The Development, Verification and Evaluation of Container Closure Integrity Assessment of Prefilled Syringes Using Fluorescence Spectroflurometer
Keywords:Prefilled Syringes, Container Closure System, Methylene Blue, Fluorescence-UV Detection
The preference of Prefilled syringes is increased over all the vials as container closure systems for liquid injections, when facilitated or self-administration is required.However, prefilled syringes are more complex compared to container closure system(CCS) consisting of vial, rubber stopper and flip off. Container closure integrity assurance and verification has been a specific challenge for prefilled syringes as they feature several sealing areas. A comprehensive understanding of the container closure system is necessary for an appropriate container closure integrity assessment as well as for packagingdevelopment and qualification.
Method for the measurement ofcontainer closure integrity(CCI) of prefilled syringes using fluorescence spectrophotometry was developed and validated with a spectroflurometer.Methylene blue solution was initially evaluated as the fluorophore ina syringe with excitation at 605 nm and emission at 678 nm, which generated a limit of detection of 0.06µg/mL. Furtherstudies were conducted using Rhodamine 123, a dye with stronger fluorescence. Using 482 nm excitation and 527 nmemission, the dye in the syringe could be easily detected at levels as low as 0.001 µg/mL. The relative standard deviationfor sixmeasurements of three different sample with different concentration was less than 2.8%. A number of operational parameters were optimized, including the photomultiplier tube voltage, excitation, andemission slit widths. The specificity of container closure integrity was checked by using marketed drug products sample,which showed no interference to the rhodamine detection. Results obtained from this study demonstrated that usingrhodamine 123 for container closure integrity testing with in syringe fluorescence measurements significantlyenhanced the sensitivity and robustness of the testing and effectively overcame limitations of the traditional methylene bluemethod with visual or UV-visible absorption detection.
Adler, M. Challenges in the development of prefilled syringes for biologics from a formulation scientist’s point of view. Am. Pharm. Rev. 2012, 15 (1), 96 –101.
Kiang, P. Recent developments in prefilled syringes.Am. Pharm. Rev. 2012, 15 (1), 104 –107.
U. S. Food and Drug Administration (FDA). Guidance for Industry Submission of Documentationfor Sterilization Process Validation in Applicationsfor Human and Veterinary Drug Products;FDA: Silver Spring, MD, 1994.
European Commission. EU Guidelines to GoodManufacturing Practice Medicinal Products forHuman and Veterinary Use. Annex 1, Manufactureof Sterile Medicinal Products; EuropeanCommission: Brussels, Belgium, 2008.
FDA. Guidance for Industry Container and ClosureSystem Integrity Testing in Lieu of SterilityTesting as a Component of the Stability Protocolfor Sterile Products; FDA: Silver Spring, MD,2008.
USP. General Chapter <1207> Sterile ProductPackaging—Integrity Evaluation; United StatesPharmacopeia; United States Pharmacopeial Convention:Rockville, MD, 2014; Vol. 37.
Carroll, M. C.; Danny, V. F.; Guazzo, D. M.; Kaiser,M. W.; Kirsch, L. E.; Ludwig, J. D.; Masover, G. K.; May, J. L.; Moldenhauer J. E., Olsen, J. I.; Polsen,T. M.; Wright, G.E. Pharmaceutical Package Integrity;PDA Technical Report #27; Parenteral
Li, L. Container closure integrity testing methoddevelopment and validation for prefilled syringes.Am. Pharm. Rev. 2013, 16 (1), 48-52.
Simonetti, A.; Amari, F. Non-destructive vacuumdecay method for pre-filled syringe closure integritytesting compared with dye ingress testing andhigh-voltage leak detection. PDA J. Pharm. Sci.and Technol. 2015, 69 (1), 108 –122.
Morton, D. K.; Lordi, N. G.; Ambrosio, T. J.Quantitative and mechanistic measurements ofparenteral vial container/closure integrity, leakagequantitation. J. Parenter. Sci. Technol. 1989, 43(2), 88 –97.
Wolf, H.; Stauffer, T.; Chen, S.-C. Y.; Lee, Y.; Foster, R.; Ludzinski, M.; Kamat, M.; Godorov,P.; Guazzo, D. M. Vacuum decay container/closureintegrity testing technology. Part 1. ASTMF2338 – 09 precision and bias studies. PDAJ. Pharm. Sci. Technol. 2009, 63 (5), 472– 488.
Wolf, H.; Stauffer, T.; Chen, S.-C. Y.; Lee, Y.;Foster, R.; Ludzinski, M.; Kamat, M.; Mulhall,B.; Guazzo, D. M. Vacuum decay container/closureintegrity testing technology. Part 2. Comparisonto dye ingress tests. PDA J. Pharm. Sci.Technol. 2009, 63 (5), 489 – 498.
Patel, J.; Mulhall, B.; Wolf, H.; Klohr, S.;Guazzo, D. M. Vacuum decay container closureintegrity leak test method development and validationfor a lyophilized product-package system.PDA J. Pharm. Sci. Technol. 2011, 65 (5), 486 –505.
How to Cite
Copyright (c) 2020 Shripad Deshpande, Deepak D. Kayande, Mazahar Farooqui, Parag Deshmukh
This work is licensed under a Creative Commons Attribution 4.0 International License.