Viability of Selected Microorganisms in Non-Cytotoxic Aseptic Preparations

Sarakbi, Iman; Heeb, Rita Marina; Thiesen, Judith; Krämer, Irene

doi:10.1515/pthp-2015-0007

Cited by 5 publications

(11 citation statements)

References 23 publications

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“…The rather high inoculum level (10 3 -10 5 CFU/mL) was chosen according to the pharmacopoeia antimicrobial effectiveness tests and our previous experiments. 4,[11][12][13][14][15] In a recently published study the level of intended microbial contamination was also 10 5 CFU/mL. 7 Less detrimental experimental conditions are achieved, when the inoculum level is adjusted to 10² CFU/mL to simulate inadvertent touch contamination (i.e., low-level contamination).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies regarding the potential of microbial growth in cytotoxic and non-cytotoxic RTA parenteral preparations have been published. 4,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Viability tests are missing for numerous recently licensed monoclonal antibodies (mAb), filgrastim, and few small molecules introduced in anti-cancer therapy in recent years. The aim of this viability study was to investigate the potential growth promoting nature of 20 RTA parenteral preparations used for SACT.…”

Section: Introductionmentioning

confidence: 99%

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Viability of selected microorganisms in parenteral preparations for novel systemic anti-cancer therapy

Almasi,

Knoll,

Thiesen

et al. 2023

J Oncol Pharm Pract

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Background Risk factors for aseptic preparation of parenteral medicines encompass the growth-promoting nature of the preparation. Although many aqueous parenteral preparations do not have growth-promoting properties, inadvertently introduced microorganisms may remain viable. Knowledge about the viability of microorganisms in parenteral preparations can add useful information for assigning shelf life to preparations used to treat cancer patients. Aim The aim of the study was to assess the viability of four different facultative pathogenic microorganisms in 20 ready-to-administer parenteral preparations aseptically prepared in hospital pharmacies. Methods Samples of 20 different biologics and small molecules for systemic anti-cancer therapy were inoculated either with different bacteria (i.e., Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium) or with Candida albicans suspension. The resulting test concentrations were 104–105 microorganisms per mL. Aliquots of inoculated test solutions were transferred in duplicate to tryptic soy agar plates at the time points 0, 4, 24, 48, 144 h. The plates were incubated for 24 h (bacterial strains) and 72 h ( C. albicans) at 37 °C and colony forming units (CFUs) were counted. Results In most test solutions, especially in monoclonal antibody solutions, increased CFU counts of P. aeruginosa and unchanged or increased CFU counts of E. faecium and S. aureus were registered . Pronounced nutritive properties of monoclonal antibodies and filgrastim were not registered. Azacitidine, pixantrone and vinflunine containing test solutions revealed species-specific bacteriostatic and even bactericidal activity. All test solutions, except nivolumab and pixantrone containing solutions, showed constant or increasing CFU counts of C. albicans after incubation. Conclusion Viability of the selected pathogenic microorganisms was retained in most of the tested biological and small molecule preparations used to treat cancer patients. Therefore, in pharmacy departments strict aseptic conditions should be regarded and the lack of antimicrobial activity should be considered when assigning shelf life to RTA parenteral preparations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Viability of selected microorganisms in parenteral preparations for novel systemic anti-cancer therapy

Almasi,

Knoll,

Thiesen

et al. 2023

J Oncol Pharm Pract

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“…This is consistent with previous observation from Krämer et al [41], showing the lack of link between chemical structure or pharmacological properties and their microbicidal or microbiostatic activity. Moreover, drug formulation may play important role in microbiological growth [42,43] and even most of the pharmaceutical aqueous solutions do not promote microbiological growth, microorganism may remain viable. For routine evaluation, a 1/10 dilution of initial cytotoxic solution should be systematically applied to limit risk of false negative.…”

Section: Discussionmentioning

confidence: 99%

Microbiological stability tests with simulated broth preparations and integrity testing for sterile standard cytotoxic preparations

