Heike Kofler, Manager, Technical Customer Support EU, West Pharmaceutical Services, elaborates on why pharma companies are increasingly turning to lyophilising in order to preserve the characteristics of a potentially unstable drug
Glass has very low moisture vapour transmission rates, so when selecting a primary container for a moisture sensitive injectable drug product, glass vials are often used. However, to ensure optimised storage and moisture protection for an injectable drug product, pharmaceutical manufacturers should be aware of the design and feature options when selecting a stopper for the system, and consider the rubber formulation as well as its processing.
This becomes increasingly critical when lyophilising (freeze-drying). Pharma companies are increasingly turning to this process because it preserves the characteristics of a potentially unstable drug while enhancing product stability in a dry state, which enables rapid and easy dissolution of a reconstituted product as well as ease of processingi.
Lyophilisation is considered an ideal process for injectable drug products that may have limited shelf lives or sensitivities to exterior influences. Some drug formulations are unstable in aqueous solutions; the molecules can interact and degrade quickly in water, so moisture sensitive drugs are often lyophilised not only to protect them from outside elements, but also to protect them from their own eventual decayii.
But there are drawbacks. Maintaining stability of the lyophilised drug product during its shelf-life can be difficult for moisture-sensitive drug products, particularly if the elastomeric component selected for the primary containment system allows moisture vapour to migrate into the drug. Proper selection of the lyophilisation component and the rubber formulation can help to prevent risks and costs associated with degradation of the lyo cake, which can result in loss of drug product and patient confidence.
Lyophilisation closures: Igloo vs. Split models
Igloo stoppers offer stable positioning in the freeze-drying phase due to their increased contact area with the glass vial orifice. They are also less flexible than split (or two-leg) designs. However, one drawback to this option is the asymmetric balance point. The stopper may get out of the vertical axis during application. This could lead to technical issues on the filling line, for example during camera inspection of the stopper as in-process-control or, in a worst-case scenario, by a closure displacement and the stopper falling off the vial.
The split design offers a more flexible option during stopper insertion, and its symmetric design keeps it horizontal during freeze-drying. However, the twinning effect, where the stopper legs could intertwine during processing, may cause issues during the filling line process, for example in the closure feeder bowl or on the transportation rails leading to the stopper insertion station.
Either option will work well for lyophilisation, as both offer a gate where water vapour can be released from the vial headspace during the freeze-drying process. Of greater concern to pharma manufacturers is that moisture can migrate through the rubber stopper itself during long-term storage of the freeze-dried drug product. Therefore, selecting the right rubber formulation and processing steps for the lyophilisation closure are of utmost importance.
Rubber formulations to reduce moisture transmission in lyophilisation stoppers
Moisture can reach a lyophilised drug product in a variety of ways. The simplest source of moisture ingress is a lack of seal integrity in the stopper-vial combination. If there is not a tight seal, moisture can travel easily into the vial and permeate into the freeze-dried drug product. Residual moisture driven into the closure—mostly during steam sterilisation and not removed due to insufficient drying conditions—may affect the drug product, as the captured excess water vapour could be released from the rubber stopper into the vial headspace and permeate into the drug over time.
Water vapour also can migrate from the environment through the rubber stopper during long-term storage. Every rubber formulation has a characteristic rate for water vapour to migrate through this material over time, called Moisture Vapour Transmission Rate (MVTR). This can be measured during development of a rubber formulation on a vulcanised rubber plate of specific thickness that is used as a permeation barrier in a humid chamber. The MVTR is expressed in [g/m2 x day], based on a 0.035 inch thick vulcanised test plate of a specific rubber formulation.
The negative impact of moisture on a drug product varies with the volume of a freeze-dried drug product and its contents. When moisture is driven into the elastomeric component during the washing and steam sterilisation processes, the rubber stopper acts like a sponge, taking in and releasing moisture. Each rubber formulation has its equilibrium moisture content under certain conditions, and the environment also influences the final moisture ingress into the vials. An environment with high humidity could affect the humidity in the headspace of the vial, which may influence the rate of moisture travelling time through the rubber closure during long-term storage.
