Calculation of MACO

GOOD VALIDATION PRACTICE (cGVP) CLEANING VALIDATION
1

dear all,
i have a doubt on calculation of MACo.
one of the guideline says that 10ppm criteria can be used. As the rule is that not more than 10ppm of the previous product should be present in the largest daily dose of the next product i use this instead of cumbersome formulas.

i have different batch sizes and i will be taking the least bacth size and the formula of MACO = 10 x least batch size in kg. = y mg

Now my MACO is this. Can i use this formula for calcualting? instead of cumbersome formulas? and obviously i am meeting the criteria. can i have a feedback. or else do we need anyother calculation. i wanna know a sound formula which has no loopholes so that tomorrow no one can question. though its a debatable point some say that their formula is correct and it goes on. So ultimately the MACO obtained by one company for the same set of products will not match the others and thus lot of variance.

so i request you all to give me feedback on this and how does the regulatory authorities view it. suggest me such that there will be no more drawbacks in that formula.

so what is correct please guide me.

and moreover the general practice of collecting swab is from an area of 4x4 etc. if the critical area included in sampling is the shaft of chopper in RMG or the inner wall of multimill blade etc then on what basis is the formula claculate?

rgds,

2

Dear aastute

For calculation of MACO I like to provide you beautiful article on “Determining Cleaning Validation Acceptance limits for Pharmaceutical Manufacturing Operations” by Fourman Gary L. and Michael V. Mullen, Pharmaceutical Technology. This article is refered by USFDA Guidline, check out reference of the cleaning validation guidline

Coming to your question of 10ppm. 10ppm is the standard set by FDA but with help of 10ppm criteria after calculation it may go below 10ppm or more than 10ppm

Regards

Francis Fernandes
Asst Manager - Validation and Training
Glenmark Pharmaceutical Ltd
Contact : francisf@glenmarkpharma.com

3

Dear fransha,
i thankyou very much for your reply. but the problem is which formula to be followed and how to document it is the main concern.
i would be thankful if you could throw light on it
cheers,
astute

4

U can choose Dose Criteria or 10 ppm criteria, whichever is lower limit (Worst Case situation)

5

dear aastute
i am trying to give you an idea about calculation of maco, i hope it would help you in calculation of maco at your premises.

suppose there is an equipment train of 4 equipments (a, b, c & d) and there are 5 products that run on these common equipments. MACO needs following information for all 5 products: minimum therapeutic dose, largest daily dose, smallest batch size, shared equipment surface area of 4 equipments (a, b, c & d), amount of sovent used for swab sampling.

once you collect all these information for your 5 products running on the equipment train in question, you can go for maco calculation by the following formula:

(i) determination of MAR (maximum allowable residue)

for example, minimum therapeutic dose out of 5 products = 2.5 mg, largest daily dose out of 5 products = 5200 mg, smallest batch size out of 5 products = 704 Kg, shared equipment surface area of 4 equipments = 476759 sq. cm and amount of solvent disorbed = 10 ml.

MAR = 2.5 x 704 x .001 x 1000000/5200 = 338.4615 mg

(ii) Swab contamination = 338.4615 x 100/476759 = 0.07099217 mg/swab

where 100 is the area of swab (10 cm x 10 cm)

(iii) contamination in ppm = 0.07099217 x 1000/10 = 7.099217 ppm

you may go doing calculation like this for your setup and you may get maximum allowable carry over for all your equipment trains.

Regards
Sanjeev Setia
India

6

Thanks setiaindia

nice post!

7

Dear All,
A lowest calculated value can obtain when the 0.1% dose limit criterion is used for the total equipment chain which is justified by the principle that an active pharmaceutical ingredient (API) at a concentration of 1/1000 of its lowest therapeutic dose will not produce any adverse effects . This accounts also for the maximum daily intake of a following product and for its batch size that will be manufactured next with the same equipment.
DS 1 (μg/cm2)
MAC = ––––––
I F A
The lowest calculated value can obtain when the 10 ppm acceptance criterion was applied. When less than 10 ppm of active were allowed into the next manufactured product, determined as MAC
MAC = 10 x S (1/A) (μg/cm2)
Where, MAC is the maximum allowable carry over residue of API permitted after cleaning, allowed into the next product; it is assumed that the total amount of residue is distributed homogenously into the following product; D the lowest daily therapeutic dose of the contaminant; S the lowest batch size of the product to follow; I the maximum daily intake of the product to follow; F the safety factor (can vary from 10 to 100 000 depending on the product nature, e.g., topical, oral or injectable preparations); A the total surface area of equipment in direct contact with the products, calculated on the basis of the assumption that all the products come into contact with all the equipment pieces of the chain.

