Assessing the risk posed by leachables from single-use assemblies can be challenging. Disposable assemblies are often constructed
of a mix of functional components, containers, tubing, valves, and filters, each made from several materials by complex manufacturing
processes. Additionally, the gamma sterilization pretreatments of such assemblies potentially can create trace-level leachables
that are nearly impossible to completely identify and quantify. Regardless of these challenges, it is necessary to assess
the risk posed by leachables for the following reasons:
- It is a regulatory requirement
- The leachable may affect the drug potency
- The leachable may interfere with the assay of the drug
- The leachable may be toxic.
This article will review the design and engineering steps used to reduce the risk from leachables, investigate methods for
assessing the risk from leachables, and present data from two case studies involving single-use systems.
Paul F. Killian, PhD,
BUILDING QUALITY IN
Quality by design (QbD) is defined as the systematic process to build quality into a product from its inception. This principle
can be leveraged during the design and engineering of components of single-use systems to minimize the risk of leachables.
Component materials should be nonreactive, 21 CFR-cleared material and pass USP Class VI specifications.
PureFlex polyethylene film (EMD Millipore) is an example of a material that can be designed into single-use systems to minimize
generation of leachables. PureFlex film is a high-purity, medical-grade coextruded film designed to provide strength, flexibility
with maximum resistance to flex-crack, excellent gas-barrier performance, and inert contact. The fluid-contact material is
ultra-low-density polyethylene (ULDPE), which was chosen because of its inertness.
The Hansen solubility parameter (HSP) is often used to evaluate solubility and shows that ULDPE is an appropriate choice for
fluid contact (1). A chemical with an HSP value similar to the solvent will more likely dissolve in the solvent, according
to the principle of "like dissolves like." The HSP value is determined by three forces: the dispersion force of a chemical,
the polar force of a chemical, and the hydrogen-bonding force of a chemical. Figure 1 shows a graph in which chemicals are
plotted based on the percentage that each force contributes to the total HSP value. As shown in the figure, polyethylene is
far removed from water and ethanol, indicating that polyethylene and its monomers would not dissolve in either of these two
Figure 1: Plot of chemicals based on the percentage that each force contributes to the total Hansen solubility parameter value.
DMSO is dimethyl sulfoxide, IPA is isopropyl alcohol.
PureFlex film is produced using additive compounds that either help process the film or help protect the film. Typical processing
additives include slip agents that reduce the film-to-film friction, thereby allowing faster processing speed. A common slip
agent is composed of fatty acid amides (e.g. erucamide). Slip agents are added at a concentration from a few parts per million
(PPM) to a few thousand PPM (2). Though these agents may be present at high concentrations, aqueous solubilities are very
low (e.g., erucamide has an aqueous solubility of 0.00045 mg/L ). Antioxidants comprise another common type of additive.
These compounds are added to the polymers to protect the film from ultraviolet radiation, and are typically large molecules
(hundreds of Daltons in size) with very low aqueous solubility. Commonly used antioxidants include Irganox 1010 (Ciba Specialty
Chemicals, 2-[3,5-di-tert-butyl-4-hydroxyphenyl] propionate), with an aqueous solubility of 2.3 × 10-16 mg/L and Irgafos 168 (Ciba Specialy Chemicals, tris[2,4-di-tert-butylphenyl] phosphite), with an aqueous solubility of <0.09