Freezing the assets

Gore-Tex membrane offered Avecia the combination of high moisture transfer and particle retention it was looking for when lyophilising a new anti-cancer drug

Lyophilisation - freeze drying - is used in the pharmaceutical industry as a means of stabilising active pharmaceutical ingredients.

Many pharmaceutical companies choose to sub-contract this work to companies such as Avecia Biotechnology, which has become a specialist in this field - not only because of its expertise in the chemical processes involved, but also because of its knowledge of the regulatory requirements such as validation and cGMP procedures and documentation.

Avecia Biotechnology is a world leader in solid phase peptide synthesis from pre-clinical trials to launched product. In Europe, its peptide pharmaceutical development facility is located in the UK at Gadbrook Park, Cheshire. With the capacity to make around 10kg of peptide annually, this facility can meet customers' clinical trial needs up to Phase II. Phase III and commercial manufacture is concentrated in Grangemouth, Scotland, where Avecia operates the UK's largest facility exclusively devoted to peptide pharmaceutical production.

When Avecia won a major contract to develop and manufacture a new peptide to form the basis of an anti-cancer drug, the team, led by development manager Dean Simpkin, decided that lyophilisation would ensure the stability and long shelf-life of the end product.

contamination concerns

The process involves placing open trays containing a solution of the api into a freeze-dryer where they sit on metal shelves and undergo freezing, followed by sublimation under heat and vacuum.

Stainless steel trays had been used successfully in other projects, but were ruled out here because of possible contamination problems. Glass trays were considered, but worries about poor heat transfer, bulkiness and the need to cover with nylon or PTFE to avoid loss, which may cause contamination, led Avecia to try the new Lyoguard freeze-dry trays from W L Gore.

Designed in consultation with the pharmaceutical industry, Lyoguard freeze-dry trays are inert and biocompatible. They are totally enclosed and feature a specially developed, integral Gore-Tex ePTFE membrane cover. Gore engineers customised the membrane construction to offer a combination of high moisture transfer and particle retention.

Therefore while vapour can pass through the cover quickly, the unique microporous structure forms a barrier which provides extremely high particle capture efficiency. This means the maximum amount of product is retained and the bacterial properties of the Gore-Tex membrane protect the product from contamination and provide maximum operator safety. Fabricated for single use, these disposable trays avoid cross contamination and eliminate tray cleaning.

'The new Lyoguard trays produced very satisfactory results,' said Simpkin. 'The flexible thin-film bottom conformed to the dryer shelf much better than glass trays, which meant more consistent heat transfer leading to a shorter drying cycle.'

Product recovery from the tray was also very good. Static build-up was low and the fine fly-away powder could be shaken loose in the tray and emptied into a funnel through a hole cut in the back.

When the process was scaled up, the advantages also multiplied. Four months were required to produce 350g of product. As the freeze-dry cycle lasted seven days with five trays used in each cycle, the issues surrounding product loss were critical. Any inconsistencies during the freeze-drying cycle could affect quality and ultimately lead to product rejection.

At Grangemouth, where the process was scaled up under the direction of peptides pharmaceuticals production manager Jim Kilbride, the benefits of using the new trays became even more evident as the project reached Phase III and commercial viability.

Kilbride explained that with bulk lyophilisation a high proportion of the manufacturing time and costs lies in cleaning. The advantage of the Lyoguard trays is that they leave the freeze-dryer clean. As the trays are totally enclosed, they are easy to handle and there is no spillage and therefore no wiping up.

cleaning costs

'The whole cleaning process including the dryer, the isolator and disposal of the trays now takes only between four and six hours,' said Kilbride, adding: 'The important thing is that we no longer have to clean the freeze-dryer more than once. This means we have only one validation period in the laboratory - and we know it will pass the validation test the first time. Also, there are no cleaning costs associated with the trays themselves as they are disposable which makes cross-contamination impossible.'

As a result of the experience gained using Lyoguard freeze-dry trays for the anti-cancer drug, Avecia at Grangemouth has extended their use to its DNA drug production, confident that the benefits of cleaning costs savings and reduced product loss will be enjoyed there too.

At Gadbrook Park, where Avecia is now exclusively using Lyoguard trays for all procedures, Simpkin commented: 'When we were using glass trays, we needed an isolator to protect the product. With these trays, that may no longer be necessary. We may now look at filling and emptying the trays in a laminar flow unit which would make the freeze-drying operation much easier.'