MACO calculation - new approach

Good evening all,
I need to look for your experience,

MACO calculations done:

Old approach:
*using TDD
*10 ppm

New approach:
*using PDE/ADE
*10 ppm

But in my experience, most of cases, the MACO calculated using PDE values are above the old criteria used in the 1st approach - TDD.

What is the approach in yours company? Are you used TDD for calculation or only PDE and 10 ppm?
Thank you in advance.

The Pde limit should be above the 10 ppm limit. It is screaming to you that it is a less risky molecule than 10 ppm indicates.

I would only use 10 ppm for a CTM (clinical trial materials) since the drug product has a very small distribution (and thus less risky to the consumer) and is not made on the final manufacturing process train.

Why be more stringent and costly (the 10 ppm limit) than is required?

I also use the TDD for a physiological enzyme replacement which is commonly found in the human physique.

According to EMA/CHMP/CVMP/SWP/169430/201:
Q6. How can limits for cleaning purposes be established?
For products classed as highly hazardous, where a thorough risk assessment can justify manufacture in shared facilities, cleaning limits should include safety factors beyond the HBEL and should not be higher than the traditional cleaning limits approach.

And traditional approach is TDD and 10 ppm. Is in this point not meaning that TDD and 10 ppm should be used for MACO calculation?

Correct! The ADE (and thus HBEL) must always take primacy since its is calculated from the toxicity of the molecule. 10 ppm and TDD are used in very special cases.

No safety factors are allowed since they are not risk based or scientifically justifiable. Seems like somebody is not keeping up their SOP and QA Manuals in line with the current guidences (Eudralex in this case).

For example: if I calculate MACO for product A using TDD - I have MACO 12 micrograms per swab, using PDE data - 88 micrograms per swab, 10 ppm-41 micrograms per swab.

If I understand correctly it mean that not necessary to use TDD criteria - and we should increase our MACO 12 micrograms per swab (calculated before using TDD/10ppm) to 41 micrograms per swab (worst case between 10 ppm and PDE) ?

Now we done all 3 calculations…But I want to change this approach…

In what cases TDD may be used? When PDE not available?

You can use 88 ug/swab since you have justification. It also means you may not have to use HPLC but just UV/Vis and thus a shorter turnaround time and less $$$.

I use to obtain my ADE or PDE values since most drug products are generics (OTC). I only use TDD in special cases like above.

Affygility costs about $600 USD, especially for many generics and OTC they will have to go back to the clinicals and calculate the ADE or PDE range.

Thank you very much for explanation.
We produce more then 25 drugs in shared facilities. And our calculated limits using TDD is so small - what we have a problem with it determination…but using PDE it is acceptable.

In cases then MACO calculated using PDE is very big - for example 600 micrograms per swab? Are you use MACO calculation by 10 ppm criteria in these cases? Or your choice would be only visual control?

Nope! I almost never use 10 ppm acceptance criteria. When the limit is high (600 ug/swab), I would use ‘visual criteria’ (VRL). See attached article;

Again many thanks, for explanation and information.

Are you know some good literature (not guidelines) about cleaning validation, written last years?

Things are in flux. The ISPE was slated to issued ‘new guidelines’ but politics interfered. Follow Dr. Andrew Walsh (chairman of ISPE committee on cleaning validation) and Stephanie Belly Wilkins on Linkedin (and Researchgate) and they will keep you up to date. They have also written several articles.

Thank you for your advices and helpful.

Do you use PDE for matrix?