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Pharmaceutical Manufacturing and Packing Sourcer

Pharma Without the Fudge Factor

Scientific modelling of fluid mechanics systems, or computational fluid dynamics (CFD), is well-established in many industries: from streamlining the flow of air over a car bonnet, to investigating the bubble behaviour in a membrane bioreactor. However, the application of these techniques to desiccant systems has been neglected.

Desiccants play a vital role in the protection of moisture-sensitive drugs and products. By removing water vapour from the air, the desiccant prevents undesirable reactions between the product and the water molecules, including degradation known as hydrolysis – the cleavage of chemical bonds by water. The desiccant and product are placed inside a protective barrier that will repel most of the external vapour from the interior.

Limitations of Established Methods

Established practice in desiccant selection has been to determine the total moisture load for the required shelf-life of the product before being exposed for use by the consumer. This is a combination of the initial water vapour and the vapour ingress through the boundary of the packaging. This mass of moisture is then fed into the desiccant’s capacity to determine the total mass of desiccant required, ensuring that the desiccant remains active during shelf-life.

However, this approach does not account for kinetic factors at play within the packaging. For example, as the desiccant reaches saturation, the rate at which it will pick up moisture will decrease. Therefore, even though the desiccant is still ‘active’, the humidity inside the package will increase. This places the product at greater risk of hydrolysis.

There is clearly demand for a more advanced method that will account for changes to both the rate of moisture ingress, which will decrease as the internal humidity increases, and the rate of moisture adsorption of the desiccant. The balance between these factors is key.

Predictive Approach

Recent analysis has been carried out to create a new predictive modelling system for desiccants based on sophisticated mathematical models, and there is substantial scope to develop such models specifically for the desiccant industry.

Extensive research and experimental tests were undertaken to develop a comprehensive understanding of desiccant adsorption behaviour in a variety of storage environments and packaging. The storage environment is defined by the temperature and relative humidity (RH) of the air, which will give the absolute humidity. The packaging includes aluminium foils of different thickness, and vials that might be employed for pharmaceutical applications. The model can be applied to any desiccant-based packaging system used in, for example, the protection of pharmaceuticals, vitamins, diagnostics kits, medical devices and healthcare products, as well as large-scale ‘work in progress’ containers.

Desiccant-CFD Modelling

The datasets from experimentation are used to develop a sophisticated desiccant ‘behaviour’ model. This is in the form of a set of differential equations that are flexible to accept all relevant variables, including size and type of package, storage conditions and type of desiccant. These are solved using normal numerical techniques. Once the desiccant behaviour is known, this can be coupled with existing fluid mechanics knowledge, creating a desiccant-CFD model for the water molecules inside the package.

The relevant fluid mechanisms to consider are advection and diffusion of water molecules. Advection refers to motion resulting from a flow of air, as driven by pressure differences. However, for most packaging and storage environments, the product is sealed and stationary in a uniform temperature field. As such, advection can typically be ignored.

Diffusion is the motion of molecules from high concentration to low concentration. This is an important mechanism when considering the interplay between desiccants and their environments. As the desiccant adsorbs moisture, it creates a low water vapour concentration around it, thus drawing in molecules throughout the package by diffusion.

The advection and diffusion of water molecules is well-understood – the original work in the model lies in the characterisation of the desiccant adsorption properties. Desiccants have a very large surface area-to-mass ratio. This surface area possesses many adsorption sites to which the water molecules can stick. Further adsorption also occurs in layers away from the desiccant by H2O-H2O bonding.

Mapping the Humidity

As the desiccant adsorbs moisture, the number of adsorption sites will decrease; hence, the probability of a water molecule being adsorbed at any given time will reduce at a given RH. This is an important consideration, as it determines the rate at which the desiccant picks up moisture.

As the desiccant approaches saturation, the rate of moisture adsorption will become much slower. Eventually, a tipping point will be reached where the partially saturated desiccant will not be able to keep up with the moisture entering the package. At this stage, the humidity will start to rise, even though the desiccant is still ‘active’.

