There are many types of pressure transducers, and a review of all of them is beyond the scope of this article. We focus on two types—thermal conductivity-type sensors and the capacitance manometer. Both types are commonly used in pharmaceutical freeze drying, but are often not applied in the most useful way.
Thermal Conductivity-Type Gauge
There are two basic types of thermal conductivity-type pressure gauge—a thermocouple gauge and a Pirani gauge. The thermocouple gauge consists of a thermocouple spot-welded to a heated filament. The filament, fed by a constant current, reaches a temperature determined by the rate of energy loss from the filament by a combination of thermal radiation and conduction through the process gas. Energy loss by thermal radiation is kept small by using a filament with a low thermal emissivity, such as platinum. The higher the pressure in the system, the more rapid the rate of energy loss from the filament. The output of this gauge is very non-linear, and the useful pressure range is rather small—only about 2 orders of magnitude. Thermocouple pressure gauges are usually found on the less expensive laboratory-scale freeze dryers.
In the Pirani gauge, two filaments are used as the two “arms” of a Wheatstone bridge. One filament is the reference filament, maintained at constant pressure and gas phase composition. The other filament is the measurement filament. In the Pirani gauge, the filament temperature is controlled at a constant value, and the current needed to do so is monitored. A Pirani gauge has about 100 times the useful range of a thermocouple gauge, and is thus the preferred thermal conductivity-type instrument for freeze drying.
An important characteristic of any thermal conductivity-type gauge is that the response is a function of the composition of the vapor phase being monitored. This is important in freeze drying because the composition of the gas phase in the chamber changes dramatically, from being essentially 100% water vapor during the primary drying phase to essentially 100% nitrogen (or whatever gas is being bled into the chamber to control pressure) late in secondary drying. The free molecular conductivity of water vapor is about 60% higher than the free molecular conductivity of nitrogen (6). This characteristic can be used to our advantage as a process monitoring tool, explained below.
It is important to keep in mind that thermal conductivity-type gauges use a hot filament. This brings up a safety concern when freeze drying formulations containing an organic solvent, such as t-butanol. In order for an explosion to take place, two criteria must be met: (1) there must be a high enough concentration of organic solvent to ignite, and (2) there must be enough oxygen present to support combustion (7). Neither criterion is met during primary drying. It appears that the time period of greatest safety risk is during the initial vacuum pull-down, where there may be a relatively high concentration of organic solvent and enough oxygen to support combustion. Because of this risk, it is considered best practice to turn off thermal conductivity-type gauges when freeze drying products containing an organic solvent. Alternatively, the product chamber could be flushed with nitrogen prior to starting freezing.
It is important to be aware that different Pirani gauges vary in their robustness to repeated steam sterilization. We are aware of no controlled studies to determine the mechanism of failure. Possible modes of failure could be overpressurization (the upper pressure limit for most Pirani gauges is about 1000 Torr) or exposure to excessively high temperature. However, it is likely that the ability to withstand repeated steam sterilization has more to do with the composition of the filament. Several filament compositions are used, including tungsten/rhenium, platinum/iridium, platinum/rhodium, platinum, and gold-plated tungsten. One of the co-authors (PC) has tested a gauge designed for corrosive environments. This gauge uses a platinum/iridium filament, and was demonstrated to withstand 80–100 steam sterilization cycles. This gauge has still not failed, although it is steam sterilized less frequently. In contrast, he tested another gauge, which uses a gold-plated tungsten filament. This gauge failed after two or three sterilization cycles. It is probably wise to assume that a Pirani gauge will fail at some point and require replacement, but it is important to be careful in selection of the gauge.
The Capacitance Manometer
All capacitance-based gauges work in one of two ways—either by keeping the geometry of the system constant and allowing the dielectric constant to vary, or by a variable geometry with a constant dielectric constant. The later mechanism is the basis for the capacitance manometer pressure gauge. There are two sides of the transducer—a reference side that is evacuated, and sealed, at a very low pressure of around 10−7 Torr, and a measurement side that is exposed to the process. The sides are isolated by a metal diaphragm, typically Inconel, a high quality stainless steel. As the process pressure changes, the diaphragm flexes, changing the geometry, and therefore the capacitance, of the instrument. Capacitance manometers are the instrument of choice for pharmaceutical freeze drying because of their wide useful range (about four orders of magnitude), accuracy, stability, and linearity. Another compelling feature is that a capacitance manometer measures true pressure—force per unit area—independent of gas phase composition. It is best practice to use a heated transducer in order to avoid the possibility of water vapor condensation inside the gauge, perhaps from steam sterilization, and to avoid the potential for zero drift caused by variation in ambient temperature.
