Lyophilisation (freeze drying) is a valuable technology in large scale use by almost all major and many smaller pharmaceutical companies somewhere in their operations.
The technology involves extreme drying of drug products through a process of freezing and then evaporation (or subliming) of the water in the product from its solid phase. It is used because lyophilised products:
- Have excellent stability periods compared with liquid formulations
- Are not damaged by the elevated processing temperatures of other drying technologies
- Achieve the desired crystalline properties for dissolution prior to, or in use
Most lyophilised products are prepared in simple vials and are reconstituted by the user in water, for injection of the dose by needle delivery systems. A growing number of products are prepared in two-chamber vials with the water for injection ready to use in the syringe . One technology - Zydis - prepares an oral dose form.
The development of biotechnology products, proteins which are heat sensitive, and of increasingly less stable chemical drug compounds will secure the place of lyophilisation in the industry for the foreseeable future.
So, everything is fine then? Not really!
The technology is old, expensive and difficult to manage
Lyophilisation as a technology has not really developed significantly since it was first used by the pharmaceutical industry over 50 years ago. Almost everything about this technology seems designed to cause excess costs and operating difficulty.
- The process combines high speed continuous filling equipment with low speed batch operation of shelf dryers. This makes automation and isolation difficult and raises issues of mechanical handling and plant design.
- Product variability is inevitable because the conditions on the shelves of the large dryer units vary so much between locations and over the long period that the product is in the dryer. This in turn has made processes difficult to validate, and the lack of in-process control and monitoring has made freeze drying a serious compliance risk
- Process variability also makes scale-up more difficult than it needs to be - what can be done in the laboratory freeze dryer cannot always be replicated easily at production scale, and this inevitably causes longer scale-up programmes than necessary
- It has been difficult to keep pace with increasing product quality requirements (for example Japan), and so process yields have reduced whilst inspection costs (usually manual labour) have risen
- The technology has to be sited in costly sterile suites because the products cannot be sterilised. Operation is expensive and inefficient, and it leads to concerns about sterility because the vials with liquid product inside are left open to the environment for long periods.
All this is exacerbated because regulatory requirements have developed much faster than the technology itself and these requirements become a barrier against innovation. As a consequence, the process as it currently stands is a liability to pharmaceutical manufacturing organisations:
So, can lyophilisation technology be brought up to date?
Yes it can. But only by radical redesign of the process. No amount of automated loading equipment will overcome the basic shortcomings of the current technology.
What kind of radical redesign? PA believes that the key to unlocking major improvement in this process is to secure:
- Fully automated production behind isolation barriers. This requires:
- Largely continuous operation (continuous automated processes always work better than batch processes) which means we need:
- Rapid processing times (a few hours rather than the two-three day cycles which are typical today). Therefore we need rapid freezing and a large surface area-volume ratio to increase evaporation rates.
For a client PA developed patented Continuous Freeze Drying technology - which dries the product in a shell rather than a cake or plug (see figure 1)
Figure 1 - Shell drying increases evaporation rates
It achieves this by rotating the vial whilst the liquid drug is being dispensed into the vial. The drug is rapidly frozen onto the wall of the spinning vial using sterile filtered nitrogen at around -60°C and then the vial is passed to a drying tunnel for evaporation to take place.
The drying tunnel uses a controlled and continuously monitored temperature profile along its length to ensure the correct temperature cycle during drying. Typically the temperature at the start of the process will be held at -20°C, and this will rise to perhaps +40°C at the end of the cycle to complete secondary drying. The process is shown schematically below.
Figure 2 - The whole process in schematic form
We have managed to meet the required dryness specification for all the products that we have tested on our partial prototype, and in times of between one and three hours where typical cycle times for these products are typically 48 hours or more.
The result is a technology that:
- can be packaged inside a clean- and sterilise-in-place isolator unit so that dirty vials enter the isolator via a typical washing and hot air steriliser system
- has a dose dispensed and quickly frozen (<30 seconds) onto the vial wall - this dose can be 100% check-weighed inside the system to ensure accuracy of fill with low cost, easily cleaned dosing pumps
- dries the dose inside the vial in a controlled manner where the drying parameters are continuously logged for traceability and consistency
- automatically plugs and caps the vial before the it comes out of the isolator
- requires no operator input and can be located in a normal pharmaceutical production environment, rather than a sterile suite
This technology has demonstrated the highest risk factors to be in control, and that drugs can be lyophilised to typical product requirements. The spinning and freezing arm is shown in figure 3.
Figure 3 - The vials held by the spinning system approach the filling needles
The Continuous Freeze Drying System demonstrates major operating benefits
The system directly attacks the problems associated with the current technology and delivers the following benefits:
- Investment in new facilities is reduced because capacity can be delivered without investment in sterile suites and all the associated expensive engineering services
- Product quality increases because of the elimination of operator handling and the continuous (and traceable) control of drying conditions for each vial, giving:
- Assurance of low risk of particle contamination
- Assurance of low microbiological risk
- Assurance of product consistency throughout the batch of product
- Easy and fast scale-up, the development system is exactly the same process as the production scale unit, but with fewer vials being filled and dried at the same time. All the process conditions optimised in development can be reproduced on the full-scale system.
- The technology is self-contained. It can be shipped to local operations in a pre-validated form and would require minimal engineering resource to convert into operation.
There are many benefits of a secondary nature including more rapid freezing and the possibility of filling the vial headspace with inert gas for unstable drug compounds, better sealing due to use of normal vial plugs and easier automated inspection for particles.
The technology is tested at prototype level
We have demonstrated that the prototype system can easily reproduce product requirements that current technology achieves with some difficulty. We have tested:
- cytotoxins
- proteins (liable to agglomeration)
- growth hormones
- colloidal suspensions
- antibiotics
- anti-virals
- excipients
However, the system is only developed to partial prototype level and substantial further development is necessary before the technology can enter production. The technology offers:
- reduced running costs
- reduced investments
- higher capacity
- higher product quality
- faster process development and scale-up times
Anybody comparing this technology to what they live with today will quickly see the advantage of the novel process.
