Post Cleaning Validation

[sburra]

I had the following concerns once we validate our cleaning processes

1. What actives and residues do we test for on a regular basis
2. Are all the actives and residues tested as they were when validation exercise was conducted
3. How do we develop a rationale for testing
4. Are there regulations for the number of tests to be carried out to ensure that cleaning has truly taken place
5. If the same product is manufactured in different lots from the same campaign, do we still test for the actives and residues

Appreciate replies, discussion and comments

Subramanya

[gokeeffe]

Hi sburra

While I am no expert in the field of Cleaning Validation I would suggest the following:

1. Using Solubility and toxicity levels determine the worst case product(s)… there may be more than one, then test for those actives on a regular basis.
2. Yes, any variability may be sufficient to render your testing invalid.
3. using the API(s) selected in 1 above.
4. Generally validation trials run 3 in numbers.
5. In this situation you would not have to test for actives and resides provided you go from lowest to highest strength during the campaign (1mg, part clean, 2mg, part clean, 5mg, part clean, etc.). Keep in mind that you would have to certainly test for API residues when different molecules are processed back to back.

I hope this helps at least a bit.

[pvalidation]

Releated to regulatory requirment,initial three runs r sufficant and for regularly basis u have to do re-qualification for once in a year and it should refelect in u r cleaning validation master plan (CVMP).

prasad…

[ys_sudarsan]

[quote=gokeeffe]Hi sburra

While I am no expert in the field of Cleaning Validation I would suggest the following:

1. Using Solubility and toxicity levels determine the worst case product(s)… there may be more than one, then test for those actives on a regular basis.
2. Yes, any variability may be sufficient to render your testing invalid.
3. using the API(s) selected in 1 above.
4. Generally validation trials run 3 in numbers.
5. In this situation you would not have to test for actives and resides provided you go from lowest to highest strength during the campaign (1mg, part clean, 2mg, part clean, 5mg, part clean, etc.). Keep in mind that you would have to certainly test for API residues when different molecules are processed back to back.

I hope this helps at least a bit.[/quote]

I do agree with Mr.gokeeffe. But,

1. Toxicity levels can not be determined by testing.
2. As part of validation, industries follow minimum 3 runs concept. But, FDA doesn’t talk about it.
3. It is applicable for APIs, but not for Parenterals, as the lot may be completed in one day (or) it may continued more than a day.

Regards,
Sudarshan Reddy
ys.sudarsan@gmail.com

[gokeeffe]

Good point Sudarshan Reddy

Tks

[Shahnawaz]

[quote=ys.sudarsan]I do agree with Mr.gokeeffe. But,

1. Toxicity levels can not be determined by testing.
2. As part of validation, industries follow minimum 3 runs concept. But, FDA doesn’t talk about it.
3. It is applicable for APIs, but not for Parenterals, as the lot may be completed in one day (or) it may continued more than a day.

Regards,
Sudarshan Reddy
ys.sudarsan@gmail.com[/quote]

1). There are a number of options available when determining acceptance criteria.
Where either toxicological or therapeutic data if available then calculation A or
B is preferable. If data is not available for either of these calculations or if the
result is more stringent calculation C should be used.
A. Limiting the level based on toxicity data.
An Acceptable Daily Intake (ADI) is calculated with suitable safety
factors applied and this is converted to the maximum allowable
carryover to the API.
B. Pharmacological Dose Method:
The philosophy is to reduce the levels of residual product in each piece
of equipment, such that no greater than 1/1000 of the normal
therapeutic dose will be present per typical dose of the next product to
be run in the equipment. The validation protocol should include a
calculation, which ties this philosophy to the acceptance criteria for the
samples to be tested.
C. Limiting the level of product which could appear in the following
products.
Limits from 10ppm up to 0.1% (based on the ICH impurity document
which indicates that up to 0.1% of an individual unknown or 0.5% total
unknowns material may be present in the product being tested ).

2. At least three (3) consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.

[ys_sudarsan]

[quote=Shahnawaz]1). There are a number of options available when determining acceptance criteria.
Where either toxicological or therapeutic data if available then calculation A or
B is preferable. If data is not available for either of these calculations or if the
result is more stringent calculation C should be used.
A. Limiting the level based on toxicity data.
An Acceptable Daily Intake (ADI) is calculated with suitable safety
factors applied and this is converted to the maximum allowable
carryover to the API.
B. Pharmacological Dose Method:
The philosophy is to reduce the levels of residual product in each piece
of equipment, such that no greater than 1/1000 of the normal
therapeutic dose will be present per typical dose of the next product to
be run in the equipment. The validation protocol should include a
calculation, which ties this philosophy to the acceptance criteria for the
samples to be tested.
C. Limiting the level of product which could appear in the following
products.
Limits from 10ppm up to 0.1% (based on the ICH impurity document
which indicates that up to 0.1% of an individual unknown or 0.5% total
unknowns material may be present in the product being tested ).