In our opinion, best practice for monitoring the pressure in the chamber and condenser of a freeze dryer is to have both a capacitance manometer and a Pirani gauge on both the chamber and the condenser. This configuration enables what has come to be called comparative pressure measurement. In this process analytical method, the chamber pressure is monitored and controlled using the capacitance manometer. Simultaneously, pressure is monitored using the Pirani gauge. This technique takes advantage of the gas phase composition dependence of the Pirani gauge, where the change in output of the gauge reflects the change in gas phase composition as the process transitions from primary drying to secondary drying. An example of this type of process data is shown in Fig. 6.
The higher apparent pressure during primary drying as measured by the Pirani gauge reflects the higher thermal conductivity of water vapor, which makes up nearly all of the vapor phase in the chamber during primary drying. As sublimation of ice is completed, the apparent chamber pressure drops. The width of the transition region from pseudo steady state during primary drying to equilibration with the capacitance manometer is a measure of the vial-to-vial consistency in primary drying rate—the more uniform the vial-to-vial sublimation rate, the sharper the apparent pressure drop during the transition. For example, the “edge effect,” where vials at the edge of an array of vials dry faster than the vials in the center of an array, would be reflected in a more gradual decrease in apparent pressure at the end of primary drying. It is considered good practice to wait until the Pirani reading has nearly reached the capacitance manometer reading before increasing the shelf temperature for secondary drying. In general, a difference in pressure readings of from 5 to 10 mT seems to work well as long as the steady-state pressure during primary drying is more than about 40 mT. Some freeze dryer manufacturers offer the very useful option of sequencing the cycle from primary to secondary drying based on the difference in apparent pressure between the capacitance manometer and the Pirani gauge.
The main advantage of comparative pressure measurement is that it does not depend on monitoring of individual product vials but rather the composition of the vapor phase in the chamber. The technique has proven to be sensitive, reliable, and robust. One note of caution is that if any vials should fall from the shelf to the bottom of the dryer, thus drying at a non-representative rate, these vials can “fool” the Pirani gauge and give an abnormal response.
As shown in Fig. 6, comparative pressure measurement is also useful for monitoring the progress of secondary drying. Typically, there is a “burst” of water vapor from the product early in secondary drying as unfrozen water from the formulation is released at higher product temperatures. As the Pirani reading returns to the capacitance manometer reading, very little additional drying takes place at that shelf temperature. It appears that the only significant process variable during secondary drying is the shelf temperature, as previously reported by Pikal and co-workers (8).
It is best practice to control chamber pressure based on the capacitance manometer, simply because it measures true pressure, independently of vapor phase composition. A capacitance manometer is more accurate, more linear, and more stable than a Pirani gauge. Some operations carry out pressure control based on the Pirani gauge, and detect the end point of primary and secondary drying by a rise in the pressure as measured by the capacitance manometer. This is not a good idea from the standpoint of process consistency, and could cause problems in transferring process conditions from one manufacturing site to another, particularly if no one is paying attention to the details of pressure measurement and control. There is also a risk of exceeding the critical product temperature when carrying out the process close to the critical product temperature near the end of primary drying. As the relative partial pressure of water vapor decreases, nitrogen flow increases to maintain the set point. This results in an increase in absolute pressure, increased heat transfer, increased product temperature, and increased risk to the product.
Why put capacitance manometers on both the chamber and the condenser? This is primarily because the ratio of the chamber pressure to the condenser pressure can serve as a measure of equipment performance. Any freeze dryer has a maximum sublimation rate that it will support at any given pressure, and there is a general lack of quantitative understanding of equipment capability across the industry. There are several factors that can limit equipment capability—refrigeration capacity, condenser surface area, and an upper limit on the attainable shelf temperature. Another limiting factor has to do with “choked flow,” first reported as a source of uncertainty in scale-up of freeze drying by Searles (9). Briefly put, choked flow arises from the fact that there is a thermodynamically imposed speed limit on how fast water vapor can travel from the chamber to the condenser—the speed of sound. As the sublimation rate increases and the vapor velocity approaches sonic velocity (about 350 m/s for water vapor at room temperature), the vapor flow rate becomes independent of the pressure on the condenser side of the duct connecting the chamber and the condenser. The choke point can be measured by ice slab testing, where tray rings are lined with plastic, and partially filled with water. The water is then frozen, the system is evacuated, and the pressure is controlled at the low end of the pressure range of the freeze dryer. Once the system equilibrates, the shelf temperature is increased until the set point pressure can no longer be maintained. The mass flow rate of water vapor at this point is the choke point of the system. A new pressure set point is then established, the shelf temperature is systematically increased again, and a new choke point is reached at the higher pressure. This task is simplified by the fact that the relationship between the choke point and the chamber pressure is linear as long as the condenser temperature does not increase significantly as the water vapor flow rate increases. An alternative approach is called the minimum controllable pressure method, where the pressure set point is at an unattainably low value, such as 10 mT. The shelf temperature is increased in stepwise fashion. At each shelf temperature, the pressure will reach a steady-state level that corresponds to choked flow.
