In sterile manufacturing with freeze dryers, CIP process plays an important role to prevent contamination to the product and to comply with current pharmaceutical regulations (CGMPs). Not to mention that a high degree of cleanliness must be secured consistently, batch after batch. It’s clear that the technology and recipe being used impacts considerably in the efficiency and effectivity of the cycle, minimizing also the turnaround time and the water consumption.
The validation method of the CIP cycle is typically done by spraying Riboflavin or even salt all over the chamber components, but this is workable only as a coverage test, typically performed during FAT. To assure the cleanability for a specific drug, a swap or rinse test should be performed instead, where specific recipe parameters are then validated. The validation step is not explained in this article.
Process Contact Parts (PCPs) may become contaminated during each batch, typically by product spillage during product loading & unloading or by flying powder during subsequent steps (backfilling, vacuum, venting, etc.). Therefore, and according to CGMPs, it is required an effective solution that can also be validated time after time. CIP technology applied in freeze dryers has been demonstrated as a reliable method, as it is an automatic and highly reproducible cleaning method, without the direct intervention of an operator. As there are currently many different solutions installed in freeze dryers from different equipment manufacturers, the final solution may significantly vary from one vendor to the other.
Saving cycle time and reducing the water consumption is not an option anymore, especially with the global alignment of SDGs, concretely SDG 12 (Sustainable Development Goal 12 -Sustainable Consumption and Production-). Thus, Testar has dedicated efforts with the development of an important R&D project obtaining very promising results :
– Reduce CIP cycle time – Reduce water consumption – Fulfill GMP and ASME BPE 2019 guidelines – Improve control of water volume to be utilized during the cycle.
Freeze dryers are very far away to be a clear tank. The shelves stack on the middle, vertical guides, guiding system linked to automatic loading & unloading systems, flexible hoses, etc. This makes it very challenging to design the optimum cleaning devices to reach with water impact all hidden corners. Also, every project needs a particular analysis with a particular combination of cleaning devices. Going into the detail, vertical manifolds with static spray nozzles pointing to shelves surface is the best choice to clean them, taking the advantage of the movement of the vertical cylinder.
Static mechanisms and hidden places are cleaned through static nozzles attached to a manifold.
The most important improvement has been the change regarding the device to clean the walls. Before the R&D project, walls were cleaned through a special manifold with spray nozzles attached on it. The manifold was fixed to the shelves stack and moved up and down covering the walls area. The main disadvantage of this system is that moving manifold needs a flexible hose to be adapted to the different positions without losing the tightness. Due to the stress of movement up and down, this flexible hose can be a source of cleaning agent leaks.
This solution also implies that the total volume of water is often oversized because it is a result of the time that it takes for the shelves stack to go up and down. The improvement has been to replace it for constant speed rotatory balls. The balls are activated to clean the walls when the shelves are stacked at the bottom of the chamber, during the time (or water volume) that is strictly required. The main challenge has been the validation of the nozzle rotation to assure that there isn’t a blockage during the cycle. This rotation is detected by rotating sensors which are conceived to work in clean tanks. These sensors shall be compatible with SIP conditions.
The sensor measures the spraying intensity of the cleaning device. The rotating phases of the rotation jet cleaner can be recognized in the diagram. The measured value has a minimum and maximum value (switching thresholds). The switching thresholds of the measured value are set so that the measured value is inside the switching thresholds during proper cleaning.
The dynamic value is proportional to the frequency of the spraying cycles. In the event of a possible error, the dynamic value is reduced due to a lack of cycles between spraying and not spraying. This enables them to detect a fault during cleaning.
The sensor (one for each cleaning ball) recognizes correct cleaning when both signals (measured value and dynamic) are between the respective switching thresholds.
Dedicated nozzles have been added to clean the shadows created when the jet impacts the manifolds and guides inside the chamber. Manifolds have been also improved to fulfill better with GMP & ASME BPE 2019 guidelines. The nozzles are now customized to be directly welded to manifolds and by thus the risk of leaks is clearly minimized.
Other changes have focused on external CIP installation. Current CIP is allowing both options of water control: condenser as a tank and direct feeding. Direct feeding is possible thanks to some changes in P&ID, that allows control the volume of water thanks to a flow sensor on the water line before the manifolds. These changes not only allow to reduce time when clients choose direct feeding (saves the time to fill the tank), but also improves the control of water volumes and allows to release alarms in case of low flow rates.
To make it possible to do direct feeding, we adapted our CIP system to a common pressure on our clients’ installations. This pressure was reduced from the initial 6 bars to 3 bars. The power of the pump was also reduced significantly.
Another point where efforts were dedicated is the standardization of the cycle receipt for each size of chamber by predefined values to the user. These values were based on internal tests to optimize water consumption. The use of rotatory balls, the pressure reduction and receipt standardization results on a reduction of the water consumption up to 20% Below, an example of comparison between two similar freeze dryers of 20m2 shelf area before and after the CIP improvements. The total amount of water has been reduced drastically. Also, the cycle time has been reduced by 30 min. Both were tested according to Telstar’s riboflavin test procedure.
Conclusions
Industrial freeze dryers for sterile production shall integrate an automatic CIP system that is capable of consistently cleaning all internal parts of the chamber and the condenser. How this solution is implemented is vital to determine the quality of the cleaning process, but it will also determine the water consumption and the cycle time. In times where sustainable goals are so important, we should choose the available technologies that are more reliable and efficient. A new technology using rotary spray balls and a smart recipe management, can reduce up to 20% of the total water consumption and minimize the cycle time considerably.
Original article written by Xavier Gómez and Pere Jover from Azbil Telstar in La Vague magazine, April 2022 (number 73).