Elemental Impurities in Drug Products

Elemental impurities are inorganic contaminants which may be present in drug products.  Examples include but are not limited to catalysts and environmental contaminants that may be present in Pharmaceutical Active Ingredients (APIs), inactive ingredients (excipients) or drug products.  These impurities may occur naturally, be added intentionally or be introduced inadvertently by leaching into drug products from processing equipment or container/closure systems.

Due to the ubiquitous nature of Arsenic, Cadmium, Lead and Mercury, all four (at a minimum) must be considered when conducting risk assessments and/or testing of elemental impurities in drug products.

On August 7, 2018 the US FDA issued a new Guidance for Industry entitled Elemental Impurities in Drug Products.  Essentially, this Guidance is nothing more than FDA’s adopting the International Council for Harmonisation (ICH) Q3D Elemental Impurities Guidance for Industry.   This FDA Guidance employs United States Pharmacopeia (USP) General Chapters <232> Elemental Impurities – Limits and USP General Chapter <233> Elemental Impurities – Procedures as a recommended program for controlling elemental impurities in drug products. 

At the offset, it is important to note that FDA Guidance Documents contain ‘nonbinding recommendations’, which represent FDA’s ‘current thinking’ on the topic addressed by the Guidance.  The Elemental Impurities in Drug Products Guidance offers recommendations for controlling elemental impurities in drug products.  Although manufacturers/owners of drug products are free to explore other means of accomplishing this goal, the bottom line is that FDA now requires a documented program for controlling elemental impurities in all Prescription and Over-the-Counter (OTC) drug products distributed in the US. 

Controlling Elemental Impurities in Drug Products

Because elemental impurities pose toxicological concerns and do not provide therapeutic benefit to the patient, their levels in drug products must be controlled within acceptable limits.  FDA’s Final Guidance provides ‘recommendations’ regarding a risk-based approach to controlling elemental impurities in human drug products marketed within the US.  This Guidance applies to both Prescription and OTC Drugs.  The process begins with the conducting of a Risk Assessment for each drug product.

Conducting a Product Risk Assessment

Step 1:  Identify All Known and Potential Sources of Elemental Impurities in the Drug Product.

This includes elements intentionally added, elements potentially present in the raw materials used to prepare the drug product, and elements potentially introduced from manufacturing equipment or container closure systems.

Step 2: Determine the Level of Each Elemental Impurity in the Drug Product.

This may be accomplished either through predictions made using information available from vendors and official sources, or through actual testing.

Step 3: Comparison to the Permitted Daily Exposure (PDE).

Compare the observed or predicted level of each element in the drug product to the PDE for that element found in USP General Chapter <232> Elemental Impurities – Limits.

Mitigation

If the risk assessment fails to show that an elemental impurity level is consistently below the control threshold (defined as 30% of the established PDE in the drug product), additional controls must be established to ensure that the elemental impurity does not exceed the PDE in the drug product.   These additional controls should be included as in-process controls or in the specifications of drug product raw materials and package components.

USP General Chapters <232> and <233>

USP introduced limits and analytical procedures for determining elemental impurities in General Chapters <232> Elemental Impurities – Limits and USP General Chapter <233> Elemental Impurities – Procedures.  The primary goals are (1) to set limits for acceptable levels of elemental impurities in finished drug products, and (2) update methodology employing modern analytical procedures.  These USP General Chapters align with ICH Q3D and subsequently, with the FDA Guidance on this topic issued in 2018.

USP General Chapters <232> and <233> do not require the routine testing of drug products to ensure compliance.  Depending upon the source of an elemental impurity and the risk that its level in the drug product may exceed the PDE, alternate approaches may be taken to ensure the compliance of the drug product.  For example, if the only source of an element is from raw materials used to prepare the drug product, routine testing of raw materials may take the place of testing each drug product batch for that element.

