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Recovery Factor in cleaning validation

Dear friends,

could you pl provide information related to

1.Relation b/w recovery factor study at laboratory and cleaning method employed inthe manufacturing equipments
2. is there any specific requirement for considering recovery factor study
i.e 10 * 10 or 4.5* 4.5 or 3*10 sq.cm area for swab sampling.

3.Reason for considering minimum dosage of previous product and max dosage of subsequent product during mac calculation

have a nice day

regards
kandasani

Q.1
Recovery work done in relation to teh laboratory has to meet teh LOD/LOQ of the detergent/residue you are detecting i.e. 10ppm.

Q.2
I always use 25cm.sq reason: This fixed limit is for residue of Product A after cleaning no matter what Product B follows on the equipment. The limit is no more than 0.1 mg per 25 cm2 surface (swab) area

Q.3
The values calculated for each acceptance criteria must be practical, achievable and verifiable. The analytical methods used must be sensitive enough to detect small residual amounts. Limits are established for the worst-case product ingredients as chosen in a section of your protocol.
The carry-over of product residues after cleaning must meet the following defined criteria. These apply to visual, rinse and surface (swab) analyses.

Therapeutic Dose Rule:
Not more than 1/1000 of a normal dose of any product (A) will appear in the maximum daily dose of the next product batch (B) processed using the same equipment.

10 ppm Rule:
Not more than 10ppm of any product (A) will appear in a subsequent product (B).

Visual Rule:
No quantity of residue will be visible on equipment after cleaning procedures are performed.

[quote=Ruth Cunniffe]Q.1
Recovery work done in relation to teh laboratory has to meet teh LOD/LOQ of the detergent/residue you are detecting i.e. 10ppm.

Q.2
I always use 25cm.sq reason: This fixed limit is for residue of Product A after cleaning no matter what Product B follows on the equipment. The limit is no more than 0.1 mg per 25 cm2 surface (swab) area

Q.3
The values calculated for each acceptance criteria must be practical, achievable and verifiable. The analytical methods used must be sensitive enough to detect small residual amounts. Limits are established for the worst-case product ingredients as chosen in a section of your protocol.
The carry-over of product residues after cleaning must meet the following defined criteria. These apply to visual, rinse and surface (swab) analyses.

Therapeutic Dose Rule:
Not more than 1/1000 of a normal dose of any product (A) will appear in the maximum daily dose of the next product batch (B) processed using the same equipment.

10 ppm Rule:
Not more than 10ppm of any product (A) will appear in a subsequent product (B).

Visual Rule:
No quantity of residue will be visible on equipment after cleaning procedures are performed.[/quote]
Dear Ruth Cunniffe,

thanks for the promt reply.

[COLOR=“Blue”]1.i need information what is the correlation b/w Recovery factor study and it’s application while calculation of MACO

2.is different sizes of swabing area will influence the MACO or not?

3.basics of 0.1% concept in cleaning validation[/color]

if u know pl share the information

have a nice day

regards
prasad
9989894084

Hi,

All the information which I have stated above has come from the followng guidelines and references. I’m very new to cleaning validation so this is a learning curve for me also. Hopefully you can get some guidence from these references and also that there must be a cleaning expert in this forum that can help.

FDA cGMP Regulations – Title 21 CFR Parts 193, 210 and 211.

‘FDA Guide to Inspections of Validation Of Cleaning Processes July 1993’

MCA Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2002.

Pharmaceutical Process Validation, 2nd Edition – Ira R. Berry and Robert A. Nash.

Pharmaceutical Quality Group Monograph No.10, Cleaning Validation – Institute of Quality Assurance 1999.

‘Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations’ – Gary L. Fourman and Michael V. Mullen, Pharm. Tech.

‘Control and Monitoring of Bioburden in Biotech/Pharmaceutical Cleanrooms’ – Jaisinghani, Smith and Macedo, J. Val. Tech. August 2000

[quote=kandasani]Dear Ruth Cunniffe,

thanks for the promt reply.

