quipment 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 inthe
theCoral
Coralinput
inputfields
fieldsas
asmentioned
mentioned(read
(readthe
the
Sampling Method Swab Sampling commentsififneeded)
needed)
comments

Parameter Description Value Units

Product A Product selected for cleaning validation study (worst ca 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 lkylBenzene 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 B 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 & B 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" on 0.001
¹ Give justification for using safety factor other than 0.001 in the CV Protocol

L im it ( m g /2 5 c m ² )
Summary: MACO for both AI & CA to subsequently manufactured product
MACO
Criterion
Active Ingredient Cleaning Agent
Dose 37.500 mg/25 cm² 40.000 Active Cleaning Agent
35.000
Toxicological 1.943 mg/25 cm² 0.630 mg/25 cm² 30.000
10 ppm 0.750 mg/25 cm² 0.750 mg/25 cm² 25.000

Visual Limit 1.000 mg/25 cm² 1.200 mg/25 cm² 20.000

15.000
10.000
5.000
0.000
Dose
Tox.
Criterion
10 ppm
Visual
5.000
0.000
Dose
Tox.
Criterion
10 ppm
Visual
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
author (mohammad@xepasp.com for for any
any changes
changes required
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:
Note:
LD50 = Lethal Dose 50 in mg/kg animal for active ingredient in product A (NOELxxRF)
(NOEL RF)==ADI
ADI(Acceptable
(AcceptableDaily
Daily
Intake)
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 B 2
N = Number of kgs per batch of final mixture of Product B 2

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 ingredien
(CEFIC, Brussels, December 2000), available at http://apic.cefic.org/pub/pub-cleaning-validation.pdf, accessed Feb 5, 2009.
quipment 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 ca 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 lkylBenzene 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 B 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 & B 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" o 0.001
* Give justification for using safety factor other than 0.001 in the CV Protocol

L im it (m g /2 5 c m ² )
Summary: MACO for both AI & CA to subsequently manufactured product
MACO
Criterion
Active Ingredient Cleaning Agent
Dose 30.000 mg/L 30.000 Active Cleaning Agent

Toxicological 1.554 mg/L 0.504 mg/L 25.000

20.000
10 ppm 0.600 mg/L 0.600 mg/L
15. 000
Visual Limit 1.000 mg/L 1.200 mg/L 10.000
5.000
0.000
Dose
Tox.
Criterion 10 ppm
Visual
 5.000
0.000
Dose
Tox.
Criterion 10 ppm
Visual

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 B 2
N = Number of kgs per batch of final mixture of Product B 2

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 ingredien
(CEFIC, Brussels, December 2000), available at http://apic.cefic.org/pub/pub-cleaning-validation.pdf, accessed Feb 5, 2009.