Assessing the Risk of Leachables from Single-Use Systems

This article is the second in a two-part series on extractables and leachables.
Feb 01, 2012
Volume 25, Issue 2

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.

Paul F. Killian, PhD,
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.


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.

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.
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 solvents.

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 [3]). 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 mg/L.

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