Importance of reduced MVTR
West Pharmaceutical Services, conducted a studyiii to determine whether various drying periods affected moisture uptake within the rubber component. In doing so, it was discovered that the MVTR was more important to long-term storage than initial dryness. Residual moisture was studied on the content of a 100 mg lactose lyo cake and lyophilisation stoppers for a three-year period. Different rubber formulations were compared to each other and different drying periods for the closures after steam sterilisation were tested.
Seal integrity was tested on all the vials using Helium-Leak detection. The results noted that moisture migrates from the environment into the stopper over time and that residual moisture in the stopper is dependent on its rubber formulation and applied drying time. In fact, the drying conditions had an effect on the residual moisture content in the stoppers. It was noted that a one-hour drying cycle is insufficient to remove the moisture driven into the stopper during the autoclave cycle. Drying for four hours returned the moisture content within the stopper back to the amount of moisture prior to steam sterilisation, but the best results were gained with an eight hour drying period at 105°C.
The findings? Bromobutyl stoppers have more moisture from the start compared to a very dry butyl rubber, but they prevent moisture from reaching the lyophilised sample over time. In contrast, a very dry butyl type rubber formulation allows water vapour to travel through the elastomer more easily – so the moisture content measured after 36 months in the contained in these vial-stopper systems was higher compared to the one in the bromobutyl sample. Elastomeric rubber formulations that have reduced moisture vapour transmission rates are better suited for keeping the drug product relatively dry after lyophilisation.
Residual moisture in elastomeric stoppers can cause degradation of lyophilised drug product. If the drying conditions for the stopper are not optimised, residual moisture can migrate into the lyophilised drug product over time. Best practices for the elastomeric components include optimised drying time after the steam sterilisation process, and consideration of a rubber formulation with a reduced MVTR.
Bottom-line findings
After drying correctly, and before introduction to the filling line, packaging must also be considered. The use of a moisture barrier bag, rather than a steam sterilisable bag, will help to maintain the achieved and specified residual moisture in the stoppers after steam sterilisation and appropriate drying process. Moisture barrier bags will help to keep the stoppers dry prior to use.
In order to select the best primary container system for a lyophilised drug product, pharma manufacturers must consider closures carefully. The design should be selected to ensure dimensional fit of the stopper to the vial, eliminating the possibility of a ‘misfit’ during the capping process, which would allow moisture to permeate through gaps between the vial and stopper. Rubber formulations with low MVTR should be selected to ensure optimised processing, and sufficient drying time should be allowed to help ensure that long-term storage will not affect the drug product.
The final finding: There is no stopping the uptake of moisture over time, but with the right consideration given to the selection and preparation of the elastomeric components of a container closure system, lyophilised drug products will maintain stability with respect to moisture sensitivity and related efficacy over the long journey to their use by the patient.
The author wishes to acknowledge that this article is based on a study conducted by Amy Miller and Jennifer Riter of West Pharmaceutical Services, without whose significant efforts this article could not have been written.
References:
1. U.S. Department of Health and Human Services, (2014). Lyophilization of Parenteral (7/93) Guide to Inspection
of Lyophilization of Parenterals. Retrieved from: http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074909.htm
2. Mayberry, J. (2012). The New Scope of Pharmaceutical Lyophilization. Retrieved from: http://www.pharmpro.com/articles/2012/06/new-scope-pharmaceutical-lyophilization
3. H Kofler, et al. Evaluation of residual moisture in lyocakes and corresponding lyophilization stoppers of different rubber formulations. http://www.westpharma.com/en/support/Scientific%20Posters/Evaluation%20of%20residual%20moisture%20in%20lyocakes%20and%20corresponding%20lyophilization%20stoppers%20of%20different%20rubber%20formulations.pdf
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