The easiest way to measure the mass flow rate at the choke point is by tunable diode laser absorption spectroscopy (10) or TDLAS (see discussion below). Where TDLAS is not available, the mass flow rate corresponding to choked flow can be measured gravimetrically after stopping the process at a point where most of the initial ice load remains. This requires more work because a separate experiment is needed at each pressure setting in order to determine the average mass flow rate. Heat flux measurement (see discussion below) is another method of measuring the sublimation rate and should give data comparable to TDLAS.
An alternative way, at least in principle, to identify the choke point is the pressure ratio between the chamber and the condenser, particularly when a cylindrical duct connects the chamber to the condenser. For a cylindrical duct, the pressure ratio corresponding to the onset of choked flow is 3:1 (11). Choked flow would not apply to freeze dryers with an internal condenser design. Some newer freeze dryers have a different chamber/condenser configuration, where the condenser is located beneath the chamber, separated by a rectangular plate that is moved up and down hydraulically (Fig. 7). It would be very useful to be able to identify the choke point by measuring the chamber to condenser pressure ratio for this configuration. A relevant research question is whether the critical pressure ratio could be calculated for this design.
While the authors are not aware of their use in freeze dry process monitoring, perhaps it should be pointed out that differential capacitance manometers are available. These instruments are used to measure pressure differences between different locations. They are commonly used in monitoring of pressure differentials in adjacent areas in the context of contamination control technology. However, we are aware of no reason why differential capacitance manometers could not be used to monitor the pressure difference between the chamber and the condenser.
Finally, why is it a good idea to have a Pirani gauge on the condenser? First, occasionally there is a leak somewhere in the system that prevents any vacuum from being established. For example, in many laboratory-scale freeze dryers, the gasket on either the chamber door or the condenser door may not seat properly. Having a Pirani gauge on both the chamber and the condenser helps to quickly locate the leak source. Although the Pirani gauge may not be very accurate at pressures just below atmospheric, this does not matter for this type of troubleshooting. The Pirani gauge should begin reading as soon as any vacuum has been established. Capacitance manometers are not useful here because they will not give a reading until the pressure reaches the upper limit of the range of that gauge, usually either 1 or 10 T. Second, having both a Pirani gauge and a capacitance manometer on both the chamber and the condenser could enable use of the connecting duct as a mass flow meter, with the aid of computational fluid dynamics. This is currently an active project in the LyoHub consortium, and it could prove useful for measurement of equipment capability curves, particularly for large freeze dryers not equipped for tunable diode laser absorption spectroscopy.
Pressure Rise Testing
The pressure rise test (PRT) is a procedure that has been used for decades and involves a quick isolation of the drying chamber from the condenser during the drying process by briefly closing the valve between the chamber and the condenser. When PRT is performed during primary drying, it results in a characteristic pressure rise pattern. Initially, when the valve is closed, the pressure rises rapidly, followed by a slow, almost linear, increase in the pressure. During secondary drying, the chamber pressure increases roughly linearly when the isolation valve is closed. Neumann (12) suggested that this inflection point in the pressure rise curve during primary drying could be considered as an indicator of the saturation pressure over the sublimation surface. He proposed using this pressure inflection point for the estimation of batch average product temperature from the vapor pressure versus temperature of pure ice. Neumann also assumed that the method could enable the measurement of the residual water content. Willemer (13) modified the PRT method to also measure sublimation rates. Many modern commercial freeze-dryers have been equipped with the PRT option. While PRT provides significant opportunities for process monitoring, it is mostly used for the end point determination for both primary and secondary drying steps.
An improvement on the pressure rise test, manometric temperature measurement (MTM), enables calculation of the product temperature during primary drying by fitting the pressure rise data to a set of equations that take into account four mechanisms that contribute to the pressure rise: (i) direct sublimation of ice through the dried product layer at a constant temperature, (ii) an increase in the temperature at the sublimation interface due to equilibration of the temperature gradient across the frozen layer, (iii) an increase in the ice temperature due to continued heating of the frozen matrix during the measurement, and (iv) leaks in the chamber, which in practice are normally negligible (14). This analysis yielded reasonable estimates of product temperature, mass transfer resistance of the cake, and vial heat transfer coefficient. A limitation of manometric temperature measurement is that it requires a valve between the chamber and condenser that cycles very rapidly compared with the time course of the pressure rise measurement, which is usually not more than 30 s. The isolation valves of most production-scale freeze dryers cycle too slowly to allow meaningful MTM measurements. However, the investigation of MTM has shown that the increase in chamber pressure during PRT/MTM is a function of load, chamber dimensions, product temperature, and progression of the primary drying step. For example, pressure increase is larger and faster with increase in a batch size, decrease in the size of the chamber and with increase in product temperature during primary drying. It is, therefore, advisable to take in account all these factors in order to establish meaningful PRT parameters during both primary and secondary drying steps.
