The Cleaning validation is performed to demonstrate the effectiveness of procedures for cleaning to remove the residue of the previous product.
After the process, equipment used for manufacturing of the product shall be cleaned as mentioned in respective SOPs for cleaning.
All procedures for cleaning of process equipment used to manufacture more than one product shall be validated.
If the product contains more than one active substance, the active substance least soluble in water and/or highly potent is tested unless otherwise specified in the individual specification.
Before initiating any cleaning validation, a product specific specification shall be prepared. The specification shall mention the acceptance criteria for the existing products, however, if acceptance criteria become stringent or maximum rinse volume is changed after addition of new products, the acceptance criteria and maximum rinse volume is communicated to the concerned department. The stringent acceptance criteria are added in the specifications during the scheduled periodic review of the specifications.
A specification shall minimally contain the following
Shall provide sampling quantity for chemical and microbiological testing or as applicable.
Shall explain briefly the procedure for sample collection.
Shall provide specifications for the applicable tests.
Shall provide analytical method for the applicable tests
All the applicable tests shall be incorporated in the specification itself.
Minimally three cleaning cycles shall be monitored and validated to establish the effectiveness of cleaning procedure.
Study of monitoring the cleaning activity before completion of the three cleaning cycles on commercial batches of the product shall be considered as cleaning verification.
Cleaning verification / validation Acceptance Criteria:
Calculation of the Maximum Allowable CarryOver ( MACO)
For the calculation by considering 0.1 % Safety factor
Daily therapeutic dose Min. Batch Size of Product B
of product A in mg (in mg)
Limit (mg) = ----------------------------------- x ------------------------------------------------
1000 Max. daily therapeutic dose of
product B in (mg)
Where,
Product A – Product manufactured before cleaning
Product B – Next Product after cleaning
For Considering 10 ppm as acceptance criteria.
The quantity equivalent to 10 mg/L of the batch size is considered as the acceptance criteria for the acceptance criteria as 10 ppm.
Calculation of acceptance criteria for swab samples
Calculation of acceptance criteria for Rinse samples
Active Ingredient Residue (For Non-dedicated equipment): Acceptance criteria based on the following rationale for swab samples :
Calculation [Applicable to all items of common equipment in product train].
1000 D
Limit (PPM) = MACO x ---------- x -----------
C V
Where,
C – the Cumulative surface area of the equipment used (in cm2).
V – Volume of solvent used to dispense swab.
1000 – Multiplication factor to convert the value in mcg from mg.
D – Swabbed Surface Area in cm 2 .
Active Ingredient Residue (For Non-dedicated equipment): Acceptance criteria based on the following rationale for rinse samples:
Calculation [Applicable to all items of common equipment in product train].
1000 1
Limit (PPM) = MACO X ---------- x ------
C V
Where,
C – the Cumulative surface area of the equipment used (in cm2).
V – Volume of solvent used for the rinse of the same in mL per cm2 of Equipment.
1000 – Multiplication factor to convert the value in mcg from mg.
Calculation of recovery factor :
% Recovery shall not be less than 75% unless otherwise specified and justified in the individual protocol of analytical method validation.
Recovery factor shall be calculated as follows:
Recovery factor = --------------------
% Recovery
Microbiological Quality:
a) A Total count limit is Not more than 10 cfu/100 ml by rinse method.
b) Not more than 5 cfu / 25 cm2
Cleaning validation shall be performed on all the products. The matrix for acceptance criteria shall be prepared when the same set of equipment is used for different products.
After addition of new product, the acceptance criteria and maximum rinse volume shall be recalculated in the matrix. If the acceptance criteria are stringent than as specified.
Revalidation of cleaning procedure is required if any of the following occur and revalidation of cleaning procedure shall be performed on a minimum of three cleaning cycles.
Modification of cleaning procedure / Surface area of product contact parts of the equipment or any modification to the equipment which has got a direct bearing on product contact parts.
Change in cleaning procedure.
Change in the analytical method for determination of residue.
Major non-traceable contamination occurrence.
Failure during cleaning verification/validation.
Monitor the validation status for cleaning during new product introduction.
In case of microbial analysis results of swab samples or rinse samples, no need to wait for the release of results.
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Great work sir. Sir kindly mention The Limit of Microbial load in Non sterile plant by swab testing in cleaning validation. is 5 cfu/25 cm^2 is ok.
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