Document Type : Original Articles
Authors
1
Physicochemistry Department, Assurance Department, Razi Vaccine and Serum Research Institute
2
Department of Chemistry, Razi Vaccine & Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
3
Department of Quality Assurance, Razi Vaccine & Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
4
Department of Quality Control, Razi Vaccine & Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
10.22092/ari.2026.371041.3904
Abstract
Introduction:
Packaging processes must be validated through media fill simulations to demonstrate sterility assurance. Traditionally, regulatory guidance recommends that containers used in media fill runs be filled to the nominal volume of the final drug product. However, this approach may be resource-intensive, especially in high-throughput or large-volume manufacturing. The rationale for this study was to determine whether reduced, or sub-nominal, fill volumes could be scientifically justified as a practical and equivalent alternative for aseptic process validation.
Material and Methods:
This investigation assessed the feasibility and performance of sub-nominal fill volumes in media fill simulations. Tryptic Soy Broth (TSB), was dispensed into 100 mL semi-transparent plastic vaccine containers at two reduced volumes. To evaluate microbial detectability, each container was deliberately inoculated with 10–100 colony-forming units (CFU) of defined challenge microorganisms. Growth Promotion Tests (GPT) were also performed on aliquots of the same TSB formulation to confirm medium fertility and suitability.
During a 14-day incubation period, all inoculated containers exhibited visible microbial growth, whereas negative controls showed no contamination. Microbial proliferation was readily observable through the semi-transparent container walls, even at reduced volumes, eliminating the need for sample transfer.
Results: The results indicate that reduced fill volumes do not compromise microbial detectability or the integrity of the visual inspection process.
Conclusion: These findings are consistent with the flexibility provided in FDA and EU GMP Annex 1 guidance, supporting the scientific justification for sub-nominal fills as a validated, resource-efficient, and cost-effective alternative to conventional full-volume media fills in aseptic process validation.
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