What could manufacturing look like in the future? Picture predictive analytics to minimize downtime and a control center to monitor the entire fleet of machines, i.e. a connected factory. To turn this vision into reality, a program for data analytics and health monitoring has been started at IMA Life North America in Tonawanda to provide augmented freeze dryer information by collecting and analyzing process and equipment data.

The freeze drying community has dedicated resources for artificially inducing nucleation since it was introduced to the community as a means for reliable prediction of product stability, scale-up and primary drying time reduction. Broadly, there are at least 5 known techniques for artificially inducing nucleation with the same basic characteristics. However, few studies have tested these processes at large scales of operation (>35 m2 shelf area, >150,000 vials) uniformly. This report herein describes the first known attempt at quantifying the success of such processes in inducing nucleation on a 56m2 freeze dryer operating at a load of 195,960 vials. It is found that thermal gradients within freeze dryer chambers typical of the production environment should be considered when designing the scale up of the freezing process in lyophilization.

Freeze-drying involves removal of solvent such that the molecular structure of the active ingredient of the drug is least disturbed, thus providing a dried drug product that is quickly and completely rehydrated upon addition of the solvent. In April 2018, an E55.05 Lyophilization sub-committee within ASTM E55 committee was created to convert guidance documents into industry standard guides. The scope of this sub-committee is to develop, disseminate and educate standard practices and guides relevant to lyophilization of parenterals and other pharmaceutical and biological products. The work of the subcommittee will cover all aspects of process and equipment design, operation and qualification, quality assessment, process understanding and control.

Freeze Dryer Equipment Capability is important in understanding the limits of operating conditions and in implementing a design space approach. The Equipment Capability Limit, expressed as a either the Minimum Controllable Pressure or the Maximum Attainable Sublimation Rate, is a function of the shelf temperature and the vapor flow rate. Two Experimental Methods, both using Ice slabs, can be used to characterize freeze dryers. The underlying approach and control offered in both these methods has different benefits, and are explored in this article.
The two tests compared are the Minimum Controllable Pressure Test and the Choked Point Flow Test. Both have been previously implemented in either production or lab dryer settings to obtain the equipment capability limits. The data from lab scale testing using the two approaches is presented and compared. Protocols followed for these testing methods are described as well. It is found that the Minimum Controllable Pressure Test is 66% faster at obtaining the same range of data than the Choked Point Flow Test. With customer requirements specifying the desired sublimation rate at certain pressures and an industry interest in characterizing all production freeze dryers, it is beneficial to understand the implications of current available techniques.

Numerous process analytical technologies are available to monitor the different stages in a freeze drying process. However, following the time intensive primary drying step, what usually follows is secondary drying, where very few sensors are available to provide information about the product and potentially about product quality. Paraphrasing from FDA guidelines on the Freeze Drying process, it is necessary to monitor for leaks into the chamber that may originate from various sources such as the shelf thermal fluid, atmospheric system leaks and condenser coils.Keeping in mind, these multi-dimensional aspects required from the next PAT tool, the Quantum mass spectrometer bridges gaps between reliable and usable sensors in an aseptic environment.

Freeze drying is a method of choice for stabilizing drug formulations which show less than desired storage stability in the liquid form. However, despite its unparalleled benefits, freeze drying is one of the most expensive unit operations in a drug development process because of high investment costs and slow drying rate required for ensuring optimal product stability. Therefore, to minimize the cost of a freeze drying operation, it is imperative that a prototype freeze drying cycle should be executed only after critically analyzing the product thermal characteristics. This brief presentation showcases the scientific approach adopted to design a baseline freeze drying cycle for an oligopeptide drug formulation. The challenges encountered in analyses of critical thermal characteristics of a peptide formulation, before and after freeze drying, are briefly discussed herein along with a note on the potential of the baseline cycle for further optimization.

Currently nearly half of the therapeutic proteins are freeze dried but the freeze-drying process does not guarantee a uniform intra- and inter-batch distribution of quality attributes in vials, partly because the product temperature during a freeze drying cycle cannot be directly controlled. Variations in product temperature can significantly impact the product critical quality attributes (CQAs), even for biosimilars having the similar formulations. Therefore, a better understanding of product temperature variations will enable development of sampling strategies to better assess the influence of distribution in CQAs, like protein degradation and aggregation, on the probability of releasing out of specification drug product.

