Geoff Smith is Reader at Pharmaceutical Technologies Group, Leicester School of Pharmacy, De Montfort University (UK).

Geoff Smith

Freeze-drying, also known as lyophilization, is a process that removes water from a frozen material by sublimation to preserve heat-sensitive materials or to make them more convenient for transportation and handling (1, 2). It is a three-step process, which starts with the pre-freezing of the material, followed by primary drying (i.e., sublimation of ice at reduced pressure) and finally, secondary drying (i.e., removal of adsorbed water at elevated temperature).

The most important objectives for the rational design of freeze-drying processes is to characterize the freezing process (i.e., the nucleation and growth of ice crystals), determine the rate of primary drying (and the dry-layer cake resistance), and assess the end point of primary drying. To achieve these objectives for individual vials within a batch requires the development and implementation of new analytical technology that can provide product and process understanding in the complex environment of low temperature and low pressure that exists within the freeze-drying chamber.

All technologies developed to date for freeze-drying process control are based on physical measurements, such as weight (freeze-drying microbalance), pressure (manometric temperature measurement [MTM]), and temperature (thermocouple), or based on the interaction of light with a material (such as in the case of near infrared spectroscopy [NIRS] and Raman). Despite that, each process analytical technology (PAT) method has inherent limitations in its application to understanding and/or control of the freeze-drying cycle (3). 

There are few examples whereby the measurement of electrical properties is used to provide information about a material during processing (4-6). This approach is in contrast to off-line electrical impedance measurements that are being used routinely to identify critical process events, such as phase transitions (i.e., freezing points and eutectics), against process set points (i.e., shelf temperature, and hence, product temperature during the pre-freezing stage) (7). By investigating the interrelations between the electrical properties and the structural characteristics of the solution, it might be possible to develop this technique towards a more comprehensive monitoring of the freeze-drying process. The development of an in-line technology based on impedance analysis, however, requires:

The close proximity of a least one electrode to the freeze-drying vial to have a chance of sensing any changes in the physical state of the material contained within 
  
  •  The integration of the cabling within the freeze-dryer, which necessitates the creation of a pass-through to the freeze-drying chamber without compromising the vacuum seal
  •  The development of a high-precision, high-impedance dielectric analyzer with a high-phase angle resolution (~ 0.001°) to detect small changes in the dielectric loss (i.e., real part impedance) of the material under test
  •  Careful control over material properties other than those of interest, such as variations in the vial wall thickness, the reproducibility of the electrode design, and the proximity of any attachment mechanisms to the vial. 
  
Through-vial impedance measurements were developed specifically to address these issues. The primary aim for the implementation of this new PAT was to demonstrate the use of impedance spectroscopy in the determination of the rate of primary drying, the end point, and the identification of product collapse. The example of a 3% lactose solution is given.


Aliquots (3 mL) of a lactose solution (3% w/v) were added to the impedance measurement vials and placed on the freeze-dryer shelf among a hexagonal array of plain vials and then connected to the data-acquisition system. For collapse measurements, the impedance measurement vials were arranged on the shelf in a straight line. Photographic images were taken every 3 minutes using a Cannon EOS 550D SLR camera. The impedance measurements were performed over a frequency range of 10-10

. The freeze-drying cycle details are shown in 

Table I: Freeze-drying cycle for collapse measurements.


The impedance technology measures the electrical impedance of the product, contained within a standard freeze-drying vial that has been modified with electrodes placed on the outside of the glass wall (8). The impedance measurement vials connect to a high impedance current to voltage converter (I-to-V converter) by a junction box within the freeze-dryer chamber, mounted close to the shelf on which the vials are located. The signals from the stimulating voltage and the signals from the resultant current from the I-to-V converter are compared to determine the impedance of the measurement vial and its contents (see 

Physical basis for through-vial impedance measurement 


The electrical impedance of a material determines how easily the material will conduct a current when an alternating voltage is applied to it. Electrical impedance is a function of both the dielectric and conductive properties of the material, which are in turn defined by the temperature, composition, and physical state of the material contained within the vial. Changes in these electrical parameters, therefore, directly mirror the condition of the sample and progression of the freeze-drying cycle. The electrical parameter that has the most significant effect on the output from the impedance measurement system is the resistance (or conversely, the conductivity) of the product contained within the glass vial. Conductivity is widely used for the determination of the physical properties of materials in a wide spectrum of applications due to the fact that the measurement technology is relatively inexpensive.

