Elemental impurity analysis in pharmaceutical products according to USP 233 (ICH Q3D context)
As a pharmaceutical manufacturer, you want to analyse your medicinal products in accordance with USP 233 / ICH Q3D
What is USP 233?
USP 233 describes the new requirements for the analysis of elemental impurities in pharmaceutical products.
More specifically, this American standard sets out the requirements for the validation of analytical methods, in particular for the quantification of elemental impurities in excipients, active ingredients and finished products. It imposes strict criteria on the accuracy, specificity and sensitivity of analyses, with preference given to the use of ICP-MS and ICP-OES.
What is ICH Q3D?
The ICH Q3D (International Conference on Harmonisation) guideline establishes the methodology for assessing elemental impurities in pharmaceutical products. This includes medicinal products for human use.
ICH Q3D focuses on managing the risks associated with elemental impurities. It classifies elements according to their toxicity and probability of occurrence, and defines maximum exposure limits. ICH Q3D requires manufacturers to carry out a rigorous assessment of impurities at every stage of the product life cycle, from raw material to finished product.
Matrices covered by the ICH Q3D analysis
Common matrices analysed according to ICH Q3D include raw materials, excipients, active substances, and finished products. FILAB can also analyse samples in various forms, such as powders, liquids, tablets, or gels, adapting the preparation and analytical methods to the specific matrix.
Why carry out an ICH Q3D laboratory analysis?
ICH Q3D analysis for the pharmaceutical industry helps to ensure the safety and efficacy of drugs available on the market by checking the specific concentrations of elemental impurities.
An ICH Q3D analysis checks for the presence of elemental impurities. This includes the analysis of heavy metals such as lead, arsenic, cadmium and mercury, among others, and other elements that may present risks at certain concentrations.
Using an ich q3d analysis laboratory enables impurities in raw materials, manufacturing processes, production equipment or packaging to be detected and quantified.
ich q3d analysis of elemental impurities addresses a number of issues, including the prevention of toxicological risks associated with the presence of impurities in medicinal products, and the harmonisation of quality standards on an international scale.
Details of analyses according to USP 233 and ICH Q3D
ICH Q3D requires a two-phase approach to the management of elemental impurities.
The first phase, called preliminary risk assessment, consists of identifying potential sources of impurities. This stage can be carried out on the basis of documentary data or via laboratory screening analyses. The aim is to determine which elements need to be controlled in finished products and to prioritise efforts to guarantee patient safety while complying with regulatory limits.
The second phase of ICH Q3D consists of controlling and managing the risks associated with the elementary impurities identified. This involves quantitative analyses using ICP-AES and ICP-MS, to check that levels are within set limits, as well as adjustments to manufacturing processes to minimise risks and ensure product compliance.
The methodology for analysing elemental impurities in medicinal products is described in USP guideline 233 (US Pharmacopoeia no. 233: Elemental Impurities - Procedures).
This analysis methodology now uses modern analytical techniques such as ICP (ICP-AES and ICP-MS), or the mercury amalgamator.
Depending on the results and consideration of the acceptable threshold (30% of the PDE), control plans can be put in place and the analytical methods validated in accordance with USP 233.
The elementary impurity classes described by ICH Q3D
Within the framework of ICH Q3D, the elementary impurities to be analysed mainly include heavy metals and other toxic elements. Impurities are classified according to their toxicological impact and their potential presence in the pharmaceutical product.
Certain elemental impurities are not classified as heavy metals, but can nevertheless pose health risks:
- Iron (Fe): although necessary in low concentrations, it can be toxic in excess.
- Zinc (Zn): an essential element, but potentially toxic at high levels.
- Calcium (Ca): in excess, it can cause electrolyte imbalances.
- Magnesium (Mg): useful in low concentrations but problematic in excess.
These impurities must therefore be controlled to guarantee the safety of pharmaceutical products.
The search for elemental impurities according to USP 233: a speciality of the FILAB laboratory
For over 30 years, the FILAB laboratory has been providing dozens of customers with elemental impurity analysis services in accordance with USP 233 and ICH Q3D, some of which are COFRAC ISO 17025 accredited.
