Attached here are two Excel spreadsheets named (a) “Cleaning_Validation_MACO_v2.0” which can be used for estimation of CV acceptance criteria for Solid and Liquid dosage forms, and (b) “MACO for Topical Formulations”, this spreadsheet calculates CV acceptance criteria for Topical Formulations (cream, ointment etc.) as per following reference:
M. Ovais and Lai Yeo Lian, “Setting Cleaning Validation Acceptance Limits for Topical Formulations,” Pharm. Technol. 32(1):96 - 102. (The article can be accessed here: http://pharmtech.findpharma.com/pharmtech/Article/Setting-Cleaning-Validation-Acceptance-Limits-for-/ArticleStandard/Article/detail/481947
)

Feel free to download and use the spreadsheets. As the attached files are for evaluation purpose, any feedback for improvement will be welcomed.

FTU stands for “fingertip unit”. A fingertip unit is a unit of measure for dose of topical dosage forms such as creams & ointments. A FTU describes the amount of cream/ointment that is to be squeezed out of its tube (with a standard 5 mm nozzle) along an adults fingertip. A finger tip is from the very end of the finger to the first crease in the finger.

As stated “C” is the Lowest available strength of the active ingredient in the product A. The value of “C” cannot be obtained by any calculation. Consider an example, assuming an active ingredient in a cream/ointment formulation is available in strengths of 1%, 2%, 3%, then C=1% (i.e. the lowest % available). You may compare your product with various marketed products (either by your own company or any other) available in the market, select the lowest possible strength for the active ingredient as “C”.

Dear sir, pls suggest me that FTU can b applicable for Shampoo? as u hav mentioned that FTU applicable for Ointments/creams, is there any separate formula for shampoo’s

FTUs cannot be applied for shampoos, reason is simple shampoos are not applied using fingertips. In order to determine the maximum amount of product applied per treatment for topical formulations such as medicated shampoos, lotions, toothpaste, and mouthwash etc., please refer to European Commission’s “Guidance for the testing of cosmetic ingredients and their safety evaluation.” The information is given in the chapter 6-2: CATEGORIES OF COSMETIC PRODUCTS AND EXPOSURE LEVELS IN USE. Aprox. 8.0g of shampoo is applied on the scalp per application.

This attachment is good, but the problem is v r into veterinary formulations, those guidelines are suitable for human formulations, pls suggest me how to calculate FTU for pet animals like dog,cat etc., this is not only for shampoos, but also for external dusting powders

This attachment is good, but the problem is v r into veterinary formulations, those guidelines are suitable for human formulations, pls suggest me how to calculate FTU for pet animals like dog,cat etc., this is not only for shampoos, but also for external dusting powders

The attached spreadsheets are really helpful.As mentioned in the spreadsheet, we need to measure product contact surface area of the equipment only but I have a query by the way. Please tell me, how to calculate surface area of equipment? Say for example, I have a tablet compression machine, then how can we consider exactly the product contact surface area of equipment?

is it possible to get surface area calculation from the supplier of the machine? I think while considering design of equipment they, must have calculated the individual change part surface area, isn’t it?

Dear Sir,
I regularly follow this site and read yuor posts. its amazing, you have enough material and references to solve query.
Few time i send you personal e mail also. and its nice to see that you are reply that also.
thanx a lot.
one query as always.
I have been downloaded your previous sheet also, in this all formula set by you is given in sheet. pls add the formula in your current sheet to understand us.

Hi ovais, it was nice done. however, just wondering why the anayltical limits are changing with different types like 10 ppm or dose?. what is relation?
Thanks for your help.

Please find the version 2.1 (containing formulae used for the calculations) of the spreadsheet as attachment.

