The primary objective of pharmaceutical regulation is to protect patient safety by preventing adverse effects caused by substances migrating from packaging materials into drug products. As a component in direct contact with pharmaceuticals, thermoplastic elastomer (TPE) closures are expected to undergo comprehensive Extractables & Leachables (E&L) studies. The purpose of these studies is to identify all chemical substances that may migrate into the drug product, evaluate their toxicological risks, and establish appropriate control strategies to ensure migration levels remain below acceptable safety thresholds.
What Are Extractables and Leachables?
Extractables are chemical compounds that can be removed from a packaging material under aggressive laboratory extraction conditions using various solvents, elevated temperatures, or extended contact times.
Leachables are compounds that actually migrate into a pharmaceutical product under normal manufacturing, storage, transportation, and clinical use conditions.
Regulatory agencies generally consider extractables studies to be predictive tools for identifying potential leachables. However, manufacturers are expected to demonstrate the scientific relationship between extractables and actual leachables found in finished drug products.
The major regulatory expectations for E&L studies of TPE closures are summarized below.
ICH Q3E: A Harmonized Global Framework for E&L Assessment
ICH Q3E establishes a risk-based framework for Extractables & Leachables evaluation and introduces concepts such as the Safety Concern Threshold (SCT) and Analytical Evaluation Threshold (AET).
The guideline emphasizes the relationship between extractables and leachables, requiring manufacturers to use extractables studies to predict potential leachables and to evaluate patient exposure accordingly.
For pharmaceutical products, the current Safety Concern Thresholds are generally defined as follows:
- Injectable products: SCT ≤ 0.1 μg/day
- Oral products: SCT ≤ 1.8 μg/day
For TPE closures, manufacturers are expected to assess every component of the formulation, including the base polymers (such as SEBS and SBS), processing oils, stabilizers, pigments, and other additives. In addition, degradation products that may be generated during sterilization, storage, or transportation should also be evaluated.
USP <1664>: Standardized E&L Testing for Pharmaceutical Packaging Materials
USP <1664> provides standardized guidance for designing and conducting Extractables & Leachables studies. It specifies appropriate extraction approaches, solvent selection, analytical techniques, and study design for pharmaceutical packaging materials.
The guideline requires comprehensive extractables studies covering volatile, semi-volatile, and non-volatile compounds. Extraction conditions should be selected according to the dosage form, route of administration, and expected contact time between the packaging material and the drug product.
For TPE closures, multiple extraction solvents, including water, ethanol, and hexane, are typically employed to simulate different pharmaceutical formulations. High-sensitivity analytical techniques such as GC-MS, LC-MS, and ICP-MS are recommended to detect organic compounds and elemental impurities.
EU MDR: Regulatory E&L Requirements for Medical Device Packaging Components
Compliance with the European Medical Device Regulation (EU MDR) requires comprehensive extractables and leachables evaluations for packaging materials used in medical devices, including TPE closure components.
Pharmaceutical packaging suppliers and manufacturers are expected to assess degradation products generated during sterilization, storage, and use, while maintaining documented risk management files describing study results and mitigation strategies. Where applicable, biological evaluation should also be performed in accordance with the ISO 10993 series of standards.
Current Regulatory Focus
Current regulatory expectations for TPE materials and finished closures are characterized by several common themes.
- First, regulators place increasing emphasis on demonstrating the correlation between extractables and leachables. Manufacturers are expected to show that extractables studies can reliably predict actual leachables under real-use conditions and provide scientific explanations whenever differences are observed.
- Second, regulatory agencies are paying greater attention to TPE formulations and manufacturing processes. Manufacturers should disclose all formulation additives and assess their toxicological risks. They are also expected to evaluate the impact of processing operations, including injection molding and sterilization, on the E&L profile of the finished closure.
- Third, post-market surveillance has become an increasingly important regulatory expectation. Manufacturers should establish systems to monitor E&L performance throughout the product lifecycle by collecting adverse event data and periodically reassessing potential risks.
- Finally, regulators expect manufacturers to implement effective process controls by optimizing injection molding parameters to minimize degradation products, selecting sterilization methods that do not adversely affect TPE materials, and ensuring safety throughout the process.a.)Comprehensive E&L testing should be conducted using validated methods to ensure accurate and reliable results.
b.)Risk management systems should be established to periodically review E&L risks and implement corrective actions when necessary.
c.)Complete documentation, including formulation information, analytical data, toxicological assessments, and evaluation reports, should be maintained to support regulatory inspections and product registrations.
Conclusion
Extractables & Leachables studies have become an essential component of pharmaceutical packaging qualification. As regulations continue to evolve through ICH Q3E, USP <1664>, EU MDR compliance, and related guidance, manufacturers of TPE closures are expected to provide comprehensive scientific evidence demonstrating the safety of their materials throughout the product lifecycle.
Companies that invest in medical-grade TPE products, robust formulation control, standardized analytical testing, comprehensive risk management, and thorough documentation will be well positioned to meet global regulatory expectations while ensuring the highest standards of patient safety.
