Equipment Name: Example Location: Tabletting Block Compiled By: Ovais

Determination of Acceptance Criteria for Cleaning Validation (CV) Studies

ORAL PRODUCTS

Add Company Name/Logo Here Date 2/7/2007

Sampling Method Swab Sampling Parameter Product A AI Product B1 Product B2 CA I J K LD50-AI LD50-Detergent W L Description Product selected for cleaning validation study (worst case) Active ingredient in Product A Product with largest MDD (Maximum Daily Dose) value Product with smallest batch size Active principle present in the cleaning agent Smallest strength of Product A manufactured Maximum number of dosage units of Product B1 taken/day Number of dosage units per batch of final mixture of Product B1 Lethal Dose 50 for active ingredient in Product A Lethal Dose 50 for the detergent Average human body weight Equipment surface area in common between Product A & B1/B2 Value Units Product No. 5 Mefenamic Acid Product No. 1 Ciprofloxacin HcL Tablet AlkylBenzene Sulphonate 500.000 mg/day 16.000 Units/day 240000.000 Units 740.000 mg/kg 240.000 mg/kg 70.000 kg 5000.000 cm 15.000 kg 25.000 cm/Swab 0.001

N Batch size of Product B2 U Swab area SF Safety Factor * * 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 Dose 37.500 mg/25 cm Toxicological 1.943 mg/25 cm 0.630 mg/25 cm 10 ppm 0.750 mg/25 cm 0.750 mg/25 cm Visual Limit 1.000 mg/25 cm 1.200 mg/25 cm

40.0 35.0 Limit (mg/25cm) 30.0

Active

Cleaning Agent

25.0
20.0 15.0 10.0 5.0 0.0 Dose Tox.

Criterion

10 ppm

Visual

Criterion

Visual

Formulas used for calculation: A) Dose criterion (0.001)

mg of active ingredient in product A permitted per 25 sq cm swab area = 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 B1 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 cm U = Swab area (25 cm/swab) (I/J) X (K/L) X U

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 S = Safety Factor = 0.01 - 0.001 (for Oral Products ) J = Maximum number of dosage units of Product B1 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 cm U = Swab area (25 cm/swab) NOEL x K x U SF x J x L

C) 10 ppm Criterion
mg of active ingredient in product A permitted per 25 sq cm swab area = Where R = 10 mg active ingredient in product A/kg Product B2 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 cm U = Swab area (25 cm/swab) R X (N/L) X U

go Here

Cleaning 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 Here Date 2/7/2007

Sampling Method Rinse Sampling Parameter Product A AI Product B1 Product B2 Detergent I J K LD50-AI LD50-Detergent Description Product selected for cleaning validation study (worst case) Active ingredient in Product A Product with largest MDD (Maximum Daily Dose) value Product with smallest batch size Active principle present in the cleaning agent Smallest strength of Product A manufactured Maximum number of dosage units of Product B1 taken/day Number of dosage units per batch of final mixture of Product B1 Lethal Dose 50 for active ingredient in Product A Value Units Product No. 5 Mefenamic Acid Product No. 1 Ciprofloxacin HcL Tablet AlkylBenzene Sulphonate 400.000 mg/day 8.000 Units/day 300000.000 Units 2300.000 mg/kg 437.000 35.000 31627.944 1000.000 97.500 50.000 0.001 mg/kg kg cm cm kg L

Lethal Dose 50 for the detergent W Average human body weight L Equipment surface area in common between Product A & B1/B2 R Surface area of the rinsed surface N Batch size of Product B2 V Rinse Volume SF Safety Factor * * 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 Dose 9.485 mg/L Toxicological 0.954 mg/L 0.181 mg/L 10 ppm 0.617 mg/L 0.617 mg/L Visual Limit 1.000 mg/L 1.200 mg/L
10.0 Limit (mg/25cm) 8.0 6.0 4.0 2.0 0.0

Active

Cleaning Agent

Dose Criterion

Tox.

10 ppm

Visual

o Here

Cleaning 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 be 6, 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 mg 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 area/ Total equipment tra

t surface area/ Total equipment train surface area