It is important to note that USP monographs and General Chapters may specify an impurity limit that differs from that found in USP <232>.  In such instances, the specific limit found in the monograph, or in a General Chapter referenced by a monograph takes precedence over the limit appearing in USP <232>.

Required Documentation for Prescription Drugs

The FDA now requires that the following documentation be generated for each Prescription Drug product distributed within the US:

1. A documented Risk Assessment to determine which elemental impurities are likely to be present in the drug product.
2. A documented assessment determining whether current controls for those impurities are adequate.
3. The listing, and a description of each additional control that is implemented to lower the risk that an impurity will exceed 30% of the PDE in the drug product.

For not-yet-approved Prescription Drug products, this documentation must be included in the drug application (NDA or ANDA).  If a drug is already approved under an NDA or ANDA, the documentation must be provided to FDA in any supplemental application or annual report. 

Required Documentation for OTC Drugs

The FDA now requires that the following documentation be generated for each OTC Drug product distributed within the US:

1. A documented Risk Assessment to determine which elemental impurities are likely to be present in the drug product.
2. A documented assessment determining whether current controls for those impurities are adequate.
3. The listing, and a description of each additional control that is implemented to lower the risk that an impurity will exceed 30% of the PDE in the drug product.

For OTC drugs manufactured by the owner of the drug, this documentation must remain at the site of manufacture for FDA review during an inspection.  If the owner of the drug is not the manufacturer, this documentation must be maintained by, or must be readily available to the owner for review during an FDA inspection.

Quantitative Analytical Procedures for Elemental Impurities

USP General Chapter <233> provides suitable analytical methods for quantitating the level of elemental impurities in drug products and the raw materials that are used to prepare them.  These methods must be verified prior to first use for each element and drug product combination.  Alternate procedures are permitted, however they must be validated prior to use.

What about Elemental Impurities in Cosmetic Products?

In the final days of 2022, Congress passed and the President signed the Modernization of Cosmetics Regulation Act of 2022 commonly known by its acronym “MoCRA”.  Its intent is to modernize federal regulatory oversight of cosmetic and personal care products and create a comprehensive and uniform national framework for their regulation.

Under MoCRA, FDA has been granted broad and far-reaching authority to ensure that cosmetic products are not adulterated.   The Food, Drug and Cosmetic (FD & C) Act defines “adulterated” as products containing poisons or other filthy, putrid, decomposing or otherwise deleterious substances, or products which have been prepared, packed or held under unsanitary conditions whereby they may have become contaminated or rendered injurious to health.  There is little doubt that the presence of toxic elemental impurities such as lead, mercury and/or others in a cosmetic product would lead FDA to conclude that the product is adulterated and demand its immediate recall.  (MoCRA also provides FDA the authority of issuing mandatory recalls of adulterated cosmetic products.)

Although USP Elemental Impurities Chapters <232> and <233> specify their application to drug products, it is prudent for cosmetic manufacturers and product owners to initiate the conducting of risk assessments and elemental impurities testing of their products and raw materials so as to avoid possible FDA enforcement action based upon the authorities now granted to FDA under MoCRA.

How Can CPT Labs Assist with Your Elemental Impurity Testing?

CPT operates an expertly staffed, state-of-the-art Analytical Chemistry Lab employing USP-specified instrumentation and procedures required for Elemental Impurities testing.  This includes Inductively Coupled Plasma with Mass Spectrometry detection (ICP-MS), Inductively Coupled Plasma with Optical Emission Spectroscopy detection (ICP-OES), and microwave digestion sample preparation systems to analyze any and all components of your product, including the assembled and filled product itself.  Our in-house experts are ready to speak with you and offer their advice as to the best approach for handling your elemental impurities testing needs for drug, cosmetic and dietary supplement products, the raw materials of which they are composed, and the container/closure systems in which they are packaged.

We can also assist in the calculation of the level of each elemental impurity in your product and comparisons with the PDE.  Give us a call, even if you only wish to learn more about Elemental Impurities testing for any type of product distributed within the US.