Matheron

Guerault

Vazquez

et al. 2020

Pharmaceutical Technology in Hospital Pharmacy

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ObjectivesThe objectives were to assess the microbiological stability and the physical enclosure integrity of the overwrapping for batch production of standard cytotoxic injectable solutions.MethodsBroth culture media were used in place of cytotoxic drugs to assess the worst case in term of microbiological contamination risk. Iterative sterility tests on batches were performed for 60 days using rapid microbiological method. Validation of microbiological growth of culture media was assessed by direct inoculation of <100 CFU/mL of six microbiological strains recommended by European Pharmacopeia. Validation of the ability of growth of microorganisms in 11 cytotoxic solutions and one monoclonal antibody was assessed using eight strains. In addition, the physical integrity of the seal of the overwrapping containing cytotoxic preparations was assessed by dynamometric method and dye penetration test.ResultsNo microbiological contamination was observed on all units of batches for 60 days of investigation. The ability to detect microbiological growth in cytotoxic solutions was validated for the eight challenge microorganisms after 1/10 dilution for cytotoxic investigated, except for 5 Fluorouracil, gemcitabine and cisplatin. In addition, physical integrity testing of the seal of overwrapping pointed out the need of specific validation of heatsealer and operator education.ConclusionsBesides physico-chemical testing, microbiological stability testing combined to physical integrity testing is the additional part of the development method for batch production of sterile drugs in hospital.

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“…In previous growth promotion tests we were able to show, that microorganisms could subsist in solutions of cytotoxic and non-cytotoxic drugs, and proliferate when transferred to proper growth media. [23][24][25] However, during these tests the GV samples showed moderate bacteriostatic and antifungal activity. 25 There is no preservative contained in the GV formulation, but the alkaline pH value might contribute to the growth inhibition of microorganisms.…”

Section: Original Researchmentioning

confidence: 99%

Implementation and microbiological stability of dose-banded ganciclovir infusion bags prepared in series by a robotic system

Krämer

Federici

2018

Eur J Hosp Pharm

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Objectives The implementation of dose-banding (DB) in centralised, pharmacy-based cytotoxic drug preparation units allows the preparation of standardised doses in series. The aim of this study was to evaluate the feasibility of DB for the prescribing of ganciclovir (GV) infusion solutions and to investigate the microbiological stability of dose-banded, automatically prepared readyto-administer GV infusion bags by media-fill simulation tests and sterility tests. Methods The frequency of prescription of GV doses was retrospectively analysed before and after implementing the DB scheme. Four dose-ranges or 'bands' and the corresponding standard doses (250, 300, 350, 400 mg) were identified. The maximum variance was set at ±10% of the individually prescribed dose. The aseptic preparation of a series of GV infusion bags was simulated with double strength tryptic soy broth as growth medium and prefilled 0.9% NaCl polyolefin infusion bags as primary packaging materials. The simulation process was performed with the APOTECAchemo robot on five consecutive days. In total, 50 infusion bags were filled, incubated and stored for 12 weeks at room temperature. The media-filled bags were visually inspected for turbidity after 2, 4, 8, 10 and 12 weeks. Following incubation, growth promotion tests were performed. During the simulation tests, airborne contamination was monitored with settle plates and microbial surface contamination with contact plates. Pooled sterility tests were performed for a series of 10 standard GV infusion bags after a 12-week storage period under refrigeration (2 °C-8 °C). results After implementation of the DB scheme, about 60% of the prescribed GV doses were prepared as standard preparations by the robotic system. The number of different GV doses was reduced by 61.8% (76 vs 29). None of the 50 media-filled bags showed turbidity after a storage period of 12 weeks, indicating the absence of microorganisms. The environmental monitoring with settle/contact plates matched the recommended limits set for cleanroom Grade A zones, except in the loading area of the robot. Media fills used for the sterility tests remained clear during the incubation period, thereby revealing sterility. Positive growth promotion tests proved the process's reliability. Conclusions A DB scheme for prescribing and preparation of standard GV infusion bags was successfully implemented. Microbiological tests of aseptic preparation of infusion bags in series by the APOTECAchemo robot revealed an adequate level of sterility and a well-controlled aseptic procedure. The sterility was maintained over extended storage periods, thereby encouraging extended beyond-use dating.

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Viability of Selected Microorganisms in Non-Cytotoxic Aseptic Preparations

Cited by 5 publications

References 23 publications

Viability of selected microorganisms in parenteral preparations for novel systemic anti-cancer therapy

Viability of selected microorganisms in parenteral preparations for novel systemic anti-cancer therapy

Microbiological stability tests with simulated broth preparations and integrity testing for sterile standard cytotoxic preparations

Implementation and microbiological stability of dose-banded ganciclovir infusion bags prepared in series by a robotic system

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