1. Equipment Name: Example
Add Company Name/Logo Here
Location: Tabletting Block
Compiled By: Ovais ORAL PRODUCTS Date 2/7/2007
Sampling Method Swab Sampling
Parameter Description Value Units
Product A Product selected for cleaning validation study (worst case) Product No. 5
AI Active ingredient in Product A Mefenamic Acid
Product with largest MDD (Maximum Daily Dose) value Product No. 1
Product with smallest batch size Ciprofloxacin HcL Tablet
CA Active principle present in the cleaning agent AlkylBenzene Sulphonate
I Smallest strength of Product A manufactured 500.000 mg/day
J 16.000 Units/day
K 240000.000 Units
Lethal Dose 50 for active ingredient in Product A 740.000 mg/kg
Lethal Dose 50 for the detergent 240.000 mg/kg
W Average human body weight 70.000 kg
L 5000.000 cm²
N 15.000 kg
U Swab area 25.000 cm²/Swab
SF Safety Factor ¹ (for "Dose criterion" only) 0.001
RF Risk Assessment Factor (for "Toxicological criterion" only) 0.001
¹ Give justification for using safety factor other than 0.001 in the CV Protocol
Summary: MACO for both AI & CA to subsequently manufactured product
Criterion
MACO
Active Ingredient Cleaning Agent
Dose 37.500 mg/25 cm²
Toxicological 1.943 mg/25 cm² 0.630 mg/25 cm²
10 ppm 0.750 mg/25 cm² 0.750 mg/25 cm²
Visual Limit 1.000 mg/25 cm² 1.200 mg/25 cm²
Determination of Acceptance Criteria for
Cleaning Validation (CV) Studies
Product B1
Product B2
Maximum number of dosage units of Product B1
taken/day
Number of dosage units per batch of final mixture of Product B1
LD50
-AI
LD50
-Detergent
Equipment surface area in common between Product A & B1
/B2
Batch size of Product B2
INSTRUCTIONS:
Fill in the Coral input fields as mentioned (read the
comments if needed)
INSTRUCTIONS:
Fill in the Coral input fields as mentioned (read the
comments if needed)
Dose
Tox.
10 ppm
Visual
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
Active Cleaning
Agent
Criterion
Limit(mg/25cm²)
3. Formulae used for calculation:
A) Dose criterion
((SF x I)/J) x (K/L) x U
Where
I = Smallest strength of product A manufactured/day expressed as mg/day & based on the number of mg of active ingredient
B) Toxicological Criterion
(NOEL x RF) x K x U
J x L
Where
NOEL = No observed Effect Level =
E = Empirical Constant = 2000
C) 10 ppm Criterion
R x (N/L) x U
Where
All the abbreviations used in the formulae are defined in the table above (see Description)
References:
Pharm. Technol. 17(4), 54-60 (1993).
Institute of Validation Technology, 1997.
(CEFIC, Brussels, December 2000), available at http://apic.cefic.org/pub/pub-cleaning-validation.pdf, accessed Feb 5, 2009.
mg of active ingredient in product A permitted per 25 sq cm swab area =
mg of active ingredient in product A permitted per 25 sq cm swab area =
NOEL = LD50
X (W/E)
LD50
= Lethal Dose 50 in mg/kg animal for active ingredient in product A
RF = Risk Assessment Factor = 0.01 - 0.001 (for Oral Products)
mg of active ingredient in product A permitted per 25 sq cm swab area =
R = 10 mg active ingredient in product A/kg Product B2
N = Number of kgs per batch of final mixture of Product B2
1. Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations
2. W.E. Hall, “Validation of Cleaning Processes for Bulk Pharmaceutical Chemical Processes”, Cleaning Validation - An Exclusive Publication,
3. CEFIC - Active Pharmaceutical Ingredients Committee (APIC), Guidance on aspects of cleaning validation in active pharmaceutical ingredient
This spreadsheet may not be resold or distributed. Please request
author (mohammad@xepasp.com for any changes required to be
made).
