In tank / fill system equipment it is necessary to “clean” the WFI from the system (after sanitisation) with a product solution flush. Can anyone help as to how this should / might be validated?
The parameters here to be considered depending on the following things attached on to system
-Size of system --Capacity
-How many ports you have?
-How many pumps attached?
-What are the sensors you have?
-Is CIP/SIP is given with the system or it is seperate?
-What is the way to take WFI into the system?
-How much WFI needed to clean the system?
-What is the the Sanitization agent , Its concentration & its contact time and what is achieved after sanitization and what is the way to clean the sanitization so that it does not contaminate the tank in later operation?
-What is the temperature of operation and how the sensors are calibrated?
-What are the valves made up of ?
-Do you use any compressed air for such valves to opearte as it is connected to WFI system and what is the quality of compressed air?
-You said you will flush with a product–What are the quality attributes, concentration and flush volume of that product?
-Do you have any opening lids on to that system or do you have ports to see its cleanability?
-Where the tank is located–Is it in Process area or outside process area?
-How that area in which the tank is placed is qualified ?
-What are the power requirements of that system?
-Do you any other mechanical attachments for this sytem which are run by power?
-What is the time of operation of this system?
-What are removable parts of this system and what are the mesaures you need to take for maintaining such systems?
-What is the Material of contrction of this system and its ports, its certificates, welds if any , what is the finish you have and what is the external finish?
-Is this system mounted on a skid or any other thing?
-Do you have a ball spraying valve for sanitary application?
-How do you passivate this system before it starts–Do you use Nitric acid or Citic acid?
These will give you an idea.
Regards
This is not just about flushing validation but an experience in flushing.
A friend of mine reported that they hade bacteria in a tank. They flushed it several times with increasing detergent levels.
Bacteria remained and were identified after each flushing.
Close to paranoia they went back to the design drawings.
They identified an overflow container, which usually escaped regular flushing.
A simple flushing of the whole system at regular detergent level exterminated all bacteria.
Lesson for flushing validation: consider the whole system. Define when to flush which parts.
Berthold,
Thanks for giving a great example.
Dead legs or even dead zones where a santizing agent cannot reach will give rise to Biofilms.
Each time you clean , new problem arises.
I assume that this product flush is a post cleaning, post sanitization rinse to remove the WFI and clear the lines for final fill. The packaged product must have a final concentration specification. We never claim 100% removal of anything from the system, so you will need to calculate and show an acceptable WFI clearance by a required number of rinses (per SOP). So, the point of this exercise is to set what level of dilution by residual WFI is acceptable, rinse the system to get within this acceptance range and show that the end product will meet the release specification.
Set the acceptable dilution in consultation with your Process Development, Quality and Regulatory groups. Assume that the worst case happened and your bulk material is at the minimum acceptable concentration. Based on the sensitivity of your concentration assay, calculate what amount of dilution would never cause the measured concentration to change (and so fail release testing). The acceptable dilution is some multiple (fraction?) of that calculated value.
Next you determine the dilution caused by residual in the system. To do this you could: dry the system completely, fill the system with a measured amount of WFI, drain and re-measure the WFI to determine how much remains in the system. Do multiple measurements and use the highest value obtained (not the average) because you are fighting the worst case again. The residual volume and the total system volume determine the % dilution caused by residue in the drained tank and piping. If your product has rheological properties similar to water (surface tension, viscosity, wetting action, etc) then you can multiply your % dilution effect for each subsequent ‘rinse’. Otherwise you’ll need to determine the residual volume left by each product rinse and its % dilution.
If the product concentration test method is sensitive enough to detect a rinse dilution, it must confirm the calculated dilution. Then you might claim a reliably defensible confirmation of the total % dilution effect. That would let you state that the required number of product rinses are reasonably certain to clear the residual WFI to the previously established acceptance level.
I am a Production Supervisor, please run this suggestion past your own Quality and Regulatory SMEs.
Best of luck,
Tom Boehme