During manufacture and use, pharmaceutical products are in contact with processing equipment (reaction vessels, tubes, filters, chromatography columns, etc), packaging (glass vials, plastic bags, etc) and delivery device components (needles, catheters, syringes, caps, seals, stoppers etc). Small amounts of chemicals may leach from any or all of these into the pharmaceutical, and subsequently be delivered to the patient along with the dose. It is critical for all parties that such leaching does not occur in quantities that significantly alter the safety, identity, strength or quality of the drug. Extractables and leachables studies play a critical role in quality control and monitoring.
E&L studies are carried out sequentially. First, the contact materials are extracted by various established solvents under exaggerated incubation conditions of time and/or temperature. A range of analytical techniques (e.g. GC-MS, HS-GC, LC-MS, ICP-OES and FTIR) are used to identify extractables (sometimes only tentatively or generically); semi-quantification is often possible at this stage. The risk assessor can use the extractables study to identify those that are critical for confirmation and better quantification in a leachables study.
We provide valuable support to the pharmaceutical, medical device and process equipment industries by producing risk assessment reports relating to extractables and leachables (E&L)
A leachables analysis is then carried out, identifying and quantifying the chemicals that actually migrate into a drug product under normal conditions of production, storage and use. This may be preceded by accelerated leaching and/or stability studies using the pharmaceutical formulation; these are very useful in the risk assessment process.
Typically, our health risk assessments are based on the leachables study results. The exposure, including treatment dose, dosing route, dosing frequency, and its likely duration would all be described to us prior to starting our evaluation. We combine the hazard evaluation of the individual chemicals with exposure information to assess whether any significant health risks exist. Worst-case assumptions are made to address uncertainties. Where substance-specific hazard data are inadequate, read-across or a TTC approach may be introduced. In addition, our risk assessors are familiar with the recently developed guidelines and draft guidelines from the Product Quality Research Institute (PQRI) on extractables and leachables in drug products.
The end product is an independent, expert risk assessment report explaining transparently whether the patients are at any significant health risks or not as a result of leaching substances. This reassures clients or provides the information needed to modify processes, and helps to ensure that patient health is not compromised by the inevitable low level migration from packaging and processing contact materials.
Recently, our Director of Toxicology (and resident E&L expert) Pete Watts, gave an interview with Smithers Rapra on the analytical and toxicological assessment of E&Ls – click here to read more.
Examples of where Extractables & Leachables are present
- Processing equipment – reaction vessels, tubes, filters, chromatography columns, etc
- Packaging – glass vials, plastic bags, etc
- Delivery device components – needles, catheters, syringes, caps, seals, stoppers etc
- We can assist with analytical techniques – advice given on GC-MS, LC-MS, ICP-OES and FTIR extractables studies to identify those that are critical for confirmation and better quantification in a leachables study
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