Good day All!

For calculation we use 3 metods:

TDD, PDE, 10 ppm.

So, worst case is TDD limit, because it is smollest. Used Safety factor - 100. Min. of TDD - finger point.0.5g

Is our approach corect?..and when we take for calculation Safaty factor 10?..is acceptable for topical product…

No always use the ‘health based limit’ or PDE calculation! All other calculations are no longer recognised by regulatory authorities. Since it is a topical use ‘finger tip units (FTU)’ in you calculations.

Thank you for anser. I know about PDE. But how about safety factor? We produce only non-prescription ointments and gels.

But one of them have API - snake poison, calculation using safety factor 100 do very smoll MACO limit…less than 1 mikrogr. per swab - 100 cm2.

With the PDE a fudge factor (sorry a safety factor) is not required. Thus, the calculation is different. But, you will only have 1 chance to get this right! Even a topical company is not immune from the regulations (see link below)!

Your ‘site cleaning validation master plan (SCVMP)’ will mandate the use of ‘health based limits’ or the PDE. The ‘carryover calculation’ will be described without a fudge factor. It will also describe the role and composition of a ‘validation review board (VRB)’. Usually this is the QC, QA, Validation, Operation Managers or designates…

The ‘cleaning validation’ protocol will list each drug product you make in the ‘risk assessment section’ with the PDE and manufacturing volume…

Thank you for your explanation.

At the moment, I not have available PDE data. Till time when we take it, we decide to start re-validation of cleaning procedures based on prior method (after PDE data will available – we will recalculate MACO in risk).

I have some doubt about our calculation.

1)

For example, for MACO calculation I use formula:

MACO (for equipment chain) = TDmin product A(AFVmg) * BS *10-6(amount of AFVmg)/(TDmax (per mg/day)*100 (safety factor))

So

TDmin (AFV) is API assay in 0,5g of product A (finger point);

BS *10-6 batch size ---- amount of AFV per full batch of product B.

TDmax- is API assay in full product tube …not correct because it may be more then 1 tube or less…

- After serfing of publications I find also one for me just clear calculation…it is

MACO (for equipment chain)= TDmin product A(AFVmg) * BS *10-6(amount of AFVmg)/(TDmax (per mg/day)*100 (safety factor))

TDmin (AFV) is API assay in 1,75mg of product A (1,75mg necessary for 1 cm2);

BS*10-6 batch size of product B in mg.*F (number of aplication)…but why in calculation take 1,75 mg , however to 25,23g (necessary for cover adult body).

TDmax- is dose of product B per cm2/day, calculated :1,75mg

What your opinion for this? According to new guide, that say that MACO will be calculated by traditional approach and PDE ( if is suitable), http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/01/WC500219500.pdf

With the PDE safety factors are no longer used. An EXAMPLE calculation would be (it depends on your process);

mass (in mg) = PDE (in mg/Kg) x 70 Kg (mass of average male) x Lot A (in Kg)/Lot B (smallest lot in Kg) x Equipment SA (in cm squared)/Total Equipment SA (in cm squared)

SA is drug product surface area. The SCVMP will required only critical process equipment with >1% SA compared to the total be evaluated.

For a swab the 2nd equation COULD be; mass per swab = mass (in mg) x 25 (where each swab has a 5 x 5 Cm surface area).

For a rinse the 2nd equation COULD be; mass per rinse = mass (in mg) x 100 (where the rinse recovery volume is 100 mL).

The 3rd equation is a SUM of the individual MSC (maximum safe concentration above for each piece of equipment). In NO case are you allowed to have a mass above the assigned value but also above the LOQ of the analytical method.

In new guideline: Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’ (EMA/CHMP/CVMP/SWP/169430/2012) is one requirement:

**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.*

For your opinion it is know that for highly hazard products MACO calculation should be included safety factor in calculation formula?

Thank you once again for answer.

No safety factor is required since the health based limit is based on the toxicity of the molecule in humans (based on Clinical Phase II data). The ADE (or PDE) is short for ‘acceptable daily exposure’ which is based on the NOAEL or ‘no observed adverse effect level’. See chapters 3 and 5 of the Eudralex which is now official (as of July 2015).

The ADE/PDE ‘IS’ the worst case. It incorporates the toxicity of the molecule without fudge factors (er safety factors). To be more stringent that that is CRAZY and poor business sense too!

So, I’ve been doing some reading on this topic, and the EU recommends PDE for surface limit calculations, and presented a white paper on how to do it.

But they also give allowances for other means to determine limits for cleanliness. They reference PDE, but also allow for TTI, 10 ppm, or 1/1000 of a therapeudic dose. They do not allow for LD50 calculations for any carryover amount though.

Here are the references which had this information.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/11/WC500177735.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/01/WC500219500.pdf

From the 3rd reference. The derivation of such a [cleanliness limit]…should be the result of a structured scientific evaluation of all available pharmacological and toxicological data including both non-clinical and clinical data.

Deviation from the [PDE] to derive such safe threshold levels could be accepted if adequately justified.