In-Depth Validation of Closed-Vial Technology - The authors describe a validation master plan for closed-vial filling technology. - BioPharm International

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In-Depth Validation of Closed-Vial Technology
The authors describe a validation master plan for closed-vial filling technology.


BioPharm International
Volume 25, Issue 9, pp. 30-42

Container–closure integrity

Container–closure integrity was assessed on vials that were pierced, filled, and laser resealed but not capped. The objective was to assess in one test the integrity at the junction between the stopper and the vial body and also the quality of the laser resealing. The dye ingress challenge test was used for validation and also for regular performance of batch release tests.

The selected dye test was based on EP 3.2.9 under the denomination "self-sealing test." The normal procedure consists of immersing vials in methylene blue solution and challenging them with a –27 kPa vacuum for 10 minutes, followed by a return to atmospheric pressure for 30 minutes. To be more challenging, three successive cycles were applied, each of them consisting of a vacuum of –30 kPa for 30 minutes, followed by an overpressure of +15 kPa for 30 minutes. The results showed the absence of dye ingress.

Microbiological tests have been conducted as well. Tests based on immersion in solution with Brevundimonas Diminuta and Proteus Mirabilis bacteria showed no contamination of vials filled with Tryptic Soy Broth and laser resealed.

Endotoxin contamination

It is crucial to ensure that the endotoxin contamination of vials is acceptable because no depyrogenization process takes place in the overall vial manufacturing and filling process. To ensure that the level of endotoxin is acceptable, both the raw material pellets and the vials are tested for endotoxin presence with an acceptable limit of 0.25 EU/mL. The method used was the Limulus Amebocyte Lysate (LAL) test using Endosafe equipment from Charles River. All batches tested until now showed low level of endotoxin on raw materials (1 g extracted with 2 mL of WFI, 0.05–0.10 EU/mL for 5 batches of raw materials) and the level inside the vial was always below the detection limit (<0.05 EU/mL UI for all vial batches). If endotoxin levels appears to be systematically low thanks to a robust process to avoid contamination, the level of control may be reduced in the future following a risk analysis.

Bioburden

Because the vials are sterilized by gamma-irradiation, the bioburden should be assessed to ensure that the irradiation dose is in line with ISO-11137 requirements. Because both vial body and stopper are molded at a temperature in the range of 200 C and directly assembled in ISO5, the bioburden should be very low. Currently, all the samples tested (10 vials from each tested batch) showed absence of bioburden. This test should be performed either each batch or every three months according to ISO-11137 guidelines.


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