Noncontact Infrared-Mediated Heat Transfer During Continuous Freeze-Drying of Unit Doses

European Journal of Pharmaceutics and Biopharmaceutics

Corver

et al. 2017

Self Cite

Traditional pharmaceutical freeze-drying is an inefficient batch process often applied to improve the stability of biopharmaceutical drug products. The freeze-drying process is regulated by the (dynamic) settings of the adaptable process parameters shelf temperature T and chamber pressure P. Mechanistic modelling of the primary drying step allows the computation of the optimal combination of T and P in function of the primary drying time. In this study, an uncertainty analysis was performed on the mechanistic primary drying model to construct the dynamic Design Space for the primary drying step of a freeze-drying process, allowing to quantitatively estimate and control the risk of cake collapse (i.e., the Risk of Failure (RoF)). The propagation of the error on the estimation of the thickness of the dried layer L as function of primary drying time was included in the uncertainty analysis. The constructed dynamic Design Space and the predicted primary drying endpoint were experimentally verified for different RoF acceptance levels (1%, 25%, 50% and 99% RoF), defined as the chance of macroscopic cake collapse in one or more vials. An acceptable cake structure was only obtained for the verification runs with a preset RoF of 1% and 25%. The run with the nominal values for the input variables (RoF of 50%) led to collapse in a significant number of vials. For each RoF acceptance level, the experimentally determined primary drying endpoint was situated below the computed endpoint, with a certainty of 99%, ensuring sublimation was finished before secondary drying was started. The uncertainty on the model input parameters demonstrates the need of the uncertainty analysis for the determination of the dynamic Design Space to quantitatively estimate the risk of batch rejection due to cake collapse.

Section: Introductionmentioning

confidence: 99%

Quantitative risk assessment via uncertainty analysis in combination with error propagation for the determination of the dynamic Design Space of the primary drying step during freeze-drying

Bockstal

European Journal of Pharmaceutics and Biopharmaceutics

Corver

et al. 2017

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“…The preferred way of stabilising these products is by removing the aqueous solvent through freeze-drying (lyophilisation) [5]. Conventional pharmaceutical freeze-drying is an inefficient batch-wise process, associated with several disadvantages leading to an uncontrolled end product variability [6][7][8]. In this respect, an innovative freeze-drying concept resolving all disadvantages of batch freeze-drying, is proposed for the continuous processing of unit-doses [9].…”

Section: Introductionmentioning

confidence: 99%

“…The continuous freeze-drying process is initiated by rapidly rotating glass vials containing the aqueous drug formulation along their longitudinal axis [7,8]. The flow of a cold, inert and sterile gas cools the solution, followed by the induction of ice nucleation [9].…”

Section: Introductionmentioning

confidence: 99%

“…This energy transfer can be provided via conduction, by placing spin frozen vials in individual, close-fitting temperature-controlled pockets [7]. Alternatively, a previous study showed the feasibility of IR radiation to provide the heat needed for drying of the spin frozen vials [8]. The IR mediated primary drying process is illustrated in figure 1.…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic modelling of infrared mediated energy transfer during the primary drying step of a continuous freeze-drying process

Bockstal

European Journal of Pharmaceutics and Biopharmaceutics

Meyer

et al. 2017

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Conventional pharmaceutical freeze-drying is an inefficient and expensive batch-wise process, associated with several disadvantages leading to an uncontrolled end product variability. The proposed continuous alternative, based on spinning the vials during freezing and on optimal energy supply during drying, strongly increases process efficiency and improves product quality (uniformity). The heat transfer during continuous drying of the spin frozen vials is provided via non-contact infrared (IR) radiation. The energy transfer to the spin frozen vials should be optimised to maximise the drying efficiency while avoiding cake collapse. Therefore, a mechanistic model was developed which allows computing the optimal, dynamic IR heater temperature in function of the primary drying progress and which, hence, also allows predicting the primary drying endpoint based on the applied dynamic IR heater temperature. The model was validated by drying spin frozen vials containing the model formulation (3.9mL in 10R vials) according to the computed IR heater temperature profile. In total, 6 validation experiments were conducted. The primary drying endpoint was experimentally determined via in-line near-infrared (NIR) spectroscopy and compared with the endpoint predicted by the model (50min). The mean ratio of the experimental drying time to the predicted value was 0.91, indicating a good agreement between the model predictions and the experimental data. The end product had an elegant product appearance (visual inspection) and an acceptable residual moisture content (Karl Fischer).

“…The continuous freeze-drying process is extensively described in previous work [4,14,15]. The most critical parameter during the primary drying step is T i .…”

Section: Introductionmentioning

confidence: 99%

Modelling the primary drying step for the determination of the optimal dynamic heating pad temperature in a continuous pharmaceutical freeze-drying process for unit doses

Meyer

Lammens

International Journal of Pharmaceutics

et al. 2017

Self Cite

In the pharmaceutical industry, traditional freeze-drying of unit doses is a batch-wise process associated with many disadvantages. To overcome these disadvantages and to guarantee a uniform product quality and high process efficiency, a continuous freeze-drying process is developed and evaluated. The main differences between the proposed continuous freeze-drying process and traditional freeze-drying can be found firstly in the freezing step during which the vials are rotated around their longitudinal axis (spin freezing), and secondly in the drying step during which the energy for sublimation and desorption is provided through the vial wall by conduction via an electrical heating pad. To obtain a more efficient drying process, the energy transfer has to be optimised without exceeding the product and process limits (e.g. cake collapse, choked flow). Therefore, a mechanistic model describing primary drying during continuous lyophilisation of unit doses based on conduction via heating pads was developed allowing the prediction of the optimal dynamic power input and temperature output of the electric heating pads. The model was verified by experimentally testing the optimal dynamic primary drying conditions calculated for a model formulation. The primary drying endpoint of the model formulation was determined via in-line NIR spectroscopy. This endpoint was then compared with the predicted model based endpoint. The mean ratio between the experimental and model based predicted drying time for six verification runs was 1.05±0.07, indicating a good accordance between the model and the experimental data.