CLEANING VALIDATION
APPROACH , Part1
Raktim Dey
DY. Manager (VALIDATIONS & QUALIFICATIONS), Granules India Limited
The FDA lists four criteria: (1) what can be reasonably achieved,
(2) what is medically safe, (3) what causes no product quality concerns, and
(4) what is visually clean.
Note: This presentation is part 1, as all aspects of Cleaning validation cannot be consolidated in one PPT.
Worst case molecules are selected basis to a Worst Case Rating of each molecule in a multi product facility. The following factors are considered while selecting a worst case molecule: a) Solubility
Emphasis shall also be given to molecule having Significant Colour, Flavor while determining worst case molecule.
The worst case rating of a molecule is given basis to it’s solubility, PDE value and Potency as follows.


Rating 
ADE/PDE (μg/day) 
1 
>500 
2 
100  500 
3 
10 – 99 
4 
1 – 9 
5 
<1 
3. Potency of the API: The therapeutic doses are typically based on oral and/or parenteral data; the rating should be carried out as given below.
Rating 
Include dose intervals (smallest therapeutic dose) ( mg ) 
1 
>1 000 
2 
100  1 000 
3 
10 – 99 
4 
1 – 9 
5 
<1 
The above mentioned parameters shall be multiplied with the weightage mentioned below for the calculating the total risk.
Rating 
*Weightage 
Rational 
Solubility 
3 
Cleaning of a molecule depends on solubility 
PDE 
2 
Health Based (PDE) value of the molecule is directly proportional to its adverse effects on the residue 
Potency 
1 
Potent nature of a molecule depends on potency; Less potency more potent molecule. 
The calculation is done for better understanding:
Product Name 
Parameters 
Description 
Rating (R) 
Weightage (W) 
Weighted Risk (R * W) 
Total score 
risk 
Product A (Existing) 
Solubility 
Very Soluble 
1 
3 
3 
12 

PDE (μg / day) 
100 
2 
2 
4 

Potency (mg) 
1 
5 
1 
5 

Product B (New product) 
Solubility 
Practically Insoluble 
3 
3 
9 
15 

PDE (μg / day) 
100 
2 
2 
4 

Potency (mg) 
100 
2 
1 
2 
Note:
1. Based on Therapeutic Dose combined with a safety factor (MethodA):
Use the following equation to calculate the maximum allowable carryover.
MiniTD (A) x Mini BS (B) x RF
MACO (AB) = F X Maxi DD (B) Where:
MACO : Maximum Allowable Carryover of previous product in subsequent product.
MiniTD (A) : Minimum therapeutic dose of previous product (A) manufactured (in mg)
Mini BS : Minimum Batch Size of next product (B) (in mg )
F : Safety Factor (1000) for OSD
Maxi DD (B): Maximum daily dose of next product (B) (in mg).
RF : Recovery Factor
2. Based on LD50 ( toxicology) data (MethodB): [ Toxicity based calculation shall be applied for Detergents/Cleaning Agents]
NOEL (A) x Mini BS (B) x RF
MACO (AB) =  or
F x Maxi DD (B)
ADI ( A) x Mini BS (B )
MACO (AB) = Maxi DD (B) Where:
Acceptable Daily Intake (ADI): The ADI is the noeffect level observed, divided by the safety factor F, depending on the route of administration.
NOEL
ADI (µg/day) = 
F
MACO : Maximum Allowable Carryover of previous product (A) in subsequent product (B).
NOEL (A) : No observed effect level (in mg )
F : Safety Factor (1000)
Mini BS : Minimum Batch Size of next product (in mg)
Maxi DD (B) : Maximum daily dose of next product (B) (in mg).
RF : Recovery Factor
NOEL shall be calculated as per the below formula:
NOEL=LD50 x 5. 10? 4 x n (Patient Weight in kg)
Where: 

LD50 
: Lethal dose 50 in mg/kg animal (mouse, rat.) 
NOEL 
: No observed effect level (in mg) 
n 
: Weight of average adult (50kg) 
3. Based on Health Based Exposure Limits (MethodC):
It is an alternative method for establishing the limits using the PDE (Permitted Daily Exposure) values for the new drug products. The PDE is based on all the adverse effects on the patient whether pharmacological or toxicological.
PDE (A) x Mini BS (B) x RF
MACO= 
Maxi DD (B)
Note: The stringent MACO value derived from the above three Methods of calculation ( i.e. Dose Based, LD50 Based and PDE based) shall be considered as acceptance criteria for Cleaning Validation , extrapolating the results upto per Swab level.
For example, let’s say the following MACO ( stringent value) value observed after calculation:
Now, It is evident that the stringent value obtained is basis to the LD50 based calculation , i.e. 95294.0 mg. and lets say the shared surface area of the equipment = 2430115 sq.cm
Hence, Swab limit shall be calculated as follows:
MACO (mg) x 100 x 1000 x 1
TARGET MACO (ppm) = 
Shared surface area of the equipment x desorbing solvent (mL)
95294.0mg x 100 x 1000 x 1
= 
2430115 x 10
= 392.10 ppm
Now, since the calculated swab limit is more than 10 ppm, the acceptance criteria for the swab limit shall be considered as NMT10 ppm.
1) For Chemical Residue (swab method):
2) For Microbial Bioload :
Take swab sticks in a test tube containing 10 ml of saline solution and autoclave/steam sterilizer at 121.0oC as per SOP No.GGMC259/GGMC/284
Note:
3) Sampling procedure for rinse Sample :
MACO (mg) x Swabbing Area (cm2 ) x 1000 ( conversion factor) x RF
Swab Residue (ppm) = Total surface Area of the Equipment in cm2 x Amount of rinsing solvent (mL)
Rinse Residue (ppm) = MACO (mg) x Rinsing Area (cm2 ) x 1000 (Conversion factor) x RF
Total surface Area of the Equipment in cm2 x Amount of rinsing Solvent (ml)
Cleaning validation shall be conducted in case of the following , but not limited to:
Following are the prerequisites for conducting cleaning validation, but not limited to:
cleaning, sampling and testing.
A Typical Cleaning Validation Flow Chart: 
Sampling site selection for swab sampling from a particular Equipment largely depends upon the following:
Sampling site selection for Rinse sampling for a particular Equipment largely depends upon the following:
OPEN FOR DISCUSSIONS Thank You