Misconceptions In Freeze Drying - Glass Vials

“It doesn’t matter what type of glass vial I choose to do my freeze dry development work in, they are all suitable for holding pharmaceuticals and so any one should be fine.”

Often at the start of a project some people look in their stores to see whether they have a container of about the right size / capacity for the project at hand, and just start to use that. This is not always a good idea……

What can be advisable is to check with a supplier of packaging that this is indeed an item that should be suitable for a freeze-dry application. Glass type (if an injectable it needs to be Type I glass for example), method of manufacture, future availability, etc can all have an influence on whether it will actually be suitable.

Pharmaceutical glass vials are available in either moulded or tubular glass options. As a rule of thumb, smaller glass vials are more economical when made from tubular glass and large capacity vials are more economical in moulded glass due to the efficiencies in the respective production process involved in manufacturing the vials.

Tubular Glass Vials are converted from glass tubing where the wall thickness is controlled and the base shape can be optimised in the converting process into a container.

Moulded Glass Vials are made from pouring liquid glass into a mould that dictates the outside shape of the container, and the wall and base thickness is not easily controlled. If you look at a moulded glass vial alongside a tubular one, the sides of the moulded glass container will appear ‘marbled’ where the wall thickness varies. This is not visible with a tubular glass container. Therefore the tubular container will also be lighter.

When freeze drying, ideally you want as flat and as thin a base to the vial as possible, to ensure optimal and consistent thermal transfer from the freeze dryer shelf. These are all attributes of tubular glass vials, which are available in 2ml - 100ml sizes.

Moulded glass vials can often have ribs around the edge of the base as well as a more concave bottom which means the base of the vial isn’t as close to the freeze dry shelf and so the product in the centre of the vial cools slower than the outsides. Additionally the base of moulded vials can be very thick, and also inconsistent in shape, meaning a variation as to how much liquid is near the freeze dry shelf and less than preferable heat-transfer. If the heat transfer takes longer, this can make the freeze dry cycle longer = more time / cost.

“Any glass vial will do” – Part 2

If you are working on a product for injection, or for a diagnostic application, then it often makes sense to do your development in a container that is both suitable for the product, and also could be used for commercial scale-up.

We have seen people do their development in a container that is not suitable for a pharma-application, spend a lot of time and money trying to get the product stable and compatible with the material, and then a few years later they have come to commercialise the product only to find that they need to transfer to a glass or alternative polymer vial to meet the relevant Pharmacopeia, and have to repeat many of the stability and validation runs to prove that the product is OK with a different container / closure. This takes time and money, and could mean a competitor could beat you to market.

In the case of some common plastics they can be permeable to oxygen and water-vapour whereas glass is not, and there can be some leachable / extractable issues on occasion too. This is less of an issue with some modern high-tech polymers (West’s CZ for example).

“The liquid fill – either before lyophilisation, or after reconstitution - is very low (say 1ml or less) therefore I must use a really tiny vial”

Not necessarily. In fact this needs to be given very careful consideration.

Very small vials do exist (for the chromatography market for example), but just because you can buy them does not mean it is a good idea to use them for your application…

First of all, the production of a vial involves heat, to get the glass to a temperature where it can be formed into the shape of a vial. The heat involved is very high and can negatively affect the surface of the glass if this process is not precisely controlled. With very small vials (below a nominal 2ml fill) there is less surface area for that heat to dissipate, and sometimes the quality of the inside surface of the vial can be degraded. In some cases very small Type I glass can have the surface quality tested on the finished vial (hydrolytic resistance testing) and you might find that the glass no longer conforms to the Type I classification.

It is also worth thinking ahead - and a little laterally. As the project scales up, who will have a filling machine that would fill such tiny vials, without special and possibly expensive change-parts? What about labelling of the vials? Is there a labelling machine that can apply labels to something that small, and will you be able to get enough information onto the label in a legible form to meet the needs of the customer? Also think about how easy it will be for someone to use the vials, and perhaps withdraw product from it with a syringe and needle without risking a needle-stick injury?

An ISO standard vial of 2ml nominal capacity is what would be generally recommended as the smallest starting point. The quality of the surface would be expected to meet the grade, filling companies are familiar with it, as are the stoppering systems on filling-lines. The labels and labelling machines are routinely familiar with this size, and fill volumes / reconstitution volumes of 200 microlitres are often packed into such vials without issue. You might not have a freeze-dried ‘cake’ at the bottom of the vial after such a process, with there being more of a ‘halo’ at the bottom of the vial.

If there is a concern about withdrawal of all of the drug from the vial in such cases, perhaps the drug product is of high value, and you don’t want to put an excess of product into the vial to allow for the residual product that typically sticks to the surface of glass, then special coatings for the inside of the vial that provide certain benefits such as being hydrophobic do exist.