Lyophilization: An ever-evolving technology
Posted: 23 May 2006 | | No comments yet
Almost 60 years have elapsed since freeze-drying/lyophilization was introduced on an industrial scale. Developed initially for the rapid delivery of human blood plasma on the World’s battle fields, lyophilization gained its credentials with the massive production of penicillin under the guidance of the late Nobel Laureate Sir Ernst Boris Chain.
Antibiotics, blood derivatives, steroids, hormones, tissue extracts and vaccines with Charles Merieux, a very large spectrum of delicate products – mostly unstable at room temperature in the liquid form – were further stabilised, stored and distributed worldwide as powders or porous cakes after careful drying from the frozen state. Even plastic and reconstructive surgery applied to freeze-drying for the preparation of stable bones, fascia, or skin to be used as grafts or dressings on injured limbs or extended burns.
At the same time, lyophilization was employed to prepare more delicate tissues such as corneas or small organ fragments for optical and electron microscopy. Even the intimate structure of isolated human and animal cells, bacteria or viruses, could be studied at high magnification thanks to gold replicas of their freeze-dried surface, etched for only a few microns.
In parallel, the rather primitive equipment of the early pioneers was progressively replaced by sophisticated instruments, geared with automatic and electronically-monitored systems across a wide range of sizes (from a few mm3 to hundreds of thousands of vials) and an equally large temperature and vacuum span. Needless to say, all of them did not meet success and drove many start-ups into bankruptcy: but, with the rising demand and pressure of the pharmaceutical industry, some equipment builders did succeed in offering reliable materials that ensured stable production for 10 to 20 years.
At that point, it could be claimed that nothing more is needed and that lyophilization is now on a steady stream since most technical, economical and compliance requirements look to be fulfilled to satisfaction.
This, however, is not the case and the freeze-drying community is still in search of new developments, new performances and more diverse fields of application.
On the technical side, some recurrent and disturbing problems still exist.
Loading of large cabinets is a difficult and time-consuming issue. This is even more prevalent when the processed products are of the hazardous type, such as oncolytic drugs, since all operations must then be carried in a remote way under isolators.
Securing homogenous drying in a multi-shelf chamber, holding tens to hundreds of thousands of small vials, is not yet a routine procedure. Remote controls are not easy to perform on those vials ‘buried’ in the depth of the equipment, since we operate at low temperatures and under vacuum.
Nearly all processes developed so far – differential pressure gauges, measurements or analyses of the gas phase to follow and track water vapour – are ‘global’ irrespective of the method used: condensation point, mass spectrometry, plasma generation. Nevertheless, the overriding question of residual moisture still exists since we know that every product has its own requirements. Too high or too low is not adequate and, with a batch of 100,000 units, it is clear that we should expect significant differences from one sample to another. Will they remain within the allowed limits?
The development of very active new products (for example, botulinum toxin) makes it compulsory to add bulking agents which are in no particular need for therapeutic purposes and are more a hindrance than a help. The possibility to adsorb the active substance on an inert porous matrix could be one way out provided, of course, that it can be freed again when extracted by the reconstitution fluid and that it does not simultaneously release undesirable particles. Some interesting developments are presently being carried out in that field and may lead to new presentations where the supporting matrix holding the dispersed freeze-dried product can be associated with a syringe-type unit containing already the dissolution liquid.
Sterility of the whole process is another issue that can pose problems, in line with the increasingly demanding requirements of compliance officers. In such a complex procedure as freeze-drying – and as it is clearly delineated into the F.D.A. “Guide to inspections of lyophilization of parenterals” – no less than seven successive steps have to be monitored and controlled to manufacture a sterile freeze-dried injectable. Each of them bears its own hazards and produces its own cost in manufacturing installations, equipment, staff training and control.
Here again, this nightmare can, sometimes, be overcome by resorting to a final sterilisation step by irradiation, as we proposed in European Pharmaceutical Review two years ago. It is not, however, a panacea and some products definitely do not stand radiation treatment, but it may solve numerous issues and appears to be a full-proof process since it is purely parametric.
In that wake, it may be of interest to consider whether the popular concept of PAT (Process Analytical Technology) can be applied to freeze-drying. In a way it looks rather attractive and there are, definitely, a certain number of steps in the process where it can easily be introduced: filling, loading, unloading and capping. But what can be done within the vacuum chamber? How can we control each and every vial inside, other than by a ‘global’ measurement which only ear-marks the ‘bad pupils’ or by sequenced extraction of a few vials, in the course of drying, with the obvious risk that they are not representative of the whole batch?
Here, again, we would like to revert to our 2004 proposal and suggest that the pharmaceutical industry indulges more time and thinking into the possibility of developing a truly continuous process. Then, the equipment being continuously fed with frozen calibrated particles, which are individually dried in a moving fluidised bed, extracted at the end through a rotating lock and finally filled by the number in clean, sterile, dry vials. Then, yes, we can think of introducing a PAT-type control on the whole freeze-drying process. To prepare a large amount of almost identical vials having an individual remote residual moisture control and filled with a strictly equal amount of dried sister particles, would no longer be a dream.
Much work must still be done, especially if we consider the great opportunities offered by mineral and organic solvents in freeze-drying (water-ice is not the only chemical susceptible to sublimate). We do believe in this search and hope that the regulatory and compliance authorities will enter the game and help us to find decent solutions to safeguard human health, without selecting the more stringent ones. A product that we cannot offer to the physicians (due to unrealistic constraints on manufacturing or clinical testing) is of no use for anyone and definitely not for those who are bound to die because it was not available.