To explain the observed impedance spectrum of the object under test and relate it to the physical properties or changes that may happen during the freeze-drying process, it is necessary to create an appropriate equivalent circuit model. The circuit model (see 

) was found to provide an approximate fit to the measured impedance spectrum, where CPE denotes a contant phase element and models the interfacial capacitance formed between the glass walls of a vial and the solution, which is charged through the resistance (R) representing the conductivity of the sample, and C represents the electrical capacitance of the material within the internal volume of a vial. This interfacial polarization imparts a frequency-dependence to the measured dielectric properties, such that the interfacial capacitance  will have sufficient time to charge completely at low frequency, but at high frequency, it will not have time to begin to accumulate any of the electrical charge that could otherwise be accommodated. 

The overall result is that the capacitance spectrum of the material under test (i.e., the glass vial, its contents, and the electrical connections to the vial) will display a step-like decrease in capacitance as the frequency is increased through that critical frequency that corresponds to the time constant for the sample (f = 1/2πτ, where τ = RC) (see 

). There is a corresponding peak in the associated imaginary capacitance spectrum as the material under test starts to conduct electricity through the phase lag between the response of the sample and the applied electric field (see 

). The step in the real part capacitance and the peak in the imaginary capacitance is known as a pseudo-relaxation process because it has the appearance of a real relaxation process within a material (i.e., one that has a frequency dependent to its dielectric properties owing to some molecular relaxation or some form of interfacial charging within the material). In reality, the dielectric properties of the material within the vial may be static (i.e., invariant with frequency), and one is simply measuring the accumulation of charge at the glass surface as ions migrate through the liquid or solid contained within the glass vial. 

It is the characteristics of this process that are used to “follow” the progression of the freeze-drying cycle. More specifically, it is the peak frequency and peak value for the imaginary capacitance (which can be considered as the magnitude of the pseudo relaxation process) that is used to monitor the freeze-drying cycle. 

 shows a typical surface plot of the imaginary capacitance as a function of frequency and time during the entire freeze-drying cycle. There are characteristic shifts in the relaxation frequency and change in the peak height as the temperature of the sample changes and when the material undergoes a phase change, for example, from liquid to ice. There is then a dramatic decrease in the magnitude of the pseudo-relaxation peak as ice is removed from the sample.

To track these transitions in greater detail, each impedance spectrum was analyzed with the data-viewing software that runs a peak-finding algorithm and displays the data in a variety of formats including peak frequency (

), and a time slice at a particular frequency. When the sample is in the liquid state (i.e., low electrical resistance/high conductivity), the time constant is relatively short and so the pseudo-relaxation peak occurs at high frequency. Conversely, when the sample is in the solid (i.e., frozen) state, the time constant deceases by a factor of ~100 and the pseudo-relaxation peaks shifts to a lower frequency by approximately two orders of magnitude (see 

 profile (see Figure 3b) effectively describes the freezing stage of lyophilization process because the product resistance is changing, both with the temperature and phase state of the liquid. The frequency position of the pseudo-relaxation peak decreases during cooling, then spikes following the onset of ice nucleation because of the sudden increase in temperature due to exothermic ice formation. It then decreases during the solidification and temperature equilibration phase. On either side of the phase transition, the frequency of the peak is strongly coupled to the temperature of the product at the specific time point suggesting a potential application as a non-invasive surrogate temperature probe.

