Dr Heike Kofler - manager Technical Customer Support Europe at West Pharmaceutical Services explores the considerations for lyophilisation closure selection and processing to protect moisture-sensitive drug products.
Cold chain
Lyophilisation or freeze-drying is known as the removal of water from a frozen liquid product by a phenomenon called sublimation. The result is a solid, dried product inside the vial. This is an ideal process for moisture-sensitive drug products that may have a limited shelf-life due to external influences such as moisture ingress. If injectable drug formulations are unstable in aqueous solutions, due to the molecular interactions. they can degrade quickly in solution, which is why these drugs are often freeze dried. This will protect them from certain external influences and potential degradation.
Lyophilising moisture-sensitive injectables enables drug stability during their assigned shelf life until they are reconstituted into their liquid presentation prior to drug administration. An increasing number of injectables are marketed in a lyophilised form for various therapeutic indications, e.g., oncology and rare metabolic diseases.
Lyophilisation involves long production cycles in high capacity freeze dryers with a significant degree of automation to simultaneously process thousands of container closure system units. Process efficiency demands that the components meet requirements for integral drug containment, dimensional fit assuring container closure integrity, support machinability in fill-finish and maintenance of drug compatibility and stability. Glass has a very low moisture vapour transmission rate (MVTR), so when selecting a primary container for a moisture-sensitive drug product, glass vials are often used. However, when selecting a rubber stopper for the system, pharmaceutical manufacturers should be aware of design features and consider the rubber formulation to ensure optimised storage and moisture protection for the drug product.
After filling the liquid drug into a vial, the stopper is halfway inserted into the vial to reach the intermediate lyophilisation position. Component design is optimised to ensure a stable lyophilisation position on the vial neck to allow moisture vapour removal through the remaining stopper-vial-gate into the freeze dryer chamber. Final stoppering to achieve full insertion into the vial occurs when the freeze dryer shelves move down after the process cycle.
Igloo stoppers offer a stable positioning in the freeze-drying phase because of their increased contact area with the glass vial. Due to their asymmetric balance point, however, the stopper may shift out of the vertical axis during stoppering, which requires optimisation on the filling line to avoid rejections during camera inspection of the seated stopper. Split designs are more flexible during stopper insertion. Their symmetric design keeps them horizontal during freeze-drying. However, prior to drug filling and stopper insertion, the two-leg design could potentially lead to closure twining, where stopper legs could intertwine during processing in the feeder bowl, which may cause issues including line stoppages and down time. Either design will work well for the freeze-drying process itself.
When considering the lyophilisation of moisture sensitive biopharmaceuticals, companies should consider that moisture transfer could occur via the stopper. High-quality elastomeric components used for aseptic filling are washed, dried, steam sterilised and dried again to help ensure cleanliness and reduced residual moisture content of the closures. There are two distinct points where moisture is driven into the stopper: initial pharmaceutical washing and the steam sterilisation process. Both are followed by a drying period that should be optimised for a moisture-sensitive drug product. Also, a protective bag packaging concept will keep stoppers dry after sterilisation and post-drying until introduction to the filling line.
The stoppers will then be used in the lyophilisation process to aseptically contain the freeze-dried drug product. The fully stoppered vials are released from the freeze drier, crimped with seals and stored.
West Pharmaceutical Services conducted a study which revealed that MVTR was more important to long-term storage of freeze-dried product than initial closure dryness.1 Results confirmed that moisture content in stoppers prior to filling the drug is dependent on its rubber formulation and applied drying conditions. It is recommended to optimise drying cycle parameters for removal of moisture driven into the stopper during the autoclave cycle of the drug product.
Measuring the moisture content of lyophilised lactose as a model for a freeze-dried product over three years showed that moisture migrates from the environment through the stopper and accumulates in the freeze-dried product over storage time. Moisture uptake by the dried product correlates with the MVTR of the rubber formulation, not solely with the moisture uptake of the stopper after washing or steam sterilisation.
Moisture can reach a lyophilised drug product in a variety of ways. The simplest source of moisture ingress is a lack of seal integrity between the stopper and the vial interface. If there is not a tight seal, moisture can travel easily into the vial and permeate into the freeze-dried drug product. Secondly, residual moisture inside insufficiently dried closures 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 lyophilised drug product over time. Finally, water vapour can constantly migrate from the environment through the rubber stopper during long-term storage. Every rubber formulation has a MVTR, a characteristic rate for water vapour to migrate through the material over time. The amount of moisture that could negatively affect the drug product varies based on the size of the freeze-dried drug product and its contents.
With these considerations for selection and preparation of packaging components for a container closure system, stability of lyophilised drug products can be maintained despite their moisture sensitivity. Compromised drug stability like the collapse of a freeze-dried product due to excessive moisture uptake during storage needs to be avoided. Making the right choice of packaging appropriate for the drug product can help reduce the risk of costly recalls or rejection of the drug product at its point of use.
References:
1: Technical Report TR 2007116 Lyophilization Stoppers and End-Product Moisture Evaluation - West Pharmaceutical Services, Inc.
ACKNOWLEDGEMENT
This article is based on a study conducted by Amy Miller and Jennifer Riter of West Pharmaceutical Services, Inc., without whose significant efforts this article could not have been written.