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There is no shortage of guidance for conducting extractables and leachables studies.
For instance, U.S. Pharmacopeia and the Product Quality Research Institute (PQRI) offer separate and useful recommendations.
However, an ideal approach is to combine guidance from both organizations, says Aryo A. Nikopour, Senior Vice President of Scientific and Technical Services at Nitto Avecia Pharma Services.
Despite differences in nomenclature, both organizations seek similar outcomes, Mr. Nikopour says.
They instruct developers to first identify extractables as tentative leachables, then asprobable leachables using model extraction (also known as simulation), and finally as confirmed leachables in support of shelf-life studies for the final container closure system, he adds.
Controlled extraction finds tentative leachables
To identify tentative leachables, the organizations describe procedures for establishing the extractable profile. The PQRI guidance refers to this as a “controlled extraction study.” It involves the qualitative and quantitative investigation of the critical components of the container closure system.
One goal of the controlled extraction study is to establish a basis for development and evaluation of the analytical method in support of routine quality control testing. It is also designed to set a basis for the development of leachable studies. And it allows for the “correlation” of extractables and leachables, says Mr. Nikopour, who has spent nearly half of his 30 years in the pharmaceutical industry with Nitto Avecia Pharma Services, formerly known as Irvine Pharmaceutical Services.
Different media are selected to identify probable leachables
With a better understanding of tentative leachables, product developers can move to the second step, identifying probable leachables using “model extraction (simulation)” studies, Mr. Nikopour says.
In this second step, product developers choose up to three different media that represent the final formulation (placebo). This could be a buffer at various pH levels, for example. The container closure is then filled with the three different formulation placebos and stored at accelerated conditions such as 40 degrees C and 75 percent humidity. Samples are analyzed at an initial point, then at one, three, and six weeks.
Representative methods from the controlled extraction studies will be employed to analyze the samples. These can include such methods as gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), or others.
These model extraction (simulation) studies are vital to ensure no probable leachables escape attention. Now with deeper insight, product developers can advance to the third step, which is to identify confirmed leachables.
Same analytical methods used to analyze confirmed leachables
In this third and final step, developers return to the initial toxicology risk assessments to review controlled extraction and model extraction studies. They review the indication and population, dose, duration, route of administration, and all the data gathered so far about the leachables. They then set up appropriate methods for this final confirmation step.
Generally, developers apply the same analytical methods used in the model extraction (simulation) step. This enables them to determine correlations between the data. In some cases — more often when working with small molecules — the method will have to be modified due to interference from the active ingredients or excipients, Mr. Nikopour says. To prevent loss of unknown leachables, do not apply filtration at this point, he adds.
It’s important to include a “scan method” at this point to catch any surprises. The scan method can catch migrant leachables. They are formed by interaction with the environment and secondary packaging.
Finally, in this third step, developers will evaluate the method for robustness and ruggedness. They will also qualify reagents from at least two manufacturers to make sure there are no impurities, identify suitable internal standards, and use surrogate standards for scanning methods.
This summary just scratches the surface of the complexity involved in extractables and leachables studies, but it shows the value of aligning different recommendations to form a coherent strategy.
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