Calibration of Pressure Sensors
For calibration of capacitance manometers, a transfer standard is used, which is another capacitance manometer. Thermal or mechanical gauges should never be used to calibrate a capacitance manometer because capacitance manometers are much more accurate. Capacitance manometers used in pharmaceutical freeze drying generally have an accuracy specification of about 0.25% of reading, as compared with 5–25% for a Pirani or thermocouple gauge in the same range (15). Capacitance manometers used as transfer standards typically have an accuracy of 0.05% of reading. There are three basic approaches to calibration—in situ, on-site, and off-site. With in situ calibration, the unit under test is not removed from the freeze dryer. Instead, the transfer standard is connected to the vacuum chamber using a port as close to the unit under test (UUT) as possible, perhaps by using a T connection where the transfer standard can be connected close to the UUT. Best practice for calibration, however, is to pump the vacuum system to below the resolution of the capacitance manometer in order to set the zero. Unfortunately, a freeze dryer cannot be evacuated to a pressure level below the resolution of the instrument. With on-site calibration, the UUT is removed from the freeze dryer and connected to a calibration system consisting of a high-vacuum pumping system, a transfer standard, and a pressure control system. With off-site calibration, the sensor is removed from the freeze dryer and sent to a calibration facility. The following guidelines apply to capacitance manometer calibration:
Both the unit under test and the transfer standard must be operated for at least 4 h after power has been applied, and must be at normal operating temperature.
The instrument must be zeroed by pumping the system to below the resolution of the UUT. A recommended zeroing pressure is four decades below full scale.
Six data points are generally considered adequate to ensure that the instrument is within calibration limits. Recommended calibration points are 10, 20, 40, 60, 80, and 100% of full scale reading.
Regarding frequency of calibration, it is good practice to collect historical data (see discussion of data historians below). Conditions of use are important in establishing the appropriate calibration interval. Most capacitance manometers on freeze dryers are routinely exposed to atmospheric pressure, as opposed to being isolated at low pressure. This would dictate more frequent calibration. Also, repeated steam sterilization would tend to require more frequent calibration. According to Osborn and Hansen (15), capacitance manometers on steam sterilized units should be calibrated every 3 months. Capacitance manometers that are isolated from atmospheric pressure can have much longer periods between calibrations.
Pirani gauges are generally calibrated using nitrogen, which explains why the apparent pressure during primary drying is well above the pressure indicated by the capacitance manometer. The approach to calibration is generally the same as discussed above, where the transfer standard is commonly a capacitance manometer. Calibration of Pirani gauges is less critical than calibration of the capacitance manometer, assuming that the capacitance manometer is used for pressure control. The reason is that, with the Pirani gauge, we are much more interested in changes in apparent pressure than in accurate absolute pressure measurement.
Summary of Best Practice for Pressure Measurement
The capacitance manometer is the instrument of choice for pressure measurement and control in a pharmaceutical freeze dryer. A temperature-controlled sensing head is highly recommended.
Best practice would include both a capacitance manometer and a Pirani gauge on both the chamber and the condenser.
Use of comparative pressure measurement is highly recommended as a process monitoring tool to determine the end point of both primary and secondary drying.
Keep in mind that both repeated exposure to atmospheric pressure and repeated steam sterilization tend to shorten the interval between calibrations of a capacitance manometer. Historical records are useful in establishing the more appropriate time interval between calibrations. In situ calibration is not considered best practice.
Other Process Measurements and Data Historians
In commercial manufacturing, it is important not only to monitor a wide range of process and equipment parameters but also have the ability to quickly retrieve these data from past manufacturing runs to observe trends. Such trending is useful as a tool to track equipment performance for maintenance and reliability purposes. It is also a key aspect of continuous process verification for pharmaceutical manufacturing (ICH Q8(R2)). There are a number of parameters that should be monitored and recorded in addition to the obligatory shelf fluid inlet temperature (often called shelf temperature): chamber pressure, product temperatures, and Pirani pressure gauge. Table II presents some examples of useful monitoring points. In general, data should be recorded at least every minute in order to detect transient events. Note that parameters necessary for monitoring and verifying cleaning and sterilization are not included here.