The sublimation phase is studied by analyzing the peak amplitude of the imaginary capacitance (

with time signifies the progressive removal of ice during the primary drying step (

). The time-derivative profile of capacitance at 1 kHz provides an estimate for the sublimation rate, which peaks at 15 h and subsequently decreases due to higher dry-layer resistance (see 

). The data illustrate how the impact of different parameters on the dry-layer resistance can be studied on a single vial, including solute concentrations, freezing rate, annealing temperatures, and hold time. Compared with gravimetric techniques, development scientists may prefer this technology for determining sublimation rates because it permits the positioning of the vials on the shelf in the hexagonal arrays and does not require the persistent perturbation in the heat flow associated with the lifting and weighing of the vial. 

, there are minimal changes in the peak frequency, and hence, time constant (τ) during primary drying (see 

). These observations can be explained in terms of the height of the ice layer across the sensing zone between the electrodes during primary drying. Both the dry layer and the ice layer are modelled as two separate series RC circuits in parallel with each other (see 

). Given the higher dielectric constant and lower resistivity of the ice layer, the impedance of the two layers can be considered simply in terms of the impedance of the ice layer. In effect, the dry-layer impedance can be ignored. The interfacial capacitance (CPE) of the ice layer/glass interface is proportional to its effective area (A) contacting the electrode (CPE α A), whereas the resistance (R) of the ice layer is inversely proportional to the contact area. It follows that as the height (h) of the ice layer decreases, the resistance of the layer decreases as a function of 1/h, whereas the interfacial capacitance decreases in proportion to h. The time constant (τ = RC), and hence, 

, remains approximately constant over the entire primary drying stage but the magnitude of the peak decreases in proportion to the height of the ice layer (h). 

During the last stage of primary drying, the spectra exhibit a certain degree of low frequency noise. At this point (> 20 h), the data-analysis software begins to “locate” the peak at a progressively lower frequency. These uncertainties preclude the use of the pseudo-relaxation peak in determining the end point of the primary-drying phase. While the peak-versus-time profiles are of value in the measurement of temperature changes and in characterizing the various stages of the freezing step, an alternative approach is required for the determination of the end point of primary drying. This alternative approach is to examine the logarithm of the time slice of the capacitance derivative at 1 kHz, which is the predominant position of the pseudo-relaxation peak during primary drying. It has been shown that the alternative approach provides acceptable information regarding the measurement of the end point of sublimation. This is illustrated in Figure 3d, in which the end point of primary drying can be observed from the sharp decrease at approximately 27 h. 


During sublimation, the time derivative of the capacitance increases to a maximum and then decreases to zero (see

), the increase in shelf temperature at 5 h into the primary-drying cycle results in an increase in product temperature and an increase in drying rate. The increased drying rate is evident from the inflection in the dC”/dt plot (left hand vertical line on 

). However, as the temperature rises further, it reaches critical levels, whereby the viscosity of the glassy matrix has decreased to such an extent that its walls are unable to support its structure. At this point, the product is seen to collapse (see 

), and there is a small spike in dC”/dt as the product at the sublimation front loses its integrity. Photographic evidence of the product collapse were found to correlate well with the occurrence of this small spike. In the later stages, the softened mass at the sublimation front merges to produce wider pores that result in higher sublimation rates, which is reflected in the further increase in dC”/dt.

Articles

A new process analytical technology based on impedance spectroscopy has potential applications for characterizing product attributes during the freeze-drying process.

Through-Vial Impedance Spectroscopy: A New In-Line Process Analytical Technology for Freeze Drying

The pharma industry traditionally utilises batchbased manufacturing methods because of traceability requirements to ensure product safety. After several years of establishing new ways of analysing drug variability and quality in various manufacturing process stages (under the PAT initiative), the industry is moving away from conventional batch sampling and analysis to embrace more advanced techniques that analyse consistency in real time. The challenge now is for the industry to take this QbD concept and look at its manufacturing processes in lean terms to adapt for a more efficient future. 

