Table of Permitted Daily Exposures (PDEs) for Elemental Impurities According to ICH Q3D, USP <232> and Ph.Eur. 5.20
The quality control of elemental impurities in pharmaceuticals is extremely important to protect patients. The ICH Q3D, USP 232> and Ph.Eur. 5.20 regulations establish limits on elemental impurities in drug substances and drug products. In accordance with these guidelines, the tracability, reliability and precision of testing is only possible through the application of Certified Reference Materials (CRMs) for elemental impurities.
ICH Q3D Guidelines for Elemental Impurities
The International Council for Harmonisation (ICH) Q3D standard refers to the limitation of elemental impurities in medicines and requires that toxic elements are measured and tamed to not be overexposed to the acceptable limit.
Guideline Overview
The ICH Q3D guideline classifies elemental impurities into three classes based on their toxicity and likelihood of occurrence:
| Class | Description |
| Class 1 | High toxicity elements that should be avoided or strictly controlled. |
| Class 2A | Elements with high potential for inclusion in the drug manufacturing process and moderate toxicity. |
| Class 2B | Elements with moderate toxicity but lower likelihood of inclusion in the process. |
| Class 3 | Low toxicity elements, typically only of concern for inhalational exposure. |
Elemental Impurity Limits
The guideline sets Permitted Daily Exposures (PDEs) for various elemental impurities, ensuring they remain within safe thresholds for oral, parenteral, and inhalational drug products. The following table summarizes the PDE limits for key elements in μg/day:
| Element | Class | Oral PDE (μg/day) | Parenteral PDE (μg/day) | Inhalational PDE (μg/day) |
| Cadmium (Cd) | Class 1 | 5 | 2 | 2.9 |
| Lead (Pb) | Class 1 | 5 | 5 | 5 |
| Arsenic (As) | Class 1 | 15 | 15 | 2 |
| Mercury (Hg) | Class 1 | 30 | 3 | 1 |
| Cobalt (Co) | Class 2A | 50 | 5 | 0.3 |
| Nickel (Ni) | Class 2A | 200 | 20 | 5 |
| Vanadium (V) | Class 2A | 100 | 10 | 1 |
| Silver (Ag) | Class 2B | 150 | 10 | 7 |
| Chromium (Cr) | Class 3 | 11000 | 1100 | 0.3 |
| Molybdenum (Mo) | Class 3 | 3000 | 150 | 10 |
| Copper (Cu) | Class 3 | 3000 | 300 | 30 |
Role of CRMs
CRMs play a crucial role in verifying the accuracy and traceability of elemental impurity testing methods. They help ensure compliance with regulatory limits and support the validation of testing equipment and procedures.
USP <232> Guidelines for Elemental Impurities
The USP <232> offers a similar set of guidelines for monitoring elemental impurities in pharmaceuticals with a concern for safety and accuracy.
Guideline Overview
USP <232> establishes quotas of elemental impurities in drugs and products based on toxicological investigations. These are ICH Q3D compliant, and they list the PDEs for all the components and assign them to risk categories
Elemental Impurity Testing
USP guidelines mandate testing for elements such as lead (Pb), cadmium (Cd), arsenic (As) and mercury (Hg), among others. It will require labs to enlist the appropriate methods such as ICP-MS (Inductively Coupled Plasma Mass Spectrometry) to find these impurities at trace levels.
Role of CRMs
For accurate elemental impurity testing, CRMs that are certified for the specific elemental impurity levels are essential. They provide the necessary standardization to confirm that analytical instruments are performing within the defined tolerances.
Ph.Eur. 5.20 Guidelines for Elemental Impurities
Ph.Eur. 5.20 prescribes the requirements to monitor elemental impurities in medicines and products of the European Union.
Guideline Overview
Like ICH Q3D and USP <232>, Ph.Eur. 5.20 Establishes safe levels of elemental impurities for drugs in products, so that patients can be protected. These are in line with ICH Q3D PDEs and provide an outline for risk-based control measures for elemental impurities.
Elemental Impurity Limits
For toxic metals like arsenic (As), lead (Pb), cadmium (Cd) and mercury (Hg), as well as other potentially toxic metals, limits are stipulated in the European Pharmacopoeia.
Role of CRMs
Conformity with ICH Q3D and USP <232>, Ph.Eur. 5.20 requires CRMs to calibrate levels of elemental impurities. These components are essential to ensure that the test techniques and equipment meet the high impurity standards imposed by the Ph.Eur.
The Role of Certified Reference Materials (CRMs)
Certified Reference Materials (CRMs) play an important role in verifying the validity and conformity of elemental impurity tests for all these pharmacopoeias. They function as follows:
Traceability and Accuracy
CRMs are produced under stringent conditions and come with certification for specific elemental impurity concentrations. This ensures that any analytical testing for elemental impurities is traceable and accurate.
Method Validation
Laboratories use CRMs to validate their testing methods, ensuring that instruments and procedures produce reliable, reproducible results.
Compliance Assurance
With CRMs approved for tested elements, producers and laboratories can meet the elemental impurity standards of ICH Q3D, USP <232>, and Ph.Eur. 5.20.
Calibration of Analytical Instruments
These CRMs are used to calibrate analytical tools like ICP-MS so that the measurements of elemental impurities at trace level can be obtained.
Proficiency Testing
CRMs also act as reference standards for proficiency testing, so labs can benchmark their performance with others at the same institution and test processes can be standardised across labs.
Commonly Used CRMs for Elemental Impurity Testing
Several certified reference materials are also widely applied in the pharmaceutical industry to test for elemental impurities. These include:
Metals and Heavy Elements
There are CRMs for harmful metals such as lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As), which are listed under ICH Q3D, USP <232> and Ph.Eur. 5.20.
Trace Elemental Impurities
CRMs are also provided for metals like cobalt (Co), nickel (Ni), and vanadium (V) applicable to certain medicines and routes of administration.
These materials assure that the laboratory's analyses conform to regulatory guidelines and maintain patient safety through rigorous impurity control.
Conclusion
Certified Reference Materials (CRMs) are a major step towards ICH Q3D, USP <232> and Ph.Eur. 5.20 guidelines for elemental impurities. Such regulations promote the protection of patient health by placing very low limits on dissolved impurities in drugs. CRMs help pharmaceutical companies achieve high accuracy, stability and traceability of impurity testing, so drug products can remain available to consumers.
