Predictive Model-Based Process Start-Up in Pharmaceutical Continuous Granulation and Drying.

Continuous manufacturing (CM) is a promising strategy to achieve various benefits in the context of quality, flexibility, safety and cost in pharmaceutical production. One of the main technical challenges of CM is that the process needs to handle transient conditions such as the start-up phase before state of control operation is reached, which can potentially cause out-of-specification (OOS) material. In this context, the presented paper aims to demonstrate that suitable process control strategies during start-up of a continuous granulation and drying operation can limit or even avoid OOS material production and hence can ensure that the provided benefits of CM are not compromised by poor production yields. In detail, heat-up of the drying chamber prior the start of production can lead to thermal energy being stored inside of the stainless-steel housing, acting as an energy buffer that is known to cause over-dried granules in the first few minutes of the drying process. To compensate this issue, an automatic ramping procedure of dryer rotation speed (and hence drying time) was introduced into the plant's process control system, which counteracts the excessive drying capacity during start-up. As a result, dry granules exiting the dryer complied with the targeted intermediate critical quality attribute loss-on-drying (LOD) from the very beginning of production.

From powder to tablets: Investigation of residence time distributions in a continuous manufacturing process train as basis for continuous process verification.

The essence of Continuous Manufacturing (CM) resides in the fact that continuous process units are directly connected to each other forming a continuous process train. The thorough understanding of material flow in this train based on suitable sensors, including on-line process analytical technologies and other sensors, is key in understanding the time-domain behavior of the system and the process. This real-time monitoring correlated with the time domain material flow behavior could be used to close control-loops. In practical terms, the implementation of such a control strategy is only feasible, if the overlying control system knows precisely what material is when and where at all times. Consequently, thorough knowledge of the residence time distribution (RTD) of the material throughout the whole manufacturing network needs to be established early on in development. Once RTD is well understood, its constant observation could also be used for continuous process verification purposes hinging on the argument that the flow pattern of the material is unchanged. As continuous processes that run over extended periods of time are susceptible to unforeseen incidents like equipment wear-out or clogging, drifts or shifts in RTD could indicate such issues early on. The presented work aims to demonstrate this proposed concept for an integrated wet-granulation CM process. To achieve this aim, three steps were completed: First, thorough RTD knowledge was generated, by inducing endogenous step-tests in active pharmaceutical ingredient (API) content in the range of ±30% at varying process conditions, and analyzing the material RTDs via NIRS analysis at four different locations in the line. Second, it was demonstrated that also low-level step tests of ±5% and even ±3% are sufficient for accurate RTD determination. This validated the possibility of continuous RTD assessment during (pre-)validation trials or even commercial manufacturing, as the drug product would comply with required quality characteristics (content uniformity, assay). In the third step, it was then demonstrated that recurring low-level step testing during routine manufacturing could be used as a way to determine the current system health, as observed changes in RTD indicated blockages and accidental material hold-up in the line. While deliberate changes in API content during commercial production might seem counter intuitive, they would actually aid in ensuring the production of quality product in a better way, than running at constant process settings over an extended period of time without the constant assessment of system health.

Continuous manufacturing process monitoring of pharmaceutical solid dosage form: A case study.

Continuous Manufacturing (CM) of pharmaceutical drug products is a rather new approach within the pharmaceutical industry. In the presented paper, a GMP continuous wet granulation line used for clinical production of solid dosage forms was investigated with a thorough monitoring strategy regarding process performance and robustness. The line was composed of the subsequent continuous unit operations feeding - twin-screw wet-granulation - fluid-bed drying - sieving and tableting; the formulation of a new pharmaceutical entity in development was selected for this study. In detail, a Design of Experiments (DoE) was used to evaluate the impact of the three main factors (amount of water, filling rate, and shear force in twin-screw granulator) on the tablet quality. The process was monitored via in-process control (IPC) tests (e.g. weight, hardness, disintegration, and loss-on-drying), Process Analytical Technologies (PAT), and through the analysis of the process parameters (multivariate process control). The tested formulation was very robust to the large process variation of the DoE: all IPC results were in specification, the PAT probes provided stable results for the content uniformity and no critical variations can be detected in the process parameters. An adequate monitoring strategy was presented and the robustness of the process with one formulation has been demonstrated. In summary, this continuous process in combination with smart formulation development allows the robust production of constant quality tablets. The synergy between PAT, process data science and IPC creates an adequate monitoring framework of the continuous manufacturing line.

Orthogonal Redundant Monitoring of a New Continuous Fluid-Bed Dryer for Pharmaceutical Processing by Means of Mass and Energy Balance Calculations and Spectroscopic Techniques.