One of the common challenges encountered in the early stages of a drug development process is the formulation of poorly water soluble drugs. A common approach employed within the pharmaceutical industry is to improve the dissolution of sparingly water soluble drug molecules by rendering them into their amorphous form.
However, amorphous materials are both physically and chemically unstable, and tend to revert back to their original state when exposed to the physical and thermal processes, that are typically associated with the development of aqueous drug formulations. Therefore, such drug candidates often require further stabilization via a suitable process like freeze drying. Freeze drying, however, is one of the most expensive unit operations in a drug manufacturing because of the slow drying rate required for ensuring product stability and the high investment costs.
To minimize the cost of freeze drying operation, it is imperative that even a prototype cycle should be executed after understanding the product limits, thorough analyses of its thermal behavior and understanding its critical physico-chemical properties, so that the freeze-drying process can be specifically tailored. This paper discusses scientific approach adopted to design a baseline freeze drying cycle for two emerging classes of drug formulations, one containing self-assembling peptides and other containing a Theranostic ultrasound contrast agent. The challenges encountered in analyses of critical thermal characteristics of formulations as well as during analyses of freeze dried product are briefly discussed in this paper.

Mass Spectrometry has commonly been used in the semi-conductor industry where maintaining a clean environment with minimum contaminants under high vacuum is crucial for successful manufacturing. Since the technology’s early usage for pharmaceutical manufacturing in the 1980 s, particularly in the freeze-drying environment, much has changed.
The focus of the current work is aimed at asking some key questions regarding the maturity of the technology, its challenges and importance of having an application-specific instrument for quantitative process analyses applied to freeze-drying. Furthermore, we compare the use of mass spectrometers in early installations from the ’80s with recent experiences of the technology in the production and laboratory environments comparing data from different MS technologies.
In addition, the manuscript covers broad application of the technology towards detection of and sensitivity for analytes including silicone oil and Helium. It also explores the option of using MS in detecting water vapor and nitrogen concentration not just in primary drying, but also in secondary drying.
The technology, when purpose built, has the potential for use as a robust, multi-purpose PAT tool in the freeze-drying laboratory and production environments.

Heat transfer in the product chamber, gaseous transport in the connecting duct and icing on the cooled surfaces of the condenser are presented.
While analytical solutions supported with experiments are used to quantify the heat transfer, computational fluid dynamics (CFD) and direct simulation Monte Carlo (DSMC) techniques are applied to model the relevant gaseous transport processes in a low-pressure environment encountered in freeze-drying.
The key heat transfer mechanisms driving primary drying are discussed for different chamber pressures and vial configurations, the effect of hardware and process conditions is used to understand transport in the connecting duct. Finally, the vapor flow dynamics in the condenser presented here discuss the role of the condenser topology on ice accretion in the condenser.
The DSMC simulations demonstrate that by tailoring the condensing surfaces topology to the flowfield structure of the water vapor jet expanding into a low-pressure reservoir, it is possible to significantly increase the total rate of vapor removal and improve the overall efficiency of the freeze-drying process.

Analysis of water vapor flows encountered in pharmaceutical freeze-drying systems, laboratory-scale and industrial, is presented based on the computational fluid dynamics (CFD) techniques. The flows under continuum gas conditions are analyzed using the solution of the Navier–Stokes equations whereas the rarefied flow solutions are obtained by the direct simulation Monte Carlo (DSMC) method for the Boltzmann equation. Examples of application of CFD techniques to laboratory-scale and industrial scale freeze-drying processes are discussed with an emphasis on the utility of CFD for improvement of design and experimental characterization of pharmaceutical freezedrying hardware and processes.
The current article presents a two-dimensional simulation of a laboratory scale dryer with an emphasis on the importance of drying conditions and hardware design on process control and a three-dimensional simulation of an industrial dryer containing a comparison of the obtained results with analytical viscous flow solutions. It was found that the presence of clean in place (CIP)/sterilize in place (SIP) piping in the duct lead to significant changes in the flow field characteristics. The simulation results for vapor flow rates in an industrial freeze-dryer have been compared to tunable diode laser absorption spectroscopy (TDLAS) and gravimetric measurements.

Freeze-drying involves removal of solvent such that the molecular structure of the active ingredient of the drug is least disturbed, thus providing a dried drug product that is quickly and completely rehydrated upon addition of the solvent. In April 2018, an E55.05 Lyophilization sub-committee within ASTM E55 committee was created to convert guidance documents into industry standard guides.
The scope of this sub-committee is to develop, disseminate and educate standard practices and guides relevant to lyophilization of parenterals and other pharmaceutical and biological products. The work of the subcommittee will cover all aspects of process and equipment design, operation and qualification, quality assessment, process understanding and control.

