Determination of Acceptance Criteria for Cleaning Validation (CV) Studies
Add Company Name/Logo Name/Logo He Date 2/7/2007
ORAL PRODUCTS
Sampling Method Swab Sampling Parameter Product A AI Product B1
Description Product selected for cleaning validation study (worst case) Active ingredient ingredient in Product A Product with largest MDD (Maximum Daily Dose) value
Value Units Product No. 5 Mefenamic Acid Product No. 1
Product B2
Product with smallest batch size
Ciprofloxacin HcL Tablet
CA I J
Active principle present in the cleaning agent Smallest strength of Product A manufactured Maximum number of dosage units of Product B 1 taken/day
Number of dosage units per batch of final mixture of Product B 1
LD50-AI
Lethal Dose 50 for active ingredient in Product A
740.000 740.000 mg/kg mg/kg
LD50-Detergent
Lethal Dose 50 for the detergent
240.000 240.000 mg/kg mg/kg
W L
Average human human body weight weight Equipment surface area in common between Product Product A & B 1/B2
N
Batch size of Product B 2
240000.00 240000.0000 Units
70.0 70.000 00 kg 5000.0 5000.000 00 cm² 15.0 15.000 00 kg
Swab area U Safety Factor * SF * Give justification for using safety factor other than 0.001 in the CV Protocol Summary: MACO for both AI & CA to subsequently manufactured product MACO Criterion Active Ingredient Cleaning Agent 37.500 mg/25 cm² Dose 1.943 mg/25 cm² Toxicological 0.630 mg/25 cm² 10 ppm 0.750 mg/25 cm² 0.750 mg/25 cm² Visual Limit Limit 1.000 mg/25 cm² 1.200 mg/25 cm²
25.000 25.000 cm²/Swab cm²/Swab 0.001
Active
40.0
Cleani
35.0 ) ² m c 5 2 / g m ( t i m i L
30.0 25.0 20.0 15.0 10.0 5.0 0.0 Dose
Tox.
Criterion
Formulas used for calculation: A) Dose criterion (0.001) mg of active ingredient in product A permitted per 25 sq cm swab area =
(I/J) X (K/L) X U
Where I = (SF * Smallest strength of product A manufactured)/day expressed as mg/day & based on the number of mg of active ingredient J = Maximum number of dosage units of Product B 1 taken/day K = Number of dosage units per batch of final mixture of Product B 1 L = Equipment surface area in common between Product A & B 1/B2 expressed as cm² U = Swab area (25 cm²/swab)
B) Toxicological Criterion mg of active ingredient in product A permitted per 25 sq cm swab area = Where NOEL = No observed Effect Level =
NOEL = LD50 X (W/E)
LD50 = Lethal Dose 50 in mg/kg animal for active ingredient in product A E = Empirical Constant = 2000 for Oral Products ) S = Safety Factor = 0.01 - 0.001 ( J = Maximum number of dosage units of Product B 1 taken/day K = Number of dosage units per batch of final mixture of Product B 1
NOEL x K x U SF x J x L
10 ppm
Visual
Formulas used for calculation: A) Dose criterion (0.001) mg of active ingredient in product A permitted per 25 sq cm swab area =
(I/J) X (K/L) X U
Where I = (SF * Smallest strength of product A manufactured)/day expressed as mg/day & based on the number of mg of active ingredient J = Maximum number of dosage units of Product B 1 taken/day K = Number of dosage units per batch of final mixture of Product B 1 L = Equipment surface area in common between Product A & B 1/B2 expressed as cm² U = Swab area (25 cm²/swab)
B) Toxicological Criterion mg of active ingredient in product A permitted per 25 sq cm swab area =
NOEL x K x U SF x J x L
Where NOEL = No observed Effect Level =
NOEL = LD50 X (W/E)
LD50 = Lethal Dose 50 in mg/kg animal for active ingredient in product A E = Empirical Constant = 2000 for Oral Products ) S = Safety Factor = 0.01 - 0.001 ( J = Maximum number of dosage units of Product B 1 taken/day K = Number of dosage units per batch of final mixture of Product B 1 L = Equipment surface area in common between Product A & B 1/B2 expressed as cm² U = Swab area (25 cm²/swab)
C) 10 ppm Criterion mg of active ingredient in product A permitted per 25 sq cm swab area = Where R = 10 mg active ingre dient in product A/kg Product B 2 N = Number of kgs per batch of final mixture of Product B 2 L = Equipment surface area in common between Product A & B 1/B2 expressed as cm² U = Swab area (25 cm²/swab)
e
R X (N/L) X U
e
ing Agent
Equipment Name: Example Location: Tabletting Block Compiled By: Ovais
Determination of Acceptance Criteria for Cleaning Validation (CV) Studies ORAL PRODUCTS
Add Company Name/Logo He Date 2/7/2007
Sampling Method Rinse Sampling Parameter Product A AI Product B1
Description Product selected for cleaning validation study (worst case) Active ingredient in Product A Product with largest MDD (Maximum Daily Dose) value
Value Units Product No. 5 Mefenamic Acid Product No. 1
Product B2
