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How to choose a stimulation study

Solvent systems for E&L material characterization need to be chosen with the intent to enable the identification and semi-quantification of target leachables for conclusive drug product assessment.

The choice and performance of these solvent systems is crucial for the overall outcome of an E&L qualification exercise as these conditions determine the ultimate list of leachables undergoing a toxicological assessment.

Various industry groups have proposed simulation solvents as a starting point for such exercises (e. g. PQRI PODP WG for final packaging systems).

While the simulation solvent should best mimic the drug product physico-chemical properties (e. g. leachables solubility) only more general rationales and initial concepts for the selection of simulation solvents are available in the public domain.
Panellists joining the E&L Europe panel discussion will answer questions on whether they see a need or a benefit of a more enhanced or precise guidance on the choice of simulation solvent systems, if for example such guidance could consist of kind of a semi-quantitative scale to assess drug-product lipophilicity. And furthermore, what would be suitable organisations to perform such research? Bearing in mind that in the food contact materials arena (EU), such research activities have been launched and supported based on officially funded projects.

Dennis Jenke, one of the session panellists has written an article on "Establishing the proper pH of simulating solvents used in organic extractables assessments for packaging systems and their materials of construction used with aqueous parenteral drug products" which is published by Pharm Outsourcing. 15(4):20, 22, 24-27 (2014).

Substances that leach into drug products from packaging systems can affect the product's suitability for use. Thus drug products may be tested for leachables or packaging systems can be tested for extractables to establish the systems' impact on the suitability of the drug product. If the purpose of the controlled extraction study is to produce a packaging system extractables profile that is similar to the drug product's leachables profile, then the extraction conditions should mimic the contact conditions between the drug product and its packaging. Extraction conditions to consider in the extraction study include the chemical nature of the extraction solvent and the drug product, especially pH.

This manuscript considers the pH range that extraction solvents should cover to produce complete extractables profiles and the proper use of intermediate pH solvents and concludes that: (1) the proper pH range for simulating extracting solvents used in controlled extraction studies designed to forecast drug product leachables spans the pH range of the relevant drug products; (2) relatively complete extractables profiles, reflecting all relevant extractables and establishing their highest possible levels as drug product leachables, are obtained at pH extremes of 2 and 10; (3) using an extraction solvent with a neutral pH between 6 and 8 adds little or no value in establishing the worst case extractables profile (greatest number of extractables at their highest levels); and (4) simulating the "leaching power" of drug products that span a specific pH range requires the extraction solvents whose pH values closely match, and do not significantly exceed, the extreme pH values of the drug products.

Panellists joining this session include: Dennis Jenke of Baxter Healthcare, Frank Welle of Fraunhofer IVV, Wolfgang Dirk of Gerresheimer and Melanie Pires of MHRA.

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