Extractables and leachables testing to quantify and assess risks associated with leachable impurities from pharmaceutical container closure systems (CCS), process equipment or medical device packaging

Extractables and leachables testing is critical to the identification and quantification of potentially harmful leachable impurities which could migrate from pharmaceutical container closure systems to contaminate a pharmaceutical product and so pose a risk to a patient's health and cause significant quality issues.

An extractables and leachables study (E&L) can help to identify potential sources of leachables, via controlled extractables studies (CES) which enable a profile of extractable components to be established. Potential sources of leachables could include antioxidants, plasticizers, dyes and metal catalysts, and polymer and degradation products. These can possibly present a toxicological risk, but may also exacerbate the degradation of the drug, particularly for biopharmaceuticals. As the construction and materials of pharmaceutical packaging, bioprocess materials, drug delivery systems, or implantable medical devices can be extremely complex, with mixtures of plastic, polymer, rubber or glass materials, printed surfaces and coatings all used, it is critical that leachables and extractables studies are designed specifically for your drug product and storage container materials (primary and secondary containers) so that the risks associated with leachable impurities can be assessed.

Meeting Regulatory Expectations for Extractables and Leachables Analysis 

Regulatory agency expectations are continually evolving with ever more stringent requirements for the evaluation of drug product packaging associated with each new product. Our scientists conduct E&L analysis studies in accordance with regional guidance and nationally/internationally recognized standards including Good Manufacturing Practice (GMP), Product Quality Research Institute - PQRI extractables and leachables guidelines, United States Pharmacopeia (USP) requirements (e.g. USP extractable and leachable USP chapters <665>, <1665>, <1663>, <1664>, and <1664.1>), European Medicines Agency (extractables and leachables EMA guidance), US Food and Drug Administration, FDA extractables and leachables guidance, the BioPhorum/ BPOG Guidance, and ISO 10993-18 extractables and leachables guidelines (Part 18)

E&L Strategies

As an initial step, we aim to gather all information about your packaging system in order to build a robust picture of potential sources of leachables. The combination of our experience in method development for a controlled extractables study, coupled with our vast knowledge of leachable compounds and guidelines, means that we can anticipate and identify potential sources of risk associated with leachable impurities through strategic screening studies. 
Typical study types include extractables assessment of container closure systems and packaging components, leachables evaluations of drug products from stability testing, and leachables evaluations of manufacturing surfaces or single-use processing materials /bioprocessing equipment

We provide leachables method validation compliant to Good Manufacturing Practice (GMP) for use in GMP stability testing and storage programs and can support a wide range of closure or drug delivery systems such as pre-filled syringes, large volume parenteral products, orally inhaled and nasal drug products (OINDP), single-use and disposable medical equipment, printed packaging or secondary packaging migration behavior (labels, inks and dyes). Leachables associated with medical devices (ISO10993-18), drug delivery systems, implantable medical devices and other devices such as e-cigarettes are also assessed. 

Our Extractables and Leachables Analysis Global Expertise

Our experts have over 30 years of experience in specialized analytical and toxicology assessment for extractable leachable testing. Intertek offers extractables and leachables testing services through GMP-compliant laboratories located in Whitehouse, NJ (USA) and Basel (Switzerland) with research support from our Mumbai (India) facility, as part of our commitment to Total Quality Assurance. Our E&L expertise reinforced by our knowledge of polymer, plastic and packaging materials, allowing us to identify components from the most complex polymer formulation including adhesives, additives and stabilizer ingredients and their degradation products. Our consultants provide first-class evaluation and assessment of existing E&L data gaps, and through strategic screening or quantitative studies, we offer the right study for your product. Intertek also provides recommendations and support for the preparation of very low risk data packages related to E&L testing and comprehensive toxicology risk assessments.

Bringing quality and safety to life, we offer Total Quality Assurance expertise to help you to meet and exceed quality, safety and regulatory standards.

Our analytical teams can determine both organic and inorganic contaminants through the application of a range of high-end analytical instrumentation including liquid chromatography hyphenated with HRAM-mass spectrometry (LC-MS/MS), gas chromatography hyphenated with enhanced resolution or HRAM-mass spectrometry (GC-MS/MS), and inductively coupled plasma spectroscopy (ICP, ICP-MS), dependent on the analysis. In addition to the solvent-based extractions, we also apply various high performance automated solventless extraction methods, such as solid-phase microextraction (SPME), dynamic head-space and thermal desorption for better characterisation and understanding of the materials.

Extractable Definition:
The US Food and Drug Administration (FDA) defines extractables as compounds that can be extracted from a container closure system or drug product packaging component (container, tubing, seal, device) during an extraction with aggressive conditions including exposure to an extraction solvent and elevated temperatures). Extractables can be potential leachables.

Leachable Definition:
A leachable substance is a compound that can migrate or leach into a drug product formulation over time from the packaging or device component or through contact with a production material or as a result of direct contact with the drug formulation. Leachables are generally a subset of extractables species - but not always. 

  • Method development for controlled extractables studies
  • Identification of extractables using GC-MS,  GC-MS/MS and LC-MS/MS, according to USP <1663> Assessment Of Extractables Associated With Pharmaceutical Packaging/Delivery Systems
  • Complex polymer formulation component identification
  • Screening or quantitative studies for additives and stabilizer ingredients and their degradation products
  • Rapid, decisive identification of extractables including transformation or degradation products
  • Modifying specific controlled extractables methods for routine E/L testing
  • Extractables studies for medical devices and medical and pharmaceutical packaging

  • Complete identification of leachables for pharmaceutical packaging, drug delivery systems, implantable medical devices and other devices such as e-cigarettes
  • Method validation compliant to Good Manufacturing Practice (GMP)
  • Assessment of leachables according to USP <1664> Assessment Of Drug Product Leachables Associated With Pharmaceutical Packaging/Delivery Systems 
  • Assessment of specific considerations for leachables in orally inhaled and nasal drug products (OINDP), including metered dose inhalers (MDIs); nasal sprays; inhalation solutions, suspensions, and sprays; and dry powder inhalers (DPIs) according to USP <1664.1> 

Toxicological assessments to quantify a patient's exposure to each chemical and gauge the level of risk posed by these materials can be conducted using the data from an extractable and leachables analysis. Our in-house toxicologist consultants  perform evaluation and safety assessment reviews in order to identify and address potential risks and to assist with comprehensive pharmaceutical impurity testing, whilst identifying any gaps in your existing data packages. We also provide recommendations and support for preparation of very low-risk data packages related to E/L testing.

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Intertek Pharmaceutical Services

P.O. Box 470
291 Route 22 East
Salem Industrial Park
Whitehouse, NJ 08888

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Intertek Switzerland Analytical Laboratory

Intertek (Schweiz) AG
TechCenter Reinach
Kägenstrasse 15
CH-4153 Reinach, Switzerland
T: +41 61 686 4800
E: business.support@intertek.com

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