5.4 Residence time distribution calculations
5.5.10 Process deviation documentation during the long runs
This set-up of continuous direct compression manufacturing process was monitored, and process parameters adjusted manually if disturbances/deviations were observed. The data was recorded using in-house software and all the disturbances and deviations were documented. These disturbances and deviations are listed in Table 11 and Table 12. This is the first time that this kind of list of process deviation document is published with respect to a continuous manufacturing process. As can be seen in Table 11 and Table 12, many intentional and unintentional deviations occurred. This was mainly due to the set-up and arrangement of the unit processes. In order to achieve a synchronized mass flow rate through all unit processes, the mass flow of API feeder and pre-mix feeder were adjusted and reduced to 5% (as the formulation was kept the same). This 5% adjustment was performed in both runs before and after the overnight hold time. The flow of all other feeders was increased to 10% only in run 2 before the overnight hold time (Table 11, Table 12). The mass stream was monitored by visually inspecting the fill level in tablet press hopper and corrected by adjusting the mass flow, since the tableting speed was kept constant. The mass flow was adjusted either by switching off the feeders (i.e. at time point of 2 h 47 min 5 s in run 1), by switching off the tablet press (several times) in the run 1 or by adjusting feed rates down by 5 or 10% in the run 2. All these corrective actions were applicable, however adjusting feed rates down was the best corrective action since this creates perhaps the smoothest effects on the mass flow and minimizes the interruptions 85
for tableting. Switching off the tablet press in run 1 had to be done since there were malfunctions with the second conveyor (not releasing product to the press) and the blend in the tablet press hopper went low fast which would have started to affect the filling of the dies. As can be seen from Table 11 and Table 12, the mass flow rates were more often decreased than increased. This is an indication that the amount of the blend in the tablet press hopper tended to be constantly increased during the runs. Thus, the mass flow rates were lowered in the feeding to the second mixer.
Table 11. The process deviation documentation during run 1.
Time Disturbance/deviation 0 Start-up the process I 5 s Normal delay in start-up I 13 min 43 s Tablet press start-up I
17 min 36 s Tablet press shut-down (mass level not acceptable) U 18 min 13 s Tablet press re-start U
1 h 4 min 30 s Feeder 5 re-fill U 1 h 7 min 25 s Feeder 5 re-fill stopped U
1 h 24 min 28 s Tablet press shut-down (software failed) U 1 h 25 min 36 s Tablet press re-start U
1 h 27 min 13 s Tablet press shut-down (mass level not acceptable) U 1 h 29 min 53 s Tablet press re-start U
1 h 34 min 5 s Feeders 4, 5 and vacuum 2. Shut-down U 1 h 36 min7 s Feeder 1 re-fill U
1 h 39 min 5 s Feeder 1 re-fill stopped U 1 h 41 min 10 s Feeders 4,5 and vacuum 2. Re-start U
1 h 48 min 23 s Tablet press shut-down (mass level not acceptable) U 1 h 50 min 23 s Tablet press re-start U
2 h 27 min 13 s Tablet press shut-down (mass level not acceptable) U 2 h 27 min 30 s Tablet press re-start U
2 h 32 min 21 s Tablet press shut-down (mass level not acceptable) U 2 h 32 min 43 s Tablet press re-start U
2 h 38 min 8 s Feeder 5 re-fill U 2 h 40 min Feeder 5 re-fill stopped U 2 h 45 min Feeder 2 re-fill U
2 h 47 min 5 s Feeder 4 and 5 shut-down (too much mass) U 2 h 49 min Feeder 2 re-fill stopped U
2 h 52 min Feeder 3 re-fill U 2 h 54 min 10 s Feeder 4 and 5 start-up U 2 h 55 min Feeder 3 re-fill stopped U
2 h 55 min 43 s Tablet press shut-down (mass level not acceptable) U 2 h 57 min 43 s Tablet press start-up U