A modeling and computational framework for analysis of rarefied water vapor flow and icing in application to pharmaceutical freeze-drying is developed.
The direct simulation Monte Carlo (DSMC) technique is applied to model the relevant gaseous transport processes in a low-pressure environment encountered in freeze-drying.
The developing ice front on a supercooled surface is simulated based on the water vapor mass flux computed from DSMC. Verification of icing simulations has been done by comparison with the analytical solution for a free-molecular flow over a circular cylinder. To validate the vapor flow and icing simulations, measurements of ice accretion in a laboratory-scale freeze-dryer are conducted with the use of time-lapse photography. The simulations corresponding to the measured time-average water sublimation rate agree well with the observed patterns and rates of ice accretion. The developed computational framework has been applied to investigate factors underlying the observed non-uniformity of ice growth. It has been shown that two key factors impact the uniformity of ice accretion: (i) the direction of the vapor flow at the inlet to the condenser which is governed by the geometry of a duct connecting the product chamber to the condenser; and (ii) the pressure of non-condensable gases in the condenser reservoir.
The DSMC simulations demonstrate that by tailoring the condensing surfaces topology to the flowfield structure of the water vapor jet expanding into a low-pressure reservoir, it is possible to significantly increase the total rate of vapor removal and improve the overall efficiency of the freeze-drying process.

The study is aimed at quantifying the relative contribution of key heat transfer modes in lyophilization.
Measurements of vial heat transfer rates in a laboratory-scale freeze dryer were performed using pure water, which was partially sublimed under various conditions. The separation distance between the shelf and the vial was systematically varied, and sublimation rates were determined gravimetrically. The heat transfer rates were observed to be independent of separation distance between the vial and the shelf and linearly dependent on pressure in the free molecular flow limit, realized at low pressures (<50 mTorr). However, under higher pressures (>120 mTorr), heat transfer rates were independent of pressure and inversely proportional to separation distance.
Previous heat transfer studies in conventional freeze-drying cycles have attributed a dominant portion of the total heat transfer to radiation, the rest to conduction, whereas convection has been found to be insignificant. Although the measurements reported here confirm the significance of the radiative and gas conduction components, the convective component has been found to be comparable to the gas conduction contribution at pressures greater than 100 mTorr.
The current investigation supports the conclusion that the convective component of the heat transfer cannot be ignored in typical laboratory-scale freeze drying conditions.

A physics-based model for the sublimation–transport–condensation processes occurring in pharmaceutical freeze-drying by coupling product attributes and equipment capabilities into a unified simulation framework is presented.
The system-level model is used to determine the effect of operating conditions such as shelf temperature, chamber pressure, and the load size on occurrence of choking for a production-scale dryer. Several data sets corresponding to production-scale runs with a load from 120 to 485 L have been compared with simulations. A subset of data is used for calibration, whereas another data set corresponding to a load of 150 L is used for model validation. The model predictions for both the onset and extent of choking as well as for the measured product temperature agree well with the production-scale measurements. Additionally, we study the effect of resistance to vapor transport presented by the duct with a valve and a baffle in the production-scale freeze-dryer. Computation Fluid Dynamics (CFD) techniques augmented with a system-level unsteady heat and mass transfer model allow to predict dynamic process conditions taking into consideration specific dryer design. CFD modeling of flow structure in the duct presented here for a production-scale freeze-dryer quantifies the benefit of reducing the obstruction to the flow through several design modifications. It is found that the use of a combined valve–baffle system can increase vapor flow rate by a factor of 2.2. Moreover, minor design changes such as moving the baffle downstream by about 10 cm can increase the flow rate by 54%.
The proposed design changes can increase drying rates, improve efficiency, and reduce cycle times due to fewer obstructions in the vapor flow path. The comprehensive simulation framework combining the system-level model and the detailed CFD computations can provide a process analytical tool for more efficient and robust freeze-drying of bio-pharmaceuticals.

