Extractables and Leachables Information

Identify and quantify leachable impurities

A drug product container-closure system should not release chemicals that can accumulate in the drug product in quantities sufficient to present a risk of toxicity, or affect its stability or efficacy.

We are unique in offering comprehensive analytical workflows including ICP-MS, GC-MS, LC-MS and advanced information to enable identification and quantification of unknown organic and elemental impurities.


Extractable and leachable impurities from pharmaceutical container-closure and production systems

In May 1999, the U.S. FDA published a guidance document on   Container Closure Systems for Packaging Human Drugs and Biologics. The FDA mandated that pharmaceutical manufacturers demonstrate the safety of materials used in production systems, container closure systems or drug delivery devices. Failure to demonstrate material safety could result in failure to receive FDA approval for a product. Everything from glass and plastic bottles to foil pouches and the ink used in labels and packaging materials has the potential to leach unwanted contaminants into a drug product.

What are "extractables"?

In order to study the risk of materials extraction studies are performed; generally using aggressive solvent conditions including acidic, basic, organic and aqueous solvents and sohxlet or accelerated solvent extraction. It is important that the extraction process does not deform the material of interest. Compounds present in the resulting extracts are called "extractables". Extractables studies are typically performed to create a "worst case scenario" and assist in materials selection and early risk assessment.

What are "leachables"?

Leachables are chemical species that make their way into the product under normal product, application or storage conditions. There is generally an overlap such that the leachables involved may be classified as a subset of the extractables. Forced or accelerated leachable studies can be performed to assess leachables that migrate under simulated environmental conditions by analyzing the drug formulation after exposure to elevated temperature. However, if the leachable interacts with the drug product or packaging materials, new components can be present. These are termed secondary leachables. Drug formulations often contain buffers, surfactants, fillers and other excipients. This complexity means that there are sometimes secondary leachables that can only be identified after long stability studies over the typical drug shelf life.


Detecting extractables and leachables: using the right tests

Extractable and leachable studies identify key components using a range of analytical technologies:

Quantification of these compounds is performed using relative reference standards, in which a qualified toxicologist calculates the analytical evaluation threshold (AET), above which an extractable or leachable needs to be reported for toxicological assessment. Analytical data for these impurity classes is meant to provide information to help customers determine what further studies are needed to mitigate risks associated with the final product.

There are currently no single regulated method prescribed for analyzing extractables and leachables. Generally, the Product Quality Research Institute (PQRI) recommendation document in the table below is accepted by the industry as a primary recommendation to follow as it was drafted with U.S. FDA involvement. However, to date it has not been formally accepted. There are several methods in draft currently being considered by global regulators and guidance documents from industry bodies, such as BioPhorum Operations Group (BPOG) and BioProcess Systems Alliance (BPSA):


Featured extractables & leachables learning content

Video

Join industry expert Dr. Jason Creasy from GlaxoSmithKline as he talks with The Medicine Maker magazine about the history, developments and future of extractable impurities testing for pharmaceuticals.

Video

Smithers Rapra are leaders in extractables and leachables testing and consultancy services. Listen to Dr. Andrew Feilden from Smithers Rapra as he discusses the changing landscape of this discipline and new technology that is making the task easier.

Webinar series

Join this 3-part webinar series to learn extractables and leachables testing for pharmaceutical container-closure systems and food contact materials. Hear from experts about regulations and the latest technologies and workflows to deliver E&L testing.

Publication

The National Institute for Bioprocessing Research and Training (NIBRT) is publishing new research investigating extractable & leachable impurities in the manufacture of biopharmaceuticals. Get their groundbreaking research report first.

Poster video

Join applications scientist Keeley Murphy as he presents this extractables and leachables poster at the American Association of Pharmaceutical Scientists (AAPS) conference.


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TypeTitleProduct FocusYear
Application NoteAccelerated Solvent Extraction for Additives in Polymer MaterialsSample Preparation2014
Application NoteAccelerated Solvent Extraction of Extractables from Polymeric Components Used in Precision Drug Delivery DevicesSample Preparation2013
Application NoteComparison of Soxhlet and Accelerated Solvent Extraction for Leachable and Extractable Analysis of Packing MaterialSample Preparation2014
Application NoteConfident Identification of Leachable Impurities from Pharmaceutical Container Closure Materials using Orbitrap-Mass-Spectrometer-Based GC-MSGas Chromatography Mass Spec2015
Application NotePharma Materials Study: GC-MS Identification of Extractables and Leachables from Elastomer MaterialGas Chromatography Mass Spec2014
BlogIt's in the bag. LiterallyWorkflow2016
Blog3 Reasons Why I’m Attending Extractables & Leachables USAWorkflow2016
BlogDetecting the UndetectableHPLC / UHPLC2016
BlogWhat No One Tells You About Plastic, Hamsters and Drug ProfitsWorkflow2016
BrochureExtractables & Leachables Workflow - Identify All SuspectsWorkflow2016
Case StudyCharacterization of Extractables and Leachables Associated with Pharmaceutically Relevant Materials: Case Studies Outlining Analytical Approaches, Challenges and ExamplesOther2011
EditorialA New Era of E&L AnalysisWorkflow2015
InfographicExtractables and Leachables InfographicWorkflow2016
PosterDosing Syringe Extractables Analysis Using Bench-Top Orbitrap Mass SpectrometerMass Spectrometry2016
PosterIdentification of IV Bag Extractables Using GCMS, LC-HRMS, and ICP-MSGCMS/LC-HRMS/ICP-MS2016
Poster NoteComparison of Soxhlet and Accelerated Solvent Extraction for Packing Material Leachable and Extractable Studies
Using LC-MS
Sample Preparation2015
Poster NoteComparison of Soxhlet and Accelerated Solvent Extraction for Packing Material Leachable and Extractable Studies Using LC-MSSample Preparation2014
Poster NoteComprehensive Analysis of Extractables from Rubber Stopper used in Medical Devices and Pharmaceutical ProductsWorkflow2014
Poster NoteComprehensive Extractables Analysis of Medical Grade O-Ring (AAPS 2015)Workflow2015
PresentationExtractables & LeachablesWorkflow2016
WebinarTesting for leachables in pharmaceutical contact closure materials; a complete ICP-MS, GC-MS & LC-MS workflow (3 Webinar Series)Workflow2015
White PaperExtractables and leachables: Regulatory requirements for vaccine and biologic productsOther2015
White PaperMass Spectral Studies of Polypropylene Chromatographic Well PlatesLife Science Mass Spec2015

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