Thanks

8

I am agreed with Sanjeev Setia’

9

Dear Sanjeev

Can u pl explain me in below calculation of maco from where 1000000 value came?

MAR = 2.5 x 704 x .001 x 1000000/5200 = 338.4615 mg

Reagrds

santosh

[quote=setiaindia]dear aastute
i am trying to give you an idea about calculation of maco, i hope it would help you in calculation of maco at your premises.

suppose there is an equipment train of 4 equipments (a, b, c & d) and there are 5 products that run on these common equipments. MACO needs following information for all 5 products: minimum therapeutic dose, largest daily dose, smallest batch size, shared equipment surface area of 4 equipments (a, b, c & d), amount of sovent used for swab sampling.

once you collect all these information for your 5 products running on the equipment train in question, you can go for maco calculation by the following formula:

(i) determination of MAR (maximum allowable residue)

for example, minimum therapeutic dose out of 5 products = 2.5 mg, largest daily dose out of 5 products = 5200 mg, smallest batch size out of 5 products = 704 Kg, shared equipment surface area of 4 equipments = 476759 sq. cm and amount of solvent disorbed = 10 ml.

MAR = 2.5 x 704 x .001 x 1000000/5200 = 338.4615 mg

(ii) Swab contamination = 338.4615 x 100/476759 = 0.07099217 mg/swab

where 100 is the area of swab (10 cm x 10 cm)

(iii) contamination in ppm = 0.07099217 x 1000/10 = 7.099217 ppm

you may go doing calculation like this for your setup and you may get maximum allowable carry over for all your equipment trains.

Regards
Sanjeev Setia
India[/quote]

10

Dear Sanjeev

Pl im i understood the formula 100% thanks for that but i didnt get from where 1000000 value came in formula?

MAR = 2.5 x 704 x .001 x 1000000/5200 = 338.4615 mg

Regards

11

Dear Aastute,

As far as your first question is concerned, one regarding the MACO calculations, please find the attached spreadsheet for the same. I have even provided formulas for your reference. Hope it would be of help.

Coming to your second question regarding the estimation of MACO for different swab sampled areas, you may calculate MACO separately for shaft or blade depending on the area swabbed. The area swabbed is not necessarily required to be = 4X4 sq inch. There is no regulatory guideline stating that the area to be swabbed should be 4x4 sq inch or 25 sq cm.

Cleaning_Validation_MACO_Swab_Rinse_Ovais_v1.1.zip (17.0 KB)

12

Thanks for u sent me that excell sheet of calculation ,
Once again thanks.

Regards

santosh

13

Dear Ovais

Once again im thankful to u regarding to excell seet of calculation (maco)that u sent to clear my doubt but now i have only one question pl guide me

In swab sampling sheet how can we calculate ‘J’ ?
i.e. J = Maximum number of dosage units of product B1 taken/day

Note: pl explain With example.

Regards
santosh

14

Dear Santosh,

Maximum Daily Dose for any product is the maximum number of dosage units (J) which could be taken daily. I try to explain you in a simple manner, assuming the next product to be manufactured on the machine after cleaning is ABC tablet (5 mg). Go back and check the package insert for that product (or any other authentic source like Martindale/Goodman & Gillman), check the maximum daily dose for similar product or active ingredient. Sometimes package inserts states that “not more than 6 tablets/day (J = 6) or 30 mg daily (J = 30mg/5mg = 6, where 5mg is the amount of the active ingredient in the tablet)”. In certain cases where maximum daily dose for the product/active ingredient is not provided, the value for “J” could be obtained from the normal daily dose for the product, e.g. the normal daily dose for the product is 3-6 tablets/day, “J” would now be 6, assuming that “6” is the maximum number of times the tablet could be consumed daily.

(FYI: I have provided all the explainations in the spreadsheet itself, please check for “comments”).

Hope it was clear!

15

Thank you sir ,have nice day

Regards

santosh

16

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

Regards,
Suchita

17

Dear Suchita,

1000000 mg/kg is a factor used for converting “Kg” units to “mg”.

Note: 1kg = 1000,000 mg.

**please feel free to ask, if you have any other queries.

18

Thank you Ovais.

1 Like
19

Dear sir…
I have a doubt about calculation of MACO as fallows

We are manufacturing two products in four equipments, in this case how can i calculate the MACO Value… please explain…
The products are Lansoprazole and Omeprazole

Thanks and regards
Narendra

20

This question is to OVAIS…Your spreadsheet was very helpful, but I wanted to know…is the mg/swab result the same as ppm limit?

Thanks.