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


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

Gas permeability

Table III: Water vapor transmission rate from 2-mL vials filled with 1.2 mL water-for-injection. RH is relative humidity.
Compared with glass, polymer materials have a significantly higher permeability to gas. COC material, used for the vial body, has been selected on basis of its well-recognized gas barrier properties. Nevertheless, gas permeability has to be assessed to ensure that products will not be subject to significant changes. In particular, water vapor transmission rate (WVTR) and oxygen exchange must be carefully checked. WVTR can lead to loss of water from liquid product, resulting in change of product concentration. Oxygen ingress can lead to oxidation of oxygen-sensitive products.

To measure WVTR, 2-mL vials filled with 1.2 mL of WFI were stored in various ICH conditions. According to the ICH Q1A (R2) guideline, semipermeable containers should be stored in the following conditions to meet the class III and IV conditions (i.e., hot conditions): –20 C for frozen products, 2–8 C (normal conditions) and 25 C 2 C / 60% 5% relative humidity (RH, accelerated conditions) for refrigerated products, 3 C 2 C / 35% 5% RH (normal conditions) and 40 C 2 C / not more than 25% RH (accelerated conditions) for products kept at room temperature. According to ICH, a loss of 5% water within a period of three months in accelerated conditions is the acceptable limit. If that limit is exceeded, investigations should be conducted to assess the effect on the product.

Table III illustrates the loss of water in various storage conditions. In both accelerated conditions, water loss was significantly below the limit. Similar experiments are on-going with other vial formats and identical conclusions can be drawn. This supports the initial expectation that COC has excellent barrier properties for water vapor.

Figure 1: Speed of oxygen depletion in 2-mL closed vials when incubated with an oxygen scavenger in aluminum pouch. Oxygen concentration was measured using a Microx TX3 fiber optic oxygen transmitter (Presens), connected to a needle-type oxygen microsensor. Vials were incubated at 25 C (blue line) and 40 C (red line).
It is less obvious how to measure oxygen permeation due to ambient oxygen. Therefore, a specific test was set up to characterize the vial behavior regarding permeation to oxygen. The vial was packed with a bag of FeO crystals, validated regarding absence of loss of crystals outside the pack, inside a sealed aluminum pouch to serve as an oxygen scavenger. Such an assembly will first deplete the oxygen around the vial, bringing the oxygen concentration inside the pouch in the range of 0.1% within 24 h. In a second phase, the oxygen will leak out of the vial because of the concentration differential. When exiting the vial, the oxygen is captured by the scavenger, keeping the external concentration permanently low. Figure 1 shows the different kinetics observed according to storage temperature, leading to residual oxygen concentration in the vial of less than 3% in two months.

A useful application of that permeation to oxygen is the opportunity to prepare oxygen-depleted vials in advance after ensuring sufficient preincubation time. When filling oxygen-depleted vials by piercing with the noncoring needle through the stopper, no significant oxygen increase was observed in the vial, maintaining the initial oxygen concentration without nitrogen flush. For example, a test made with 2 mL oxygen depleted vials (pre-incubated for four months) showed that before and after filling, the concentration remained around 0.5% oxygen. After filling, the vials were kept under aluminum pouch protection with an oxygen scavenger for six months. The oxygen concentration inside the vials continued to decrease down to 0.1%. Although it requires an additional secondary packaging, closed vials are able to decrease the level of oxygen to significantly lower levels than classical procedures applied to glass vials, showing significant benefit for oxygen-sensitive products.

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