5.6 Conclusion
6.3.12 Dissolution profile
The dissolution rate was clearly lower in batch based HSWG tablets than in the continuous RC tablets, but nonetheless the dissolution fulfilled the requirements at the time point of 15 minutes according to QA (Table 14), being 87.3 % (HSWG 5kg/h) and 88.1
% (HSWG 15kg/h) (Figure 40). Only minor variations were observed between RC runs, and thus it can be concluded that feed rate and the intra-granular lubricant concentration did not exert any effect on the dissolution profile of tablets from the RC runs. Granule porosity has been found to correlate with the final blend compaction and tablet dissolution (Tao J, et al, 2015), which could explain the results. Furthermore, it can be concluded that the dissolved amount fulfilled the similarity requirements (EMA, 2010) in all runs. The dissolution profiles are shown in Figure 40. Dissolution data is presented in more detail in Supplementary data.
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Figure 40. Dissolution profiles of HSWG and RC runs. Error bars are excluded for the sake of clarity.
6.4 CONCLUSION
The change of the manufacturing principle from HSWG to DG is a challenging task, although the motivation behind this change lies in being able to exploit the more simple and attractive continuous manufacturing technology. In this comparative study, this change was examined by minimizing the effects of formulation by keeping the formulations as similar as possible. This indicates that the change of the manufacturing principle from HSWG to continuous manufacturing DG can be a relevant way to enhance productivity.
Some important details in relation to continuous RC manufacturing process were revealed in this study. With the formulation including MCC as main component and 25mg/tbl ketoprofen as the API, the location of lubricant feeding could be observed to influence the compression force. No evidence of over-lubrication was detected, but there was a clear effect of the feeding location of the lubricant to the final product: a higher amount of lubricant inside the granules led to a lower compression force in both studied feed rates.
The studied processes were rather stable, and observed variations seemed to have only minor influence on the final product. The RC granules had slightly poorer flow properties than their HSWG counterparts, still without having any notable effect on tablet weight.
The tableting compression force was stable, but a higher compression force was needed for DG than for HSWG during the tableting process. Furthermore, the tablet breaking force was lower in the continuous RC runs than in batch based HSWG runs. This might be partially due the study set-up, since the granules seemed to lose some of their compactability properties during the roller compaction before the actual tableting, which is of course one known disadvantage of dry granulation. A decreased tablet mass with a
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higher total feed rate in RC runs gives an indication of another drawback underlying this process change; the poorer flow properties of RC granules might set limitations on higher production speeds. This is only a very preliminary observation because the tablet press settings were not optimized in this study for different production speeds, and these could have compensated for the differences. The expected outcome was observed with the dissolution rate as it was lower with HSWG tablets than with their DG counterparts, which could be due to the stronger granule and tablet structure of HSWG granules.
However, with both manufacturing methods, the dissolution rate of API fulfilled the similarity requirements for an immediate release tablet.
This study investigated the possibilities to convert a batch based HSWG process to a continuous RC process by adopting a flexible and effective approach i.e. changing towards a more modern manufacturing process. On the basis of the results of this study, it is concluded that in the future, if a good product/process understanding of the alternative manufacturing process with different techniques can be obtained, it will be possible to devise more flexible and effective ways to allow the pharmaceutical industry to switch from batch manufacturing towards CM.
Acknowledgements
Krista Taipale-Kovalainen gratefully acknowledges the material support from Vitabalans Oy. The authors also thank the PROMIS Centre consortium, funded by Tekes/Business Finland (ERDF), the North Savo Centre for Economic Development, Transport and the Environment, for providing excellent research facilities. The authors acknowledge Prince Bawuah for his help during the test runs with the continuous manufacturing line.
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7 GENERAL DISCUSSION AND FUTURE PERSPECTIVES
It is evident that the transition from a conventional batch process to a continuous process has proved to be a challenging problem for the traditional pharmaceutical industry. In 2019, FDA published a new draft guideline Quality considerations for continuous manufacturing that addresses quality aspects in the continuous manufacturing of medicinal products. This was concerned with hot topics, challenges and efforts related to development, process validation, marketing authorisation and routine production.
Nonetheless, it represents an important step in harmonizing the concept of continuous manufacturing in the global pharmaceutical field. By including these possibilities in the list of definitions that are needed for submission, these regulatory efforts are an opportunity to convince the traditional pharmaceutical industry, which is based mainly on batch mode, to switch to CM. However, there are still not any real global harmonized regulatory approval processes for CM (country-specific nor global ones) (Moghtadernejed et al., 2018). The need to take into account environmental issues is also a relatively new challenge faced by the pharmaceutical industry. It has been estimated based on experimental results obtained from a pilot plant stage, that the amount of detergent needed for cleaning steps in CM can be reduced by 95% as compared to batch production manufacturing (Grundemann et al., 2012). There are virtually no studies of this area concerning CM pharmaceutical processes. This is noteworthy, as residues are strictly controlled.
The challenges are the global level issues e.g. how to make patients aware that if they choose a product produced by a continuous process, then its carbon footprint is much smaller. The real weakness lies in the lack of knowledge in the area of continuous manufacturing. Continuous manufacturing is a new way of thinking about manufacturing pharmaceuticals and if employees are not encouraged to work towards CM, it is evident that its implementation will be negligible. Consulting CM experts could offer a competitive advantage to a pharmaceutical enterprise, as incorporating these new ways of manufacturing and working does represent a highly attractive and efficient working environment. Instead of simply operating the continuous process, the employee must be able to monitor the process and obviously this requires a much deeper knowledge of the process itself and increases the demand for training. The intention of this present thesis study was to show good ways that the pharmaceutical industry could be encouraged to adopt CM. And the best way to achieve this goal is that their employees should acquire a deeper knowledge of the function of the whole process line.
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Thus more professionals would be needed with experience and knowledge of implementing CM in the manufacturing plant (Moghtadernejed et al., 2018). Material tracebility and batch definition are significant challenges, demanding a knowledge of the experimental determination of residence time (Billup and Singh, 2012). Thus, the CM experts are the key factor in the implementation process of CM. While compared to the traditional batch manufacturing methods, the material consumption would probably be about the same if a batch of the same size (production rate and time for tableting) was produced. Usually in batch processing, if one wishes to increase the batch size, then larger equipment is needed, and the new equipment can vary in its design. Thus, more runs compared to continuous manufacturing are needed. This is reflected in larger material consumption if batch processing is used. The clear advantage of using CM is that one can increase the batch size simply by varying the feed rate or prolonging the process time with the same continuous manufacturing set-up without the need to change equipment.
When performing process and product development studies with CM, another clear strength is also the possibility to have a smaller production rate e.g. lower material consumption. For the pharmaceutical industry, this kind of flexibility would be a huge advantage i.e. the batch size can be altered based on the development phase or market demands by using the continuous manufacturing process.
This dissertation “Impact of formulation and process design on tablet quality in continuous manufacturing” demonstrates to the reader the context of the continuous manufacturing from a pharmaceutical industrial perspective and how the guidelines can encourage the changeover towards continuous production. The aim was to highlight the benefits as well as pointing out the challenges of continuous manufacturing process, and to help the reader to understand the differences between batch and continuous manufacturing.