Process qualification
Figure 4: Lyophilization unit loaded with closed vials; lyophilized products inside closed vials. (ALL FIGURES ARE COURTESY
OF THE AUTHORS.)
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To ensure that Crystal technology is suitable for lyophilization, several tests have been conducted using various products,
quantities, and conditions. For example, the authors:
- Used various excipients to investigate lyophilization feasibility: qualification started with an easily lyophilized excipient
(lactose 5%) and finished with a complex one (glass transition point below –38 °C).
- Increased vial quantities per lyophilization cycle: starting with a few vials and using glass vials as a control, lyophilization
cycles were made with up to 720 vials placed on two shelves (see Figure 4).
- Used sensitive products to assess the quality of the lyophilization process for the product. (Living viruses that are particularly
sensitive to lyophilization have been used to assess the recovery after lyophilization).
All tests were performed in a Christ Epsilon 2.25 D freeze dryer with seven shelves and an industrial controlling system,
using 2-mL closed vials (22.25-mm diameter) and penetrators molded in high-density polyethylene, from a two-cavity mold.
Closure integrity after laser resealing has been tested, as has effective protection of the plastic cap. The following aspects
were observed and analyzed for most cycles:
- Correct lift-back of pushers at time of shelf's upward movement at the end of the cycle.
- Quality of the closure integrity after resealing.
- Humidity content of cakes (target is 1%, +/- 0.2%).
- Visual aspect of cakes.
- For viruses, content titer was measured at cycle end and after accelerated aging (seven days at 37 °C), compared with lyophilized
glass vials. In some cycles, temperature was recorded with probes installed in plastic vials and in control glass vials to
analyze temperature curves.
The outcomes of these tests were:
- Closed vials and their closure integrity remain unaffected after undergoing temperature and pressure cycles of a freeze-drying
cycle.
- Plastic material and elevated bottom of the vial are not deterrent to effective energy transfers. It is likely that the combination
of a continuous pressure over the vial top applied by the upper shelf during the complete cycle and a perfectly flat vial
bottom help the contact between the vial and the shelves and therefore the conductive part of the heat exchange process.
- Cycle is extended by 20 min during the first phase of freezing, right after the change of phase and temperature uplift. However,
the same terminal temperature (–55 °C) is reached in the same manner at the end of the freezing phase.
- All tests are successful even for most complex excipients when similar cycles are used compared with a glass vial (2-mL vial).
- Highly sensitive viruses are recovered with similar titers in Crystal and glass vials when both are being processed together
in the same cycle.
- To ensure that the vial is effectively self-resealed after the cycle, high negative pressure inside the vial at exit of the
chamber is not recommended.
Conclusion
The ready-to-fill closed vial used for liquid products is suitable for freeze-drying without modification. It also holds substantial
containment and functional advantages over the glass vial. This vial is suitable for classical freeze dryers with minimal
impact on cycles. Even though the quality of the lyophilized product in a ready-to-fill closed vial remains at same level
as a lyophilized product in a glass vial, the ready-to-fill closed vial process is easier and product sterility assurance
is at a higher level. Useful for all kinds of products, freeze-drying in a plastic, closed vial brings additional definitive
benefits to both the patient, the healthcare specialist, and the manufacturer when product containment is mandatory such as
with cytotoxic and biohazard products.
References
1. B. Verjans, J. Thilly, and C. Vandecasserie, "A New Concept in Aseptic Filling: Closed-Vial Technology," Pharm. Technol., Aseptic Processing supplement, s24–s29 (2005).
2. J. Thilly, D. Conrad, and C. Vandecasserie, "Aseptic Filling of Closed, Ready-to-Fill Containers," Pharm. Eng., 26 (2), 66–74 (2006).
Acknowledgments
The authors would like to thank Romain Veillon at Glaxo-SmithKline Biologicals for his supportive contribution to the experimental
tests as well as his technical expertise and advice. Aseptic Technologies benefits from grants from the Walloon Region and
the Agence Wallone à L'Exportation (AWEX). Core closed-vial technology has been licensed by Medical Instill Technologies.
Jacques Thilly* is director of research and development at Aseptic Technologies, Rue Camille Hubert 7-9, B-5032 Gembloux, Belgium, tel. +32
81 409 413, fax +32 81 409 411, jacques.thilly@aseptictech.com
Yves Mayeresse is senior manager and head of freeze-drying at GlaxoSmithKline Biologicals.
*To whom all correspondence should be addressed.
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