Evaluation of use of the Standard Framework in Construction of mAb

The mAb model was based on two previous models built during the design stages of the process. The functionality of the new model compliments the new scope which has various overlaps with the scopes of the original models. In order to understand and evaluate the value of using the Standards Version 2 framework to construct the mAb model a qualitative analysis must take place. In an ideal world, a quantitative analysis would also be performed however it is exceedingly difficult to quantify the comparison between the process of two construction methods. What can be offered is the feedback from the end users and the validation outcomes of data/trend verification, using the requirement specifications as a guide.

Intuitive to user

Under Chapter 3 it was discussed that in order for a model to be intuitive to the user, certain guidelines can be followed, as given by Valentin and Verbraceck (2002).

These are that the ‘Interactions between model parts...should represent interactions in the real system’, ‘Use concepts that represent functionalities as found in reality and that can be used for visualisation purposes’ and ‘Visualise a system in such a way that complexity is reduced but the essential processes are still shown’. The latter point simply ensures that the level of detail built into the model, both in terms of coding and blocks, is sufficient to meet the immediate scope and likely additions in the future (in order to maximise reusability) but no more. This works on two levels;

firstly, limiting the level of detail to the necessary amount limits the resulting model run time and secondly, the risk of confusing the user is minimised if they can associate the level of detail with the well defined model scope. The first two points ensure that the visual parts of the model represent the real system so that the user can easily associate model elements to the system elements. In the case of mAb the user does not see the actual model itself (unless structural changes are being made) and only the input/output Excel files are seen. These however, as stated under the next section, have been designed to maximise user intuitiveness.

Relevance and Ease of Data Input/Output

In order to enter data into the database, the original models used the SDI link offered by the Extend platform. This meant that: the database source within Excel had to

have the SDI structure, the Excel database would have to be manually exported and imported in order for any changes to be applied in the model and the Extend file would have to be accessed in order to achieve this.

The new model however has been built such that the Extend file need never be seen by the end user unless they need to make structural changes to the model. The input file or the source database has a user-friendly structure which industrialists have indicated is in the format that they are used to seeing. Using a macro the Extend model automatically imports the data it needs, runs and then outputs the results into a different Excel file where the data is already set up to be in a user friendly format, with Gantt charts and tables of data summarising the process output. This method of construction means that an end user can easily vary any input parameter (all parameters have been set to be variable) and needs not have any Extend experience.

Maximised reusability and sustainability

The inputs and outputs to the mAb model are quite extensive, covering labour/operating shifts, utilities usage, multiproduct changeover and mass balancing.

The number of fermenters can also be changed by inputting the number desired, although greater than four 5k fermenters will require a structural change. Currently the facility is set to be used for one product only however a number of monoclonal antibody products could be manufactured using the same platform process. The set up of the model accommodates for the introduction of these new products, but with a maximum of three different products produced in the facility during any one year or model time horizon. This limit reflects the typical number of products expected in a commercial facility (personal communication, Roger L Scott, Eli Lilly, Indianapolis) Also, the use of the mAb model to perform the deterministic and scenarios analysis is a further testament to its capabilities. In this chapter is has been shown that the robustness of the system can be tested through a deterministic analysis, very simply carried out by changing the input parameters made readily available to the user. The scenarios analyses have also shown that more in-depth analysis can be made, making the model a useful decisional tool in strategic analysis based on future uncertainties.

The following chapter will go on to illustrate the models capabilities in a multiproduct setting.

5.5 Conclusion

Much like the BioSynT case, the mAb case study was used to demonstrate the ability of a model, built using the standard version 2, of being used as a decisional tool. A deterministic study was first carried out in order to determine those parameters whose variability would significantly impact the output metric, kg throughput. It showed that at different titres, different parameters had impact, with the capture column parameters becoming more significant as the titre increased.

A stochastic study was then carried out using the results of the deterministic analysis, looking at the impact of different scenarios combined with process uncertainties to determine how these would affect the running of the process. Combining these with a cost analysis of various process options it was found that at all titres it would be beneficial to upgrade the resin used for the capture step in order to gain a higher dynamic binding capacity and that a new column (for increased height) would give greater process binding efficiency.

Furthermore, in order to achieve a % process throughput of greater than 95%, the failure rate would have to remain below 3% for all titres.

The study also found that as the number of cycles allowed increases, the % processed increases also. When the limit equals the required split, % Processed jumps to 100%.

At 4.5g/L, this is 18. At 10g/L this would be 40. Therefore, an alternative to making expensive column changes would be to increase the split ratio limit.

Finally the mAb case study was used to implement the Standard Framework 2, testing its ability to guide the construction of a manufacturing capacity management model capable of meeting the requirement specifications stated under the standard. A qualitative analysis showed that these were met to a far greater degree than illustrated with the BioSynT model, with significant improvements in model development time, user intuitiveness, reusability and sustainability, and ease of data input/output. Some shortcomings were also identified however (as discussed in Chapter 3) which necessitate further development of the standard framework.

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