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.
SUMMARY
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
