FDA´s final Guidance on Elemental Impurities in Drug Products

The U.S. Food and Drug Administration, FDA, recently published its final guidance on Elemental Impurities in Drug Products which finalizes the draft guidance issued July 1, 2016. The guidance provides recommendations regarding the required documentation related to the control of elemental impurities (EIs) consistent with ICH Q3D and USP General Chapters <232> and <233>. The new document applies to manufacturers of noncompendial and compendial drug products. The control of EIs for all finished drug products is also addressed in 21 CFR part 211.

In detail the guidance deals with the following:

  • How applicants submitting new drug applications (NDAs) or abbreviated new drug applications (ANDAs, Generics) for noncompendial drug products should control EIs as described in ICH Q3D.
  • How manufacturers of compendial drug products that are not marketed under an approved NDA or ANDA can comply with United States Pharmacopeia, USP, General Chapters <232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures.
  • How holders of NDAs or ANDAs for compendial drug products should report CMC changes to FDA to comply with General Chapters <232> and <233>.
  • How manufacturers of noncompendial drug products that are marketed without an approved NDA or ANDA should control EIs (e.g. nonprescription OTC products marketed under an FDA monograph).

The first step according to ICH Q3D is to conduct a product risk assessment by identifying known and potential sources of EIs (i.e. elements intentionally added, elements potentially present in the materials used to prepare the drug product, elements potentially introduced from manufacturing or packaging systems). The second step is (if the risk assessment fails to show that an EI level is less than 30 percent of the established PDE (Permitted Daily Exposure) in the drug product (= control threshold)) to establish additional controls (for example included as in-process controls or in the specifications of the drug product or components), to ensure that the EI level does not exceed the PDE in the drug product.

However, the USP recently introduced new limits and analytical procedures for EIs in General Chapters <232> and <233>. Their primary goals are to

  • set limits for acceptable levels of EIs in finished drug products, and
  • update the methodology used to test for EIs in drug products to include modern analytical procedures.

As of January 1, 2018, the USP chapters <232> and <233> replaced <231> Heavy Metals. Additionally, <232> is applicable to all drug products with USP monographs (except for those drug products specifically excluded in <232>). USP may retain other specific metal limit tests (e.g., <211> Arsenic or Zinc in general packaging chapter on elastomeric closures <381>) that appear in a particular monograph. Furthermore, USP monographs and General Chapters may specify impurity limits or reporting levels that differ from <232>. When specific limits are included in a monograph or in a General Chapter referenced by a monograph, those limits are the official limits with which manufacturers must comply. However, <232> does not require routine testing of the drug product to ensure compliance. Depending on the source of an EI and the risk that its level in the finished drug product will exceed the PDE, alternative approaches to ensure compliance can be taken (e.g., routine testing of the components instead of the finished drug product). In addition, if the risk that the amount of an EI will exceed its PDE in the drug product is sufficiently low, it may not be necessary to test each batch of drug product for that impurity.

FDA recommends that the manufacturer of any U.S. marketed drug product follows ICH Q3D recommendations, unless the drug product must comply with USP requirements:

  • All new NDAs and ANDAs for drug products with an official USP monograph are now expected to meet the requirements for control of EIs described in <232> and <233>. New NDAs and ANDAs after January 1, 2018 for drug products without an official USP monograph should follow ICH Q3D. Applicants should include a summary of the risk assessment in any new application to which <232> and <233> or ICH Q3D apply.
  • Marketed compendial drug products not approved under an NDA or ANDA are expected to meet the requirements described in <232> and <233>. Marketed drug products not approved under an NDA or ANDA that do not have an official USP monograph should follow ICH Q3D. Manufacturers should include the risk assessment in the documentation maintained at the manufacturing site for Agency review during an inspection.
  • Changes to approved NDAs and ANDAs: Changes made to comply with <232> and <233> or changes made to follow the recommendations in ICH Q3D must be documented by the applicant in the next annual report. If a drug product approved under an NDA or ANDA does not meet the requirements described in <232> or the recommendations in ICH Q3D, documenting changes in an annual report is not appropriate. Those changes, for example manufacturing changes implemented to reduce the amounts of EIs, should be submitted according to existing post-approval CMC change guidance documents. Applicants should include a summary of the risk assessment in any supplemental application or annual report describing those changes.

If the analytical procedures described in General Chapter <233> cannot be used (for example in case of APIs, excipients, packaging components), USP permits the use of alternative procedures in accordance with General Notices and Requirements. Any analytical procedure must meet the validation requirements described in <233>. Alternative procedures should be properly described, and if used for routine testing, their suitability must be verified under actual conditions of use. However, ICH Q3D does not describe specific analytical procedures for routine testing of materials or for performing a risk assessment. Therefore, FDA recommends that manufacturers use the analytical procedures described in <233> or analytical procedures that meet the validation requirements described in <233> (in addition to ICH Q2).

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