Cleaning Validation Study

Guidelines-

1. PDA Technical report No.: 29 (Revised- 2012)- Points to be considered for Cleaning Validation.

Cleaning Validation Study necessary to validate cleaning process to be used before start of batch execution, and it gives-

Assurance that the established cleaning process is effective and it prevents the carryover of previous product/ cleaning agents in subsequent batch.

It Limits potential carryover to an acceptable level.

Controls potential carryover of the products, intermediate, and impurity. 

Quality of the next product does not compromised with the waste of previous product. 

TRF (Total Risk Factor) - Decides the selection of worst case molecule (Marker compound) for validation of cleaning process.

TRF components are Toxicity (OEB), Solubility, Potency (Minimum therapeutic dose), and other factors as cytotoxicity.

OEB and Solubility are the major component and shall be added as multiplier of 6.

Potency and other factors (if any) shall be added as multiplier of 5.

TRF= OEB*6 + Solubility*6 + Potency*5 +...

MACO (Maximum Allowable Carry Over) - Is the maximum amount of worst case molecule allowed as residue in final sample sent for analysis after cleaning of equipment.

Worst case molecule shall be selected on the basis of -
1. TRF Value- Molecule with Highest Value
2. MACO Value- Molecule with Lowest Value.

Dirty Hold Time (Soiled Hold Time)- The time from the end of manufacturing until the beginning of cleaning process.

Clean Hold Time- The time from the end of cleaning process until the equipment is used again (which may be product manufacture/ autoclaving/ or SIP Cycle).

The cleaning process requires design and development prior to implementation in manufacturing plant to ensure the cleaning process and equipment are acceptable for use.

Operation parameter for cleaning process-

1. Cleaning agent

2. Concentration

3. Contact Time

4. Temperature

Factors which affect Cleaning process-

1. Product characteristics

2. Product condition

Relevant specifics about the cleaning equipment's-

1. Automated cleaning pathways

2. Sequence of manual or automated cleaning steps

3. Flow rates during each steps

Above operational parameters shall be determined prior to implementation.

Steps for cleaning process-
1. Vacuum or Pre-rinse- Removal of non-adhering or readily soluble residue (for reduction of soil load prior to start of washing).
2. Wash with cleaning solution- Removal of soluble and dried residue (Primary step for soil or bioburden removal and performed at elevated temperature).
3. Rinse- Removal of suspended/ solubilized soil/ cleaning solution (May includes a series of pulse rinses & includes final rinse with higher grade of rinse solvent).
4. Dry- Removal of water and other solvent (By air or nitrogen flow or by heat).

TACT- Principal cleaning input parameters or Variables-
1. Time= Length of time for the cycle steps.
2. Action= Mechanism used to deliver cleaning agent (SOAK/ SCRUBBING/ IMPINGEMENT/ TURBULENT FLOW)
3. Concentration= Cleaning agent concentration having direct impact of cleaning process.
4. Temperature= It vary for different steps (Initial solvent rinse are typically performed at ambient temperatures to minimize any denaturation or degradation effect and to maximize the dilution effects/ Cleaning solution may be heated to increase their cleaning effectiveness/ Final rinse may be performed at high temperature to increase the solubility of cleaning process residue and to increase the drying rate of rinse solvent)

- These four variables are interrelated and have a direct relationship on each phase in the cleaning cycle.

Acceptable concentration of residue in next product-
1. ARL (Acceptable Residue Level) Based on Drug active dose-

ARL= (MDDxSF)/ LDD

MDD= minimum daily dose of active of cleaned product
SF= safety factor which is typically 0.001
LDD= Largest daily dose of next product to be manufactured in same equipment.

2. ARL (Acceptable Residue Level) Based on Toxicity-
Generally two types of calculation based on Toxicity-
A) NOAEL (No observable adverse effect level)- Risk mapp acceptable daily exposure (ADE) approach and applicable for drug actives/ intermediate/ degradants.
B) LD₅₀- Used for cleaning agent which do not have dose.

Acceptable total carryover-
Once the ARL is determined, the MAC or MACO (Maximum allowable carryover) can be calculated.

MAC= ARLxMBS

MBS= Minimum batch size of next product.