In line with the ongoing shift from batch to continuous pharmaceutical production of solid oral dosage forms, a novel continuous fluid-bed dryer was developed. The forced feed nature of the Glatt GPCG2 CM fluid-bed dryer allows continuous, first-in-first-out drying of wet granulate materials based on its compartmentalized, rotating fluidizing chamber. The presented work aims to introduce the dryer's functionalities in detail, and to demonstrate that the rotating fluid-bed chambers facilitates a stable drying behavior, which ensures robust and repeatable residual moisture contents (loss-on-drying [LOD]) of the discharged granules. Furthermore, a mass and energy balance (MEB) is derived, based on the logged process values of the granulating and drying units. Two independent test experiments demonstrate that precise LOD prediction in real time is achievable by MEB to serve as an orthogonal process analytical technology method to common near-infrared spectroscopy. On average, MEB results differed by 0.36% LOD (absolute) from offline reference analyses, and by 0.61% LOD from predictions made with an in-house available near-infrared spectroscopy method. Furthermore, good correlation between the observed and expected thermal energy loss was found. The derived MEB is solely based on physical principles; hence it is product independent and transferable to other materials that are processed on the described equipment.

Real-time monitoring of particle size distribution in a continuous granulation and drying process by near infrared spectroscopy.

In continuous granulation, it can be important to control granules particle size distribution (PSD), as it may affect final product quality. Near infrared spectroscopy (NIRS) is already a routine analytical procedure within pharmaceutical continuous manufacturing for the in-line analysis of chemical material-characteristics. Consequently, the extraction of additional information related to granules' physical properties like particle size distribution is tempting, as it would enhance process knowledge without the need for new capital investments. Three in-line NIRS methods were developed via partial least squares regression, to predict dried granules PSD-fractions X10, X50, and X90 within a GMP-qualified continuous twin-screw wet granulation and fluid-bed drying process. Methods were developed for the size range of 20-234 µm (X10), 98-1017 µm (X50), and 748-2297 µm (X90) and assessed with one internal and three external validation datasets in agreement with current guidelines on NIRS. Internal validation indicated root mean square error of predictions (RMSEPs) of 17 µm, 97 µm, and 174 µm, for PSD X10, X50, and X90 respectively, with acceptable linearity, slope, and bias. Furthermore, the ratio of prediction to deviation (RPD), the ratio of prediction error to laboratory error (PRL), and the range error ratio (RER) were evaluated, with all values within the acceptance range for adequate to good NIR methods (1.75 > RPD < 3, PRL ≤ 2, RER ≥ 10). Methods applicability to in-line processes and their robustness towards water content and active pharmaceutical ingredient content was further demonstrated with three independent in-line datasets in real-time, showing good agreement between predicted and reference values. In summary, methods demonstrated to be sufficient for their intended purpose to monitor trends and sudden changes in dried granules PSD during continuous granulation and drying. Because of their fast response time, they are unique tools to characterize the dynamic behavior and navigate the agglomeration state of the material in static and transient process conditions during continuous granulation and drying.

Process analytical technology for continuous manufacturing tableting processing: A case study.

The use of Near Infrared Spectroscopy (NIRS) as a fast and non-destructive technique was employed for the control and monitoring of the tableting step during a continuous manufacturing process. Two NIRS methods were optimized in order to in-line control the blend uniformity in the tablet feed frame and the API concentration of freshly pressed tablets prior the ejection. The novelty of this work first lies in the acquisition speed of NIR spectra reaching up to 70,000 tablets/h. Partial Least Square (PLS) regression was used as chemometric tool for the computation that resulted in excellent predictive calibration results. A coefficient of correlation (r) value of 0.99 was obtained for both probes. The root mean square error of calibration (RMSEC) and the root mean square error of prediction (RMSEP) were respectively 1.8% and 1.8% for active content in the tablet feeder and 2.2% and 2.3% for the tablet content. In addition, calibration performance and robustness of the methods were evaluated. Moreover several qualitative methods were proposed to monitor the tableting process in different stages of development (single wavelength, Principal Component Analysis, and Independent Component Analysis). In early phase development, the requirement/quality of the input material is not established yet; hence the use of a qualitative approach allows to confirm the suitability of the PAT methodology for in-process material monitoring & control. Later, the qualitative approach constitutes the foundation for the quantitative approach when input materials are fixed and larger production size occurs. The proposed strategy is a performant PAT tool for continuous manufacturing and a step forward to real time release.

Evaluation of Heat Flux Measurement as a New Process Analytical Technology Monitoring Tool in Freeze Drying.

This study investigates the suitability of heat flux measurement as a new technique for monitoring product temperature and critical end points during freeze drying. The heat flux sensor is tightly mounted on the shelf and measures non-invasively (no contact with the product) the heat transferred from shelf to vial. Heat flux data were compared to comparative pressure measurement, thermocouple readings, and Karl Fischer titration as current state of the art monitoring techniques. The whole freeze drying process including freezing (both by ramp freezing and controlled nucleation) and primary and secondary drying was considered. We found that direct measurement of the transferred heat enables more insights into thermodynamics of the freezing process. Furthermore, a vial heat transfer coefficient can be calculated from heat flux data, which ultimately provides a non-invasive method to monitor product temperature throughout primary drying. The end point of primary drying determined by heat flux measurements was in accordance with the one defined by thermocouples. During secondary drying, heat flux measurements could not indicate the progress of drying as monitoring the residual moisture content. In conclusion, heat flux measurements are a promising new non-invasive tool for lyophilization process monitoring and development using energy transfer as a control parameter.