ICPMS: A Key Tool For Elemental Impurities Analysis in Pharmaceuticals

ICPMS (Inductively Coupled Plasma Mass Spectrometry) is an analytical technique used to detect and measure elemental impurities in pharmaceuticals.

In the realm of pharmaceutical development, ensuring the safety and efficacy of medications is paramount. One critical aspect often overlooked is the control of elemental impurities, which can pose significant risks to patient health. This is where Control of Elemental Impurities (CPI) comes into play, offering a robust framework to safeguard drug quality. At the heart of CPI strategies lies ICP-MS (Inductively Coupled Plasma Mass Spectrometry), a cutting-edge analytical technique revolutionising how pharmaceutical companies monitor and control trace elements. In this article, we’ll delve into the world of ICP-MS-exploring its applications in pharmaceutical development, highlighting its advantages and limitations, and addressing common questions to give you a comprehensive understanding of this vital technology.

Inductively Coupled Plasma Mass Spectrometry (ICP-MS)

ICPMS is an advanced analytical technique widely used in pharmaceutical development for detecting trace metals, including both essential and potentially harmful elements, at very low concentrations. Its high sensitivity and precision make it invaluable in a range of applications, from raw material testing to quality control of final APIs (Active Pharmaceutical Ingredients).

You may like: How to control impurities in pharmaceuticals?

ICP MS Principle

The basic principle involves ionising the sample with an inductively coupled plasma (ICP) and then analyzing the ions using a mass spectrometer (MS) based on their mass-to-charge ratio (m/z).

Step-by-Step Process

1. Sample Introduction:
   • The sample (usually a liquid) is introduced into the system via a nebuliser, forming an aerosol.
2. Ionisation (ICP Source):
   • The aerosol is carried into a plasma torch, where an argon plasma (~6000–10,000 K) ionizes the atoms in the sample.
   • The high-energy plasma breaks molecules into atoms and ionises them, producing mainly singly charged positive ions (M⁺).
3. Ion Extraction:
   • The ions are extracted from the plasma through a series of cones (sampler and skimmer cones) into the vacuum system of the mass spectrometer.
4. Mass Analysis (MS):
   • The ions are separated based on their mass-to-charge ratio (m/z) using a quadrupole, time-of-flight, or sector field mass analyser.
5. Detection:
   • The ions are detected by a detector (usually an electron multiplier), and their intensities are recorded.
6. Data Output:
   • The detected signals are converted into concentration data using calibration curves.

Applications of Inductively Coupled Plasma Mass Spectrometry

The primary application of ICP-MS in pharmaceuticals is the detection and quantification of elemental impurities. Regulatory agencies like the International Council for Harmonisation (ICH) and the U.S. Pharmacopoeia (USP) have set guidelines for permissible limits of elemental impurities in drug products, which are often present as contaminants in raw materials, excipients, and the final drug product. ICPMS is also used in other industries such as:

• Environmental analysis (e.g., heavy metals in water)
• Clinical and biomedical research (e.g., trace elements in blood)
• Geology and mining (e.g., rare earth elements)
• Food safety and quality control

Case Study: Detection of Heavy Metals in a Tablet Using ICP-MS

Background:

A multinational pharmaceutical company manufacturing herbal supplements received a regulatory warning after routine quality checks by the FDA found elevated levels of lead (Pb) and arsenic (As) in a batch of its product. To address the issue and comply with ICH Q3D guidelines for elemental impurities, the company initiated a thorough analysis using ICP-MS.

Objective:

To quantify the levels of heavy metals (Pb, As, Cd, Hg) in herbal supplement tablets and determine compliance with permitted daily exposure (PDE) limits under ICH Q3D guidelines.

Materials and Methods:

Sample:

• Herbal supplement tablets (Batch #HS2023-A)
• Target elements: Pb, As, Cd, Hg

Sample Preparation:

• Tablets were digested using microwave-assisted acid digestion with nitric acid (HNO₃) and hydrogen peroxide (H₂O₂).
• Internal standard (e.g., indium) added for quantification.
• Final solution diluted to appropriate volume.

Instrumentation:

• ICP-MS System: Agilent 7900
• Operating Mode: Collision/reaction cell mode (He gas) to reduce interferences.
• Detection Limit: ppt to ppb level

Calibration:

• External calibration using certified multi-element standards.
• Validation for linearity, precision, accuracy, and limit of detection (LOD).

Results Summary

Conclusion:

• Lead levels exceeded the ICH Q3D oral daily limit, making the product non-compliant.
• Investigation revealed contaminated raw plant material as the source.
• The supplier was placed on hold, and a new raw material specification with ICP-MS screening was implemented.
• The company implemented routine ICP-MS testing in its Quality Control (QC) workflow for all future batches.

Elemental Impurities Testing Guidelines

• ICH Q3D Guideline: This guideline provides a comprehensive framework for controlling elemental impurities in pharmaceutical products, with specific limits set for 24 different elements, including heavy metals like lead (Pb), arsenic (As), cadmium (Cd), and mercury (Hg).
• USP Chapter <232> and <233>: These chapters outline requirements for elemental impurity testing and the use of techniques such as ICP-MS for quantifying elemental impurities in drug products.

Advantages of ICP-MS in Pharmaceutical Development

• High Sensitivity: ICP-MS can detect elements at very low concentrations (ppt levels), which is crucial for regulatory compliance.
• Multielemental Analysis: It allows the simultaneous detection of multiple elements, reducing the time and cost associated with analysing individual elements.
• Wide Elemental Range: It can detect a broad spectrum of elements, including metals, metalloids, and certain non-metals, providing a comprehensive analysis.
• Minimal Sample Preparation: Sample preparation for ICP-MS can be relatively straightforward, depending on the matrix being analysed.
• Isotopic analysis: Can distinguish isotopes of an element.
• Wide dynamic range: Capable of detecting trace levels of metals and some non-metals at concentrations as low as parts per trillion (ppt).
• Rapid detection

Challenges and Disadvantages of ICP-MS

• Matrix Effects: Samples with high concentrations of organic compounds or complex matrices (e.g., biological samples, solid dosage forms) may require special sample preparation (e.g., digestion) to avoid matrix interference.
• Cost and Complexity: ICP-MS equipment is expensive and requires skilled operators to maintain and run the system.
• Interference from Isotopes: Some elements may have isotopic interferences that can complicate the analysis, though modern ICP-MS instruments often have solutions for this.

Conclusion

ICP-MS stands out as an indispensable tool in this endeavour, providing precise, reliable, and efficient analysis of trace elements in drug development. I hope this article has helped you understand ICPMS. I hope this article has helped you understand ICPMS. You may also want to check out other articles on my blog, such as:

• What is the Analytical Method Validation?
• The 7 Key Differences Between Validation and Verification
• How to perform cleaning validation?
• What Is Forced Degradation Studies Of Pharmaceuticals and How To Perform?
• What Is Photostability Testing Of New Drug Substances: Learn in 5 minutes
• What is CSV (Computer System Validation): Learn in 12 Easy Steps

References:

• <233> ELEMENTAL IMPURITIES—PROCEDURES

FAQs on ICPMS