Bulk freeze drying has common applications mainly in the food industry for instant coffee, fresh fruits, and dairy products such as milk. Enabling a longer shelf life whilst maintaining desired attributes of the finished food products such as colour, taste and high nutritional value, bulk freeze drying remains a highly desirable and proven option to manufacturers over other drying technologies.
For decades, bulk drying has also established itself as an extremely useful technique in the pharmaceutical industry for drying a variety of materials. Some typical examples of what bulk drying has been utilised for are fermentation of bacterial samples, to some lower value solutions, small molecules and large amounts of active pharmaceutical ingredients (APIs) during early stage research and development, and as manufacturing process intermediates.
Bulk freeze drying is governed by similar mass transfer mechanisms found in traditional glass vial systems but, in certain circumstances, it may demand closer attention to detail to ensure success due to the larger volume of liquid or solvent being removed per container.
The three main stages of freeze drying are:
- Freezing/Thermal Treatment
- Primary drying
- Secondary drying
One major benefit of bulk drying over lyophilising in vials is that vials are generally arranged hexagonally across a freeze dryer shelf (Fig.1 left) and, it has been argued that about 20-30% of the freeze dryer shelf is unused when employing this commonly used hexagonal arrangement in industry1. In contrast, drying larger volumes of material in the bulk format benefits an operator by having a larger surface area available, and the use of more shelf space than that found with vial only systems, allows higher productivity where the product material and purpose allows.
This article seeks to briefly highlight considerations for the successful adoption of a bulk freeze drying process for pharmaceuticals.
Fig. 1 left: Section of a typical freeze dryer shelf with hexagonal packing of vials showing a grey area of dead space1. Basic trigonometry allows the volume not used to be calculated considering vial dimensions, nominal vial wall thickness of about 1 mm and known shelf specifications of pilot or production freeze dryers. 20-30% of shelf space is not used. Fig. 1 right: A bulk freeze dried process intermediate in a bulk stainless steel tray in a non-sterile GMP environment
The major considerations when adopting bulk freeze drying are:
- sample depth used
- solid content of the material itself
- choice of container system
- specifications of the available freeze dryer
- cycle recipe
- further processing requirements of the final dried bulk powder.
Knowledge of the freeze dryer specifications is paramount especially during the scale up of any bulk drying process. The maximum trapping rate and condenser capacity need to be commensurate with the sublimation rate of the bulk solution batch to prevent condenser overload and exceeding drying chamber vacuum safety limits (a phenomenon referred to as choked flow where chamber pressure is lost) which could cause a bulk drying cycle to fail.
Consistent fill depths per choice of bulk container across the shelves and a total batch size meeting the dryer’s condenser capacity are key and should always be taken into account.
Scale is another major factor to consider, because while freeze drying recipes can be scaled up to meet increased throughput demands, the larger the volume of sample to dry, the greater the handling element of loading/unloading shelves becomes a key objective. Some material may need to be kept in a cold room, during the loading process to ensure material doesn’t become compromised – these are all areas that can be easily addressed.
A cycle recipe should be optimised whilst maintaining the desired attributes of the dried material. Conservative bulk drying cycles may take several days and drive process economics, whereas others may be successfully optimised to process over a 24 hour period. Such optimised cycles are fed by full formulation characterisation which must have determined, as a minimum, critical temperatures via microscopy and thermal analysis to fully inform the freeze drying behaviour of the bulk formulation.
Further processing of the finished bulk product may involve either storage into large intermediate containers for future use or dispensing into smaller containers with closures. The successful manipulation of the finished product, whether it be a drug, dairy or food sample, into smaller volumes will also depend on the type of formulation (crystalline or amorphous) and powder disruption techniques if manual or automated powder dispensing is demanded.
In conclusion, bulk freeze drying continues to be a useful and extremely popular method of drying a range of materials in the food, dairy, bio-tech, and pharmaceutical industries. Despite some of the additional optimisation considerations of both the formulation and cycle recipe involved to make the process as efficient as possible, the benefits received from maximising shelf space and the use of basic containers help to make large volume freeze drying a less labour and cost intensive process, which is why it is highly used within the produce industries in particular and is becoming a more viable and attractive option for the pharmaceutical industry.
The Biopharma Group has been at the forefront of providing freeze drying equipment since 1989, from benchtop R&D, to full scale production –with >100m2 shelf area–, suitable for bulk lyophilisation, in conjunction with independent contract research and formulation development in both bulk and vial freeze drying.
Our extensive knowledge, derived from a near 30 years in the industry, gives companies the confidence that with Biopharma, you have a partner capable of specifying the best suited model/configuration to meet your specific processing needs.
Whether the interest be a 3 x stainless shelf benchtop VirTis AdVantage Pro, designed with bulk drying in mind at the smaller scale, or a pilot/production machine, compliant with 21 CFR Part 11, CIP/SIP, or instruments to automatically load/unload product, we have the solution.
Equally, implementing our practical expertise and range of analytical tools to identify inherent sample characteristics, Biopharma’s track record is well established to aid formulation characterisation, development and product scale up from initial consultation through development, analysis, full Quality-by-Design programs, and beyond.
To find out more about the benefits of bulk freeze drying or to discuss your requirements, please contact Richard Lewis at
+44 (0)1962 841092 or rlewis@biopharma.co.uk
References
- Ekenlebie, E. P. Pharmaceutical process optimisation of bulk lyophilisates: implications of powder handling. PhD Thesis, Birmingham: Aston University, 2015.