Product temperature during the primary drying step of freeze-drying is controlled by a set point chamber pressure and shelf temperature. However, recent computational modeling suggests a possible variation in local chamber pressure.
The current work presents an experimental verification of the local chamber pressure gradients in a lab-scale freeze-dryer. Pressure differences between the center and the edges of a lab-scale freeze-dryer shelf were measured as a function of sublimation flux and clearance between the sublimation front and the shelf above. A modest 3-mTorr difference in pressure was observed as the sublimation flux was doubled from 0.5 to 1.0 kg/h/1m² at a clearance of 2.6 cm. Further, at a constant sublimation flux of 1.0 kg/h/1m², an 8-fold increase in the pressure drop was observed across the shelf as the clearance was decreased from 4 to 1.6 cm.
Scale-up of the pressure variation from lab- to a manufacturing-scale freeze-dryer predicted an increased uniformity in drying rates across the batch for two frequently used pharmaceutical excipients (mannitol and sucrose at 5% w/w). However, at an atypical condition of shelf temperature of +10°C and chamber pressure of 50 mTorr, the product temperature in the center vials was calculated to be a degree higher than the edge vial for a low resistance product, thus reversing the typical edge and center vial behavior. Thus, the effect of local pressure variation is more significant at the manufacturing-scale than at a lab-scale and accounting for the contribution of variations in the local chamber pressures can improve success in scale-up.

The flow physics in the product chamber of a freeze dryer involves coupled heat and mass transfer at different length and time scales. The low-pressure environment and the relatively small flow velocities make it difficult to quantify the flow structure experimentally.
The current work presents the three-dimensional computational fluid dynamics (CFD) modeling for vapor flow in a laboratory scale freeze dryer validated with experimental data and theory. The model accounts for the presence of a non-condensable gas such as nitrogen or air using a continuum multi-species model. The flow structure at different sublimation rates, chamber pressures, and shelf-gaps are systematically investigated. Emphasis has been placed on accurately predicting the pressure variation across the subliming front. At a chamber set pressure of 115 mTorr and a sublimation rate of 1.3 kg/h/m2, the pressure variation reaches about 9 mTorr. The pressure variation increased linearly with sublimation rate in the range of 0.5 to 1.3 kg/h/m2. The dependence of pressure variation on the shelf-gap was also studied both computationally and experimentally. The CFD modeling results are found to agree within 10% with the experimental measurements. The computational model was also compared to analytical solution valid for small shelf-gaps. Thus, the current work presents validation study motivating broader use of CFD in optimizing freeze-drying process and equipment design.

Recommended best practices in monitoring of product status during pharmaceutical freeze drying are presented, focusing on methods that apply to both laboratory and product ion scale. With respect to product temperature measurement, sources of uncertainty associated with any type of measurement probe are discussed, as well as important differences between the two most common types of temperature – measuring instruments — thermocouples and resistance temperature detectors (RTD).
Two types of pressure transducers are discussed – thermal conductivity – type gauges and capacitance manometers, with the Pirani gauge being the thermal conductivity-type gauge of choice. It is recommended that both types of pressure gauge be used on both the product chamber and the condenser for freeze dryers with an external condenser, and the reasoning for this recommendation is discussed. Developing technology for process monitoring worthy of further investigation is also briefly reviewed , including wireless product temperature monitoring tunable diode laser absorption spectroscopy at manufacturing scale, heat flux measurement, and mass spectrometry as process monitoring tools.

By Joe Azzarella, Vamsi K. Mudhivarthi, Eugene Wexler, PhD, Arnab Ganguly
BioPharm International, Volume 29, Issue 12, pg 36–41, 55The freeze drying community has dedicated resources for artificially inducing nucleation since it was introduced to the community as a means for reliable prediction of product stability, scale-up and primary drying time reduction. Broadly, there are at least 5 known techniques for artificially inducing nucleation with the same basic characteristics. However, few studies have tested these processes at large scales of operation (>35 m2 shelf area, >150,000 vials) uniformly. This report herein describes the first known attempt at quantifying the success of such processes in inducing nucleation on a 56m2 freeze dryer operating at a load of 195,960 vials. It is found that thermal gradients within freeze dryer chambers typical of the production environment should be considered when designing the scale up of the freezing process in lyophilisation.

Freeze-drying is a low-pressure, low-temperature condensation pumping process used in the manufacture of biological and pharmaceutical products. It involves a 3-stage process initiated by freezing (A-B), then reducing pressure below the triple point (B-C). Heat is then provided for sublimation of the ice in the primary drying (C-D).
Performance of a freeze-dryer is governed by the vapor and ice dynamics in the low-pressure environment. One of the most important physical processes relevant to the freeze-dryer design is the formation of ice on the condensing surfaces during the drying stage. Non-uniform ice growth on the coils hinders the vapor trapping capability of the condenser. Understanding and controlling the ice build-up is needed for improved freeze-drying systems.
Direct Simulation Monte Carlo (DSMC) techniques are applied to model relevant physical processes accompanying low-pressure vapor flow in the condenser. Low-temperature water vapor molecular model is used in the DSMC solver SMILE to simulate the flow field structure. Experimental Measurements include ice accretion measurements in laboratory and industrial scale dryer under various loads and cycle parameters.