Tablet manufacture is traditionally a batch-based wet granulation process. Dry granulation, on the other hand, can be used as a semibatch process but could also emerge as one of the main continuous processing solutions due to its simplicity. There are other forms of dry granulation, but the most commonly used is roller compaction, which is a continuous technology by design that has been significantly further developed in recent years. In particular, a number of important changes have been made that differentiate novel technologies from conventional roller compactors (

 Sidebar 1: Key advances made by new roller compaction systems  

Combined with PAT techniques, roller compaction can help achieve a continuous granulation process. Depending on the objectives and site PAT strategy, measurements prior to the process can be taken to establish raw material consistency and blend uniformity. Essentially, this will enable a consistent processing window with established boundary limits to be achieved. 

 provides an example of PAT analysis data based on the measurement of terahertz wave forms, which are reflected from pharmaceutical roller compactions of various densities. The example demonstrates the potential for the technique as an in-line technology to analyse critical material attributes of compacted ribbons prior to milling to establish increased process understanding. 

Sidebar 2: Terahertz pulsed imaging of pharmaceutical compacts  

Wet granulation requires various quality stages, including materials quarantined, sampled and analysed prior to release. Because of this, equipment asset utilisation is inherently low; cleaning time and costs are substantial; and in-train material, capital equipment cost, building costs and energy consumption costs are all high.  

Dry granulation also has its disadvantages, some of which are shared with direct compression to a degree. One of the main drawbacks is challenging formulation because of the physical characteristics of a particular API; for example, it may be cohesive with poor flowability, or have a low bulk density and be difficult to contain and feed, or it could be micronised and very fast flowing. Feeding dry powders and avoiding segregation is challenging, requiring helical feed screws called augers. If a product is considered cohesive or 'fluffy' because of its low bulk density then filling the auger is difficult. If it is not possible to fill the auger screw consistently, then compaction is not possible because of density variation at best, and no feed at worst.  

At the other end of the scale, fast flowing materials can escape through the feed rollers, leading to a very high number of uncompacting fines that require re-compaction or a recycling system. It is sometimes possible to overcome these difficulties by adding specialist excipients or additives, but these can be costly. 

Developing a suitable formulation that balances drug bioavailability with the ability to efficiently process on a realistic cost basis when additives are required has proven difficult with dry granulation. To overcome these issues, many formulation developers turned to wet granulation and fluid bed drying. Despite its initial drawbacks, dry granulation offers a number of benefits over wet granulation including: 

a simpler, shorter process with increased flexibility

reduced quality assurance and validation costs

The details of some of these benefits are explained in more detail below.  

A typical dry granulation process line consists of an IBC dry blending stage that would feed into the compactor. After the compactor, the granules would be collected into an IBC and be fed directly into the tablet press, or possibly re-blended in the IBC with a tabletting lubricant and then discharged into the tablet press.  

A conventional wet granulation line typically requires more equipment and technology compared with a dry granulation roller compaction system. This additional equipment will probably include a liquid dispensary, wet granulator high shear mixer, wet mill and transfer system, fluid bed dryer, dry mill and transfer system, larger IBC handling system, automated IBC cleaning and an integrated computer control system. 

Dry granulation also offers benefits when it comes to commissioning. Typically, a wet granulation suite will take 3–6 months to commission, validate and qualify. This is because there are many individual machines and control systems to qualify, or a large complex and bespoke integrated control system for the whole granulation suite. A roller compactor, however, will often fit into an existing standard process room as a self-contained machine with a standard control system. It can be operational in a week, and validated and qualified within three weeks.  

Process plant designs and configurations for both roller compaction and wet granulation will depend on the process need (e.g., larger dedicated campaigns or multi-product, small flexible campaigns). A roller compaction installation can be adapted, so is flexible for future changes in demands. A wet granulation line is, however, invariably fixed as an integral part of the building, requiring significant safety considerations and almost always multilevel building structural integration making it inflexible. 

Batch size flexibility is also challenging to achieve with a high shear mixer or a fluid bed dryer and the associated large IBC configuration. The working volumes are relatively fixed at the time of design and purchase, limiting flexibility to the number of batches that can be produced rather than a flexible batch size. Typically, a wet granulation line will produce 1–2 batches per shift, requiring cleaning after about six batches, depending on the product. Roller compaction systems are available that do not have filter cleaning requirements, potentially enabling them to run 24/7 for weeks on end.  

