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FDA to Set Safety Limits for Potential Toxic Elemental Impurities in Approved Drugs

Written by Michael A. Walsh on October 22, 2013

A New FDA Draft Guidance Adds Significant Compliance Obligations and Potential for Adulteration and Manufacturing Defect Claims.

FDA’s proposed Draft Guidance entitled “Guideline for Elemental Impurities Q3D” establishes, for the first time, “acceptable safety limits of potentially toxic elemental impurities” or “Permitted Daily Exposure (PDE) levels. Establishing a PDE does not mean the FDA found or permits impurities in finished drug products. What the Draft Guidance does mean for the drug industry is more stringent compliance requirements, particularly as relates to supply chain. The Draft Guidance applies to finished drug products, but not to drug products used in clinical research or other products such as herbal products, vaccines, blood, or products of animal or plant origin. 

The Draft Guidance adopts (copyright notice and all) the draft consensus guidelines of the “International Conference on Harmonisation” (ICH), a consortium of pharmaceutical regulatory and industry authorities from Europe, Japan and the US. In the Draft Guidance, the FDA recognizes that there may be detectable or trace amounts of elemental impurities (i.e. deleterious and potentially dangerous substances) in pharmaceutical products at levels that do not present a health risk, constitute a manufacturing defect, or render the product adulterated. “Impurities” enter products because they are naturally present in the components of the product or through the manufacturing process. The upward limit for impurities in each component and cumulatively in finished drug products are disclosed to FDA as part of the drug approval process. This Draft Guidance reveals to the medical community and provides greater transparency for the consuming public that there may be potentially harmful “impurities” in FDA approved drugs. 

Until now a manufacturing defect was largely defined by whether the manufacturer met the “requirements” established by the FDA in the drug approval process. This Guidance sets topsy-turvy the primary jurisdiction and preemption effect of complying with FDA approved manufacturing requirements established through the drug approval process by inserting a wild card into the compliance equation. The Guidance places a burden on manufacturers to test, monitor, report and control for substances at levels that do not cause harm but where the failure to test, monitor, report and control is a violation rendering a product adulterated.

The proposed Guidance establishes 4 toxicity classes, a 4 step process to control impurities and some potential unintended consequences:

4 Classes of Impurities:


  • Class 1: four elemental impurities that are considered “significantly toxic across all routes of administration.” The elements in this class have limited or no use in the manufacture of pharmaceuticals but can be present as impurities in commonly used materials (e.g., mined excipients) and cannot be readily removed from the material.
  • Class 2: impurities that are considered “toxic to a greater or lesser extent based on route of administration.”
  • Class 3: impurities with relatively low toxicity.
  • Class 4: elements with “low inherent toxicity”

4 Step Process to Assess and Control Potential Elemental Impurity in Drug Products:

  • Identify: The Draft Guidance recognizes a sliding scale for identifying the known or potential sources of “impurities” from those that are naturally present, intentionally added as part of a preparation or process, introduced in the manufacturing process, or introduced through the packaging and containers. Oversight includes “periodic verification testing” of processes, materials and the finished product, including evaluation of toxicity data for elemental impurities.
  • Analyze: Manufacturers are required to analyze “the probability of observance of a particular elemental impurity in the drug product.” The assessment process should consider prior knowledge, published literature, data from similar processes, supplier data, analysis of components and analysis of the finished drug product. Speciation (i.e. determining more precisely the species of the element) is recommended to justify higher levels for less toxic species.
  • Evaluate: The observed or predicted levels of elemental impurities based upon the established “Permitted Daily Exposure (PDE) level.
  • Control: The Guidance proposes developing a “Control Strategy” and risk assessment “proportional to the level of risk” applying the risk management strategies in the ICH Q9 and assessing the levels of impurities based upon the PDEs. The Draft Guidance calls for a manufacturing compliance policy that documents the steps taken. The steps include identifying where the element enters the product, in-process and upstream manufacturing controls and setting requirements for suppliers. The control component requires the manufacturer to obtain data from suppliers and testing of the finished product to account for impurities that may arise in the manufacturing process or in the packaging.

What does this mean for drug approval and compliance?

While much of the content in the Draft Guidance has been available through the ICH Guidelines and US Pharmacopeial Convention (USP)for a number of years, manufacturers and component suppliers (at all levels of the manufacturing chain) must establish and confirm that procedures are in place for their own operations and their suppliers for testing for elemental impurities or explaining why they are not testing. Even if a manufacturer has procedures in place and routinely tests, you cannot test every molecule and still may, in the words of the FDA Deputy Commissioner concerning arsenic in food, have “occasional lots with [elemental impurities] above those permitted…”

Failure to have and implement a Control Strategy for elemental impurities in place may be the difference between a corrective measure on the one hand and being subject to criminal and/or civil enforcement on the other. In all events, these new requirements threaten to increase the risk of civil tort and consumer litigation.