- E&L Study
- E&L case study
- USP 1663
- USP 1664
- USP 1664.1
- ICH Q3E
- Medical Device
<1664> ASSESSMENT OF DRUG PRODUCT LEACHABLES ASSOCIATED WITH PHARMACEUTICAL PACKAGING/DELIVERY SYSTEMS
Occasions may arise in which it is not analytically feasible (due to challenging thresholds, for example) to successfully discover and identify all actual leachables in a drug product leachables study. This circumstance can be managed if the activities of discovery and identification of probable leachables are accomplished in an extraction study, where samples and analyte concentrations are more easily manipulated to achieve the necessary analytical performance. In such a circumstance, the actual drug product leachables assessment is simplified to a high-sensitivity quantitation of targeted leachables that have been discovered and identified as part of this extraction study.
In order to facilitate the discovery and identification of probable leachables, the extraction study must be similar in design to a drug product leachables study. Such an extraction study seeks to simulate the circumstances experienced by the drug product but should produce a test sample that is easier to characterize than the drug product itself. For such a study to be relevant in establishing appropriate target leachables, the solvent(s) used to generate the test sample must have nearly the identical propensity to leach as the drug product formulation. Such a study should be accelerated versus the leachables study so that the extractables, reflecting potential target leachables, can be discovered and identified in a timely fashion.
Differences in the study design between this simulation study and the drug product leachables study are: 1) that the drug product formulation has been replaced with a simulating solvent that mimics the formulation; 2) that the conditions of contact have been accelerated, so as to increase both the concentrations of probable leachables and the rates of migration of probable leachables into the simulating solvent; and 3) that the test article can be either the complete packaging and delivery system or separate components of that system. Factors to consider in designing and justifying the simulating solvent(s), along with recommendations on the analytical approach used to characterize the simulating extract for extractables as potential target leachables are discussed in 1663. Given the intent of the simulation study, which is the discovery and identification of extractables as target leachables, simulation studies must also be driven by relevant thresholds.
It is possible that in cases of very low thresholds (e.g., AETs), quantitation of drug product leachables might still not be analytically feasible, even with high sensitivity target compound analytical methods. In such cases, the results of the simulation study (probable leachables identities and concentrations) may be sufficient to establish patient safety and the quality impact of the actual drug product leachables. To the extent that the simulation study mimics the drug product leachables study, the potential safety or quality impact of a compound as an extractable is an estimate of the potential safety or quality impact of the compound as an actual leachable.
If it can be established that a compound quantitated as an extractable under these conditions has an acceptably small impact on safety and quality, then it follows that the same compound as a leachable in the drug product formulation may be assumed to have a similarly low impact on safety and quality as a leachable in the drug product formulation. The acceptability of this approach for any particular drug product needs to be scientifically justified by the drug product applicant.
If a compound is measured as an extractable in a simulation study and targeted as a leachable in a drug product leachables study, the extractables and leachables data for that compound become the basis upon which a leachables–extractables correlation can be made. For such a correlation to be considered to be valid, it is necessary that each leachable concentration in the drug product be less than or equal to the corresponding extractable concentration in the simulated extract, accounting for the uncertainty in the analytical measurements and any justifiable “exaggeration factors” that may have been utilized in the simulation study. Note that in certain justifiable circumstances drug product placebo batches may be used as test articles in drug product leachables studies (stability studies). However, there are also circumstances when placebo batches are not acceptable, such as when there is significant reason to believe that leachables might have an adverse effect on an active pharmaceutical ingredient (e.g., therapeutic proteins).
Inorganic (Elemental) Leachables
The topic of leachables as elemental impurities in pharmaceuticals can be addressed within the overall context of elemental impurities in drug products (e.g., Elemental Impurities—Limits 232. Elemental impurities leached from packaging or delivery systems represent only one source of elemental impurities in a drug product, and thus testing a drug product for elemental impurities does not establish that the impurities are leachables.
Testing of the plastic packaging systems and their materials of construction will establish those extractable elemental impurities that are relevant to a particular packaging system, and it may be appropriate to quantify such elemental impurities as leachables in the drug product. Therefore, the results of testing plastic packaging systems should be used to establish those elemental impurities that should be monitored as targeted elemental leachables in the drug product.
In general, guidelines and recommendations about elemental impurities in drug products address safety concerns associated with the elemental impurities. However, it is proper to consider elemental leachables from the broader perspective of the overall quality of the drug product. Thus the process of evaluating elemental leachables may include both the aspects of user safety and product quality.
Note that one of the differences between the testing for organic leachables (and extractables) and for elemental impurities is the nature of the information generated. The testing for organic leachables is based on having established the identity of the chemical compound that is the leachable. Alternatively, the test methods most commonly employed to address elemental impurities (atomic spectroscopy) do not establish the compound, or form, that the detected element is present in. For example, sulfur might be present in the form of elemental sulfur (S8), as the sulfate (SO42), or as a sulfur-containing organic compound (e.g., 2-mercaptobenzothiazole). Also, silicon might be present either as silicone oil or as silicon dioxide (SiO2). As the form of the elemental impurity may have a marked effect on the impurity's impact on product quality or safety, it may be the case that testing beyond elemental impurity profiling may be necessary to establish the exact chemical form of the elemental impurity and thus ascertain its potential safety or product impact.
An important issue to consider in testing drug products for elemental leachables is establishing which elements to measure as leachables. Considering this, it is noted that testing of the plastic packaging systems and their materials of construction will establish those extractable elemental impurities that are relevant to a specific packaging system. Therefore, the results of testing plastic packaging systems should be used as one means of establishing those elemental impurities that should be monitored as targeted elemental leachables.
The requirement for, and completeness of, a leachables assessment for any particular drug product can only be determined by the drug product applicant with reference to appropriate regulatory guidance documents. Detailed recommendations for OINDP are presented in 1664.1.
Reference is also made to other compendial chapters in this Pharmacopeia that describe related extraction studies:
- Biological Reactivity Tests, In Vitro 87
- Biological Reactivity Tests, In Vivo 88
- Elastomeric Closures for Injection 381
- Containers—Plastics 661