GENERAL EXTRACTABLES AND LEACHABLES STUDY APPROACH
Although PQRI's recommendations to the FDA are specific to orally inhaled and nasal drug products, the general approach presented
therein can be applied to materials used in disposable bioprocess manufacturing systems. Figure 1 shows a step-by-step approach
for performing extractables and leachables studies for materials used in disposable bioprocess manufacturing systems.
Figure 1. A step-by-step approach for performing extractables and leachables studies for materials used in disposable bioprocess
Stage One: Compiling and Evaluating Information
Because studies of extractables and leachables (E/L) require a thorough understanding of the materials and the drug to construct
an effective study plan, the first stage entails compiling and evaluating the following information:
1. Drug dosage form and formulation composition, including excipients and the active pharmaceutical ingredient.
2. Understanding the manufacturing process, including process conditions; evaluating which materials the drug formulation
comes into contact with during the manufacturing process; and assessing the duration and types of interactions with these
3. Understanding vendor-supplied disposable product components and the compositions of those materials; evaluating information
from the manufacturers of these materials as to material matrix compositions; and assessing any extractables data that already
may have been generated about these vendor-supplied materials.
The dosage regimen and the volume of product administered per unit time are the critical information required in calculating
an analytical evaluation threshold (AET). The AET defines the required sensitivity of the analytical methodologies (instrumentation)
for acceptably monitoring E/L at a specified safety threshold. PQRI defines a safety concern threshold (SCT) for OINDP of
0.15 µg leachable per day. (Note that the SCT for other delivery systems has not been specified by PQRI.) Therefore, based
on the amount of product exposed to the patient per day, the leachable quantity per material can be calculated and the method
sensitivity requirements in µg/mL of extracted solvent can be obtained based on the extraction study design.
Stage Two: Designing the Extraction Methods
The next stage involves designing the extraction methods for the applicable process and disposable product materials. Typically,
at least three extraction solvents that bracket the polarity of the drug are chosen. For some studies it is advisable to include
the drug vehicle or placebo, itself a fourth extraction solvent. Extraction conditions such as temperature, pressure, extraction
time, and material-to-solvent ratios should be chosen to provide a thorough, complete extraction profile for the materials
under evaluation, and to provide sufficient sensitivity per the analytical evaluation threshold (AET) calculations performed.
The most common extraction technique is refluxing. Alternatives include Soxhlet extraction, which exposes the sample to less
extreme temperatures and can be chosen for materials that may degrade under standard reflux conditions; and time-abbreviated
techniques, such as the use of an accelerated solvent extractor, sonication, or extraction in a sealed container placed in
an oven or autoclave.
As noted above, the calculated AET is based on the total daily intake (TDI) of the potential leachables or extractables in
the drug product. Depending on the dosage regimen and administered amount, achieving the required instrument sensitivity may
be a challenge. Sample extracts may also require treatment or modification to be appropriate for analysis using the specified