Impact of Natural Variations in Freeze-Drying Parameters on Product Temperature History: Application of Quasi Steady-State Heat and Mass Transfer and Simple Statistics

Pikal, Michael J.; Pande, Paritosh; Bogner, Robin H.; Sane, Pooja; Mudhivarthi, Vamsi K.; Sharma, Puneet

doi:10.1208/s12249-018-1155-4

Cited by 23 publications

(14 citation statements)

References 6 publications

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“…Figure 6a contains the average product temperature of the front edge vials in the x-axis and the minimum sublimation rate of the center vials in the y-axis. As reported in the literature [42][43][44]54 and determined experimentally in this study, the center vials have the lowest sublimation rate in the vial arrays. Therefore, Figure 6a allows consideration of the minimum sublimation rate during the construction of the PDS.…”

Section: Construction Of Process Design Space For Mf1supporting

confidence: 77%

An Experimental-Based Approach to Construct the Process Design Space of a Freeze-Drying Process: An Effective Tool to Design an Optimum and Robust Freeze-Drying Process for Pharmaceuticals

Assegehegn

Fuente

Franco

et al. 2020

Journal of Pharmaceutical Sciences

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The application of quality by design (QbD) is becoming an integral part of the formulation and process development for pharmaceutical products. An essential feature of the QbD philosophy is the design space. In this sense, a new approach to construct a process design space (PDS) for the primary drying section of a freeze-drying process is addressed in this paper. An effective customized design of experiments (DoE) is developed for freeze-drying experiments. The results obtained from the DoE are then used to construct the product-based PDS. The proposed product-based PDS construction approach has several advantages, including (1) eliminating assumptions on the heat transfer coefficient and dried product resistance, as it is constructed from experimental results specifically obtained from a given formulation, yielding more realistic and reliable results and (2) PDS construction based on a narrow range of product temperatures and considering the variations in product temperature and sublimation rate of vials across a shelf. This guarantees the effectiveness and robustness of the process and facilitates the process scale-up and transfer. The PDS developed herein was experimentally verified. The PDS predicted parameters were in excellent agreement with the experimentally obtained parameters.

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Section: Construction Of Process Design Space For Mf1supporting

confidence: 77%

An Experimental-Based Approach to Construct the Process Design Space of a Freeze-Drying Process: An Effective Tool to Design an Optimum and Robust Freeze-Drying Process for Pharmaceuticals

Assegehegn

Fuente

Franco

et al. 2020

Journal of Pharmaceutical Sciences

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“…First-principle equations for steady-state heat and mass transfer during lyophilization are well-known in the literature (20,21). These equations are used to determine how sublimation rate during primary drying can be optimized by modulation of the vial heat transfer coefficient and the formulation mass transfer resistance term.…”

Section: First-principle Modelingmentioning

confidence: 99%

Evaluation of Microwave Vacuum Drying as an Alternative to Freeze-Drying of Biologics and Vaccines: the Power of Simple Modeling to Identify a Mechanism for Faster Drying Times Achieved with Microwave

Bhambhani¹,

Stanbro²,

Roth³

et al. 2021

AAPS PharmSciTech

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Vial-based lyophilization for biopharmaceuticals has been an indispensable cornerstone process for over 50 years. However, the process is not without significant challenges. Capital costs to realize a lyophilized drug product facility, for example, are very high. Similarly, heat and mass transfer limitations inherent in lyophilization result in drying cycle on the order of several days while putting practical constraints on available formulation space, such as solute mass percentage or fill volume in a vial. Through collaboration with an external partner, we are exploring microwave vacuum drying (MVD) as a faster drying process to vial lyophilization wherein the heat transfer process occurs by microwave radiation instead of pure conduction from the vial. Drying using this radiative process demonstrates greater than 80% reduction in drying time over traditional freeze-drying times while maintaining product activity and stability. Such reduction in freeze-drying process times from days to several hours is a welcome change as it enables flexible manufacturing by being able to better react to changes either in terms of product volume for on-demand manufacturing scenarios or facilities for production (e.g., scale-out over scale-up). Additionally, by utilizing first-principle modeling coupled with experimental verification, a mechanism for faster drying times associated with MVD is proposed in this article. This research, to the best of our knowledge, forms the very first report of utilizing microwave vacuum drying for vaccines while utilizing the power of simplified models to understand drying principles associated with MVD.