3 h 0 min 28 s Tablet press shut-down (mass level not acceptable) U 3 h 3 min 28 s Tablet press re-start U
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Time Disturbance/deviation
3 h 9 min 3 s Tablet press shut-down (mass level not acceptable) U 3 h 9 min 54 s Tablet press re-start U
3 h 50 min 33 s Tablet press shut-down (mass level not acceptable) U 3 h 51 min 58 s Tablet press start-up U
4 h 2 min Feeder 5 re-fill U 4 h 3 min Feeder 5 re-fill stopped U
4 h 15 min 43 s Tablet press shut-down (tablets were jammed) U 4 h 17 min 3 s Tablet press re-start U
4 h 24 min Feeder 4 and 5 re-start U 4 h 55 min Feeder 1 re-fill U 4 h 57 min 47 s Feeder 1 re-fill stopped U 5 h 11 min Feeder 5 re-fill U 5 h 13 min Feeder 5 re-fill stopped U 6 h 17 min Feeder 1 re-fill U 6 h 17 min 54 s Feeder 1 re-fill stopped U 6 h 27 min Feeder 5 re-fill U 6 h 30 min Feeder 5 re-fill stopped U 6 h 35 min Feeder 2 re-fil U 6 h 35 min 37 s Feeder 2 re-fill stopped U 6 h 39 min Feeder 3 re-fill U 6 h 40 min Feeder 3 re-fill stopped U 7 h 18 min 16 s Labview software failed 7 h 28 min 54 s Process shut-down I
Overnight hold time I 0 Start-up the process I 8 s Normal delay in start-up I 0 h 11 min 10 s Feeder 4, 5 and mixer 2. start-up U 0 h 11 min 48 s Tablet press start-up I 0 h 21 min 20 s Vacuum 2 shut-down U 0 h 27 min 20 s All feeders shut-down U 0 h 30 min 16 s All feeders re-start U 0 h 30 min 45 s Vacuum 2 re-start U
1 h 1 min 18 s Tablet press shut-down (mass level not acceptable) U 1 h 4 min 3 s Tablet press re-start U
1 h 19 min Feeder 5 re-fill U 1 h 20 min 55 s Feeder 5 re-fill stopped U 1 h 22 min 35 s Feeder 1 re-fill U 1 h 23 min 30 s Feeder 1re-fill stopped U
1 h 25 min 23 s Tablet press shut-down (software failed) U 1 h 26 min 23 s Tablet press re-start U
1 h 30 min Formulation 2 (feeders 1,2,3) I 1 h 47 min 50 s Feeder 2 re-fill U
1 h 48 min 38 s Feeder 2 re-fill stopped U
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Time Disturbance/deviation
1 h 54 min Feed rates 5% decreased of all feeders U 2 h 45 min Feeders 1,2,3 shutdown I
2 h 51 min 31 s Vacuum 1 shut-down I 2 h 54 min 37 s Feeders 4 and 5 shut-down I 2 h 55 min 32s Mixer 2. shut-down I 3 h Shut-down the process I
3 h10 min 48 s The last tablet sampling was obtained I
(U = unintentional, I = intentional).
Table 12. The process deviation documentation during run 2.
Time Disturbance/deviation 0 Start-up the process I 7 s Norma delay in the process I 1 h 11 min Feeder 2,4 and mixer 2. start-up I 1 h 18 min 14 s Tablet press start-up I 1 h 31 min 35 s Feeder 5 re-fill U 1 h 34 min 35 s Feeder 5 re-fill stopped U 1 h 48 min Feeder 1 re-fill U 1 h 50 min Feeder 1 re-fill stopped U
1 h 58 min 49 s Table press shut-down (mass level not acceptable) U 2 h 1 min 4 s Tablet press start-up U
2 h 51 min 25 s Feeder 2,4 and mixer 2 shut-down U 2 h 55 min 25 s Feeder 2,4 and mixer 2 start-up U 3 h 13 min 20 s Feeder 5 re-fill U
3 h 15 min 30 s Feeder 5re-fill stopped U 3 h 18 min 14 s Tablet press clock failed, re-start U 3 h 24 min Feeder 1 re-fill U
3 h 25 min 46 s Feeder 1 re-fill stopped U
3 h 32 min 19 s Tablet press shut-down (mass level not acceptable) U 3 h 33 min 34 s Tablet press re-start U
3 h 41 min Feeder 2 and 4 feed rate 5% decreased U 3 h 45 min 11 s Tablet press shut-down (tablets jammed)U 3 h 46 min 14 s Tablet press re-start U
3 h 56 min Feeder 1,3,5 feed rate 10% increased U 4 h 15 min 45 s Feeder 2 re-fill U
4 h 16 min 37 s Feeder 2 re-fill stopped U 4 h 20 min 40 s Feeder 3 re-fill U 4 h 21 min 37 s Feeder 3 re-fill stopped U 4 h 22 min 45 s Feeder 5 re-fill U 4 h 24 min 15 s Feeder 5 re-fill stopped U
4 h 26 min Feeder 2 and 4 feed rate 5% decreased U
