During manufacture and use, pharmaceutical products make contact with processing equipment, packaging and delivery device components (see below for examples). 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 (E&L) 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-MS, LC-MS, ICP-MS, ICP-OES) are used to identify extractables (sometimes only tentatively or generically); semi-quantification is often possible at this stage. Bibra health risk assessors can use the extractables study to identify those that are critical for confirmation and better quantification in a leachables study. Sometimes, a full health risk assessment is carried out by bibra toxicologists on the extractables data.
Leachables studies are then carried out, identifying and quantifying the chemicals that actually migrate into a drug product under normal conditions of production, storage for a full shelf-life, and use. This may be preceded by accelerated leaching and/or stability studies using the pharmaceutical formulation, which can be used to predict likely leaching during normal shelf-life storage.
Health risk assessment
Typically, bibra health risk assessments are based on the leachables study results. The exposure, including treatment dose, dosing route, dosing frequency, and its likely duration are key elements of the assessment. We combine the hazard evaluation of the individual chemicals with exposure information to assess whether any significant health risks exist. Worst-case assumptions on exposure and (for unidentified peaks) structure are made to address uncertainties. Where substance-specific hazard data are inadequate, read-across or a conservative Threshold of Toxicological Concern (TTC) approach may be applied. In addition, our risk assessors are familiar with guidance from the US Product Quality Research Institute (PQRI) on extractables and leachables in drug products, notably PODPs and OINDPs.
The end product is an independent, bibra 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, processing and drug delivery contact materials.
Examples of sources of leachables:
- 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
Extractables and Leachables
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