The aim was to determine robust and stable continuous manufacturing process settings, by devising a design space based on the investigation of lubrication dependent attributes which would influence continuous direct compression tableting of high dose paracetamol tablets. The obtained data verifies that a continuous manufacturing process is feasible for high dose direct compressible paracetamol tablets. The material properties of the main components have the most important influence on the process performance of a continuous manufacturing process. In this current study, the accuracy of feed rate of pre-blends was excellent. Interestingly, a high variation in the feed rates of lubricants did not exert a negative effect on the final product quality. It can be concluded that high variation in feed rates of lubricants could be eliminated with the good flow rate of main components and efficient blending unit operation. The type and concentration of lubricant had the greatest statistically significant effect on the studied responses. Stearic 67
acid was better than magnesium stearate. The selection of lubricant type and its concentration have an effect on the dissolution profile only at the beginning of the dissolution (at the dissolution time point of 2.5 min), the ejection force, tablet strength and flowability. It can be concluded that continuous direct compression tableting process is rather insensitive and robust with respect to variations in lubrication. The process parameters have only a slight influence on the tablet properties. Adjusting the total feed rate and selection of inlet port might alter the flowability properties and maximum ejection force. Based on the tableting results, even a high variation in the feed rate of lubricants had no influence on the tableting process or the quality of the final product.
However, the process parameters did not affect the quality of the tablet properties; in contrast, formulation parameters did exert a major influence on the properties of the end product. The created design space showed that this type of continuous manufacturing process line is suitable for producing high dose direct compressible paracetamol tablet which possessed a predetermined acceptable quality. However, in the future, longer runs should be completed to observe whether the quality of the product can be preserved as a function of time.
Acknowledgements
Authors gratefully acknowledge Vitabalans Oy for providing materials to this study. The authors also thank the PROMIS Centre consortium, funded by Tekes (A31473) (ERDF), the North Savo Centre for Economic Development, Transport and the Environment, for providing excellent research facilities. Jari Leskinen is acknowledged for his assistance in SEM images. Göran Salminen and Pasi Tapanainen are acknowledged for their assistance in setting up the dissolution and analysis method.
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5 THE EFFECTS OF UNINTENTIONAL AND INTENTIONAL PROCESS DISTURBANCES ON TABLET QUALITY DURING LONG
CONTINUOUS MANUFACTURING RUNS
2ABSTRACT
Several kinds of process disturbances can occur during (continuous) tablet manufacturing, i.e. unintentional or intentional disturbances. Long run-time continuous manufacturing studies are used to investigate the effects of intentional and unintentional deviations. In this study, the horizontal continuous manufacturing line included a double mixing - direct compression set up. The study consisted of two long duration test runs.
In the first run, the API (paracetamol) was fed in during the first feeding and blending stage with lubricant (Mg.Stear.) added during the second feeding and blending stage. In the second run, the API and lubricant feeding stages were reversed. The run protocol included a long run with several feeder re-fills and an overnight hold-time, continuing with the same API concentration followed by a change to a higher API concentration on the fly (without cleaning). The objectives of this pilot study were to determine the intentional (e.g. overnight hold time, product concentration change) and unintentional (e.g. equipment or software failures) deviations, which could affect the critical quality attributes (CQA's) of the final product and to create a deviation document which would reveal the changes that had occurred in the product concentration during the runs.
Another goal was to study the effect of feeding location of lubricant and API feeding. The CQA's were the assayed values of API, tablet strength, friability, tablet weight and its dissolution profile. The vacuum conveyors, which were needed to transfer materials in the horizontal set-up, were observed to introduce variation into the mass flow rates and feeding. Thus, there were significant challenges to ensuring a constant mass flow rate during the runs. One expected effect was that over-lubrication was evident when the lubricant was fed during the first feeding and mixing stage, resulting in a significantly reduced tablet strength and a slower dissolution of API. There were no observable trends over time in the process parameters or CQAs i.e. evidence of a stable process. The overnight hold-time did not affect the CQAs of tablets. Moreover, the variation in all CQAs was smaller after the overnight hold-time which was particularly unexpected. In conclusion, the results reveal that the process itself was able to produce a quality end product, but the set-up needs to be better designed and controlled to ensure a constant mass flow and prevent over-lubrication.
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2 Adapted with permission of Elsevier from: Taipale-Kovalainen K, Karttunen A-P, Niinikoski H, Ketolainen J, Korhonen O. The effects of unintentional and intentional process disturbances on tablet quality during long continuous manufacturing runs. European Journal of Pharmaceutical Sciences. 129: 10-20, 2019
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5.1 INTRODUCTION
In recent years, there has been increasing interest towards the continuous manufacturing of drug products and this is being already utilized by some pharmaceutical companies.
