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Quality control of cytostatic drug preparations—comparison of workflow and performance of Raman/UV and high-performance liquid chromatography coupled with diode array detection (HPLC-DAD)

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Abstract

The drugs used for treatment during chemotherapy are manufactured individually for each patient in specialised pharmacies. Thorough quality control to confirm the identity of the delivered active pharmaceutical ingredient and the final concentration of the prepared application solution is not standardized yet except for optical or gravimetric testing. However, solution stability problems, counterfeit drugs, and erroneous or deliberate underdosage may occur and negatively influence the quality of the product and could cause severe health risks for the patient. To take a step towards analytical quality control, an on-site analytical instrument using Raman and UV absorption spectroscopy was employed and the results were compared to high-performance liquid chromatography coupled to diode array detection. Within the scope of the technology evaluation, the uncertainty of measurement was determined for the analysis of the five frequently used cytostatic drugs 5-fluorouracil, cyclophosphamide, gemcitabine, irinotecan and paclitaxel. The Raman/UV technique (2.0–3.2% uncertainty of measurement; level of confidence: 95%) achieves a combined uncertainty of measurement comparable to HPLC-DAD (1.7–3.2% uncertainty of measurement; level of confidence: 95%) for the substances 5-fluorouracil, cyclophosphamide and gemcitabine. However, the uncertainty of measurement for the substances irinotecan and paclitaxel is three times higher when the Raman/UV technique is used. This is due to the fact that the Raman/UV technique analyses the undiluted sample; therefore, the sample has a higher viscosity and tendency to foam. Out of 136 patient-specific preparations analysed within this study, 96% had a deviation of less than 10% from the target content.

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Abbreviations

API:

Active pharmaceutical ingredients

HPLC-DAD:

High-performance liquid chromatography coupled with diode array detection

Raman/UV:

Raman spectroscopy combined with ultraviolet detection

CP:

Cyclophosphamide

IF:

Ifosfamide

Ph. Eur.:

European Pharmacopoeia

USP:

United States Pharmacopeia

Ph. Helv.:

Pharmacopoea Helvetica

5-FU:

5-Fluorouracil

Gem:

Gemcitabine

Irino:

Irinotecan

Pac:

Paclitaxel

FA:

Formic acid

UV:

Ultraviolet

MAGS:

Ministry of Labour, Health and Social Affairs of the state of North Rhine-Westphalia in Germany

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Acknowledgements

We want to thank the company B&W Tek for providing the i-QCRx and Sara Seiffert for her kind support and fruitful discussion.

Funding

We would like to thank the Federal Ministry for Economic Affairs and Energy for funding the INNO-KOM project “Sensitive method for the detection of airborne proteins” (49VF170039).

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Authors and Affiliations

  1. Institut für Energie und Umwelttechnik e. V. (IUTA, Institute of Energy and Environmental Technology), Bliersheimer Str. 58-60, 47229, Duisburg, Germany

    Lars M. H. Reinders, Martin D. Klassen, Claudia vom Eyser, Thorsten Teutenberg & Jochen Tuerk

  2. Hochschule Niederrhein (University of Applied Science), Reinarzstr. 49, 47805, Krefeld, Germany

    Lars M. H. Reinders & Martin Jaeger

  3. Faculty of Chemistry, Instrumental Analytical Chemistry, University Duisburg-Essen, Universitätsstr. 5, 45141, Essen, Germany

    Lars M. H. Reinders & Torsten C. Schmidt

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  1. Lars M. H. Reinders
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Contributions

Lars M. H. Reinders: Conceptualization, methodology, validation, formal analysis, investigation, data curation, writing (original draft), writing (review and editing), visualization, project administration, funding acquisition. Martin D. Klassen: Conceptualization, methodology, writing (review and editing), supervision, funding acquisition. Claudia vom Eyser: Writing (review and editing), project administration. Thorsten Teutenberg: Conceptualization, writing (review and editing), supervision, funding acquisition. Martin Jaeger: Writing (review and editing), supervision. Torsten C. Schmidt: Writing (review and editing), supervision. Jochen Tuerk: Conceptualization, writing (review and editing), supervision, funding acquisition.

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Correspondence to Thorsten Teutenberg.

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Reinders, L.M.H., Klassen, M.D., vom Eyser, C. et al. Quality control of cytostatic drug preparations—comparison of workflow and performance of Raman/UV and high-performance liquid chromatography coupled with diode array detection (HPLC-DAD). Anal Bioanal Chem 413, 2587–2596 (2021). https://doi.org/10.1007/s00216-021-03223-9

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