2. At least three (3) consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.[/quote]

Dear Shahnawaz,

A. Limiting the level based on toxicity data.

Acceptance criteria for Toxicity can be calculated by using ADI & MACO. But, for this, we need to have the data of Empirical Factor, which is not available all the times. Hence, now-a-days, even FDA is not interested in setting the limits of Toxicity for Cleaning Validation.

Please refer: Mr. LeBlanc guidelines

B) Pharmacological Dose Method:

Safety factor will differ for the application.
For Orals, we can use 1/1000
For Parenterals, we can use 1/1000 to 1/10,000

C. Limiting the level of product which could appear in the following
products.

This limit is purely based on MACO calculation. For some products, even 10 ppm is not acceptable.

With Best Regards,
Sudarshan Reddy
ys.sudarsan@gmail.com

[ys_sudarsan]

[quote=gokeeffe]Good point Sudarshan Reddy

Tks[/quote]

Mr.Gokeeffe,
Thank you verymuch for your support.

With Best Regards,
Sudarshan Reddy
ys.sudarsan@gmail.com

[Shahnawaz]

[quote=ys.sudarsan]Dear Shahnawaz,

A. Limiting the level based on toxicity data.

Acceptance criteria for Toxicity can be calculated by using ADI & MACO. But, for this, we need to have the data of Empirical Factor, which is not available all the times. Hence, now-a-days, even FDA is not interested in setting the limits of Toxicity for Cleaning Validation.

Please refer: Mr. LeBlanc guidelines

B) Pharmacological Dose Method:

Safety factor will differ for the application.
For Orals, we can use 1/1000
For Parenterals, we can use 1/1000 to 1/10,000

C. Limiting the level of product which could appear in the following
products.

This limit is purely based on MACO calculation. For some products, even 10 ppm is not acceptable.

With Best Regards,
Sudarshan Reddy
ys.sudarsan@gmail.com[/quote]
Dear Sudarsan,

A) You said in earlier post that " Toxicity levels can not be determined" so i explained the methodology how to calculate the MAC by toxicity data.

B) The safety factor varies depending on the route of administration. Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms. Safety factor can vary depending on substance/dosage form according to suppose toxicity values from oral administration.
Safety factor for different dosage forms:-
Topicals 10 –- 100
Oral products 100 – -1000
Parenterals 1000 -– 10 000
so for the safer side, usually take 1/1000 as safety factor.

C) MAC derived from 10 ppm approach, it doesn’t means 10 ppm is acceptable limit, it is an approach which came from ICH impurity document.so i think you didn’t get my earlier answer, it just a calculation approach and i will explain it later in detail.

Thanks and best regards

[ys_sudarsan]

[quote=Shahnawaz]Dear Sudarsan,

A) You said in earlier post that " Toxicity levels can not be determined" so i explained the methodology how to calculate the MAC by toxicity data.

B) The safety factor varies depending on the route of administration. Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms. Safety factor can vary depending on substance/dosage form according to suppose toxicity values from oral administration.
Safety factor for different dosage forms:-
Topicals 10 –- 100
Oral products 100 – -1000
Parenterals 1000 -– 10 000
so for the safer side, usually take 1/1000 as safety factor.

C) MAC derived from 10 ppm approach, it doesn’t means 10 ppm is acceptable limit, it is an approach which came from ICH impurity document.so i think you didn’t get my earlier answer, it just a calculation approach and i will explain it later in detail.

Thanks and best regards[/quote]

Dear Shahnawaz,
C) I got your answer.

I am elaborating the concept of MACO here. Sometimes, the acceptable limit may be less than 10ppm, through MACO…special cases.

And you are co-relating it with ICH Guidelines w.r.t Impurities level, I know that. Even Canadian guidelines says about the same…

With Best Regards,
Sudarshan Reddy
ys.sudarsan@gmail.com

[ys_sudarsan]

[quote=Shahnawaz]Dear Sudarsan,

A) You said in earlier post that " Toxicity levels can not be determined" so i explained the methodology how to calculate the MAC by toxicity data.

B) The safety factor varies depending on the route of administration. Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms. Safety factor can vary depending on substance/dosage form according to suppose toxicity values from oral administration.
Safety factor for different dosage forms:-
Topicals 10 –- 100
Oral products 100 – -1000
Parenterals 1000 -– 10 000
so for the safer side, usually take 1/1000 as safety factor.

C) MAC derived from 10 ppm approach, it doesn’t means 10 ppm is acceptable limit, it is an approach which came from ICH impurity document.so i think you didn’t get my earlier answer, it just a calculation approach and i will explain it later in detail.

Thanks and best regards[/quote]

Dear Shahnawaz,
C) I got your answer.

I am elaborating the concept of MACO here. Sometimes, the acceptable limit may be less than 10ppm, through MACO…special cases.

And you are co-relating it with ICH Guidelines w.r.t Impurities level, I know that. Even Canadian guidelines says about the same…

With Best Regards,
Sudarshan Reddy
ys.sudarsan@gmail.com