Marketing Authorization (MA) has been approved for a few continuously manufactured products, i.e. Orkambi, Symdeko, Prezista (Continuous Manufacturing Symposium, 2014). There are several approaches to integrating different unit operations into a continuous manufacturing line (Badman and Trout, 2015; Singh et al., 2013). The manufacturing line can consist of many units such as feeders, mixers, vacuum conveyors, roller compactors and a tablet press. Most of the direct compression lines are constructed with a top-down set-up but less attention has been paid to the horizontal set-up with multiple integrated unit operations. Although, continuous wet granulation and drying set-up has been studied (De Leersnyder et al., 2018). The processes can be end-to-end, where the drug substance and product manufacturing are integrated into the same continuous process or the drug substance is produced separately (Burcham et al., 2018).
It is also possible to have a hybrid semi-continuous process combination of batch and continuous process steps. Furthermore the quasi-continuous processing, including multiple production steps in small sub-batches can improve the productivity e.g. the granulation step in continuous manufacturing (Werani et al., 2004).
Under industrial conditions, it is not uncommon that disturbances or variability may occur during the manufacturing process, i.e. equipment failures or changes in material attributes such as variations inside or between the raw material batches (particle size distribution, water content or electric charge of particles). These variabilities can be intentional or unintentional and their consequences expected or unexpected (Holt, 2018).
Thus, during the process and formulation development, it is very important to study both intentional and unintentional process and formulation events in order to gain a deeper understanding of the entire process. All pieces of equipment and unit process have their own typical start-up and shut-down behaviors, which need to be understood and controlled (Almaya et al., 2017). The critical quality attributes (CQAs) differ with each material, product and line, thus CQA's must be determined separately for each product and line. Similarly, each product and line have different flow and mixing behavior that affect the residence time distribution (RTD) of the material which needs to be characterized. Disturbances can be tracked through the continuous process line using RTD. It is also used in building a control strategy (Mangal and Kleinebudde, 2017, Van Snick et al., 2017, Kruisz et al., 2017). The knowledge of RTDs can be utilized for batch definition in the production and it is also needed when making product changes on the fly (Engisch and Muzzio, 2016).Furthermore, RTDs can be utilized to increase understanding of the manufacturing process in development studies (Gao et al., 2011;
Vanarase et al., 2013). Nasr et al. (2017) have claimed that normally there are no steady state conditions in continuous manufacturing due to the disturbances occurring in the process. The main goal is to keep the process parameters within a range of target values.
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Portillo et al. (2010) observed that variations in the mixing parameters, i.e. rotation rate and flow rate exert a significant influence on outputs. Van Snick et al. (2017) demonstrated that the concentration of MgSt had a significant impact on the variability of feeding, but the robustness in combatting feeding disturbances could be improved by optimizing the mixer impeller configurations. Material attributes have also been studied in our previous study with a top-down continuous direct compression manufacturing process (Taipale-Kovalainen et al., 2018). The studied process parameters had only a very minor effect on the quality of the final product and the design space. It has been reported that both the feeding rate of MgSt and the location of the MgSt inlet port in the mixer can influence the variability in the mass flow properties. It was concluded that the continuous direct compression tableting process itself was insensitive and was able to cope with changes in lubrication, whereas formulation parameters (Lakio et al., 2017) exerted a major influence on the quality of the end product.
Pre-development studies which investigate the impact of multiple disturbances (unintentional or intentional) on the product quality attributes during long runs, especially with a continuous horizontal process line, are needed to understand the capabilities of the line. Vargas et al. (2018) developed a monitoring and control system for an FDA approved commercial manufactured product and provided details of a 28 h long continuous manufacturing run capable of achieving a stable product quality. Berthiaux et al. (2008) revealed that mixer speed and the re-filling of feeders influenced the homogeneity of API. These operations need to be stopped during filling of the feeders to prevent the risk of variations in API homogeneity, as the volume of the feeders will affect the precision and sensitivity of feeding. In the literature, unknown deviations, failures or intentional disturbances have not been systemically measured and documented during long continuous manufacturing runs. According to ICH Q10, all process deviations should be documented and analyzed in a regulatory and quality manner. This kind of industrial-like approach should be conducted with long runs utilizing an operation with multiple integrated process units. The literature describing continuous manufacturing has described runs of only short durations, thus this recent development study is clearly needed to help in future continuous process optimization and feasibility studies. The aim of this study was to reveal the intentional and unintentional deviations which could affect the quality of the final product (CQAs) and to create a deviation protocol, which would highlight the effects of alterations in product concentration occurring during the run including those conducted on the fly (without cleaning). Other goals were to study the effect of inlet location of lubricant and API feeding in a long run continuous manufacturing process involving several units and to study the stability of the process throughout the processing time.
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