Is a minimum FH necessary?

The initial qualification of a Depyrogenation Tunnel has the greatest technical scope within the life cycle of this equipment referred to validation tasks.

At this step, not only are the verification associated with the IQ and the OQ carried out, but as part of the performance qualification, studies related to heat penetration are developed for each of the formats that′ll ?be used, determining in turn the worst case, which will become the objective to be demonstrated in each of the subsequent re qualification, unless changes are made to the operating parameters of the equipment or other vial formats are added.

In heat penetration studies, the worst case is established, that is, the vial format combined with the temperature parameters in the sterilization/depyrogenization zone, speed of movement of the belt, a variable that defines the exposure time, where reaches the smallest value of accumulated lethality according to:

In our study case, it was found that 100R size, with a temperature of 290℃ in the depyrogenation zone and a speed belt of 81 mm/min, reached the lowest value of accumulated lethality, compared to the rest of the size used (Tables #1 and #2).

These results led to selecting the size of the 100R vials for the endotoxin challenge, under the same working conditions mentioned above.

?The endotoxins challenge reduction studies were carried out in three runs, and the results associated with the accumulated lethality in each one showed in Table #3.

The values of residual concentration of challenge endotoxins subjected to the depyrogenization process showed that, for the parameters of temperature and belt velocity, there weren′t reduction above or equal to the acceptance criterion of 3 logarithmic in any of the three runs.

Since there is no minimum FH value stated or recommended, even in technical papers or guidelines such as PDA Technical Report 3, where is stated that: “There is no minimum FH-value acceptance criterion for depyrogenation. Endotoxin inactivation efficacy cannot be accurately correlated with standard dry-heat lethality conventions (FH) which rely upon a linear destruction model.” (1), these studies should be developed until the end with the waste of time and resources.

Taking into account the results achieved in reduction of EU used as a challenge were not higher than of 3 log reduction, we had to rise the value of temperature from 290℃ to 305℃ for this size, keeping the rest of the parameters with the same values.

The heat penetration study was repeated for the 100R size, evaluating the position of the basket where the thermocouples were placed to determine the two points with the lowest accumulated lethality.

The results of these studies are showed in Table #5

For this new condition, the 3 runs were repeated and the results are shown in tables 6 and 7 respectively.

Conclusions

?Although there is no regulatory acceptance criterion for dry heat depyrogenation processes, they remain as particular experiences for the validation specialist based on which FH values to make changes to the operating parameters of a Tunnel or oven used for this objective, in such a way that highly time-consuming and resource-consuming studies such as LAL reagents are avoided, while at the same time the regulatory criterion of achieving at least a reduction of 3 logarithms in the reduction of the concentration of challenge endotoxin.

?Bibliography

?1. Technical Report No. 3. Validation of Dry Heat Processes Used for Depyrogenation and Sterilization.