Equipment Name: Example Determination of Acceptance Criteria for

Add Company Name/Logo Here

Location: Tabletting Block Cleaning Validation (CV) Studies
Compiled By: Ovais ORAL PRODUCTS Date 2/7/2007

INSTRUCTIONS:
INSTRUCTIONS:
Fillin
Fill in the
the Coral
Coralinput
inputfields
fieldsas
asmentioned
mentioned(read
(readthe
the
Sampling Method Swab Sampling comments ifif needed)
needed)
comments

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 B1 Product with largest MDD (Maximum Daily Dose) value Product No. 1
Product B2 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 Maximum number of dosage units of Product B1 taken/day 16.000 Units/day
K Number of dosage units per batch of final mixture of Product B1 240000.000 Units
LD50-AI Lethal Dose 50 for active ingredient in Product A 740.000 mg/kg
LD50-Detergent Lethal Dose 50 for the detergent 240.000 mg/kg
W Average human body weight 70.000 kg
L Equipment surface area in common between Product A & B1/B2 5000.000 cm²
N Batch size of Product B2 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 Active Cleaning
40.0
MACO Agent
35.0
Criterion
Active Ingredient Cleaning Agent 30.0

Limit (mg/25cm²)
Dose 37.500 mg/25 cm² 25.0
20.0
Toxicological 1.943 mg/25 cm² 0.630 mg/25 cm²
15.0
10 ppm 0.750 mg/25 cm² 0.750 mg/25 cm² 10.0
Visual Limit 1.000 mg/25 cm² 1.200 mg/25 cm² 5.0
0.0
Dose
Tox.
10 ppm
Visual
Criterion
Dose
Tox.
10 ppm
Visual
Criterion
Formulae used for calculation:
This spreadsheet
This spreadsheet may
may not
not be
be resold
resold or
or distributed.
distributed. Please
Please request
request
author (mohammad@xepasp.com for any changes required
author (mohammad@xepasp.com for any changes required to to be
be
A) Dose criterion made).
made).

mg of active ingredient in product A permitted per 25 sq cm swab area = ((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

mg of active ingredient in product A permitted per 25 sq cm swab area = (NOEL x RF) x K x U

JxL
Where
NOEL = No observed Effect Level = NOEL = LD50 X (W/E) Note:
LD50 = Lethal Dose 50 in mg/kg animal for active ingredient in product A (NOEL x RF) = ADI (Acceptable Daily
Intake)
E = Empirical Constant = 2000
RF = Risk Assessment Factor = 0.01 - 0.001 (for Oral Products)

C) 10 ppm Criterion

mg of active ingredient in product A permitted per 25 sq cm swab area = R x (N/L) x U

Where
R = 10 mg active ingredient in product A/kg Product B2
N = Number of kgs per batch of final mixture of Product B2

All the abbreviations used in the formulae are defined in the table above (see Description)

References:
1. Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations
Pharm. Technol. 17(4), 54-60 (1993).
2. W.E. Hall, “Validation of Cleaning Processes for Bulk Pharmaceutical Chemical Processes”, Cleaning Validation - An Exclusive Publication,
Institute of Validation Technology, 1997.
3. CEFIC - Active Pharmaceutical Ingredients Committee (APIC), Guidance on aspects of cleaning validation in active pharmaceutical ingredient
(CEFIC, Brussels, December 2000), available at http://apic.cefic.org/pub/pub-cleaning-validation.pdf, accessed Feb 5, 2009.
Equipment Name: Example Determination of Acceptance Criteria for
Add Company Name/Logo Here
Location: Tabletting Block Cleaning Validation (CV) Studies
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 B1 Product with largest MDD (Maximum Daily Dose) value Product No. 1
Product B2 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 Maximum number of dosage units of Product B1 taken/day 16.000 Units/day
K Number of dosage units per batch of final mixture of Product B1 240000.000 Units
LD50-AI Lethal Dose 50 for active ingredient in Product A 740.000 mg/kg
LD50-Detergent Lethal Dose 50 for the detergent 240.000 mg/kg
W Average human body weight 70.000 kg
L Equipment surface area in common between Product A & B1/B2 5000.000 cm²
RS Surface area of the rinsed surface 1000.000 cm²
N Batch size of Product B2 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 Active Cleaning
30.0
MACO Agent
Criterion 25.0
Active Ingredient Cleaning Agent

Limit (mg/25cm²)
20.0
Dose 30.000 mg/L 15.0
Toxicological 1.554 mg/L 0.504 mg/L 10.0
10 ppm 0.600 mg/L 0.600 mg/L 5.0
Visual Limit 1.000 mg/L 1.200 mg/L 0.0
Dose
Tox.
10 ppm
Visual
Criterion
 Dose
Tox.
10 ppm
Visual
Criterion

Formulae used for calculation:

A) Dose criterion

mg of active ingredient in product A permitted per 'Litre' of rinsate = ((SF x I)/J) x (K/L) x (RS/V)

B) Toxicological Criterion

mg of active ingredient in product A permitted per 25 sq cm swab area = (NOEL x RF) x K x RS

JxLxV
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
RF = Risk Assessment Factor = 0.01 - 0.001 (for Oral Products)

C) 10 ppm Criterion

mg of active ingredient in product A permitted per 25 sq cm swab area = R x (N/L) x (RS/V)

Where
R = 10 mg active ingredient in product A/kg Product B2
N = Number of kgs per batch of final mixture of Product B2

All the abbreviations used in the formulae are defined in the table above (see Description)

References:
1. Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations
Pharm. Technol. 17(4), 54-60 (1993).
2. W.E. Hall, “Validation of Cleaning Processes for Bulk Pharmaceutical Chemical Processes”, Cleaning Validation - An Exclusive Publication,
Institute of Validation Technology, 1997.
3. CEFIC - Active Pharmaceutical Ingredients Committee (APIC), Guidance on aspects of cleaning validation in active pharmaceutical ingredient
(CEFIC, Brussels, December 2000), available at http://apic.cefic.org/pub/pub-cleaning-validation.pdf, accessed Feb 5, 2009.