(JANIS CHRISTIE/GETTY IMAGES)
The production of lyophilised medicinal products raises many challenges, including identifying critical temperatures, ensuring
that the product is processed accordingly, optimising cycles to reduce run times and manufacturing costs, making sure the
right containers are used and fit for purpose, and ensuring product uniformity, activity and stability.
In the past few years, theories and practices in lyophilisation technology have largely remained the same except for small
incremental changes, which means that the process as a whole tends to evolve slowly over time. Extensive research is still
being conducted to produce a reliable and easy-to-implement endpoint identification method, negating the need for pressure
rise tests or temperature probe monitoring. However, several processes and products have recently come on to the market that
may benefit the pharma industry.
One recent innovation is Praxair's Control Lyo Nucleation technology, which allows the freezing point of solutions in freeze
dryers to be precisely controlled. Generally, solutions are cooled to below their critical temperature before primary drying
is commenced, but the freezing point of different vials can be somewhat random resulting in a non-uniform ice structure, which
introduces variability in the drying rate. Praxair's solution could increase control of the process to decrease moisture variability
within the product, leading to narrower moisture ranges and potentially reducing the secondary drying time required to achieve
acceptable product quality.
Other developments have come onto the market in terms of packaging; Lyoseal technology (Biocorp) enables vials to be stoppered
and crimped within the freeze dryer, potentially saving capping time and helping to ensure container seal integrity. Improvements
in glass design, geometry and surface coatings have also helped to reduce vial breakage and cycle times; for example, Easy
Lyo (SGD) vials are 30% lighter than traditional vials, and therefore feature improved heat transfer to reduce cycle times.
Top Lyo (Adelphi) vials have an ultra-thin hydrophobic transparent layer (40-100 nm) on the internal surface of the vial that
helps prevent the collapse of the lyophilisation cake and can almost completely reduce the residual volume. Enhanced vial
geometry also provides improved thermal transfer and a dramatic reduction in vial breakage during lyophilisation. There are
also products coming onto the market that enable remote temperature probe monitoring.
These products are relatively new and have yet to be widely used, but all offer potential advantages to the pharma industry
in terms of product quality and cost.
The bio challenge
The challenges of lyophilising bio-based products mainly relate to the identification of critical temperatures and product
behaviour during the drying process. Freeze-drying microscopy (Lyostat3; Biopharma Technology) can be used to measure collapse
or eutectic temperature and identify skin formation potential (which may prevent or slow the drying process), while the polarised
light application can enable visual observation of the degree of crystallinity within a sample. Differential thermal analysis
and impedance analysis (Lyotherm2; Biopharma Technology) enables the identification of glass transitions, crystallisation
and changes in structural mobility. Modulated differential scanning calorimetry (MDSC) analysis (TA Instruments) can also
provide information on the frozen state and dried product stability.
As well as the initial characterisation of the active ingredient, bio-based entities require appropriate formulation to protect
them from freezing- or drying-induced damage. With proteins, it is important to prevent the molecule from unfolding (from
which it can often not recover), which may, for example, require certain sugars to protect it whilst the water is being removed.
Prokaryotic or eukaryotic cells may demand certain freezing rates or special processes to prevent cell breakage. Naturally-derived
products can be particularly challenging because of their inherent variability; robustness needs to be built into the formulation
and lyophilisation-cycle. Certain products, such as collagen, may also require the production of a consistent, specific pore
size and shape to be effective. It is also important to ensure that the dried-state storage temperature is practical for the
product being developed because this affects how long the product can be stored and what storage temperatures are required.
Careful analysis and monitoring of the whole lyophilisation process is crucial to achieve the correct product parameters.
This can involve monitoring the product temperature during drying, pressure rise tests or a capacitance manometer and pirani
gauge. In addition, moisture analysis of samples (moisture is critical to product stability) should be performed along with
stability/activity analysis relevant to the product. These activities, as well as characterisation of the frozen state prior
to freeze drying, are important to ensure product quality.