Freeze-drying is a low-pressure, low-temperature condensation pumping process used in the manufacture of biological and pharmaceutical products. Freeze-drying is run as a batch process and is both, time and energy intensive. It involves a 3-stage process initiated by freezing (stage A-B), then reducing pressure below the triple point (stage B-C). Heat is then provided for sublimation of the ice in the primary drying (stage C-D).
Performance of a freeze-dryer is governed by the vapor and ice dynamics in the low-pressure environment.
One of the most important physical processes relevant to the freeze-dryer design is the formation of ice on the condensing surfaces during the drying stage. A development cycle in a lab-scale freeze-dryer with 100 vials, drying at 0.5 g/hr, leads to the formation of 3.6 kg of ice. If the ice build-up is assumed to be uniform on the coils of the Lyostar condenser, a layer of ice about 1 cm thick is formed. In reality, the coils at the center receive much more ice than those at the periphery. The non-uniform ice growth hinders the vapor trapping capability of the condenser. Understanding and controlling the ice build-up is needed for improved freeze-drying systems.

Freeze-drying is a low-pressure, low-temperature condensation pumping process used in the manufacture of biological and pharmaceutical products. Freeze-drying is run as a batch process and is both, time and energy intensive. It involves a 3-stage process initiated by freezing (stage A-B), then reducing pressure below the triple point (stage B-C). Heat is then provided for sublimation of the ice in the primary drying (stage C-D).
A key step in the development and scale-up of pharmaceutical lyophilisation processes is quantification of limits of the design space for a product-equipment combination (Nail and Searles, 2008). This could often rely on trial and error techniques with limited success (Speaker and Teagarden, 2008).
Scale-up inaccuracies could arise from: a) degree of supercooling of the product during the freezing stage (Rambhatla et al., 2004); b) variations in the heat and mass transfer mechanisms (Ganguly et al., 2010); c) differences in the capability of the condenser (Rambhatla and Pikal, 2003) and d) the dynamics of vapor flow in the freeze-dryer (Rasetto et al, 2010).
Amongst these, the dynamics of vapor flow in the chamber and the contribution of convection has been the hardest to quantify accurately. Recently the use of Tunable Diode Laser Absorption Spectroscopy (Gieseler et al., 2007) has made it possible to measure the instantaneous mass flow rate and velocity of flow in the duct; however it has its limitations. Alexeenko et al. (2009) showed that the specifics of freeze-dryer design and the use of simplified models could lead to inaccurate vapor flow characterization. The low-pressure environment and the relatively small flow velocities in the product chamber make it difficult to quantify the flow structure experimentally. Thus, physics-based computational models that provide detailed information on the flow structure are valuable.

Analysis of water vapor flows encountered in pharmaceutical freeze-drying systems, laboratory-scale and industrial, is presented based on the computational fluid dynamics (CFD) techniques. The flows under continuum gas conditions are analyzed using the solution of the Navier–Stokes equations whereas the rarefied flow solutions are obtained by the direct simulation Monte Carlo (DSMC) method for the Boltzmann equation. Examples of application of CFD techniques to laboratory-scale and industrial scale freeze-drying processes are discussed with an emphasis on the utility of CFD for improvement of design and experimental characterization of pharmaceutical freeze-drying hardware and processes.
The current article presents a two-dimensional simulation of a laboratory scale dryer with an emphasis on the importance of drying conditions and hardware design on process control and a three-dimensional simulation of an industrial dryer containing a comparison of the obtained results with analytical viscous flow solutions. It was found that the presence of clean in place (CIP)/sterilize in place (SIP) piping in the duct lead to significant changes in the flow field characteristics. The simulation results for vapor flow rates in an industrial freeze-dryer have been compared to tunable diode laser absorption spectroscopy (TDLAS) and gravimetric measurements.

The aim of advanced aseptic processing is the elimination and absolute control of all sources of contaminants – most importantly, human generated contamination. Automation and Robotics will be the core technologies to advance this initiative further. The industrial manufacturing of injectable drug products presents very different and difficult challenges when compared with other industrial manufacturing applications. In order to enhance patient safety and ensure product quality, the pharmaceutical industry has been implementing advanced aseptic processing (AAP) systems that utilize advanced forms of automation, robotics and machine vision in an effort to protect the pharmaceutical product from contamination.