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Identification of an Oxidizing Leachable from a Clinical Syringe Rubber Stopper

Single-use polymeric materials are increasingly used in various biopharmaceutical processing steps . This can mainly be attributed to their wide range of applications and the associated flexibility andadaptability, as well as to their relatively low costs and because a cleaning validation is not required.[1][2]

Generally, under normal use conditions migrating chemical compounds are referred to as“leachables,” while com-pounds that migrate under exaggerated laboratory conditions are often termed“extractables.” The occurrence of leachables may espe-cially be of greater concern with regards to medical industry,as therapeutic proteins are often prone to structural modifications potentially caused by the presence of the contaminants, if those bear reactive functional groups.[3][4] Leaching from administration materials can be considered a high risk, although contact duration may not be very long compared to product long-term storage.[5]
With respect to regulatory requirements, the US Code of Federal Regulations Title 21 states that manufacturing equipment[6] as well as container closures[7] shall not alter the safety, quality or purity of a drug. Consequently and in order to ensure product quality and patients safety, the occurrence of these contaminants, which may originate from the vast amount of DP contact materials, needs to be monitored and controlled throughout all processing steps,during manufacturing, storage and final administration.
Since administration materials are generally classified as medical devices, suppliers and manufacturers often determine and evaluate the occurrence of chemical migrants according to the intended use of a particular product, e.g.,for infusion bags, only the aqueous solution contained, e.g., 0.9% (w/v) NaCl, is examined. However, it was previously shown that the presence of formulation ingredients with solubilizing properties, such as the therapeutic protein itself or non-ionic surfactants may change and enhance the migration tendency of non-polar compounds compared to simple aqueous solutions.[7][8]
It was therefore the aim of the present project to identify potentially leaching compounds from a commonly used clinical syringe. Hence, we performed simulated in-use leachable studies using aqueous 0.1% (w/v) PS20 as a DP surrogate solution. The obtained leachables solutions were analyzed by standard extractables and leachables analytical approaches. Syringe components were disassembled to identify the primary leachable releasing source.[9]
During an in-use leachables study on a clinically used and CE-certified disposable administration syringe a potentially carcinogenic41 chemical compound, namely 1,1 ,2,2-tetrachloroethane was detected in concentrations above the from ICH M7-derived analytical evaluation threshold (AET). A thorough investigation was started to identify the contained rubber stopper as the primary TCE source.[10]
Indeed, we could unequivocally show that TCE was not a leachable from the rubber stopper. In addition, the experiment revealed that a so far unknown compound with oxidizing properties was leaching from the rubber stopper, that was capable to oxidize DCM to TCE.[11]
In order to identify the leaching compound, the rubber stopper and its extract were characterized with various analytical methodologies.Different organic peroxides, that can be used as polymerization initiators during the manufacturing of plastic,materials were investigated for their abilities to oxidize DCM to TCE.For an unequivocal confirmation of the intact Luperox⑧ 101 structure as the oxidizing leachable compound, NMR analysis was performed. A methanolic rubber extract and a methanolic Luperox 101 reference standard were evaporated to dryness. The residues were reconstituted in methanol-d4 and analyzed by NMR. The polymerization initiator Luperox⑧101 was thus confirmed to be the oxidizing leachable of the disposable syringe rubber stopper.[12]
With the here presented study, the authors aim to raise awareness about the chemical leaching propensity from clinically used administration materials, particularly with respect to the presence of “invisible” but highly reactive leaching chemicals. Monitoring of TCE might thus be a versatile and convenient approach to monitor DP quality throughout all processing steps and thereby contribute to patients’ safety. [13]

 

References

[1] Shukla AA, Gottschalk U. Single-use disposable technologies for biopharmaceutical manufacturing. Trends Biotechnol. 2013;31(3):147-154.

[2] Lopes AG. Single-use in the biopharmaceutical industry: a review of current tech-nology impact, challenges and limitations. Food Bioprod Process. 2015;93:98-114.

[3] Paskiet D, Jenke D, Ball D, Houston C, Norwood DL, Markovic I. The Product QualityResearch Institute (PQRI) leachables and extractables working group initiatives forparenteral and ophthalmic drug product (PODP). PDA ] Pharm Sci Technol. 2013;67(5):430- 447.

[4] Wang W, Ignatius AA, Thakkar SV. Impact of residual impurities and contaminants on protein stability. J Pharmaceut Sci.2014;103(5):1315-1330.

[5] Paudel K, Hauk A, Maier TV, Menzel R. Quantitative characterization of leachables sinks in biopharmaceutical downstream processing. Eur J Pharmaceut Sci. 2020;143: 1 05069.

[6] United States Food and Drug Administration FDA. 21 CFR Sec.211.65, Equipment construction. Revised as of April 1, 2019.

[7] United States Food and Drug Administration FDA. 21 CFR Sec.211.94, Drug product containers and closures. Revised as of April 1, 2020.

[8] Jenke DR, Brennan J, Doty M, Poss M. Use of binary ethanol/water model solutions to mimic the interaction between a plastic material and pharmaceutical formulations. [Appl Polvmer Sci. 2003:89(4):1049- 1057.

[9] BioPhorum Operations Group BPOG. Best practice guide for extractables testing of polymeric single-use components used in biopharmaceutical manufacturing. BioPhorum Operations Group Ltd (online publication); 2020.

[10] Khan TA, Mahler HC, Kishore RS. Key interactions of surfactants in therapeutic protein formulations: a review. FurJ Pharm Riopharm. 2015;97(Pt A):60- -67.

[11] United States Department of Health and Human Services, Food and Drug Administration FDA, Center for Drug Evaluation and Research CDER, Center for BiologicsEvaluation and Reseach CBER. Guidance for industry – immunogenicity assessement

[12] Bee JS, Randolph TW, Carpenter JF, Bishop SM, Dimitrova MN. Effects of surfaces and leachables on the stability of biopharmaceuticals. J Pharmaceut Sci. 2011;100 (10):4158- -4170.

[13] Kishore RS, Kiese S, Fischer S, Pappenberger A, Grauschopf U, Mahler HC. The degradation of polysorbates 20 and 80 and its potential impact on the stability of biotherapeutics. Pharm Res.2011;28(5):1194-1210.


Post time: Sep-23-2022