Thanks to its state-of-the-art analytical equipment (12 ICP-MS and ICP-AES, 1 mercury amalgamator with autosampler, plate or microwave mineralisation techniques) and its high-level skills in elemental analysis and pharmaceutical analysis, the FILAB laboratory offers you its elemental impurity analysis services to meet the requirements of USP 233:
Our services according to ICH Q3D
Analytical validation according to USP 233 for the analysis of elemental impurities
Analysis of heavy metals and elemental impurities ICH Q3D by ICP-MS
Identification of impurities by RMN analysis
Did you know that?
FILAB laboratory is COFRAC ISO 17025 accredited on the following scope since 2015: Analysis and determination of elemental impurities and minerals including heavy metals by ICP-AES and ICP-MS in cosmetic and pharmaceutical products according to European Pharmacopoeia 2.4.20 and USP 233
FAQ
Depending on the client's needs, FILAB offers several analytical validation approaches.
The most complete validation will follow the requirements of the chosen standard (ICH Q2 or USP 233) and will be based on a matrix.
For a complete validation, it takes between 6 and 8 weeks. For routine assays, analysis times are between 5 and 10 working days.
The ICH Q3D guidelines apply to the quantification and control of elemental impurities in all types of pharmaceutical products, including :
human medicinal products,
veterinary medicinal products,
and biological products.
These guidelines are designed to help drug manufacturers assess the health risks associated with the levels of elemental impurities present in pharmaceutical products, and to put in place control measures to ensure that these levels are safe.
The ICH Q3D guidelines also apply to
raw materials
excipients used in the manufacture of medicinal products
as well as to finished products.
They cover the 24 chemical elements considered to be of greatest concern in terms of potential toxicity to patients, including lead, cadmium, mercury, arsenic, etc.
To verify compliance with ICH Q3D, pharmaceutical companies need to follow several key steps, incorporating a systematic and rigorous approach to the assessment and control of elemental impurities in their products.
These steps can be carried out by a laboratory with expertise in ICH Q3D analysis:
Identification of potential sources of elemental impurities in products, including raw materials and manufacturing processes.
Identification of elements to be analysed based on their toxicity and probability of presence, in accordance with ICH Q3D.
Development and validation of analytical methods to measure impurities, in accordance with USP 233 recommendations.
Analysis of products and batches to compare impurity levels with the acceptable limits of ICH Q3D.
Management and correction, if necessary, of processes to reduce impurities.
This methodical approach ensures the safety of pharmaceutical products by controlling the levels of elementary impurities.
The main difference between USP 233 and ICH Q3D lies in their scope and application in the control of elemental impurities in pharmaceutical products.
USP 233 focuses specifically on methodology (233) and limits for the quantification of elemental impurities (232), providing detailed guidance on analytical techniques, such as mass spectrometry or atomic absorption spectroscopy, for measuring these impurities.
On the other hand, ICH Q3D takes a more holistic approach, providing a framework for the identification, assessment, and risk management of elemental impurities throughout the life cycle of a pharmaceutical product. This encompasses not only analytical methods, but also toxicological considerations to define safety limits for patients, and applies internationally (such as Europe, the USA and Japan).
In addition to ICH Q3D and USP 232/233, other standards and guidelines for elemental impurities exist: the European Pharmacopoeia, European Medicines Agency guidelines, US Food and Drug Administration guidelines, and World Health Organization guidelines. These standards aim to guarantee the safety of pharmaceutical products by controlling the levels of elementary impurities, with specificities that may vary from country to country and from organisation to organisation. Contact the FILAB laboratory for advice.
FILAB combines the requirements of USP <233> and ICH Q3D to offer comprehensive analysis of elemental impurities in pharmaceutical products. USP <233> provides specific guidance on preparation and analytical methods, focusing on the quantification of impurities in pharmaceutical samples. FILAB uses these methods in parallel with the requirements of ICH Q3D, which focuses on the risk assessment of trace elements in products. This harmonised approach ensures both patient safety and regulatory compliance.
In the event of non-compliance, FILAB works closely with manufacturers to identify the source of the problem. This may include re-evaluating manufacturing processes, modifying formulations, or implementing additional controls. FILAB can also provide revalidation services or additional analysis to ensure that products meet regulatory requirements.
ICP techniques, particularly ICP-MS, are extremely sensitive. This high sensitivity is essential to ensure that pharmaceutical products comply with the strict limits imposed by ICH Q3D.