Product with smallest batch size
Ciprofloxacin HcL Tablet
Detergent I J
Active principle present in the cleaning agent Smallest strength of Product A manufactured Maximum number of dosage units of Product B 1 taken/day
Number of dosage units per batch of final mixture of Product B 1
LD50-AI
Lethal Dose 50 for active ingredient in Product A
LD50-Detergent
Lethal Dose 50 for the detergent
W L R N
Average human body weight Equipment surface area in common between Product A & B 1/B2 Surface area of the rinsed surface Batch size of Product B 2
V SF
Rinse Volume Safety Factor *
300000.000 Units 2300.000 mg/kg 437.000 mg/kg 35.000 kg 31627.944 cm² 1000.000 cm² 97.500 kg 50.000 L 0.001
Equipment Name: Example Location: Tabletting Block Compiled By: Ovais
Determination of Acceptance Criteria for Cleaning Validation (CV) Studies
Add Company Name/Logo He Date 2/7/2007
ORAL PRODUCTS
Sampling Method Rinse Sampling Parameter Product A AI Product B1
Description Product selected for cleaning validation study (worst case) Active ingredient in Product A Product with largest MDD (Maximum Daily Dose) value
Value Units Product No. 5 Mefenamic Acid Product No. 1
Product B2
Product with smallest batch size
Ciprofloxacin HcL Tablet
Detergent I J
Active principle present in the cleaning agent Smallest strength of Product A manufactured Maximum number of dosage units of Product B 1 taken/day
Number of dosage units per batch of final mixture of Product B 1
LD50-AI
Lethal Dose 50 for active ingredient in Product A
LD50-Detergent
Lethal Dose 50 for the detergent
W L
Average human body weight Equipment surface area in common between Product A & B 1/B2
R N
Surface area of the rinsed surface Batch size of Product B 2
300000.000 Units 2300.000 mg/kg 437.000 mg/kg 35.000 kg 31627.944 cm² 1000.000 cm² 97.500 kg
Rinse Volume V Safety Factor * SF * Give justification for using safety factor other than 0.001 in the CV Protocol Summary: MACO for both AI & CA to subsequently manufactured product MACO Criterion Active Ingredient Cleaning Agent 9.485 mg/L Dose 0.954 mg/L Toxicological 0.181 mg/L 10 ppm 0.617 mg/L 0.617 mg/L Visual Limit 1.000 mg/L 1.200 mg/L
50.000 L 0.001
Active
10.0 ) 8.0 ² m c 5 2 6.0 / g m 4.0 ( t i m 2.0 i L
0.0 Dose Criterion
e
Cleaning
Tox.
10 ppm
Visual
e
Agent
Question regarding Calculation of J 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 be6, assuming that "6" is the maximum number of times the tablet could be consumed daily.
Please note to calculate the MACO, first you should know the both products TDD (Therepetic daily dose) then you can calculate the MACO as per the equation given in the APIC cleaning validation guide. Then you can get the MACO in mg. If you don't have the TDD of the products , you can calculate the MACO as per general limit
Question regarding Calculation of J 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 be6, assuming that "6" is the maximum number of times the tablet could be consumed daily.
Please note to calculate the MACO, first you should know the both products TDD (Therepetic daily dose) then you can calculate the MACO as per the equation given in the APIC cleaning validation guide. Then you can get the MACO in mg. If you don't have the TDD of the products , you can calculate the MACO as per general limit criteria. O.1% general limit for intermediates and 0.01% criteria for finished products. You can multiply the subsequent product batch size in m g and devided by 100 to get the MACO in mg. If you have TDD of the products, then also you can calculate the MACO as per general limit criteria and compare the both carryover and you can consider which ever is lower value [Worst case]. You can calculate the MACO in ppm, you should know the surface areas of the equipment train of the facility. Please note only common equipments surface areas shall be considered for calculation.
First you shall calculate the MACO of existing product to subsequent product as per TDD and General limit methods. Consider the lowest MACO value from the both methods. The considered MACO value shall be divided by total rinse volume of the equipment train and then you will get the total equipment train MACO limit for rinse. Eg: MACO value as per TDD: 850 ppm MACO value as per General limit: 758 ppm Consider the General limit MACO value (758 PPM) for further calculation MACO value for total equipment train = MACO value/Total equipment train rinse volume i.e. 758/75 = 10.1 ppm MACO value for individual equipment = MACO of total equipment train X individual equipment surface ar
