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Moisture analysis

Europe | Manufacturing | Measurement+Analysis | Regulatory


Abstract

How Biopharma Technology is using laser-based headspace moisture analysis for moisture
determination

Fig. 1: Freeze-dried vials
Freelance Sarah Webster describes how Biopharma Technology is using laser-based
headspace moisture analysis for rapid and non-destructive moisture determination of freeze-
dried pharmaceutical products
Moisture analysis is a fundamental aspect of the complete freeze-drying process to ensure the
system is efficient and performing as it should. Consequently, moisture analysis is performed in
both product and process development, as well as in manufacturing to specify and control the
maximum allowable moisture content.
Replacing the slow traditional methods, such as Karl Fischer titration (KF) and thermo-
gravimetric analysis (TGA) with a rapid, non-destructive method would streamline moisture
analysis efforts and help improve the quality of the finished product.
Capitalising on the development of an instrument that uses frequency modulation spectroscopy
(FMS) to perform laser-based headspace inspection as a rapid method to analyse and inspect the
moisture in a finished drug product,
1
Biopharma Technology (BTL) has carried out extensive
testing of the FMS method on freeze-dried materials.
Industry applications of headspace moisture analysis include freeze-drying cycle optimisation,
lyo-chamber moisture distribution mapping and complete-batch moisture inspection of
commercial freeze-dried products. Headspace moisture analysis has the potential to be a new
primary method for lyo-moisture determination that is both rapid and non-destructive.
Freeze-drying is a well-established and standard process in the pharmaceutical industry to
stabilise drug products, with associated benefits (increase in shelf life, ease of transport, fewer
temperature controls). There are three main stages in the freeze-drying process: freezing, primary
drying and secondary drying. If inefficiencies occur at any stage, the moisture content and active
viability in the finished product could be compromised.

Fig. 2: Moisture map demonstrating variability in moisture content in the same batch (units of
moisture measured in torr)
For example, the moisture map shown in Figure 2 demonstrates the variability of moisture
content when a process is changed, showing a set of samples placed on a tray in the freeze-dryer
rather than in direct contact with the shelf.
Freeze-drying process variables include:
1. Degree of shelf contact
Container geometry (tray, vial, stopper)
Differences in container shelf contact (e.g. due to warping of trays, uneven vial base)
2. Efficiency of heat transfer conduction and convection, container material
3. Drying rate variations due to product temperature differences, resulting from:
Shelf temperature variation (ramp, hold)
Radiative heating effects (various patterns e.g. related to door, positioning of
condenser)
Flat spots in chamber pressure (particularly if insufficient shelf spacing)
Annealed or non-annealed ice crystal size, pathways for vapour to escape
4. Process parameters used (shelf temperature and chamber pressure)
5. Cooling and re-warming rates/capacity
6. Condenser trapping rate
Variables also arise from the excipients/active material due to:
7. The nature of the formulation itself
Format (solution, suspension, pellets, etc)
Ingredients individual and combined behaviour and material type/structure e.g.
amorphous or crystalline.
Successful freeze-drying relies on choosing suitable components for the formulation and
establishing the critical temperatures for the product. It is important to understand fully the
reasons for moisture variation due to processing and material choices. This understanding can
assist in validation and in assessing any changes made based on results of moisture analysis.
Moisture analysis following freeze-drying needs to be fast and accurate, particularly for the often
expensive, complex and lengthy procedure of pharma manufacture. Residual product moisture
content is critical when considering the stability, shelf life and storage temperature of lyophilised
pharmaceutical product.
Stability studies have shown that the degradation of the API correlates to the initial water vapour
concentration present in the freeze-dried vial. This means that the moisture analysis performed in
product and process development, as well as in commercial manufacturing, is vital in specifying
and controlling the maximum allowable moisture content to ensure the quality of the finished
product.
Water content also affects the Tg of amorphous materials (the Tg is the point at which a material
can be observed to undergo structural change), which could further affect stability and long term
storage temperature.
Moisture analysis is traditionally performed using KF titration or TGA methods, which are time
consuming, involve chemical reagents and, critically, destroy the sample. Furthermore, KF
titration and TGA do not distinguish between active water and bound water. Water is present in a
lyophilised cake in a variety of forms (including free, adsorbed, chemically bound and water of
crystallisation) and not all of these are linked to product stability through degradation of
excipients and active ingredients. Generally, free or active water is available for chemical
reaction and has the greatest impact on product stability.
Replacing these slow traditional methods with a rapid, non-destructive method could streamline
moisture analysis and help improve the quality of finished product.
Under the guidance of Isobel Cook, principal research scientist at BTL, a headspace moisture
analysis method has been investigated. As a rapid and non-destructive method, it could be an
ideal tool to characterise lyophilisation cycle efficiency and freeze-dryer performance across
shelves, between shelves and as a function of drying cycle parameters. The method may also be
suitable for performing moisture inspection of 100% of the finished product and even monitoring
moisture content of individual vials over the entire shelf life.
The headspace moisture analysis method being investigated by BTL uses FMS. This involves
passing a laser light through the vial headspace; the laser is tuned to the absorption wavelength
of the water molecule and the absorption signal analysed to determine the headspace vapour
pressure. The vial headspace vapour pressure can allow determination of the moisture content of
a lyophilised cake by performing a correlation between FMS and KF using a set of samples with
moisture ranging from below the target moisture level to 150% above the specification.
2

