General Concepts and Critical Experimental Design Parameters 

Extractables are derived from a variety of sources and exhibit extensive chemical diversity. Primary sources of extractables include:

  • Chemical additives in individual elastomeric/polymeric packaging components and raw materials, including contaminants in these additives

  • Monomers and higher molecular weight oligomers derived from incomplete polymerization 

  • Migrants from secondary and tertiary packaging components, such as inks, label adhesives, and volatiles from cardboard shipping containers, plastic storage bags, and wooden pallets

  • Surface residues, such as heavy oils and degreasing agents on metal canisters and containers 

  • Chemical substances on the surfaces of component fabrication machinery or other drug product manufacturing systems, such as mold release agents, antistatic and antislip agents

  • Chemical additives, monomers/oligomers, contaminants, etc., in various parts of component fabrication machinery or other drug product manufacturing systems

 As noted above, the chemical diversity of extractables is significant. For example, the chemical additive category antioxidants includes hindered phenols, secondary aromatic amines, hindered amines, organosulfur compounds, organophosphorus compounds, and other chemical classes.   

Extraction is a process of treating a material with a solvent to remove soluble substances. Extraction is a complex process influenced by time, temperature, surface area to volume ratio (i.e., stoichiometry), extraction medium, and the phase equilibrium of the material (3). There are two reasons why an extraction study is the necessary and appropriate means of accomplishing the various objectives of an extractables assessment. 

First, there is no other viable analytical alternative. Characterizing a material for potential leachables in its natural solid state is a goal of modern analytical chemistry rather than an accomplishment. Second, even if a direct characterization could be accomplished, it would at best only establish the identities and levels of chemical entities present in the material, and not assess the leaching characteristics of these chemical entities. 

A compositional assessment does not take into account any chemical reactions that can alter the molecular structures of potential leachables over the dosage form's lifecycle. For example, in the case of phenolic antioxidants that are leached by an aqueous drug product, hydrolysis and oxidation products can accumulate in the drug product. 

The only viable means for producing data related to leaching is to use a process such as laboratory extraction that is mechanistically similar to leaching.   The design of an extraction study is dictated by the purpose of the extractables assessment and the question(s) being asked, as well as the available information regarding the chemical composition of the test article(s) to be extracted. Extraction studies can be designed to answer questions such as:  

  • What are the chemical additives in a particular packaging component or material of construction? 

  • What are the maximum accumulations of chemical additives from a particular packaging component into the dosage form?

  •  What are the likely contents of an end-of-shelf-life drug product leachables profile?

 Addressing each of these questions requires a particular set of parameters, such as extraction time, extraction temperature, extracting solvent, extraction technique, sample surface area to extracting solvent volume ratio, etc. Clearly, the intent of the extractables assessment must be established before the study design is finalized. For example, if the purpose of the extraction study is to simulate a worst-case leachables profile, then the study can be termed a simulation study that should produce an extract that:

  • Contains all the substances (extractables) that could leach into the final product at levels considered potentially significant 

  • Contains these extractables at concentrations that are greater than or equal to the maximum concentration that these chemical entities will accumulate in the drug product as leachables at any time during the shelf-life 

  • Is generated more efficiently and in less time than that required for a drug product leachables study 

  • Is amenable to chemical analysis 

 The means by which an extraction process is accomplished are reflected in the juxtaposition of several experimental parameters including: 

  • The chemical nature of the extracting media

  • The time duration of the extraction process 

  • The temperature at which the extraction is performed 

  • The stoichiometry of the extraction process (extracted surface area per unit volume of extracting solution) 

  • The mechanism or process by which the extraction is accomplished

Extraction processes have been described as “accelerated”, “aggressive”, “exhaustive”, “vigorous”, “harsh”, and so on, and for medical device studies certain of these terms have been defined (7). In general, extraction processes should allow completion in a reasonable time frame but should not be so aggressive that they alter the qualitative and/or quantitative nature of the resulting extractables profile. The most aggressive extraction conditions are reserved for the quantitative determination of chemical additive contents in components and materials. Because such studies are intended to quantitate specific known chemical additives and not to simulate a drug product leachables profile, it is acceptable to use extraction conditions which disrupt or dissolve the component or material being extracted, and thus to alter the resulting extractables profile, while recovering the target additive(s) without loss or chemical decomposition.