As per PDA TR 29 and APIC; (Topical: 10-100, Oral products: 100-1000, Parenteral: 1,000-10,000)
Suppose “X” facility uses, 1000 for solid oral , 10000 for parenteral MACO calculation.
So my question is to put safety factor for MACO calculation in detergent LD50 based MACO caculation
- Same safety factor to be applied which is applied for the dosage form. Suppose detergent used for tablet facility, than the safety factor 1000 and if detergent used for parenteral facility than 10000.
OR
detergent used for tablet facility, than the safety factor 100 and if detergent used for parenteral facility than 1000, lower than that of API MACO calculation
What is advisable ? reference ?
Thanks
Sandip
This is the reason why the ISPE was going to issue a new guidance on ‘cleaning validation’ (until it got hung up on politics). The carryover is now based on the toxicity of the molecule and in particular the ADE (acceptable daily exposure). Now people use chapter 3 and 5 of the Eudralex (not an obsolete technical report)!
Dear Boomer, Thanks
am aware about health based CV, my question is centered to choose safety factor for detergent, which will still cont., as LD50 based approach here instead PDE.
So , it can be justified by using lower side safety factor for detergent, like, 10 for topical, 100 for oral and 1000 for injectable facility.
While we were used to use for API, 100 for topical, 1000 for oral and 10000 for injectable.
The ISPE cleaning validation guideline (which is in committee, politics) recommended use of the ADE for cleaning agents. Remember, it was KOH from the cleaning agent CIP 100 that killed several Americans in 1968.
Hi Boomer,
Thanks again.
Now I am eager to know the detail of that incident, I had google it out, unable find related news.
Will please share link/article/news on that incident please
Sandip
One more thing I think, the PDE value determined by using POD and NOAEL, where in most case detergent having only LD50 value, studies value. (and off course it is possible to further calculate NOEL based on LD50 and than PDE, by applying F1 to F5).
Is it advisable to use PDE for detergent, where we need various extrapolation to get PDE ?
1st question; See history by Dr. Andrew Walsh from Stevens Institute. I was only 16 at the time and had better things to do!
2nd question; See articles by Dr. Andrew Walsh, particularly on ‘Cleaning Validation in the 21st Century (parts I and II)’. He was also chair of the ISPE committee on cleaning validation. They are on his website.
PDE can be extrapolated but it depends on the molecule and other factors (species, site, formulation…). I get my ADE values from a registered toxicologist at www.affygility.com
If you choose to use the LD50 method, the equations do use the safety factors you discussed in your original post.
Here is a pretty good article with those calculations, using that slighly older method of calculations.
http://apic.cefic.org/pub/pub-cleaning-validation.pdf
The paper is for API manufacturing specifically, but applies to pharma/biotech manufacturing pretty well.
You have to ensure you’re using current APIC calculations (2014). The world has changed since 2000. You must be compliant!
Boomer Chemist, please correct me if I’m wrong. I’m reviewing the APIC guideline which you recently posted referenced (the one which I posted the link for). My post regarding use/chloice of using the LD50 calculation aligns with the guidance. The LD50 is referenced in the 2014 APIC guide for cleaning validation. It is not the most robust method for calculating cleaning limits, but it is given as a suitable method, when the ADE data is not available.
Update to the link for APIC regarding cleaning validion limits
http://apic.cefic.org/pub/APIC_Cleaning_Validation_2014.pdf
See section 4.2.3 for how to calculate limits based on LD50, and using the 2014 guideline.
It depends on where the the drug product is marketed. If it is Europe or a global plant, then it must be the ADE method. Thus, it is the manufacturer who must develop the ADE value (via clinicals).