Figure 4: Performance of the buffer management system during 11 days of operation of a continuous antibody production.
The requirement on quality analysis can be handled almost in the same way as the buffer management system. As discussed above the continuous downstream process could assume the conditions in the harvest tank to be almost constant or changing very slowly. A set of performance and quality attributes were measured through chemical analysis of samples taken from different positions in the process flow path once a day. The sampling of the flow path were performed by the automation system but the chemical analyses were performed off-line and the actual attribute were calculated after the process were completed. The quality analyses were not used for monitoring of the operation, which would had been beneficial.
In lab-scale continuous downstream process there is no need to sample the flow path more often than a couple of times per day for any upstream based disturbance, based on the slow upstream dynamics compared to downstream. Assume that an HPLC analysis of a quality attribute takes 30 min and it is performed twice a day, then the HPLC is idle 23 hours every day. A general analysis system like HPLC can be configured to do a set of different analysis. If an analysis takes, in average, 30 min to perform it means that an on-line HPLC can handle almost 50 analysis per day. In lab-scale development resources are limited and an on-line HPLC needs to handle all on-line analysis in the processes. One such system was implemented and studied in Tallvod et al 2023 and 2022B. It is called quality analysis system, QAS. The physical configuration of the QAS was composed of two setups, one for sample handling and preparation, and a second dedicated analysis system, here a HPLC. The preparation setup handled the sample from the process and performed needed preparation, like dilution, conditioning buffer exchange and chemical modifications. The second setup, the HPLC, were configured to perform a set of different analysis. The automation part of the QAS is composed of three parts; i) sampling of the processing flow path, ii) queue system for orders of needed analyses iii) prepare the sample for analysis, and iv) preform the HPLC analysis and send data to database, see Figure 5.
The client application procedure does the necessary operations to do the actual sampling of the processing flow path. This sampling operation can be performed on demand based on an external order or by the client itself. The sampling can be a small amount directed to a sample loop or a complete pool shortly stored in a container, which is then pumped into a sample loop, before further processing in the process. The size of the sample depends on the analysis and the number of differ of analysis needed. Each sample point in the downstream process has a collection loop on the preparation system. When the sampling of the process flow path is completed, an order for analysis is sent to the QAS queue controller.
The queue in the queue controller, in an orbitX controller, is a first-in-first-out, but it is possible to rank the analysis in an importance order. Particularly if a time-critical-analysis is need for on-line control, which means that the analysis needs to be performed to generate a result in a given timeframe. The queue controller adds new orders into the queue and removes orders that are completed.
When the preparation/analysis unit is ready, it gets the first order in the queue from the controller. When the unit has performed the analysis it communicates that the analysis has been done and the queue controller removes the order from the queue. Note that the order can contain multiple analysis for different attributes. The generated data from preparation and analysis is sent to the Orbit database for further data processing. In some situations, it is convenient to do the data analysis locally, which is straightforward to do as a computation extension in the local Orbit controller.