Cleaning validation calculation

GOOD VALIDATION PRACTICE (cGVP) CLEANING VALIDATION
1

Hi,

I want to know some information about calculation for cleaning(swab) study.

If I scrub in 4x4 inch area of equipment which is cleaned either by cleaning agent or by solvent and then inject this solution in to HPLC after making equal concentration with standard solution,how I calculate amount of previous product in particular equipment?

Also I want to know that what limit is desirable of previous product in next manufacturing product based on dose unit and batch size?

What is the 10 ppm criteria for cleaning validation?

2

[quote=hhd_hrdjobs]Hi,

I want to know some information about calculation for cleaning(swab) study.

If I scrub in 4x4 inch area of equipment which is cleaned either by cleaning agent or by solvent and then inject this solution in to HPLC after making equal concentration with standard solution,how I calculate amount of previous product in particular equipment?

Also I want to know that what limit is desirable of previous product in next manufacturing product based on dose unit and batch size?

What is the 10 ppm criteria for cleaning validation?[/quote]

Dear hhd_hrdjobs,

first question is simple: Multiply the amount of product (or better: contaminant, because you dont test for the entire product but only for one or few contaminating target substances) found in your 4x4 inch area, by the area of the equipment surface that is in product contact (in square inches) and divide by the 16 inch² swabbed area. This is the absolute amount of contamination in the whole equipment.

The desirable limit is a little more complicated and there is more than one approach, so I give you ours: Assuming the worst case, that the whole contamination present in the equipment goes into the batch of the next product, you need to calculate the amount of contaminant allowed in one batch of the next product. To make it clearer, lets assume the following as an example:

Contaminant: Substance C, with therapeutic dosages of 2 mg, 4 mg and 10 mg, all taken once a day.
Next product: Product N, with batch size 500 kg, dosage 10 mg and 20 mg, maximum intake of its active is 50 mg/day, dosage unit weight of N is 200 mg.
Shared equipment product contact surface: 10 000 inch²

Starting point is the amount of contaminant (from the previous product) accepted as being taken with the “next” product. Common approach is to regard the active ingredient of the previous product as the contaminant to look for. For solids, an active ingredient intake of 1/1000th of the lowest therapeutic dosage of that active is usually regarded as harmless (for parenterals this factor is 1/10000th).

So, in the example, the maximum amount of contaminant allowed to be taken in per day is 2 mg/1000=0,002 mg/day.

This means that with the daily intake of the next product, the maximum allowed of contamination is 1/1000th of the daily therapeutic dosage of the contaminant. To be on the safe side, the maximum daily intake of the next product is considered. So, in the example:

Maximum daily takings of N is 50 mg/10 mg= 5 takings a day. This means that the 0,002 mg of C are allowed to be contaminating these 5 takings, so per taking of N, 0,002/5= 0,0004 mg C is allowed, or, what is the same, 0,0004 mg of C in 200 mg (one dosage unit) of N. The batch size of N is 500 kg, equivalent to 500.000.000 mg N, so if there are 0,0004 mg C allowed in 200 mg of N, in 5000.000.000 mg N there will be allowed :

(0,0004 mg C * 500.000.000 mg N)/200 mg N= 1000 mg C per batch N.

This is the maximum amount of contaminant C allowed to be present in one batch of the next product N, and thus distributed over the entire equipment surface which is in contact with product. With an equipment product contact surface of 10 000 inch², the limit of contaminant per 16 inch² swabbed area will be: (1000 mg C/10 000 inch²)*16 inch²= 1,6 mg C

Last question: The 10 ppm criteria is essentially the same, only that it does not use the minimum therapeutic daily dosage of the contaminant as the starting point, but takes an (arbitrary) limit of 10 ppm (= 10 mg/kg) of contaminant (10 mg contaminant per 1 kg of next product). This criteria is normally used in cases where the minimum therapeutic dosage of the cntaminant is relatively high, and the calculated limit contamination would allow a visibly dirty equipment. Common practice is to use the lowest calculated limit between both criteria.

Hope this is understandable, and that I have not made any calculation mistakes!

Best regards

Alfred

3

Alfred,

Thanks a lot.

Still I have a question.

Assume that I am doing recovery study for cleaning validation and I get recovery 80%.Should I include recovery factor in calculation while I do analysis of cleaning samples and what is the criteria for recovery?

I want to confirm below mentioned calculation for 10 ppm (10mg/kg)criteria.

Batch size:500 Kg
Equipment surface area:10000 sq.inch
Sampling area:16 sq.inch

C=(5000mg/10000 sq.inch)*16 sq.inch=8 mg

Thanks,

Haresh Donda

4

Dear Haresh,

you are right, the recovery factor should be included in the calculation of the actual contamination. So, if you get an analytical result of 1 mg/inch², and your recovery rate is 80%, the actual contamination to be compared against your acceptance limit is 1,25 mg/inch². Currently, recoveries above 50% are considered acceptable, but personally I prefer to set it to 70% because the lower the recovery, the lower the confidence in the results is (imagine the resulting error from a recovery of 1%, with its associated analytical error, and then multiplying your results by 100!). Our current acceptance criteria for recovery is an average of 70% with a relative standard deviation between sampling technicians (at least three) of 15%, but it is an internal specification and not backed by any regulatory requirement or guidance.

