Extractables & Leachables Testing

The examination of extractables & leachables from materials in contact with a drug product or the patient is growing in importance due in part to increased regulatory scrutiny from organisations such as the FDA and EMEA. Regulators are concerned with the interaction of various drug delivery devices (such as inhalers, nasal sprays and injection pens), medical devices and pharmaceutical process equipment with drug products and patients. Extractables & leachables assessment of all materials, especially from elastomeric & plastic components, forms an integral part of the submission for approval of a new drug product or medical device.

For drug delivery devices various guidelines are available from the FDA and EMEA.  Many of these guidelines are concerned with inhalation devices, such as meter dose inhalers (MDI) and dry powder inhalers (DPI), and cover a wide range of aspects including extractables and leachables from rubber and plastic components in these devices.

Whilst these guidelines have brought much needed clarification to the pharmaceutical development process, the PQRI Leachables and Extractables Working Group has submitted best practice guidelines for Extractables and Leachables Testing to address remaining uncertainties.  This bests practice has made an important contribution to Extractables and Leachables Testing of Orally Inhaled and Nasal Drug Products (OINDP).  More recently this working group has turned it’s attention to Parenteral and Ophthalmic Drug Products (POPD) and guidelines are expected soon

Smithers Rapra have considerable experience working for a wide client base with extractables and leachables test results & data generated by Smithers Rapra often being used to support successful regulatory submissions to both the FDA & EMEA.

Generally a four stage approach is taken to Extractables and Leachables (E&L) testing at Smithers Rapra, although the scope of E&L testing can vary considerably depending on the nature of the drug product and its packaging:

• Extractables Testing of the Various Delivery Device Components or Packaging Elements.
• Leachables Method Development
• Leachables Method Validation
• Leachables Testing

Extractables Testing of the Various Delivery Device Components or Packaging Elements.

Here the device or packaging components, including the inks and adhesives associated with labels, are extracted with one to three different solvents.  The extract(s) is then analysed (GC-MS, LC-MS and infrared spectroscopy) to identify the chemicals that have been extracted from the component or packaging.  The components analysed directly for metals and for determination of any highly volatile species are present (ICP-OES, GC-MS headspace).  In this way a qualitative extractables profiles of the device components and packaging are established.  This group of extractable chemicals are potential leachables.

A review of this group of extractables is conducted to assess which of these chemicals should be considered in the subsequent leachables study.  This assessment is based on the approximate amounts extracted and their toxicological relevance.

If the drug product is an orally inhaled or nasal product (OINDP) quantitative extractables profiles of the various device components may be required.  This requires additional quantitative analysis of the component extracts.

This stage of the testing is conducted in a cGMP compliant manner and typically requires 4 to 6 weeks to complete.

Leachables Method Development

Analytical methods need to be developed to quantify leachables present in the drug matrix.  The leachables to be considered are selected on the basis of the findings of Stage 1. The methods developed need to be robust, repeatable, precise, sufficiently selective and have a suitable range and quantification limit, as they will be used to analyse samples over a period of up to 3 years.  They are generally based on Gas Chromatography Mass Spectroscopy (GC-MS), Liquid Chromatography Mass Spectroscopy (LC-MS) and ICP-OES.

Method development generally requires 4 to 6 weeks to complete.

Leachables Method Validation

The analytical methods developed in Stage 2 need to be validated according to ICH Q2A guidelines to demonstrate that they are fit for purpose.

This validation study is carried out in compliance with the principles of cGMP and typically requires 2 to 4 weeks to complete.

Leachables Testing

Samples of the drug product in the packaging are stored under ICH Q1A conditions.  Two or three batches of packaging are generally considered and the drug product may be stored in a number of orientations (e.g. ‘inverted’ and ‘upright’).

For product stored at ambient temperature accelerated storage is carried out at 40 °C/75% RH and real time at 25 °C/60% RH. If the product is to be refrigerated during storage, accelerated storage is carried out at 25 °C/60% RH and real time at 5 °C. Samples are removed at various intervals and the leachables present quantified using the analytical methods developed and validated in Stages 2 & 3.

Examples of the times at which samples are removed for analysis are, for real time storage, 6, 12, 24 and 36 months, and for accelerated storage, 3, 6 and 12 months.  Zero point samples are also analysed to provide base line data.

The storage and analysis of the drug product is carried out in compliance with cGMP.  In this way a leachables profile for the drug product under various storage conditions and orientations is developed.
This is a long term storage study and can take up to 3 years, however accelerated and 12 month real time data would be available after a year. For each time point the analysis would be turned around within 4 weeks.

Smithers Rapra Extractables and Leachables Testing Experience

A summary of Smithers Rapra activities and experience in Extractables and Leachables Testing of Drug Delivery and Medical Devices is provided:

• Smithers Rapra was founded over 90 years ago to provide industry with technology, information and consultancy on all aspects of elastomers and plastics.
• We have been working in the food, pharmaceutical and medical devices arena’s for nearly twenty five years.
• In that time we have worked in the following therapeutic areas:
• Inhalation products; Nasal products; Medical Devices; Oral; Injectable/Parenterals; Implantable; Opthalmic; Topical; Drug Substances
• We have a track record of working with the following items:
• Stoppers; DPI’s; pMDI’s; Elastomeric Closures (vials and pre-filled syringes) Nebulizers; Endoscopes; Catheters; API’s; Stents; Topical Creams
• During this period we have completed numerous studies for a wide range of clients, who have used Smithers Rapra as an extension to their own laboratory facilities and used our test results and data in their regulatory submissions.
• Due to confidentiality agreements we are unable to divulge the names of companies or products, but they have not had a submission rejected by the regulatory bodies.
• We have conducted studies which have gone on to submissions to the FDA and the EMEA. As a result of this work the FDA carried out an Establishment Inspection of our laboratories at Shawbury, UK in August 2008. This was a successful inspection and the FDA’s report stated that ‘no objectionable’ conditions were observed and no FDA-483 was issued to the facility.
• Smithers Rapra also conducts final batch release analysis on a leading manufacture’s pMDI valve.
• Smithers Rapra tailors reports to meet the exact requirements of the individual customer’s wishes and therefore most reports come in slightly different formats and we are happy to listen to any special requests which may help the smooth passage of any regulatory submission.
• Smithers Rapra has an open door policy and sponsors are welcome to visit our site and discuss any issues with us directly.