Cleaning Validation approach


We have a GMP manufacturing facility. We manufacture creams which are basically either health supplements or traditional medicines.
At present our Cleaning method is an HPLC method.

I have following Queries:

a) We have based our Residual Allowable Limit(RAL) on 10ppm of product;
10ppm is RAL from batch to batch.

10 g à 1000kg

0.01 mg/g

(mg/g) x B/A x 100 cm2

B = minimum batch size in g

A = surface area of vessel in cm2.

0.01 x 250000/ 47676 x 100 = 5.2mg/100cm2

Which means 5.2gms of my cream/100cm2.
My cream has 10% active A (which is a safe non-toxic active).
Further swab dilution is as follows swab (considering it has 5.2 of max allowed residue)/10ml --> 0.125ml/5ml = 13 ppm

So we prepare a std (of the active) at this 13 ppm conc, analyse the swab and our acceptance criteria is the area of swab should not be more than the std area.

Is this approach correct?
Since my product has 10% active, should i prepare a std 10 times lower in conc i.e., 1.3ppm and compare the swab result against this std?
The problem in the second approach is detecting something at 1.3ppm is difficult by HPLC. Secondly do we need to be so stringent with health supplement type of products specially with non-toxic active.
Is there any other approach that we may consider?

b) If we consider TOC as a method for detecting residues of contaminants, is it necessary to correlate it to a validated HPLC method? (For example, if out of 10 components we know that component A contributes maximum to the TOC value, is it necessary to develop a HPLC method for that component and correlate to TOC value. Or can we use only TOC method for routine and cleaning validation purpose).


Dear Suchita,

  1. Your approach for setting 13ppm(preparing to target level is correct),
    Even though your product/active A is non toxic, try to establish a LOD & LOQ level. Don’t keep the area comparison, of swab sample to the standard.
    Try to quantitate your product A which is determined in swab.
    Think of this possibility??. On the day of swab sample analysis, knowingly/ unknowingly, if the analyst is taking the standard weight on higher side, then think the Area counts of standard
  2. Cleaning validation method by TOC , will be only good for discussion.
    But many concerns, after starting the experimental work, they have withdrawn.Main issues in TOC methods; SPECIFICITY
    Even we have tried, TOC validation using GE -TOC [which doesnt employs combustion technique with NDIR], but no fruitful results.

Dear Tarun,

Thank you for replying.

One confusion that still exists is that the PICs Guideline states “10ppm” of product", and as mentioned earlier my product has 10% of active.
So shoudent my std (which is active) be 1.3 ppm and not 13 ppm.

Coz 13ppm accounts for 10ppm product, and this we are comparing with the active which is 10%?

Please guide me on this.


We need to consider to a working level, which will be equivalent to 10 ppm of Product.

Dear Tarun,

Its not quite clear to me. So in other words is 13 ppm the right way of calculating the RAL?


Dear Ms Suchita,

To begin with, first we need to understand the regulatory guidelines. Although the PICs Guideline states that “No more than 10 ppm of any product will appear in another product”, it is always referred to as “No more than 10 ppm of contaminant (active ingredient which is present in Product being cleaned or simply Product A) will appear in the subsequently produced product. Using “product” in the 10ppm criterion would tend to give non-achievable values. For more information I would suggest you to go through following articles:

  • Fourman, G.L. and Mullen, M.V., "[b]Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations[/b]," Pharm. Technol. 17(4), 54-60 (1993).
  • D.A. LeBlanc, "[b]Establishing Scientifically Justified Acceptance Criteria for Cleaning Validation of Finished Drug Products[/b]," Pharm. Technol. 22 (10), 136–148 (1998). That means your formula for calculation of limit based on “10 ppm criterion” is correct. The RAL for active A should be 5.2mg/100cm2. For calculation of analytical limits you have to include recovery factor also. Assuming that you obtained a factor (% recovery) of 70% after performing recovery studies, in that case the analytical limit would become 13ppm*70% = 9.1 ppm. After analyzing samples, none of the result should be more than 9.1 ppm. Like what Mr Arun pointed out, you have to make sure the LOD & LOQ for the analytical method should be well below this level. Another important factor which should be taken into consideration is the Validation of analytical method. I am assuming here that your analytical method is validated.

    As far as topical formulations (such as creams, ointments etc.) are concerned, 10 ppm is not the only criterion which could be used for estimation of MACO (Maximum Allowable Carry-Over) or RAL (as mentioned by you). For that please check this article: M. Ovais, Lai Yeo Lian, “Setting Cleaning Validation Acceptance Limits for Topical Formulations,” Pharm. Technol, Volume 32(1), 96-102 (2008), which is available online at
    . Please don’t forget to include visual cleanliness criterion, as it would be of great help especially for non-toxic type ingredients.

    For the detection of residues I would still prefer HPLC as it is more specific than TOC. TOC is an universal method and tends to give results, combined for all the residues including detergent residues (if it has organic carbon). If you decide to use TOC for the analysis purpose, you needn’t to correlate it with HPLC method, but you have to perform the validation for TOC method.

  • Dear Ovais,

    I am using your pharmtech paper "Setting Cleaning Validation …for TF"
    I need your advice on “where does the 1000000 mg/kg” come from in the below formula:

    Maco = o.oo162 g x 300 kg x 1000000 mg/kg / 81 g = 6000 mg


    it is just the conversion of kg to mg…:slight_smile: