My equipment train is composed of SUT except for 316L filling needles.
The needles are dedicated for each product (2-3 strengths for each product).
Parts washer is multiproduct-macromoleucle.
Final rinse is 720L
Product is degraded during cleaning cycle.
I cannot swab needles.
i use 10ppm method as others are not applicable/data not available.
My MACO calculation gives me a value of <200ppb when I use final rinse volume of 720L.
When I use surface area of needles/ volume required to rinse needles I get a MACO limit >>100ppm
Should I default to WFI spec for rinse from partswasher? Visual?
Confused…
No. When I was confronted by this problem of a low surface area and thus low MACO, I just sum them with the surface area of the filling machine. The largest ‘drug product contact area’ was the filling machine manifold.
Because the drug product is degraded you might use a TOC method (water rinse).
Thanks Boomer, our filling manifold is SUT so cannot use this .
In your experience, how do auditors react to the use of WFI spec for TOC
Auditors do not react well to using the WFI spec. for TOC cleaning validation which is 500 ppb or 0.5 ppm. It means you have not done your home work in using a Health Based Exposure Limit (HBEL) based on risk assessment and toxicity of the molecule. Typically, using 500 ppb is FAR too tight particularly when MACO based on HBEL is 10 ppm (20 times higher!).
If I have shown that active is degraded and my HBEL (PDE) is therefore not relevant as per Annex 15, is the WFI spec then appropriate? (Assuming I have documented all of this this in a RA)
Also as the WFI spec is tight-what alternative do you have?
Considering I have a MACO limit that isn’t practical, achievable or verifiable i.e. v high or v low?
Is a lab study where I rinse in a low volume i.e. 1L (my final rinse in 720L) to get a verifiable limit useful to allay auditors fear
Before I answer what is SUT?
Single Use Technology-Filling needles are the only part of equipment train that is re-used. They are also dedicated for each product. Issue is proving they are clean. Thanks boomer.
Cleaning validation is only performed and quantitates toxic residues that can potentially cross-contaminate another drug product. If you don’t believe me the EMA has issued a guidance on shared facilities. Since;
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You’re using SUT there is no possibility of contaminating another drug product. Therefore, no cleaning validation is required.
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Similarly, filling needles are only used for one drug product and are dedicated therefore, there is no possibility of contaminating another drug product. No cleaning validation is required.
Be sure you go through the entire manufacturing process train and ensure disposable items (like Tygon tubing) are disposed properly and not subject to cleaning validation.
Thanks Boomer for your advice, I am definitely overthinking this issue 
While ‘risk assessment’ will help you target the most toxic molecule you make, it does not cover all of your drug product process train (like the filling machine). In order to include this share piece of equipment you can ‘secondarily’ target the hardest to clean formulation which SURPRISE has an easily detectable API like Acetaminophen.
Remember, it is your cleaning procedures (including work instructions) that are being evaluated for effectiveness and the residual molecules are used as the yardstick. Thus, if you have 10 separate cleaning procedures (and 10 separate risk assessments), you can have 10 separate cleaning validation protocols and final reports.
In addition the above ‘strategy’ should be explained in a 'site cleaning master validation plan (SCVMP). Tis plan should also specify that only equipment whose drug product contact surface area above 1.0% of the entire manufacturing process train will be evaluated.
It will look forward to your business strategy (like making INDs or CTMs) and list possible members of the ‘validation review board (VRB)’ like QA, QC, QE, RA, Validation, Operations…
Be aware that the filling needle is a very important area to clean. It is understood that it is a smaller area, but since it is closer to the final fill, a contaminated needle could potentially drop any/all contamination in one single unit. A contamination on the fill needle could result in a higher concentrated contamination compared to a process tank upstream, where a contamination would be diluted throughout the whole bulk.
So not all sites are considered equal, and a filling needle would be considered highest risk location.
A cleaning validation might not be required, but you might want to have a “risk assessment” paper detailing why cleaning validation is not required. In this risk assessment you should discuss the dedicated needle/product line, and also any cleaning method, cleaning agents/chemicals, hold times, etc. You could also discuss possibility for microbial contamination. You might want to clean the needle immediately after use to get the material oof, then somehow sanitize prior to use using autoclave, or other methods to be doubly sure there is no microbial contamination. For a sterile filler operation, the autoclave should take care of everything. Also, microbial control would be supported using a media fill process simulation (if applicable).
There are a few other things to consider - such as removal of cleaning detergent (if applicable). But this should help get you started.
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