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“…With respect to the sublimation rate, that is, the weight loss in each vial during the test, the target is to get a mean value of weight loss in edge vials as close as possible to that of the central vials and, in general, a standard deviation of the weight loss in the whole batch close to the values typical of a large-scale unit. With respect to this, data of the distribution of K v may be found in the literature 35,36 and may be considered representative of the nonuniformity of drying rate as the sublimation flux is proportional to the heat flux and the driving force for the heat transfer calculation is assumed to be the same in all the batch. Values ranging from 3% to 7% of the relative standard deviation of K v values are not unusual for a glass tubing vials batch, 36 being even higher for molded vials.…”

Section: Study Of the Effect Of Lyosim®mentioning

confidence: 99%

“…With respect to this, data of the distribution of K v may be found in the literature 35,36 and may be considered representative of the nonuniformity of drying rate as the sublimation flux is proportional to the heat flux and the driving force for the heat transfer calculation is assumed to be the same in all the batch. Values ranging from 3% to 7% of the relative standard deviation of K v values are not unusual for a glass tubing vials batch, 36 being even higher for molded vials. Fissore et al 28 found that a temperature offset ranging from À3 C to À5 C was able to provide good results with respect to drying rate homogeneity and, in particular, with À5 C also the temperature profiles in edge and central vials were in excellent agreement.…”

Section: Study Of the Effect Of Lyosim®mentioning

confidence: 99%

Development of Freeze-Drying Cycles for Pharmaceutical Products Using a Micro Freeze-Dryer

Fissore

Harguindeguy

Ramirez

et al. 2020

Journal of Pharmaceutical Sciences

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This article aims to investigate how a small-scale freeze-dryer can be used for process design. The system encompasses a temperature controlled metallic ring that surrounds a small batch of vials, in contact with the external vials through removable thermal conductors. The temperature of the ring can be modified to keep a constant difference with the temperature of one or more vials of the batch. In this article, an extensive validation of the system is given, considering 10% w/w sucrose and 5% w/w mannitol solutions, processed in different types of vials (6 R and 20 R) and in different operating conditions. The micro freezedryer was also shown to be able to provide accurate estimates of the overall heat transfer coefficient from the shelf to the product in the vials (K v) and of the resistance of the dried cake to vapor flux (R p): both values appeared to be very close to those obtained for the same case studies in a pilot-scale unit. Finally, the use of the micro freeze-dryer to control product temperature and drying time values to simulate a pilot-scale unit was addressed, thus demonstrating the adequacy of this system for process scaleup.

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Impact of Natural Variations in Freeze-Drying Parameters on Product Temperature History: Application of Quasi Steady-State Heat and Mass Transfer and Simple Statistics

Cited by 23 publications

References 6 publications

An Experimental-Based Approach to Construct the Process Design Space of a Freeze-Drying Process: An Effective Tool to Design an Optimum and Robust Freeze-Drying Process for Pharmaceuticals

An Experimental-Based Approach to Construct the Process Design Space of a Freeze-Drying Process: An Effective Tool to Design an Optimum and Robust Freeze-Drying Process for Pharmaceuticals

Evaluation of Microwave Vacuum Drying as an Alternative to Freeze-Drying of Biologics and Vaccines: the Power of Simple Modeling to Identify a Mechanism for Faster Drying Times Achieved with Microwave

Development of Freeze-Drying Cycles for Pharmaceutical Products Using a Micro Freeze-Dryer

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