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Extractables and Leachables- What do you need to know

Extractables and Leachables- What do you need to know?
Interview by Mike Ludlow

Extractables and Leachables (E&L): analysis is an essential component in many fields, but mainly though in food safety and the pharmaceutical industry.
However, what actually are they, why do we need to analyse them and what are the regulations surrounding extractables and leachables? Our Standards division had the opportunity to pose these questions to our colleague Mike Ludlow. Mike is the Technical Study Manager within our CMC team, part of LGC’s Drug Development Services division, located at our UK sites in Fordham and Sandwich

  1. Mike, what are Extractables and Leachables?
    An extractable is defined as “any chemical species that can be extracted from a container, closure system, process component or drug delivery system that can contaminate the dosage form under exaggerated conditions of solvent, temperature and time”
    A leachable on the other hand is “a chemical species that has migrated from packaging or other components into the dosage form under normal conditions of use or during stability studies”.
    These are of course not our definitions, but stem from the PQRI best practice guidelines for E&L.
  2. Why is it important to perform E&L studies?
    For the safety of medicines, it is mandatory nowadays to perform analytical investigation of primary drug packaging and also delivery devices, such as inhalers and pre-filled syringes, to identify any species which may adversely impact the final drug product.
    Leachables may present a direct risk in terms of toxicity to the patient or they can cause potential compatibility risks. These risks are diverse and could include the following:
    - Interaction with or degradation of the drug substance,
    - pH changes,
    - appearance changes,
    - particle formation,
    - and protein aggregation resp. structural changes.
  3. Is this of importance only in the pharma area?
    The primary focus for E&L is concerned with pharmaceutical products but testing essentially originated in the food area, for any materials which are in direct contact with the food. Similar testing is performed extensively in the consumer healthcare sector, e.g. with supplements including herbals.

E&L is also becoming a hot topic in the area of Biopharmaceuticals where processing components such as filters and transfer tubing can be a potential source of leachables which can adversely impact both the production process and the final drug product.

  1. Is there any kind of regulation on the topic? And if so, also a standardised approach (method) to test?
    There are two USP informational chapters which were issued in 2015, describing the general approach required for E&L testing:
    - USP <1663> on the “Assessment of extractables associated with pharmaceutical packaging / delivery systems”
    - and USP <1664> on “Assessment of drug product leachables associated with pharmaceutical packaging delivery systems”
    These chapters are further developments from USP <661> and related monographs which deal with release testing of polymers for medical devices.
    There are also a number of relevant ISO documents* (please see footnote).
  2. What is a typical service you provide for your customers?
    The studies we perform do tend to be customer specific. They depend on device type and on the mode of administration and also at what stage the product is in the drug development process.
    The typical approach would include the initial screening of samples from the extraction study using a combination of GC-MS, LC-MS and ICP-OES / MS (ICH Q3D). This often followed by development and validation of related assay methods for stability testing.
  3. Can you reveal customer names for whom you are working?
    I would love to, but I’m afraid this would be considered confidential. We work with a wide range of clients including large pharma, generics and device manufacturers.

Mike, thank you very much for introducing us into the topic.

>>Want to dive further into these specific services we provide?
Check out our E&L webinar and our video

*BS EN ISO 10993-12:2012:
Biological evaluation of medical devices Part 12: Sample preparation and reference materials
BS EN ISO 10993-18:2009:
Biological evaluation of medical devices. Chemical characterisation of material

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