Dear Mr. cs2009,

“Analytical limits” (as given in the spreadsheet) shows how much amount of the residue should be present in the samples being analysed as per the given criterion. Let me explain you with an example, assuming the MACO as per dose criterion = 10 mg/batch (i.e. 10 mg of residue is only allowed to be carried over to whole batch of product B). Now if I want to calculate the limit based on surface area (as required for swab sampling), I have to divide the MACO by equipment surface area (in common between product A and product B). For an equipment surface area of 10000 sq cm the limit/surface area would be given as 10 / 10000 = 0.001 mg/cm2 (i.e. MACO divided by Equipment Surface area). Lets assume I swab an area of 25 sq cm and want to calculate the expected amount of residue in the sample then I have to use this formula Expected amount = 25cm2 x 0.001 mg/cm2 = 0.025mg (i.e. swab area multiplied by limit/surface area). However, when we analyze the samples (e.g. by HPLC) we don’t get the results like that. Hence, we need to convert the “expected amount” value to a figure which could easily be compared with the HPLC results. For this we use analytical limits. Analytical limits are calculated using the formula Analytical limit = (Expected Amount x Recovery Factor) / (Volume of solution used for extraction of residue from swabs). Assuming the recovery factor (obtained from spiking studies)= 70% and Volume of solution used for extraction of residue from swabs = 5ml, then the analytical limit would be = (0.025mg x 70%) / 5ml = 0.0035mg/ml. Now, whatever result (i.e. amount detected) I get from analysis (e.g. HPLC) it has to be compared with the analytical limit. The analytical limits are calculated separately for each criterion, this is the reason why analytical limits are changing for each criterion (as the starting MACO is different for different criterion). Please don’t confuse this (analytical limit) with the analytical limits based on Limit of Detection (LOD) or Limit of Quantitation (LOQ) which are generally fixed and are not affected by criterion selected for calculation of CV acceptance limits.
FYI: You may refer to the spreadsheet for formulae used for calculations.

Dear Mr. simonraju,

No, Recovery factor (RF) and Visual residual limit (VRL) are not constant values. These values are obtained from spiking studies.

Your feedback (regarding the spreadsheet) will be greatly appreciated.

Thanks for your explanation. However, this is of more confusing because this method yields so many acceptance criteria’s with various factors. E.g I have various different surfaces with different recovery factors like SS,PVc, Rubber etc. it is very difficult to arrive at analytical limits. Ideally Analytical limit = (Expected Amount (instead of this) put your actual value from your chromatogram) x Recovery Factor) / (Volume of solution used for extraction of residue from swabs). Assuming the recovery factor (obtained from spiking studies). Whatever the value comes from this will be compared with MACO to determine whether this is pass or fail.
Secondly, the visual limit is not typically calculated, it assumed to be e.g. 100 micro gram per square inches of the surface (based on the industry practice). Could you also please explain how the 5.0 micro gram per cm is coming from?. Smallest strength – could it be a minimum therapeutic dose of product?. If it is a scoring tablet, typically the dose can be half the 100 mg tablet? which is 50mg.

I understand your concerns. It is because of this reason I have used three ways of describing CV limits which are related to each other. You have the choice to use MACO or Limit/Surface Area or analytical limit for describing CV acceptance limit in the protocol. In your case, where you have different materials and hence different recovery factors, you may use either MACO or Limit/Surface Area i.e. don’t show analytical limits in the protocol. The final results, as obtained from analysis, can then be converted accordingly to be compared with the limits. For the purpose of conversion (i.e. amount detected to amount expected) and comparison, you may use the formulae given in the spreadsheet.

Coming to your second question regarding Visual Limits, I have never come across “100 micro gram per square inches” as a standard used for describing visual limits, which as per you is an industry practice (please forward me the reference if you have any). The standard for visual limit commonly quoted is the one set by Fourman and Mullen as described in the article “Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing” Pharm. Technol. 17 (4), 54-60 (1993). The visual limit as per the reference is 100 microgram per 2 x 2 inch. swab area which is approximately equal to 100 microgram per 5 x 5 cm. swab area = 4 microgram per sq. cm. It is commonly assumed that “the visual limits are not calculated,” which is in violation to regulatory requirements. PIC/S in its guideline (PIC/S PI 006: Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation) on cleaning validation under section 7.11 Establishment of Limits, clearly mentions that “No quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible.” This clearly explains that we have to perform spiking studies to determine visual limits and that visual limit is not a “fixed” value. This is one of the reasons I am getting 5.0 micro gram per sq cm as the visual limit. The values I used in the spreadsheet are only examples, you are free to use other values (as derived from spiking studies) or even 4 microgram per sq. cm.

Yes, smallest strength is the minimum therapeutic dose of a product. For a scored tablet you may use half of the total dose as the minimum therapeutic dose (i.e. 50 mg in your case) provided it is meant to be given in halves as per package insert or your company’s “directions for use” instructions. If the tablet is not advised to be broken then there is no need for you to use 50 mg as the minimum therapeutic dose (as this will make your CV limits unnecessarily lower).

the spreadsheets are very amazing and is so helpful to me, but I want to know about empirical factor, that developed by Layton, I looking for everywhere this bibliography but cannot found.

I want to understand the mathematical model, becouse I need to demostrate that formula I dont understant when use (1/1000 or 1/2000?) it is confuse to me.

Why 1000, why 2000? which is the origin of these numbers?

Further that, I found another empirical factor (weight of adult human / animal weight) ^ 2/3 , which I would like to compare with the model of Layton

Many thanks and so sorry my english is not good, I’m spanish speaking. I hope you will get the message