The dispensing of raw materials and dry blending of powders prior to compaction for batchbased processing essentially remains unchanged for campaignbased dry granulation. Should true continuous processing be adopted, then further efficiency improvements can be achieved by automated dispensing and continuous blending, which eliminates more intermediate processing steps and product handling; however, this is subject to the development of a suitable quality and validation strategy to monitor the feeding system and blending technology to ensure blend uniformity. 

Assuming that the dry blending process remains unchanged (i.e., an IBC dry blend is performed), the main process of feeding the roller compactor, from powders arriving at the infeed hopper until discharged as a finished granule, takes only a few minutes.  

Wet granulation typically requires five or more process steps and can take 60–80 min. The process can also result in yield losses due to high shear granulation residue, fluid bed filter and bowl product retention, and vacuum transfer losses. Yield losses may also occur in continuous processing 

roller compaction during process start up and close down; however, technologies are available that can mitigate this issue by creating an immediate stable, steady state process.  

Establishing a stable and repeatable process with conventional wet granulation is often deemed more of an art than a science.

  Although this is achievable in production, it requires a high degree of quality control, highly skilled and experienced operators, and a good control system because of the variability that can occur with large volumes of materials; for instance, variable air flow patterns, moisture content, particle sizes and agglomeration. With dry granulation, the volume of product being 'acted on' at any moment of time is constant and is in grams rather than hundreds of kilograms. The compaction process starts as the product is drawn into the compaction rollers — this is a precompression stage that continues to gradually increase the pressure on the product until it reaches the central point between the rollers, called the roller gap. At this point the product is compacted and has formed a ribbon. This is a very short process in terms of time and surface area with compression force only being applied to a small volume of material at any given moment in time, which is a significant QbD difference. 

A wet granulation line typically has 15 to 20 variable critical control parameters, creating a substantial amount of validation and critical control activities. With roller compaction, quality assurance only needs to focus on a single process, and there is a much smaller number of control parameters that are process critical.

Being able to define and control the process is important because it enables developers to predict and establish the correct parameters for scaleup. Roller compactors also offer substantial cost and time savings for this transition because the process conditions that act on the product are exactly the same on both large production and small scale development machines. In fact, scaleup from the laboratory to production can take place the following day. 

Sustainability is now a key focus of the industry, but most activity in this area is directed at the energy savings and carbon footprint of a new facility rather than internal manufacturing processes. According to our research, adopting dry granulation methods can reduce the size of GMP processing areas, from approximately 80 m

  using wet granulation equipment to 10 m

  with dry granulation. Typically, up to 70% of a pharma site's energy costs can be attributed to HVAC so process design footprint requirements have a direct impact on energy consumption.  

Reducing the amount of required process equipment, process steps and product contact surfaces will also significantly reduce the cleaning burden in terms of water supply requirements, water supply capacity and purified water demand, as well as the use of detergents and surfactants. Some roller compactors also incorporate high-efficiency cleaning design and high-pressure lowflow water, which in most cases negates the need for detergents and minimises water effluent disposal.  

Roller compaction technology has been used for many years, but up-to-date technology, good process understanding and user familiarity are key to successful process development. Moreover, roller compaction could be the key to achieving a continuous granulation process. Over the next decade, the industry will adopt continuous processing for many products at many production sites. The technology is already well suited to meet this shift; if a product can be tabletted it can usually be roller compacted, although sophisticated roller compaction systems will be required for more complex formulations and challenging APIs. Whereas the auger system may assist in homogenisation in some cases, it is essential that blend content uniformity is established prior to feeding the machine. Establishing a design space for the product is also important to optimise final granule density and particle size distribution

  for achieving optimum tablet press performance. 

The authors acknowledge the support of Gerteis Maschinen & Process engineering AG (Switzerland), and Alex Well from De Montfort University (UK) for the TPI images of pharmaceutical compacts 

is Reader at Pharmaceutical Technologies Group, Leicester School of Pharmacy, De Montfort University (UK). 

et al., Journal of Pharmacy and Pharmacology

Although tablet manufacture is traditionally a batchbased wet granulation process, there are many advantages to be gained by adopting dry granulation, including lower costs and increased yields.