This spreadsheet may not be resold or distributed. Please request
author (mohammad@xepasp.com for any changes required to be
made).
Note:
(NOEL x RF) = ADI (Acceptable Daily
Intake)
4. Equipment Name: Example
Add Company Name/Logo Here
Location: Tabletting Block
Compiled By: Ovais ORAL PRODUCTS Date 2/7/2007
Sampling Method Rinse Sampling
Parameter Description Value Units
Product A Product selected for cleaning validation study (worst case) Product No. 5
AI Active ingredient in Product A Mefenamic Acid
Product with largest MDD (Maximum Daily Dose) value Product No. 1
Product with smallest batch size Ciprofloxacin HcL Tablet
Detergent Active principle present in the cleaning agent AlkylBenzene Sulphonate
I Smallest strength of Product A manufactured 500.000 mg/day
J 16.000 Units/day
K 240000.000 Units
Lethal Dose 50 for active ingredient in Product A 740.000 mg/kg
Lethal Dose 50 for the detergent 240.000 mg/kg
W Average human body weight 70.000 kg
L 5000.000 cm²
RS Surface area of the rinsed surface 1000.000 cm²
N 15.000 kg
V Rinse Volume 50.000 L
SF Safety Factor ¹ (for "Dose criterion" only) 0.001
RF Risk Assessment Factor (for "Toxicological criterion" only) 0.001
* Give justification for using safety factor other than 0.001 in the CV Protocol
Summary: MACO for both AI & CA to subsequently manufactured product
Criterion
MACO
Active Ingredient Cleaning Agent
Dose 30.000 mg/L
Toxicological 1.554 mg/L 0.504 mg/L
10 ppm 0.600 mg/L 0.600 mg/L
Visual Limit 1.000 mg/L 1.200 mg/L
Determination of Acceptance Criteria for
Cleaning Validation (CV) Studies
Product B1
Product B2
Maximum number of dosage units of Product B1
taken/day
Number of dosage units per batch of final mixture of Product B1
LD50
-AI
LD50
-Detergent
Equipment surface area in common between Product A & B1
/B2
Batch size of Product B2
Dose
Tox.
10 ppm
Visual
0.0
5.0
10.0
15.0
20.0
25.0
30.0 Active Cleaning
Agent
Criterion
Limit(mg/25cm²)
5. Formulae used for calculation:
A) Dose criterion
((SF x I)/J) x (K/L) x (RS/V)
B) Toxicological Criterion
(NOEL x RF) x K x RS
J x L x V
Where
NOEL = No observed Effect Level =
E = Empirical Constant = 2000
C) 10 ppm Criterion
R x (N/L) x (RS/V)
Where
All the abbreviations used in the formulae are defined in the table above (see Description)
References:
Pharm. Technol. 17(4), 54-60 (1993).
Institute of Validation Technology, 1997.
(CEFIC, Brussels, December 2000), available at http://apic.cefic.org/pub/pub-cleaning-validation.pdf, accessed Feb 5, 2009.
mg of active ingredient in product A permitted per 'Litre' of rinsate =
mg of active ingredient in product A permitted per 25 sq cm swab area =
NOEL = LD50
X (W/E)
LD50
= Lethal Dose 50 in mg/kg animal for active ingredient in product A
RF = Risk Assessment Factor = 0.01 - 0.001 (for Oral Products)
mg of active ingredient in product A permitted per 25 sq cm swab area =
R = 10 mg active ingredient in product A/kg Product B2
N = Number of kgs per batch of final mixture of Product B2
1. Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations
2. W.E. Hall, “Validation of Cleaning Processes for Bulk Pharmaceutical Chemical Processes”, Cleaning Validation - An Exclusive Publication,
3. CEFIC - Active Pharmaceutical Ingredients Committee (APIC), Guidance on aspects of cleaning validation in active pharmaceutical ingredient
Dose
Tox.
10 ppm
Visual
Criterion
