ICH Releases Final Guidance on Elemental Impurities in Finished Drugs

Despite industry concerns that ICH’s proposed new limits on metals are too strict, the organization released final guidance on elemental impurities in finished drugs that appears little changed from an earlier draft.

The new limits — laid out in Guideline for Elemental Impurities Q3D — vary based on how the drug is administered and require more rigorous testing than the impurity limits set by the U.S. Pharmacopeia. If possible, drugmakers should assess the bioavailability of the element via the intended route of administration and compare that with the bioavailability of the element by the route with an established permitted daily exposure, ICH says.

In comments on the draft, drugmakers said it would be difficult to obtain information on metal impurities in reagents, active pharmaceutical ingredients and excipients, and argued that the guideline envisioned a level of cooperation with suppliers that would be impossible to attain.

The ICH Steering Committee acknowledged those concerns, noting that a comprehensive training program will be needed to ensure implementation of Q3D on a global basis.

Under the final guideline, drugmakers must evaluate toxicity data for potential elemental impurities, establish PDEs for each element that raises toxicology concerns and apply a risk-based approach to control elemental impurities.

The guideline divides metals into three classes based on toxicity:

• Class 1 metals include mercury, lead, cadmium and arsenic. These metals are significantly toxic across all routes of administration;
• Class 2 metals include vanadium, molybdenum and cobalt — metals considered toxic based on how they are administered; and
• Class 3 impurities have relatively low toxicity if taken orally, but require risk assessment for other types of administration, such as inhalation. Metals in this class include chromium, copper, tin and nickel.

The guideline highlights ICH Q9 on quality risk management as a starting point for determining risk for elemental impurities. Risk assessments should:

• Identify known and potential sources of elemental impurities;
• Evaluate the presence of the impurity by comparing its level with the established PDE; and
• Determine if built-in controls are sufficient or identify additional controls to limit impurities.

Existing drugs have until September 2018 to comply with the guideline. Developers and sponsors of new drugs should follow it now.

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