A Short Introduction to Extractables and Leachables in Pharmaceuticals

Extractable and leachable (E&L) impurities can occur when drug products interact with a wide and complex range of packaging, drug delivery, and manufacturing components. But a lack of internationally-agreed guidance on E&Ls is hampering our efforts to understand them. Fortunately, this situation looks set to change in the near future - with positive developments on ICH 3QE, the International Council for Harmonisation’s proposed new E&L guideline, as well as the US Pharmacopeia’s work on developing new system suitability standard mixtures under USP-NF49(4).

Extractables and leachables are an impurity subset resulting from the interaction of pharmaceutical products with their packaging, drug delivery systems, and manufacturing components. Common E&Ls include plasticisers, antioxidants and Polycyclic Aromatic Hydrocarbons (PAHs), and they can migrate from numerous sources into a dosage form.

An extractable may be defined as a substance that can be ‘pulled out’ of devices, components and packaging materials using deliberate ‘stressing’ conditions – such as strong solvents, high temperatures, and increased surface area. Leachables, meanwhile, are substances that are “released under the gentler conditions of on-shelf storage.” Extractables are also regarded as representing “the worst-case scenario” in terms of impurities that can be released from manufacturing and packaging components, while leachables mostly – but not always - represent a subset of chemical species that can be extracted.

The purpose of attempting to identify potential E&L impurities is “" to determine the impact to human health and/or drug efficacy that those chemicals pose.” Perhaps the main negative effects that a leachable can have on a pharmaceutical product stream are 1) that it is toxic, and thus poses a risk to consumers; 2) that it interacts with the drug and alters its stability or potency; or 3) it interferes with an assay that measures the drug’s essential properties.

Extractable and Leachable Sources

The very complex processes involved in producing packaging materials, drug delivery systems, implantable medical devices, and bioprocess materials mean that E&L impurities can derive from multiple potential sources. Amongst these are packaging materials such as vials, foils, inks, and coatings, as well as production components like bags, tubing, and filters. An additional risk factor is that many of today’s manufacturing components are made from single-use plastic and elastomeric materials – the nature of which can significantly increase potential exposure to extractables, or lead to “a much greater chance of having... leachables with direct health risks .”

Risk assessment and analysis 

Experts agree that, given the “plethora of component parts used during product manufacture and storage”, and the large number of potential leachables, “a structured and thorough E&L study” is essential to guarantee the safety and efficacy of each drug product. Due to the many different types of materials used during production, such studies must also be tailored to the specific product to ensure accurate assessment. One way of ensuring that all risks are covered is to take a Quality By Design (QBD) approach to E&L studies, based on a thorough understanding of the manufacturing process, from sourcing of raw materials to disposal. 

The purpose of the extractables study is then to identify compounds that could migrate into the pharmaceutical product upon storage under normal conditions, and establish “a baseline for the following leachables study, a series of tests carried out at predefined time-points on the pharmaceutical product for the duration of its shelf-life.” The drug product is screened in order to discover, identify and quantify leachables, which can then themselves be assessed for their potential adverse effects in a chemical safety risk assessment – a process that compares a consumer’s exposure to individual leachables with toxicologically established exposure thresholds. Analysts will also refer to general E&L risk considerations, such as those set out in USP 1664, which classifies the likelihood of interaction between packaging components and dosage forms based on the drug’s route of administration.

Meanwhile, to generate a complete leachables profile, “an analytical strategy involving multiple, orthogonal analytical methods is necessary” – including qualitative screening by GC-MS and/or LC-Q-TOF. For quantitative leachables testing, GC/MS, TDS-GC MS/MS and GC-FID can all be employed for volatile/semi-volatile impurities; while UPLC-UV/MS/MS, HPLC-UV/PDA-FLD and LC-Q-TOF are suitable for non-volatiles. Ion chromatography is, meanwhile, useful for the analysis of anionic impurities, with ICP-MS and ICP-OES preferred for elemental impurities.

