Chemical safety assessment, including extractables and leachables testing and evaluation, is no different from other scientific endeavors in that it has its associated generalizations, rules of thumb, and urban myths. In the early days of E&L, one of the most pervasive, and potentially impactful, myths was the concept of direct solution contact, which goes something like this: “if a container-closure system component does not directly contact the drug product during manufacturing, storage and distribution, and clinical use, then extractables from the component will not become drug product leachables since there is at least one barrier between the component and the drug product.”
Although this may be true for certain materials (e.g., glass, metallic, specifically constructed polymeric barrier films), many of the most commonly employed plastic-based primary packaging systems have limited barrier properties, especially when one considers certain extenuating conditions of clinical use [e.g., long shelf lives, exposure to high temperature (terminal sterilization, pasteurization), large surface area to volume ratios].
While debunking this particular urban myth has ramifications for all items external to a drug product‘s primary packaging (e.g., secondary packaging such as overpouches, tertiary packaging such as shipping cartons, and environmental sources such as wooden shipping pallets), perhaps the most profound effect is recognizing printing and labels as meaningful potential sources of leachables.
Although container-closure systems have numerous functional requirements, one that often goes under-appreciated is the requirement that they transmit valuable and critical information about the product, its proper clinical use, and its packaging. This requirement for information communication has driven the proliferation of printing and the expanded use of labels on primary, secondary, and tertiary packaging.
Leachables from printing and labels is a topic of concern to global regulatory agencies, at least in part due to the recognition that this topic was oftentimes under-addressed in the past. It is almost a certainty that a product description in a regulatory file that establishes the use of printing and labels will result in the question “has the sponsor properly evaluated leachables associated with the printing and label?” Providing an unacceptable answer to this question is surely a direct path to complications in terms of securing regulatory approval.
The issue of leachables from printing and labels has many complicating factors. First, there is the composition of the printing inks and labels, as ingredients drive extractables which in turn drives leachables. Then there is the primary packaging itself. While the barrier properties of the primary packaging are the major concern, certain compositional properties are also relevant. Consider, for example, the case of plasticized PVC. Although plasticized PVC has some barrier properties, conditions of use for plasticized PVC packaging (e.g., IV bags) are quite challenging in terms of extractables breaching the barrier (e.g., high temperature terminal sterilization, long shelf lives).
Considering only migration, plasticized PVC bags are at risk in terms of label- or printing-related extractable migration over shelf life. And yet, the accumulation of leachables from these sources is somewhat uncommon for drug products in plasticized PVC bags. The reason for this is the plasticizer itself. Unlike polyolefin bags, which have additives present in quantities on the order of tenths of a weigh percent, the primary additive (the plasticizer) in plasticized PVC is present in quantities of 20% by weight or higher.
Additionally, the plasticizers have a high affinity for organic molecules, acting essentially as sponges to sorb such substances. This is why plasticized PVC bags cannot be used with certain drug products, as drug product efficacy is reduced due to drug substance binding. Thus, while extractables from printing and labels can theoretically migrate through the plasticized PVC, they do so to a limited extent because they migrate in but cannot migrate out.
Then there are the circumstances of contact. A label placed on the outside of a primary package has two interfaces, the label-package interface and the label-air interface. Thus, extractables flow from the label in two directions, through the packaging (toward the drug product) and into the air (away from the drug product). Depending on the extractable and the conditions of contact, the relative movement of extractables, through the packaging or away from the package, can be quite variable.
The point of this discussion is to establish that properly accounting for leachables derived from labels and printing can be a complicated proposition, affecting both the design of extractables and leachables studies and the interpretation of the study results.
Nelson Labs Europe has extensive experience in designing, implementing, interpreting, and reporting label migration studies for a wide variety of applications (ophthalmic containers, IV bags, containers used for inhalation administration, polymer vials, prefilled syringes, etc.). Supporting this activity, Nelson Labs Europe can draw on its extensive library of in-house protocols and procedures relevant to label migration research as well as its advanced, state-of-the-art analytical capabilities, including Headspace GC/MS, PTV-GC/MS, GC/MS, LC/MS, LC/MS/MS, etc.
