Microbiological stability of Rituximab bags

A. Iwanoff, C. Djayet, A-S. Martin, C. Davoine, F. El Alaoui, M. Rigal, A. Jacolot, M. Apparuit
Hôpital Avicenne, Bobigny, France

The preparation of anticancer drugs is anticipated on D-1 of the administration. In case of deprogramming, the preparations are reallocated within 7 days (in case of physico-chemical stability).
The objective of this study is to extend the shelf life of preparations by carrying out a microbiological stability study. Our study concerns a drug that does not have an inhibitory effect on bacterial growth according to the literature and that meets the criteria of the 2011 European guidelines on stability studies of anti-cancer drugs (protein drugs): Rituximab.

Material and method
Our study proceeds in 3 steps: the fertility test, the applicability test and the sterility test. The chosen method is direct inoculation with the 6 strains of the European Pharmacopoeia 9.0 for the microbiological stability study. To perform the fertility, applicability and sterility tests, 100 mL broth cultures of thioglycolate and tripticase soy were used. The applicability test was performed in triplicate (from bags at a concentration of 4 mg/mL of Rituximab diluted in 0.9% NaCl). In addition to a visual control, we measured the turbidity of the broths culture by using Mac Farland Densitometer® (except for Aspergillus brasiliensis). For the sterility test, 9 bags of Rituximab (1 mg/mL) were prepared and tested at 3 times (D0, D14, D28) by direct inoculation in broths culture.

For fertility, applicability and sterility testing after incubation, the results are as follows: visually comparable growth was observed for each strain between the broths containing only the strains and those containing the drug and the strains. After reading with the densitometer, the difference between the turbidity value of the positive control and the value of at least one of the three broths in the applicability test was less than 10% for all strains. Moreover, the viability of our strains has been proved by re-inoculation on solid agar after incubation. The absence of inhibitory character was proven, the sterility test could therefore be carried out and showed no bacterial growth at 3 times after 14 days of incubation.

The absence of bacterial growth during the sterility test will allow us to extend the shelf life of this preparation. Our study is only representative of one day’s production, a routine control may be necessary. The implementation of this type of study is a prerequisite to consider extending the shelf life of our preparations. Furthermore, we could consider extrapolating our results to other monoclonal antibodies, given the similar profiles and formulations, in case of physico-chemical stability documented greater than 7 days.

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