‘Disconnected’ regulations

There are currently no safety-based International Council for Harmonisation (ICH) guidelines specifically addressing E&Ls, as general guidance papers on impurities in pharmaceuticals (ICH Q3A-C) focus primarily on impurities caused during drug synthesis and degradation, or by residual solvents. Although they make reference to “extraneous contamination that should not be present” and should be controlled by good manufacturing practices, these documents do not directly address extractables or leachables.

Published in 1999, the US Food and Drug Administration (FDA) Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics still offers some of the most specific advice available to laboratories on E&Ls, although some observers have criticised its “very general”  risk assessment advice on leachables, as well as its failure to discuss further purification steps. 

In 2013, the US Pharmacopeia published general chapters 1663 “Assessment of Extractables” and 1664 “Assessment of Leachables”, which establish critical dimensions for extractable and leachable assessments respectively. However, neither chapter establishes specific analytical methods, extraction methods, leachable specifications or acceptance criteria for any dosage form, packaging system or drug product combination.

In addition, USP 661.1 “Plastic Materials of Construction” and 661.2 “Plastic Packaging Systems for Pharmaceutical Use”, provide bases for the assessment of “established tests and acceptance criteria to ensure packaging systems do not materially impact the effectiveness of the drug product”. Both chapters become official guidance on December 1, 2025.

Despite the existence of the advice above, many within the E&L testing community believe that “Extractables and leachables risk assessments, testing, and safety-based limits, have become disconnected from other relevant impurity initiatives, particularly ICH M7, ICH Q3C and ICH Q3D.” Specifically, they would like to see E&L regulations based on metrics such as Permitted Daily Allowances (PDEs) and Thresholds of Toxicological Concern (TTC) – arguing that the current system of assessing leachables against a Safety Concern Threshold (SCT) is “an overly conservative approach”, which “wastes time, money and effort” and reduces industry efficiency. Significantly, this view appears to be shared within the ICH, which also stated in 2020 that a lack of internationally harmonised guidance on E&Ls “generates uncertainty for industry and regulators.... (and) ultimately creates potential delays in the approval of regulatory applications, (which) can lead to variable interpretation (and) may cause delays in the accessibility of medicines to patients.” It has therefore tasked a committee of experts with drafting new guidelines that specifically address E&L issues. Known as ICH Q3E, the committee's final guidance paper is expected to be published by November 2025.

ICH Q3E – closing the guidance gap

The committee's 2020 concept paper anticipates that ICH 3QE’s scope will include: “chemical, biological and biotechnicological products, including drug-device combination drug products” – but not medical devices. It will, however, include “all associated dosages forms and take into account the extracting/leaching conditions, the route of administration, drug indication and patient exposure.”

The concept paper also sets out a series of key E&L issues it hopes to resolve with the introduction of the new guideline, including:

·       Agreeing a global ICH guideline for E&Ls, “to harmonize current expectations covering all medicines, allowing clearer definition of scope and focus on critical quality and safety aspects.”

·       Developing principles for E&L control strategies and studies, based on science and risk-based principles for container closure and manufacturing systems, plus drug delivery device components.

·       Introducing harmonised, future-proofed, thresholds for reporting and identifying E&Ls and qualifying leachables, in the context of route of administration, drug indication and patient exposure.

·       Establishing safety limits taking into account route of administration, drug indication and patient exposure, and agreeing a common strategy for additional safety studies.

·       Investigating additional options for mitigating and controlling process-derived leachables.

·       Using existing principles to align Q3E with current ICH impurity guidelines (ICH 3-7 and M7).

·       Aligning existing national and regional E&L standards under a new guidance framework.

USP-NF49(4) - further improving standards

In another sign that the international testing community is becoming more aligned in its approach to E&L issues, a US Pharmacopeia Pharmaceutical Forum published a stimuli article in July, inviting comments on its proposals to develop system suitability standard mixtures supporting the screening of organic E&Ls.

The article provided details of the proposed mixture’s performance using HS-GC/MS, GC/MS, LC/MS-APCI and LC/MS-ESI, and also discussed next steps in the project: including feedback from stakeholders, revisions to the mixtures, qualifying batches of the materials as reference standards, stability assessments, and the development of additional mixtures.

 USP 661.1