Drugmakers Say ICH Guideline for Metal Impurities is Impractical

Proposed international guidelines on metal impurities in finished drugs may be impossible to meet because they lack specificity and are impractical for suppliers, drugmakers say.

These comments came in response to the International Conference on Harmonisation’s Q3D draft guideline that sets the permitted daily exposure (PDE) limits for metals based on safety and toxicology data. The new limits — which impose specific limits on metals that vary based on how the drug is administered — require much more rigorous testing than the impurity limits set by the U.S. Pharmacopeia.

The guideline addresses a key concern among regulators that some excipient makers test their products for heavy metals infrequently — in some cases, testing only once a year.

However, drugmakers said it is difficult to obtain information on metal impurities in reagents, APIs and excipients, and the guideline envisions a level of cooperation with suppliers that will be impossible to attain.

“In many cases suppliers are willing, but unable to provide the required data due to lack of time, capability and/or resources,” said AstraZeneca, one of 15 stakeholders to submit comments.

For other suppliers, manufacturing drug materials may be a small part of their total business, AstraZeneca said, and investing in increased testing capacity would likely drive some to give up serving the pharma industry altogether.

Another problem is that the guidelines are confusing about what information suppliers must provide. GSK and AstraZeneca recommend that the guidance include a new section with acceptable examples of information a supplier could provide to a manufacturer.

Drugmakers also are concerned that the Q3D guideline is limited to oral, inhalation and parenteral drugs. More guidance is needed for other routes of administration, such as topical/dermal products, Merck said.

GSK echoed Merck’s concern. “If this issue is not addressed, it will most likely lead to different interpretations by regulators and companies and result in numerous questions during reviews,” the pharma giant said.

According to the guideline, sponsors should determine acceptable limits for other routes of administration based on a risk assessment. To avoid unnecessary work, ICH needs to spell out what should be included in the risk assessment, GSK said.

Meanwhile, drugmakers say, the inclusion of inhalation drugs for many impurities is overkill because it would be impossible for them to contain enough of a metal impurity to cause harm.

The type of administration isn’t the only thing that requires additional clarity. Drugmakers also took issue with the guideline’s metals classification system.

The guideline divides metals into classes based on their toxicity:

• Class 1 metals include mercury, lead, cadmium and arsenic. These metals are significantly toxic across all routes of administration and typically have limited or no use in the manufacturing of pharmaceuticals;

• Class 2 metals include vanadium, molybdenum and cobalt — metals considered toxic to a greater or lesser extent based on how they are administered;

• Class 3 impurities have a relatively low toxicity if taken orally but require consideration in the risk assessment for other types of administration, such as inhalation. Metals in this class include chromium, copper, tin and nickel; and

• Class 4 metals — such as sodium, calcium and zinc — don’t have a PDE because their toxicity is very low, but are still mentioned throughout the guidance.

Since no safety data or limits for Class 4 metals are provided in the guideline, these metals shouldn’t be mentioned, said Novartis. “The focus should be kept strictly on elements with attached safety data information and respective limits,” the drugmaker said.

The comment period on Guideline for Elemental Impurities Q3D has closed. While no date has been set for finalizing the guideline, officials involved in its publication have said the goal is for the guideline to be completed this summer.

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