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An Introduction to Extractables and Leachables Testing

The examination of Extractable and Leachable substances is extremely important for the protection of patients and for regulatory documentation destined for authorities such as the FDA and EMA.

The examination of Extractable and Leachable substances is extremely important for the protection of patients and for regulatory documentation destined for authorities such as the FDA and EMA.

In recent years, the pharmaceutical industry has developed a better understanding of the impact of extractables and leachables on patient safety and drug product interaction, leading to increased scrutiny by the regulators. When there is a change in a drug product’s immediate packaging materials, there is a regulatory requirement to assess the impact of the change.

Smithers Rapra is a leading authority for E&L assessments. Our experts have a proven track record of developing and delivering comprehensive E&L assessments tailored to your specific needs in our FDA registered laboratories.

This expertise derives from Smithers Rapra's 90 year history of working with rubber and plastic materials, our medical and pharmaceutical industry experience and our excellent understanding of analytical chemistry.

You can benefit from one of our expert's extensive expertise in the E&L USA pre-conference workshop, bringing you up to speed with all of the basics for E&L testing, but a brief overview of the basics is included for your information below and more information can be found at https://www.smithersrapra.com/testing-services/by-sector/medical-and-pharmaceutical/extractables-and-leachables

What is E&L testing?

Regulators are concerned with substances migrating from different materials (polymers, metals, glass etc.) which patients may be exposed to through many different routes of administration, such as:

  • Orally Inhaled Nasal Drug Products
  • Parenteral
  • Production equipment - Single Use Systems
  • Medical Devices

Extractables studies - definition

Extractables studies are an assessment performed on a material. Extractables studies are performed to identify substances that a patient may be exposed to.

Leachables studies - definition

Leachables studies are an assessment performed on the drug product. Leachables studies are performed to identify substances that patients are exposed to. Leachables are typically a subset of extractables, but not always.


Analytical Techniques for Extractables and Leachables Studies

Numerous analytical techniques are used for E&L studies because no single analytical technique can detect them all.

The techniques used typically include:

  • Gas Chromatography Mass Spectrometry (GC-MS)
  • 3D Gas Chromatography Mass Spectrometry (GCxGC-ToF-MS)
  • Liquid Chromatography Mass Spectrometry (LC-MS)
  • pH
  • Conductivity
  • Non-Volatile Residue (NVR) and Fourier Transform Infrared (FT-IR) spectroscopy
  • Total Organic Carbon (TOC)
  • Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES)
  • Ion Chromatography (IC)

E&Ls are assessed for a number of different materials and medical devices, and a couple of the main areas of testing are described below:

Single Use Systems

The use of Single Use Systems (SUS) can be hugely beneficial in biopharmaceutical manufacturing processes. An assessment of Extractables and Leachables is important for patient safety and to assess any potential impact on the process and product.

SUS are increasingly being used at every stage of biopharmaceutical manufacturing processes. SUS components include:

  • Filters

  • Process containers (bags)

  • Tubing

  • Connectors

  • Gaskets

  • Valves

All product contact surfaces have the potential to release extractable material into a process. In a biopharmaceutical process, a risk assessment for E&L should be made. Factors that affect that assessment include:

  • Nature of the extractable species

  • Process fluid

  • Contact time

  • Contact temperature

  • Downstream processes, (holding tanks, diafiltration, chromatography etc.)

Container / Closures

In order to obtain successful regulatory approval for new drug applications, packaging interactions with the drug product should be evaluated to ensure product safety.

The degree of interaction between the drug product and the primary packaging is dependent on the product type, as is the risk to the patient. The FDA summarises this in a table which is can be viewed here:https://www.smithersrapra.com/testing-services/by-sector/medical-and-pharmaceutical/extractables-and-leachables/container-closures

Smithers Rapra follow best practice guidelines, such as those provided by the PQRI for OINDP and USP draft chapters <1663> and <1664>.

The extractables study:

  • Design and execution of the extractables study on critical components of the primary packaging, covering inorganic and organic extractables.

  • Determination of the Analytical Evaluation Threshold (AET) from the Safety Concern Threshold (SCT)

  • Use of a number of extraction methods, employing multiple analytical techniques, as no one analytical technique is capable of detecting all extractable substances

  • Provision of a detailed technical report, containing full results and chromatograms

  • Option for undertaking a literature based toxicological assessment of the detected extractables to identify target leachables

The leachable study:

  • Development and validation of methods for the assessment of leachables in the drug product according to ICH Q2(R1)

  • Analysis of stability time point samples for leachables

Don’t miss out on hearing from our experts in person at one of our training courses, and if you have any questions about our E&L testing capabilities, contact us now.