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Elemental Impurities Guidance

As the one-year anniversary of the implementation of new elemental impurities requirements for brand and generic drug products approaches on January 1, the FDA has released a Guidance Document entitled, “Elemental Impurities in Drug Products: Guidance for Industry.”

The Guidance Document, issued on August 1st, provides recommendations for:

  • How applicants submitting new drug applications (NDAs) or abbreviated new drug applications (ANDAs) for noncompendial drug products should control elemental impurities as described in ICH Q3D. ICH Q3D contains recommendations on applying a risk-based approach to control elemental impurities and permitted daily exposure (PDE).
  • How manufacturers of compendial drug products that are not marketed under an approved NDA or ANDA can comply with USP General Chapters <232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures and the Federal Food, Drug, and Cosmetic (FD&C) Act.
  • How holders of NDAs or ANDAs for compendial drug products should report changes in chemistry, manufacturing, and controls specifications to FDA to comply with General Chapters <232> and <233> and 21 CFR 314.70.
  • How manufacturers of noncompendial drug products that are marketed without an approved NDA or ANDA should control elemental impurities.

The FDA recommends following the ICH Harmonised Guideline Q3D for specific directions on the evaluation of toxicity data for potential elemental impurities, application of a risk-based approach to control elemental impurities in drug products, or Permitted Daily Exposures for individual elements.

The Guidance explains how the compliance process should begin, “(a)s described in ICH Q3D and General Chapter <232>, the first step in a risk-based approach to the control of elemental impurities is performing a risk assessment. Manufacturers should use the results from the risk assessment to determine which elemental impurities are likely to be present in the drug product and whether current controls for those elemental impurities are adequate. If additional controls should be put in place, the results of the risk assessment can also help determine which types of controls should be used.”

Performing the methods in USP/NF Chapter <233> is generally straightforward, and a qualified laboratory with the proper instrumentation will be able to follow the instructions given in the specific monograph for each drug product or ingredient. However, for drug materials without a USP Monograph, a qualified laboratory must perform a validation study demonstrating the methodology utilized is sufficient. The validation study must establish, “that the analytical procedures used during risk assessments possess characteristics (e.g., accuracy, precision, specificity) such that the manufacturers can be reasonably certain (e.g., at the 95-percent confidence level) that the measurements can be relied upon to decide whether to include routine testing of materials in the control strategy. This decision depends on whether the amounts of the elemental impurities in the materials are consistently below control thresholds. The analytical procedures should be validated with this goal in mind.”

The Guidance recommends following, “ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology” and “FDA Guidance for Industry, Analytical Procedures and Methods Validation for Drugs and Biologics,” for validation studies.

To View the FDA Guidance Document Click Here

To View the ICH Q3D Guidance Document Click Here

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