Experiments have also demonstrated that the amount of headspace water vapour can be directly
correlated to levels of drug product stability.
2


Fig. 3: Diagram of FMS shows path of laser through vial
As mentioned above, one of the most important benefits of headspace moisture analysis is the
ability to test entire batches. This can provide insight into the efficiency of the drying process
and the dynamics of freeze-drying in different locations within the freeze-dryer. In addition,
quality control groups would benefit from being able to non-destructively sample a statistically
significant number of finished product vials as part of a release test as well as monitoring
individual vials repeatedly over the product shelf life.
Finally, 100% moisture inspection of finished vials would guarantee the quality of finished
product with respect to stability against moisture.
FMS is a high sensitivity laser absorption technique. The laser is tuned to match the internal
water absorption frequency at 1,400nm; the amount of laser light absorbed is proportional to the
water vapour concentration. Analysis time is around 5 seconds per vial, is non-destructive (the
same vial can be monitored over time) and enables complete batch inspection.
Diode laser-based systems can be configured in a variety of ways to monitor and control
processes and/or inspect individual containers for headspace oxygen, moisture or vacuum. The
two basic configurations include bench-top systems for use off- or at-line and fully automated
systems for 100% monitoring, control and inspection.

Fig. 4: The instrument used the FMS-1400 from Lighthouse Instruments
In summary, headspace moisture analysis based on FMS can be used as a method to further our
understanding of the factors involved in obtaining uniform moisture content and to control the
quality of finished product.
Data has shown that even for an apparently well-developed lyophilisation cycle a number of
random vials may occur with out-of-specification moisture content. The only way to identify
those random out-of-specification vials is to perform moisture inspection across the entire batch.
Once headspace moisture studies have been more thoroughly investigated and understood, this
method could be applied to the non-intrusive and rapid analysis allowing the monitoring of large
production batches, ideally on a 100% inspection basis.
FMS can also be used in conjunction with KF analysis to assist in fast and efficient analysis of a
large number of samples and to yield important information about the freeze-dried product,
namely enabling the elucidation of the location and dynamics of water present in lyophilised
cakes. It is also possible to investigate changes within a series of samples and assess how they
are related to amorphous/crystalline changes, as well as headspace moisture resulting from vial
stoppers and temperature effects.
Any in-depth moisture study surrounding freeze-dried products demonstrates the complexities
involved in understanding the nature of the water present in lyophilised products and
establishes the importance of gaining a thorough understanding of the excipients, the various
process conditions, temperature, storage and stopper properties in order to understand and
evaluate results for repeatable and accurate FMS analysis.
Further temperature and headspace moisture studies are warranted to increase understanding of
the location and dynamics of the water within the system. Once constant parameters have been
established and temperature tightly controlled, chemical and physical changes could be more
accurately monitored and predicted over time. However, initial results indicate that rapid
moisture determination with headspace analysis using FMS could replace the slow and
destructive traditional methods for the moisture analysis of freeze-dried products.
References
1. Cook, I., Ward, K. and Duncan, D. (2008) Freeze dried cakes Where is the water?,
Conference on Freeze Drying of Pharmaceuticals and Biologicals Breckenridge, Colorado,
August.
2. Peeters, M., (2006) Results FMS vs KF Analysis, Lighthouse Instruments European User
Symposium June.
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