Extractables and leachables are potentially hazardous chemicals that a patient can be exposed to when using medical devices or drug products. These chemicals may be present as impurities in the materials used, but also may be introduced during manufacturing or storage.  Management of the risks that these chemicals pose to patients can be managed, but requires robust quality control and careful study design. The cost of getting it wrong could include unexpected performance of the device or drug product due to these chemicals, plus the regulatory non-compliance issues that result. At worst, leachables may prove toxic to end-users, posing serious health risks.

Part of any robust pharmaceutical or medical device manufacturing process is a risk assessment that considers not only the product and included materials but also the manufacturing environment, any needed packaging materials, and the potential alterations resulting from sterilization procedures. Because leachable chemicals can be the result of complex interactions between both intentionally added and unanticipated chemicals, evaluation of the materials being used must be bolstered by a carefully designed laboratory study (often referred to as chemical characterization of extractables and leachables or simply E&L).

Extractables and leachables refer to compounds which can be either extracted or leached from a container into a drug formulation or from a medical device contacting a patient.

  • Extractables: Compounds that can be extracted from the container closure system under specific laboratory conditions — typically more aggressive than the use condition.
  • Leachables: Compounds that leach into the drug product formulation from the container closure as a result of direct contact with the formulation, or compounds that a patient may be exposed to through contact with a medical device.

What are Extractables?

Extractables are chemicals which can be extracted when in contact with a solvent as part of a laboratory study. To study the risk of  a wide range of chemicals to be extracted, experiments are done generally using a range of solvents such as basic, acidic, aqueous and organic solvents in addition to using elevated temperature to increase extraction rates. It is critical that the process of extraction does not alter or degrade the material of interest. In the resulting extracts, compounds which are present are known as “extractables” and studies are designed to result in a worst-case estimate of exposure to the patient. This can aid in materials selection and early risk assessment. When a study is properly designed, the expectation is that all observed extractables are potential leachables.

What are Leachables?

Leachables are chemicals that are introduced into the product during conditions more closely resembling drug product storage conditions or clinical use of a medical device. However, especially for implantable medical devices, the conditions the device is exposed to cannot be replicated in the laboratory.  For these studies, the laboratory must consider carefully the nature of the device to design an appropriate simulated leachables experiment.

For drug products, it is necessary to evaluate the potential evolution of leachables during the shelf-life of the product (stability leachables).  These studies are carried out to understand leachables which migrate under simulated environmental conditions. In these studies it is important to consider the possibility that the leachable interacts with the drug product itself, forming new  ‘secondary leachables’.

How are Extractables and Leachables Detected?

There are a range of analytical techniques that can be used to identify extractables and leachables. Volatile organic compounds are frequently analyzed using headspace GCMS. Semi-volatile organic compounds are usually assessed employing GCMS. Semi-volatile and Non-volatile ionizable organic compounds are typically analyzed with HRAM LC-MS/MS and elemental impurities are identified using ICP-MS.

Typically, for screening surrogate reference standards are used to quantify these compounds and a toxicologist provides a risk assessment based on the extractables which fall above the analytical evaluation threshold (AET). The process involves steps like acquiring background information, designing the study, preparing samples, extraction, identification, quantification, and toxicology evaluations.  For drug container closure systems, leachables monitoring requires further development, resulting in validated quantitative methods for monitored chemicals. It is crucial to select samples carefully, choose appropriate solvents for extraction, include analysis blanks and control samples, and identify unknown compounds during the process.

Extractables and Leachables from RQM+ Lab Services

RQM+ offers a wide range of laboratory services to clients in the pharmaceutical, medical device, food and beverage, agricultural industries, among others. Our services include detection and identification of contaminants, analysis of packaging materials, deformulation, physical testing, contamination and failure investigations, and more. We also provide expert witness services for litigation cases involving product failures, liability issues, patent infringements, and more. We partner with our customers to create studies backed up by over 40 years of experience.

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