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Time Disturbance/deviation 4 h 29 min 10 s Feeder 1 re-fill U 4 h 30 min 20 s Feeder 1 re-fill stopped U
4 h 58 min Adjusting the cleaning filter for vacuum1 U 5 h 40 min 35 Feeder 5 re-fill U
5 h 42 min 50 Feeder 5 re-fill stopped U 5 h 46 min 20 s Feeder 1 re-fill U 5 h 47 min 30 s Feeder 1 re-fill stopped U 5 h 57 min Feeder 2 and 4 shut-down U 6 h 6 min 13 s Feeder 2,4 and mixer 2 re-start U 6 h 6 min Tablet press shut-down U 6 h 12 min 44 s Tablet press re-start U
6 h 28 min Feeder 1,3,5 feed rate 10% decreased U 6 h 32 min 52 s Tablet press shut-down (mass finished) U 6 h 34 min Feeder 2,4 feed rate 10% increased U 6 h 33 min 49 s Tablet press re-start U
7 h 3 min 49 s Feeder 2 re-fill U 7 h 4 min 35 s Feeder 2 re-fill stopped U 7 h 8 min 30 s Feeder 3 re-fill U 7 h 9 min 28 s Feeder 3 re-fill stopped U 7 h 13 min 59 s Feeder 1 re-fill U 7 h 15 min 4 s Feeder 1 re-fill stopped U 7 h 16 min 17 s Feeder 5 re-fill U 7 h 18 min 12 s Feeder 5 re-fill stopped U
7 h 34 min 19 s Tablet press shut-down (mass finished) U 7 h 37 min 45 s Tablet press re-start U
8 h 26 min 38 s Labv software failed U Overnight holdtime I
0 Process start-up I
8 s Norma delay in the process I 0 h 8 min 55 min Vacuum 1 start-up I 0 h 33 min 30 s Feeder 2,4 and mixer 2 start-up I 0 h 34 min 40 s Tablet press and vacuum 2 start-up I 1 h 30 min 0 s Formulation 2 (Feeder 2,4,1,3) I 2 h 6 min 40 s Feeder 5 re-fill U
2 h 8 min 15 s Feeder 5 re-fill stopped U 2 h 12 min Feeder 1 re-fill U 2 h 12 min 55 s Feeder 1 re-fill stopped U 2 h 20 min Feeder 2 re-fill U 2 h 21 min Feeder 2 re-fill stopped U
2 h 32 min Feeder 2 and 4 feed rate 5% decreased U 2 h 58 min Feeder 2 and 4 feed rate 5% decreased U 4 h 25 min 26 s Tablet press 37 rpm U
3 h 59 min 20 s Feeder 5 re-fill U 4 h 2 min 3 s Feeder 5 re-fill stopped U
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Time Disturbance/deviation 4 h 2 min 35 s Feeder 2 re-fill U 4 h 3 min 8 s Feeder 2 re-fill stopped U 4 h 20 min Feeder 1,3,5 shut-down I 4 h 21 min 30 s Mixer 1 shut-down I 4 h 26 min Feeder 2 and 4 shut-down I 4 h 27 min 15 s Mixer 2 shut-down I 4 h 32 min 20 s Labv software shut-down I 5 h 18 min 14 s The last tablet samples was obtained I
(U = unintentional, I = intentional).
Figure 35 illustrates the effect of re-fill step of API feeder on the feeding accuracy and tablet strength. As seen in Fig 35a, during the re-fill of the API feeder at the 140 minute time point after the overnight hold time in run 2, the mass flow (kg/h) of API was decreased. By examining the mean residence time distribution value for run 2 (approx.
30.6 min), the effect of the re-fill step should have reached the tablets collected at the 175 minute time point (Fig 35b). It can be concluded that the re-fill steps could not be analyzed clearly from the feeding data nor from the final tablets, due to the variation in the results. As seen in Table 11, Table 12, several additional API re-fill (5 g) were performed to determine if these kinds of short disturbances would be smoothened out in the process or would they still be detectable in the tablets. By applying the mean residence time distribution value for run 1 (approx. 44.3 min), the effect of the API additions should have reached the tablets collected at the 120 minute time point. It is seen that the characteristics of tablet decreased up to 140 min but then started to increased. It seems that the process has a smoothening potential for these kinds of short-term disturbances.
Figure 35. The effect of the re-fill step (at time point 140 min) of API feeder in run 2 after the overnight hold time a) on the mass flow of API (kg/h) and b) on the tablet strength (kP) at the 175 minute time point.
A B
API re-fill API re-fill step reached
the tablet
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