The interior of the package in the desiccant-CFD model is represented as a Cartesian or cylindrical grid, depending on its geometry. The ingress-diffusionadsorption equations are solved over the grid points, giving a two- or three-dimensional (3D) view of the humidity inside the package. These are progressed over each time period for the required shelf-life of the product; thus, the humidity for any given point inside the package can be determined at any time. This knowledge is especially powerful to minimise the work and costs associated with getting a product to market.

Accelerated Stability Trials

In order to establish that the desiccant is doing its job in protecting the product, stability trials are undertaken. To help speed up new product launches, accelerated tests can be carried out. Packaging containing the product and desiccant is subjected to a very high humidity, using the principle that if the test is conducted at five times the actual storage humidity, one month under test conditions equates to five months in storage. This is an effective and established test method of more rapidly determining product efficacy.

However, it is not without its limitations. The timescales involved make it important to minimise the number of trials undertaken. Even at an accelerated rate, a two-year shelf-life evaluation can still take six months to complete. In addition, there is a risk of overdesiccation, as during an accelerated trial, the ingress through the packaging will place a greater burden on the desiccant adsorption rate – resulting in a higher internal humidity than would be present under non-accelerated conditions.

Performance in Practice

A snapshot of the result of modelling the humidity inside a typical effervescent tablet vial can be seen. Here, the desiccant is in the lid at the top of the vial. As such, the desiccant will remove moisture from the top first.

In practice, vials can be repeatedly opened and closed over a significant amount of time as the consumer removes each tablet one by one.

This raises the question: what effect will repeated opening and closing have on the actual product shelf-life? A product may be designed to perform satisfactorily while closed, but may fail if repeatedly opened in a humid bathroom; when opened, the desiccant in the lid will be exposed and the vial headspace filled with humid air. The flexibility of the 3D model allows the effects of regular opening and closing of the package to be considered. This will ensure the quality of the product is maintained until the last tablet is removed.

Optimised Packaging

By including all critical variables, the desiccant-CFD model can help companies supplying pharmaceuticals and medical devices to optimise existing desiccant packaging specifications, or to develop ultrareliable packaging solutions with predictable humidity ranges. The mathematical model significantly improves accuracy in desiccant specification to offer a high confidence level in the shelf-life and storage performance of a packaging system – regardless of the environment and climatic conditions.

By obtaining a full understanding of a product’s thermo-fluidic environment, companies can achieve both the optimal quantity and ideal placement of the desiccant within the packaging. This helps to maintain an ideal humidity, and guarantees the stated shelf-life and storage requirements.

The major advantage of the 3D modelling system is that one is able to get an in-depth mathematical analysis of moisture loading and desiccant requirements, tailored for specific atmospheric conditions from tropical to temperate. This ensures that the correct packaging and amount of desiccant materials are used to safeguard product stability.

Range of Benefits

The quality of the desiccant selection in a packaging specification is vital. An inaccurate initial desiccant quantity can lead to stability failures and insufficient shelf-life performance, adding months to a product’s development time and delays in getting new products to market. Additionally, any excess desiccant used builds in extra costs for the entire line.

Using new 3D modelling techniques offers significant benefits to companies, especially smaller organisations that often lack in-house packaging expertise. Lowering desiccant costs by eliminating excess usage, improving shelf-life and performance by better desiccant selection and placement, and reducing packaging bulk volume and weight for lower packing and transport costs, are among the many advantages to be obtained from a much more considered approach.

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Dr Mark Valentine joined Baltimore Innovations Ltd after completing his PhD at Oxford University, where he worked in the Chemical Engineering Group in the field of fluid mechanics and multiphase flow. In his current role as R&D Director, he works closely with the in-house business development team, strategic manufacturers and key supply partners to develop new moisture control-related packaging products, as well as providing desiccant consultancy advice and technical support to customers within the pharma, medical device and food packaging industries.
Dr Mark Valentine
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