<1663> ASSESSMENT OF EXTRACTABLES ASSOCIATED WITH PHARMACEUTICAL PACKAGING/DELIVERY SYSTEMS 

Chemical Nature of the Extracting Medium  

 Extraction time and temperature are critical factors in the extraction process. Although the nature of the extraction solvent establishes the magnitude of the extraction (i.e., the amount of substances that can be extracted from a material at equilibrium), the combination of extraction time and temperature establishes the magnitude of the driving force and the degree to which equilibrium is actually achieved. In a simulating extraction study the purpose of elevated temperature is to increase the extraction rate, so that a short experimental time may simulate longer leaching times (1, 5–9).Because extraction is a diffusion process, the relationship between the diffusion rate and temperature can be expressed empirically by the Arrhenius equation. 

The mathematics involved in a process that is driven by Arrhenius kinetics have been established in ASTM F1980-07 (2011) Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices (10), which may be a useful guide for establishing accelerated contact conditions. As with all such models, the proper use of this model requires an understanding of the model's basis and essential principles, assumptions, and limitations (2).Extractables profiles obtained with a given extracting medium and extraction technique can and should be monitored for equilibrium or the attainment of asymptotic levels of extractables (see Figure 1). 

Figure 1. A graphical representation of an extraction that has attained equilibrium as indicated by the achievement of asymptotic levels of target individual extractables as a function of extraction time (i.e., GC/MS peak area ratios of target extractables relative to an internal standard plotted versus extraction time). 

Extraction stoichiometry considers the physical mass and/or surface area of the test article relative to the volume of the extracting medium, and the actual physical state of the material when it is extracted. Extraction stoichiometry can be manipulated to facilitate production of a more concentrated extract. For example, consider the case of a rubber stopper for a vial that contains 5 mL of a liquid drug product. 

A more concentrated extract than the drug product (i.e., an extract that contains higher levels of extractables than the leachables level in the drug product) could be produced by extracting 20 stoppers in 200 mL of extracting solvent. Another aspect of extraction stoichiometry is the physical state of the test article. 

It is not uncommon that components or materials are cut, opened, ground, or otherwise altered in size or configuration prior to being extracted. For inhomogeneous or layered materials such as film laminates, the process of cutting or grinding prior to extraction may alter the extractables profile as it may provide a means for the extracting solvent to come into contact with (and thus more effectively extract) materials (layers) that are shielded from contact with the solution under normal conditions of use. 

One can argue that the use of such sized material further facilitates the extraction process, however it is possible for sizing to reveal extractables that might not appear as leachables. Nevertheless, some sizing of components or materials before extraction can be useful in certain situations and for certain purposes, including: (a) reducing sample-to-sample variability by the consistent preparation of ground homogeneous polymeric material; (b) reducing the sizes of large packaging components to allow use of standard laboratory glassware for extraction studies; (c) increasing the surface area of a packaging component or material test article (e.g., via extruding, pressing, or grinding) in order to increase extraction efficiency. In any event, careful consideration should be given to the effect of physical sizing of test articles on the extractables profile before such sizing methods are employed in extraction studies.

For extractables assessments involving components or materials whose chemical ingredients are known based on information from the supplier or fabricator, analysts can manipulate extraction stoichiometry based on the known levels of chemical additives and the known sensitivity of the analytical technique(s) that will be used to characterize the extract. For example, consider the formulation for a peroxide-cured ethylene-propylene-diene-monomer (i.e., EPDM) gasket from an MDI valve shown in Table 2.

Such information, when available from component and material suppliers, can be useful in designing an extraction study.Analysts can also base the extraction stoichiometry on established safety thresholds for leachables. For example, an exposure of 0.15 µg/day total daily intake for an individual organic leachable has been proposed as an SCT for inhalation drug products, also termed orally inhaled and nasal drug products (5). 

Leachables present at or above the SCT, in an MDI for example, should be analytically and toxicologically evaluated, suggesting that extractables assessment also should be guided with the SCT in mind. The application of thresholds such as the SCT and AET to leachables assessments is discussed in greater detail in Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems <1664>.In summary, extraction stoichiometry (and thus the “sensitivity” of an extraction study) can be based on:

• The known chemical ingredients in a component or material

• Safety-based thresholds for drug product leachables

• The known or determined sensitivities of analytical instrumentation used for extract characterization

An extraction can be accomplished in a variety of ways. It is necessary that the means of performing the extraction match the objectives of the extractables assessment. Common laboratory extraction techniques include:

• Maceration (solvent soaking)—in which the test article is allowed to soak for a period of time in an organic or aqueous extracting solvent at temperatures below the solvent's boiling point. Analysts can also fill packaging system units with extracting solvent and store them at relevant temperatures.

• Reflux—in which the test article is immersed in boiling solvent for a period of time.

• Soxhlet—in which the test article is placed in the “thimble” of a Soxhlet extraction apparatus that is slowly filled with redistilled solvent from a boiling flask/condenser system; and periodically, the extracting solvent (containing extractables) is siphoned back into the boiling flask and the process begins again (for as many times as required to attain equilibrium).

• Sealed vessel—in which the test article and extracting solvent are sealed inside a container capable of withstanding elevated temperatures and pressures, placed into a laboratory autoclave and heated with steam for a period of time.

• Instrument-based solvent extraction—in which the test article is placed inside a sealed apparatus and extracted in an automated cycle; examples include pressurized fluid extraction, microwave-assisted extraction, and supercritical fluid extraction.

• Sonication—in which the test article and extracting solvent are placed into a glass container and partly immersed in water inside an ultrasonic bath.

Not all drug product or material-contact situations are solution mediated and not all issues related to leaching of material-derived entities involve a solution phase. 

For example, doses of inhalation powder contained in a capsule or blister pack for use in a dry powder inhaler may have volatiles leached from the capsule or blister material, or by specialty surface additives such as mold-release agents; a solid oral dosage form could contain volatile leachables derived from the adhesive of a paper label affixed to the plastic bottle that contains the dosage form; and inhalation solutions packaged in low-density polyethylene containers could contain volatile migrants from tertiary packaging or auxiliary components such as wooden shipping pallets. 

In the latter two cases, chemical entities can migrate through the plastic containers and volatilize into the airspace, subsequently accumulating as migrants in the dosage forms.Extraction techniques specifically designed for application to volatile organic compounds are usually directly coupled to analytical instruments. These extraction techniques include headspace analysis (as headspace gas chromatography; HD/GC), direct thermal desorption (usually coupled to gas chromatography; TD/GC), and thermogravimetric analysis (TGA/GC).