Analysis of a pharmaceutical batch freeze dryer: resource consumption, hotspots, and factors for potential improvement

Gamiz, Ana Gabriela Renteria; Bockstal, Pieter-Jan Van; Meester, Steven De; Beer, Thomas De; Corver, Jos; Dewulf, Jo

doi:10.1080/07373937.2018.1518916

Cited by 7 publications

(6 citation statements)

References 42 publications

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“…A two-stage cascade refrigeration system similar to the one installed on the pilot-scale freeze-dryer LyoBeta 25 (Telstar, Terrassa, Spain) was considered to calculate the energy consumption of the process. The cascade system works with two different refrigerants-R-404A for the high-temperature circuit (HTC) and R-23 for the low-temperature circuit (LTC)-and the two circuits are thermally connected by a cascade heat exchanger, which works as a condenser for the LTC and as an evaporator for the HTC [7], as described in Figure 1. It is assumed that the two stages are always active, and the cycle works between T H = T amb + 10 • C and T C = T cond -10 • C. For simplicity in the calculations of the thermodynamic cycles, some other assumptions were made, as follows: (i) there is no superheating after evaporation, (ii) no undercooling after condensation, and (iii) the compressors work under adiabatic conditions with an isentropic efficiency η is .…”

Section: Refrigerating Apparatusmentioning

confidence: 99%

“…However, part of these focuses only on specific steps of the process, i.e., freezing [4,5] or drying [6]. In contrast, articles that describe the entire process [7,8] are efficiency oriented and do not consider the economic aspects like the capital costs of the apparatus. Moreover, even though economic evaluations have been presented in the past [9][10][11], they are often too broad or too specific to be used for making comparisons between different process strategies.…”

Section: Introductionmentioning

confidence: 99%

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Economic Analysis of a Freeze-Drying Cycle

et al. 2020

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Freeze-drying has always been considered an extremely expensive procedure to dehydrate food or pharmaceutical products, and for this reason, it has been employed only if strictly necessary or when the high added value of the final product could justify the costs. However, little effort has been made to analyze the factors that make this technology so unaffordable. In this work, a model was proposed to calculate in detail the operational (OC) and capital costs (CC) of a freeze-drying cycle and an evaluation of the process bottlenecks was made. The main result is that the process itself, contrary to the classic belief, is not the most expensive part of freeze-drying, while the initial investment is the real limiting factor. Under this consideration, the optimization of a freeze-drying cycle should be formulated in order to fit more cycles in the lifespan of the apparatus, instead of merely reducing the power consumption of the machine.

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Section: Refrigerating Apparatusmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Economic Analysis of a Freeze-Drying Cycle

et al. 2020

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“…Freeze-drying or lyophilisation consists of three consecutive steps: freezing, primary drying (i.e., sublimation) and secondary drying (i.e., desorption) [2]. Despite its popularity, freeze-drying is still an inefficient process associated with high production costs and long process times [3]. A reduction in production cost and process time can be achieved by shifting from batch freeze-drying to continuous freeze-drying.…”

Section: Introductionmentioning

confidence: 99%

4D Micro-Computed X-ray Tomography as a Tool to Determine Critical Process and Product Information of Spin Freeze-Dried Unit Doses

et al. 2020

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Maintaining chemical and physical stability of the product during freeze-drying is important but challenging. In addition, freeze-drying is typically associated with long process times. Therefore, mechanistic models have been developed to maximize drying efficiency without altering the chemical or physical stability of the product. Dried product mass transfer resistance ( R p ) is a critical input for these mechanistic models. Currently available techniques to determine R p only provide an estimation of the mean R p and do not allow measuring and determining essential local (i.e., intra-vial) R p differences. In this study, we present an analytical method, based on four-dimensional micro-computed tomography (4D- μ CT), which enables the possibility to determine intra-vial R p differences. Subsequently, these obtained R p values are used in a mechanistic model to predict the drying time distribution of a spin-frozen vial. Finally, this predicted primary drying time distribution is experimentally verified via thermal imaging during drying. It was further found during this study that 4D- μ CT uniquely allows measuring and determining other essential freeze-drying process parameters such as the moving direction(s) of the sublimation front and frozen product layer thickness, which allows gaining accurate process knowledge. To conclude, the study reveals that the variation in the end of primary drying time of a single vial could be predicted accurately using 4D- μ CT as similar results were found during the verification using thermal imaging.

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“…The mean K v as well as the relative standard deviation (RSD) were calculated for each group at the five different pressure levels. By using Equation 5, K v could be described in function of the chamber pressure using the α [J/m 2…”

Section: Determination Of the Heat Transfer Coefficientmentioning

confidence: 99%

“…Therefore, many of the approved biopharmaceuticals by the FDA and EMA are stabilized by lyophilisation [1]. However, freeze-drying is a long and costly process that require a lot of aseptic floor space [2].…”

Section: Introductionmentioning

confidence: 99%

Model-Based Optimisation and Control Strategy for the Primary Drying Phase of a Lyophilisation Process

et al. 2020

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The standard operation of a batch freeze-dryer is protocol driven. All freeze-drying phases (i.e., freezing, primary and secondary drying) are programmed sequentially at fixed time points and within each phase critical process parameters (CPPs) are typically kept constant or linearly interpolated between two setpoints. This way of operating batch freeze-dryers is shown to be time consuming and inefficient. A model-based optimisation and real-time control strategy that includes model output uncertainty could help in accelerating the primary drying phase while controlling the risk of failure of the critical quality attributes (CQAs). In each iteration of the real-time control strategy, a design space is computed to select an optimal set of CPPs. The aim of the control strategy is to avoid product structure loss, which occurs when the sublimation interface temperature ( T i ) exceeds the the collapse temperature ( T c ) common during unexpected disturbances, while preventing the choked flow conditions leading to a loss of pressure control. The proposed methodology was experimentally verified when the chamber pressure and shelf fluid system were intentionally subjected to moderate process disturbances. Moreover, the end of the primary drying phase was predicted using both uncertainty analysis and a comparative pressure measurement technique. Both the prediction of T i and end of primary drying were in agreement with the experimental data. Hence, it was confirmed that the proposed real-time control strategy is capable of mitigating the effect of moderate disturbances during batch freeze-drying.

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Analysis of a pharmaceutical batch freeze dryer: resource consumption, hotspots, and factors for potential improvement

Cited by 7 publications

References 42 publications

Economic Analysis of a Freeze-Drying Cycle

Economic Analysis of a Freeze-Drying Cycle

4D Micro-Computed X-ray Tomography as a Tool to Determine Critical Process and Product Information of Spin Freeze-Dried Unit Doses

Model-Based Optimisation and Control Strategy for the Primary Drying Phase of a Lyophilisation Process

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