Your calculation for the acceptance limit of 10 ppm is right, only I would like to stress out that the batch size should be the lowest one (to be on the safe side and in order to avoid rechecking of results for each new product in the equipment, you can take the lowest batch size that can potentially be manufactured in that equipment (it should be in the PQ of the equipment). The other issue is that you cannot consider only one piece of equipment for the limit calculation, but the whole equipment train that is shared between the “contaminating” and the “next” product. The allowed contamination can then roughly be distributed over the train proportional to the individual surface of each equipment.

Best regards and a nice weekend

Alfred

5

You have to used recoveru factor in your caluculations

[quote=hhd_hrdjobs]Alfred,

Thanks a lot.

Still I have a question.

Assume that I am doing recovery study for cleaning validation and I get recovery 80%.Should I include recovery factor in calculation while I do analysis of cleaning samples and what is the criteria for recovery?

I want to confirm below mentioned calculation for 10 ppm (10mg/kg)criteria.

Batch size:500 Kg
Equipment surface area:10000 sq.inch
Sampling area:16 sq.inch

C=(5000mg/10000 sq.inch)*16 sq.inch=8 mg

Thanks,

Haresh Donda[/quote]

6

Dear Alfred,

I do understand that I consider entire equipment,but for sampling purpose I should consider 4-16 sq.inch equipment area and based on result obtained from particular sq.inch area I can calculate contamination in entire equipment am I right?

Only 100% recovery level should be required in triplicate or other level(i.e.50%,150%) also be required?

Have a nice weekend.

Regards,

Haresh Donda

7

Dear Haresh,

don´t get confused between calculating the accepted contamination level and the sampling itself. To set the acceptance criteria, the swabbed area is irrelevant (actually, if the accepted level is very low and the analytical method is not sensitive enough, one way to get quantifiable levels for the analysis is to increase the swabbed area). This is the reason for why it is better to set the accepted contamination level in µg/inch² of equipment surface rather than in µg/inch² swabbed area. The first limit does not change with the swabbed area, the second does.

Back to the question: What I meant to say with entire equipment train is that if the “contaminant” and the “next product” share more than one piece of equipment, the surface that goes into the accepted contamination calculation is the sum of the surfaces of all the shared equipment, and not only the one you are considering for the cleaning validation.

Of course you can calculate the contamination in the equipment based on the result of the swabbed surface, but be sure to verify the the contamination at each sampling location in the equipment is below the accepted level, and then take the result of the worst location to calculate (better: estimate) the overall equipment contamination.

Regarding the recovery percentage, the recovery test is normally carried out at 50% and 150% of the calculated accepted contamination level, for three technicians trained in the sampling operation. In the above example, the accepted contamination in the equipment is 0,1 mg C/inch² and thus 1,6 mg/16 inch² swabbed area, thus you will spike (at least) three 16 inch² coupons with 0,8 mg contaminant (50% calculated level), three 16 inch² coupons with 1,6 mg contaminant (100% calculated level), and three 16 inch² coupons with 2,4 mg contaminant (150% calculated level), and the get the coupons swabbed by each of the three technicians at the three contamination levels. You will get nine recovery percentages, and each of them has to be above your required recovery rate (e.g 50%). Again, there is more than one way to carry out the recovery test and to set your acceptance criteria.

Best regards

Alfred

8

dear all,
why do we have to search the recovery factor for cleaning validation? and when do we use that recovery factor? i’m still not clear bout that.
and can you please give me an example for that.

thanks

9

[quote=rika_ndry]dear all,
why do we have to search the recovery factor for cleaning validation? and when do we use that recovery factor? i’m still not clear bout that.
and can you please give me an example for that.

thanks[/quote]

Dear rika_ndry,

the recovery factor is needed to correlate the analytical result of the amount of contamination with the actual and real contamination present in the equipment. The recovery factor accounts for losses of analyte during the sampling and the analysis.

For example, lets assume that your method (including sampling and analysis) has a recovery rate of 75%. After swabing 100 cm² of the equipment and analizing the samples, you determine that you had 150 µg of analyte in your swab. To get the real contamination in the equipment, you need to multiply the analytical result with the recovery factor, that is the inverse recovery rate. In the above example: 150 [µg/100 cm²]/75[%]= 200 [µg/100cm²]=2 [µg/cm²], that means the equipment has a real contamination of 2 µg/cm², even if you found analytically 1,5 µ/cm².

The recovery factor is usually determined in the laboratory, spiking pieces (coupons) of the materials present in the equipment (stainless steel in different finishes, teflon®, aluminium, glass, etc.) with a known amount of your analyte, near to the target level, and sampling and analizing it exactly the same way you will do it in the equipment. The ratio between the analytical result you get, and the spiked amount, is the recovery rate.

Best regards

Alfred