – 07198 10101 or UK – 0203 475 0375