[COLOR=“Blue”]1.i need information what is the correlation b/w Recovery factor study and it’s application while calculation of MACO

2.is different sizes of swabing area will influence the MACO or not?

3.basics of 0.1% concept in cleaning validation[/color]

if u know pl share the information

have a nice day

regards
prasad
9989894084[/quote]

Dear Ruth Cunniffe,
Your first query,
correlation b/w Recovery factor study and it’s application while calculation of MACO
The requirement of determining recovery is to determine the accuracy and precission of your analytical method which is challenged with sampling procedure. Recovery determines to what extent (expressed in percent) your sampling and analytical methods are able to determine the residue. It is generally determined by coupon sampling.

Lets suppose you got the recovery of 80%, then the recovery factor will be 80% i.e. 0.8. And now, you have to divide the MACO (calculated with respect to 0.1% dose or 10 ppm criteria) by the recovery factor. And this will be your new MACO against which you should test the residue for acceptance of cleaning validation.

is different sizes of swabing area will influence the MACO or not?
Regarding this I would like to say that the MACO are generally determined in unit of weight per surface area (e.g. mcg/sq.cm). So, what the swabing area you may have it will not affect your MACO as it is in terms of the mcg/sq. cm. Increasing swabing area is helpful when your analytical method do have LOQ higher than your residue. Suppose your analytical method have LOQ of 10 mcg and you do have residue of 5 mcg per 25 sq. cm, then in this case you could increase swab area to 100 sq.cm and can increase the residue to 20 mcg which is higher than your LOQ and your analytical method will certainly detect it.

basics of 0.1% concept in cleaning validation
While using 10 ppm criteria it was considered that the residues are equally toxic to heavy materials. According to 10 ppm criteria all the residues have same acceptance criteria despite of their toxicity. But there are many pharmaceutical products which are more toxic than heacy materials. So, taking this into consideration 0.1% concept was developed which somehow relate the toxicity of the materials in term of the dose. According to this if the dose is high (drugs are less toxic), then the acceptance criteria is high and if the dose is very low (more toxic) then the acceptance criteria is very small.

Many pharmaceutical companies have acceptance criteria directly in term of toxicity which is determined from Acceptable Daily Intake (calculated by taking reference of LD 50) of the drug. But I would like to prefer 0.1% dose criteria and believe that this should be used only when you do not have dose of the residue. e.g. in case of detergents.

Hope you got your answer,

Prawan Dahal

[quote=kandasani]Dear Ruth Cunniffe,

thanks for the promt reply.

[COLOR=“Blue”]1.i need information what is the correlation b/w Recovery factor study and it’s application while calculation of MACO

2.is different sizes of swabing area will influence the MACO or not?

3.basics of 0.1% concept in cleaning validation[/color]

if u know pl share the information

have a nice day

regards
prasad
9989894084[/quote]

Dear Ruth Cunniffe,
Your first query,
correlation b/w Recovery factor study and it’s application while calculation of MACO
The requirement of determining recovery is to determine the accuracy and precission of your analytical method which is challenged with sampling procedure. Recovery determines to waht extent (expressed in percent) your sampling and analytical methods are able to determine the residue. It is generally determined by coupon sampling. Suppose you got the recovery of 80%, then the recovery factor will be 80% i.e. 0.8. And now, what you have to do is to multiply the MACO calculated with respect to 0.1% dose or 10 ppm criteria by the recovery factor. And this will be your new MACO against which you should tested the residue left after your cleaning procedure. i.e. New MACO = MACO (0.1% and 10 ppm) X Recovery factor.

