United States: FDA To Set Safety Limits For Potential Toxic Elemental Impurities In Approved Drugs

Last Updated: October 26 2013
Article by Michael A. Walsh

A New FDA Draft Guidance Adds Significant Compliance Obligations and Potential for Adulteration and Manufacturing Defect Claims.

FDA's proposed Draft Guidance entitled "Guideline for Elemental Impurities Q3D" establishes, for the first time, "acceptable safety limits of potentially toxic elemental impurities" or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 What the Draft Guidance does mean for the drug industry is more stringent compliance requirements, particularly as relates to supply chain. The Draft Guidance applies to finished drug products, but not to drug products used in clinical research or other products such as herbal products, vaccines, blood, or products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The Draft Guidance adopts (copyright notice and all) the draft consensus guidelines of the "International Conference on Harmonisation" (ICH), a consortium of pharmaceutical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 In the Draft Guidance, the FDA recognizes that there may be detectable or trace amounts of elemental impurities (i.e. deleterious and potentially dangerous substances) in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 This Draft Guidance reveals to the medical community and provides greater transparency for the consuming public that there may be potentially harmful "impurities" in FDA approved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:

  1. 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.
  2. 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.
  3. Evaluate: The observed or predicted levels of elemental impurities based upon the established "Permitted Daily Exposure (PDE) level.
  4. 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.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on Mondaq.com.

Click to Login as an existing user or Register so you can print this article.

Michael A. Walsh
In association with
Related Topics
Related Articles
Related Video
Up-coming Events Search
Font Size:
Mondaq on Twitter
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
Email Address
Company Name
Confirm Password
Mondaq Topics -- Select your Interests
 Law Performance
 Law Practice
 Media & IT
 Real Estate
 Wealth Mgt
Asia Pacific
European Union
Latin America
Middle East
United States
Worldwide Updates
Registration (you must scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions

Mondaq.com (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of www.mondaq.com

To Use Mondaq.com you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.


The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.


Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions