Extractables/leachables from plastic tubing used in product manufacturing

https://doi.org/10.1016/j.ijpharm.2006.02.011Get rights and content

Abstract

While the ability of packaging systems to contribute leached substances to finished drug products is well established, increasing interest is being focused on the potential contamination of drug substances by plastic materials encountered during their production. The direct contact of such plastic parts (such as tubing, gaskets, filters and temporary storage containers) with the drug substance at some point in its production raises the possibility that plastic-related contaminants (leachables) may be present in the finished drug product. In this study, eight tubing materials potentially encountered in pharmaceutical production facilities, including six silicone materials and two Santoprene materials, were characterized for their extractable substances by static extraction coupled with comprehensive chemical characterization of the resulting extracts. Based on the extractables profiles thus generated, target leachables were identified for each tubing material. The accumulation of these target leachables was studied by subjecting the tubing to dynamic flow, simulated use extractions. The primary organic extractables from the silicone tubing were a homologous series of silicone oligomers, with most of the tubings demonstrating a unique distribution of oligomers. Several of the silicone tubings also possessed extractable dioctyl phthalate and dioctyl adipate. The primary organic extractables from the Santoprene-type tubing included a number of phthalates, a series of alkyl phenols and decomposition products of Irganox-type antioxidants. Inorganic extractables associated with many of the tubings included Ca, Mg, Zn and B. In general, the levels of targeted leachables extracted from the tubing materials under simulated use (flow) conditions was much smaller than the total amount of these leachables in the tubing.

Introduction

Plastic materials are widely used in medical items, such as solution containers, associated closures, delivery sets, transfer tubing, and devices. The physiochemical nature of these materials provides medical products with their necessary, desirable performance characteristics. While it is important that plastics used in medical application be chemically inert, leaching of plastic materials by pharmaceutical products is well documented (Arbin et al., 1986, Berg et al., 1993, Danielson et al., 1983, Goydan et al., 1990, Kim-Kang and Gilbert, 1991, Kim et al., 1990, Reif et al., 1996, Sarbach et al., 1996, Snell, 1993, Ulsaker and Hoem, 1978), with both the identities of the leached substances and their accumulation levels impacting product utility.

Interactions between a finished drug product and its packaging (container/closure system) are well known. Regulatory approval of finished drug products and their associated packaging systems is predicated on an extensive assessment of the magnitude and impact of any drug product–packaging system interaction. However, many drug products, especially biotechnology drugs, contact plastic materials during the various phases of their production (generation/synthesis, processing, purification, intermediate storage), including plastic tubing, gaskets, filters, intermediate storage containers, tank liners and the like. It is not unreasonable to hypothesize that plastic-related contaminants (leachables) could be present in the drug products as a result of this contact. In addition to this direct contamination, opportunities for secondary contamination also exist. For example, plastic tubing is used to transport flushing or cleaning solutions through prep-scale chromatography columns used for drug product purification. If such solutions leach substances from the tubing and these substances are sequestered by the chromatography column, these substances could be mobilized into the drug product during its chromatographic purification.

To investigate this phenomenon, the interaction between eight tubing materials potentially used in drug product manufacturing operations and several representative test solutions was investigated. To delineate the materials’ extractables profiles, the materials were statically extracted with simulating solvents and the resulting extracts were chemically characterized. To assess the leaching behavior of the materials, targeted leachables were identified for each material, the materials were dynamically extracted (flow conditions) with solutions typically encountered in pharmaceutical manufacturing and the levels of the targeted leachables in the dynamic extracts were measured.

Section snippets

Tubing materials

Eight commercially available tubing materials that are potentially applicable in pharmaceutical manufacturing operations were examined in this study, including six that were silicone-based and two that were Santoprene-based. The silicone tubing materials are referred to as materials 1 through 6, while the Santoprene materials are designated as materials 7 and 8. Of the silicone materials, materials 3 and 5 were re-enforced with embedded wire.

Static extractions

Test articles were generated for an extractables

Static extractions, inorganic extractables profiles

The ICP-AES analysis included 29 elements (other than silicon), many of which were either not found in detectable levels in any of the tested samples (extracts or extraction controls) or were present in the extracts at the same (or lower) levels than in the extraction controls. Such elements are not extracted from the tubing in measurable amounts.

Inorganics that were not extracted from the tubing materials in measurable levels by ethanol included: Sr, Be, Co, Cr, Al, Zn, Se, V, Ge, Pb, and Bi.

Conclusions

Eight types of tubing potentially used in pharmaceutical production facilities, including six silicone materials and two Santoprene materials, were characterized for their extractable substances by static extraction coupled with comprehensive chemical characterization of the resulting extracts. Based on the extractables profiles thus generated, target leachables were identified for each tubing material. The accumulation of these target leachables was studied by subjecting the tubing to dynamic

Acknowledgements

The authors gratefully acknowledge the technical contributions of the following members of Baxter's technical community: Salma Sadain, Eric Edgcomb, Tammy Mortensen, Molly Chacko, Dave Zietlow, Mary Jo Garber, Thang Tran, Ed Chess, Trang Hyung and Colleene Jaime.

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