Or you could also keep the MACO unchanged and consider the Recovery factor during analysis. In this case you should analyse the sample and quantify the residue. Then divide the quantity of the residue by the recovery factor and you will get the actual quantity of the residue. Then make comparison between obtained quantity of the residue and your acceptance criteria.

is different sizes of swabing area will influence the MACO or not?
Regarding this I would like to say that the MACO are generally determined in unit of weight per surface area (e.g. mcg/sq.cm). So, what the swabing area you may have it will not affect your MACO as it is in terms of the mcg/sq. cm. Increasing swabing area is helpful when your analytical method do have LOQ higher than your residue. Suppose your analytical method have LOQ of 10 mcg and you do have residue of 5 mcg per 25 sq. cm, then in this case you could increase swab area to 100 sq.cm and can increase the residue to 20 mcg which is higher than your LOQ and your analytical method will certainly detect it.

basics of 0.1% concept in cleaning validation
While using 10 ppm criteria it was considered that the residues are equally toxic to heavy materials. According to 10 ppm criteria all the residues have same acceptance criteria despite of their toxicity. But there are many pharmaceutical products which are more toxic than heacy materials. So, taking this into consideration 0.1% concept was developed which somehow relate the toxicity of the materials in term of the dose. According to this if the dose is high (drugs are less toxic), then the acceptance criteria is high and if the dose is very low (more toxic) then the acceptance criteria is very small.

Many pharmaceutical companies have acceptance criteria directly in term of toxicity which is determined from Acceptable Daily Intake (calculated by taking reference of LD 50) of the drug. But I would like to prefer 0.1% dose criteria and believe that this should be used only when you do not have dose of the residue. e.g. in case of detergents.

Hope you got your answer,

Prawan Dahal

[quote=daprawan]Dear Ruth Cunniffe,
Your first query,
correlation b/w Recovery factor study and it’s application while calculation of MACO
The requirement of determining recovery is to determine the accuracy and precission of your analytical method which is challenged with sampling procedure. Recovery determines to waht extent (expressed in percent) your sampling and analytical methods are able to determine the residue. It is generally determined by coupon sampling. Suppose you got the recovery of 80%, then the recovery factor will be 80% i.e. 0.8. And now, what you have to do is to divide the MACO calculated with respect to 0.1% dose or 10 ppm criteria by the recovery factor. And this will be your new MACO against which you should tested the residue left after your cleaning procedure.

is different sizes of swabing area will influence the MACO or not?
Regarding this I would like to say that the MACO are generally determined in unit of weight per surface area (e.g. mcg/sq.cm). So, what the swabing area you may have it will not affect your MACO as it is in terms of the mcg/sq. cm. Increasing swabing area is helpful when your analytical method do have LOQ higher than your residue. Suppose your analytical method have LOQ of 10 mcg and you do have residue of 5 mcg per 25 sq. cm, then in this case you could increase swab area to 100 sq.cm and can increase the residue to 20 mcg which is higher than your LOQ and your analytical method will certainly detect it.
basics of 0.1% concept in cleaning validation
While using 10 ppm criteria it was considered that the residues are equally toxic to heavy materials. According to 10 ppm criteria all the residues have same acceptance criteria despite of their toxicity. But there are many pharmaceutical products which are more toxic than heacy materials. So, taking this into consideration 0.1% concept was developed which somehow relate the toxicity of the materials in term of the dose. According to this if the dose is high (drugs are less toxic), then the acceptance criteria is high and if the dose is very low (more toxic) then the acceptance criteria is very small.

Many pharmaceutical companies have acceptance criteria directly in term of toxicity which is determined from Acceptable Daily Intake (calculated by taking reference of LD 50) of the drug. But I would like to prefer 0.1% dose criteria and believe that this should be used only when you do not have dose of the residue. e.g. in case of detergents.

Hope you got your answer,

Prawan Dahal[/quote]

There was an error in my above quote. I was meant to say that the new MACO is obtained by multiplying by the recovery factor. Bust mistakely, I wrote MACO (obtained from 0.1% or 10 ppm) when divided by recovery will make the new MACO against which we should test the residues.