Author: Ronak Patel, Analytical Chemistry Manager
Elemental impurities in drug products can arise from multiple sources. They may be intentionally added, such as residual catalysts used during the manufacturing process, or introduced unintentionally through interactions with processing equipment, container systems, closure components, or other parts of the drug product. Since these impurities provide no therapeutic benefit to the patient, it is critical that their levels are tightly controlled within acceptable limits to ensure patient safety.
Starting April 1, 2025, the European Pharmacopoeia (EP) introduced a major update with the release of General Chapter 2.4.35 – Extractable Elements in Plastic Materials for Pharmaceutical Use. This new chapter was recently introduced in the 11th Edition, Supplement 11.7, marking a significant evolution in the approach to elemental impurity control.
This shift aligns with the broader industry movement driven by the ICH Q3D guideline, which encourages a transition from traditional, substance-based testing to a more holistic, finished product control strategy. The goal: enhanced patient safety through more robust, risk-based monitoring of elemental contaminants throughout the drug manufacturing and packaging process.
It is foreseen that all existing Ph. Eur. general chapters covering plastic materials will eventually cross-reference chapter 2.4.35. As a first step, references are being incorporated into new chapters for:
3.1.16 – Cyclo-olefin polymers
3.1.17 – Cyclo-olefin copolymers
3.1.18 – Styrene block copolymers
These updated chapters are set to become legally binding on January 1, 2026.
Additionally, it is anticipated that older Ph. Eur. chapters on plastics will be revised to remove the traditional heavy metals testing, transitioning instead to the targeted extractable elements testing outlined in 2.4.35.
The move from older, qualitative colorimetric tests to quantitative ICP-MS-based methods represents a major advancement. This ensures a more accurate and reproducible measurement of elemental impurities, allowing for a scientifically sound evaluation of potential risks associated with plastic packaging materials.
Testing under EP 2.4.35 requires:
- Extraction Flask – PTFE flask with a volume of 480 mL or equivalent (e.g., PTFE Jar from VWR, 216-0170)
- Laboratory Scale Autoclave
- Inductively Coupled Plasma-Mass Spectrometer (ICP-MS)
Sample preparation involves mass-to-volume extraction in a heavy metals-free acidic medium, autoclaved at 121 °C for 60 minutes. Blank solutions are prepared simultaneously.
Analysis of extractable elements is performed using ICP-MS according to EP chapter 2.2.58.
Initially, when chapter 2.4.35 was proposed in Pharmeuropa 32.2 (April 2020), it included stringent mandatory limits for ten elements:
| Element | Proposed Limit |
|---|---|
| Antimony | 0.10 |
| Arsenic | 0.01 |
| Cadmium | 0.01 |
| Cobalt | 0.01 |
| Copper | 0.30 |
| Lead | 0.01 |
| Lithium | 0.30 |
| Mercury | 0.01 |
| Nickel | 0.01 |
However, during the public consultation phases — published in Pharmeuropa 32.2 and 32.3 — stakeholders across the pharmaceutical and packaging sectors voiced strong concerns regarding the initially proposed mandatory limits for 10 specific elemental impurities. Industry experts highlighted that applying fixed limits universally across all material types and drug products failed to account for the diversity of real-world scenarios, where risk levels can vary significantly depending on factors such as material composition, intended use, and patient exposure.
In response, the European Pharmacopoeia Commission revised the chapter by removing the fixed limits, focusing solely on the analytical procedure. Specific recommendations will be provided separately in a new general text, 5.42.
This flexible approach supports the broader ICH Q3D philosophy of tailored, risk-based control strategies rather than rigid, one-size-fits-all limits.
At CS Analytical, we have been closely monitoring these regulatory changes and are fully equipped to help our clients navigate this new environment with confidence.
Our state-of-the-art laboratory in Clifton, New Jersey, features the powerful Agilent ICP-MS 7900 Series — one of the industry’s leading platforms for ultra-trace elemental analysis. Supported by a team of highly skilled and experienced scientists, CS Analytical has developed internally validated test methods that are meticulously aligned with both the ICH Q3D guideline and the Ph. Eur. 2.4.35 procedure for extractable elements determination.
Our validation process rigorously addresses critical analytical parameters such as sensitivity, specificity, linearity, precision, accuracy etc., ensuring that every test result you receive is scientifically defendable and regulatorily compliant.
Beyond the European Pharmacopoeia, CS Analytical offers validated extractable metals testing for a wide range of plastic materials, including but not limited to those covered under USP <661.1> and Ph. Eur. plastic material chapters such as 3.1.3, 3.1.5, 3.1.6, and 3.1.15.
Why CS Analytical?
In a world where regulatory expectations are constantly evolving, choosing the right partner makes all the difference. CS Analytical is proud to be the world’s only cGMP, FDA-registered and audited laboratory exclusively dedicated to container and package system testing for the pharmaceutical, biotechnology, and medical device industries.
Here’s why clients choose us:
- Exclusive Expertise: At CS Analytical, container and packaging system testing isn’t just something we offer — it’s the foundation of everything we do. Unlike general-purpose laboratories where packaging tests are often treated as a side service, we are 100% dedicated to this critical field. Our entire team, facility, and expertise are singularly focused on the unique challenges and regulatory demands of container and package system testing, making it not an afterthought, but our true area of mastery.
- Regulatory Alignment: Deep, hands-on experience with FDA, USP, Ph. Eur., ICH guidelines etc.
- Tailored Testing Strategies: We reject the “fast-food” approach to lab testing. Instead, we build customized, risk-based test programs that meet your unique material and regulatory needs.
- Unwavering Quality Commitment: Precision, accuracy, transparency, and traceability are embedded in everything we do.
- Collaborative Partnership: We work with you, not just for you — ensuring the best outcomes for your regulatory and business success.
CS Analytical stands ready to be your trusted partner through every step of this transition. Whether you need method development, validation, routine extractable metals testing, or regulatory consulting, we are here to deliver scientifically rigorous, regulatorily compliant solutions tailored specifically to your product needs.
Contact us today to learn how we can help you stay ahead of the curve and ensure the safety, efficacy, and regulatory success of your pharmaceutical products.
Visit us at: csanalytical.com
Email us at: engage@csanalytical.com
Call us at: 1-888-571-1207.