Regulatory Expectations for Cleaning Validation
Cleaning validation is an integral part of the pharmaceutical manufacturing
process. A piece of equipment itself can contaminate the product if it is not
cleaned properly. Improperly cleaned manufacturing equipment is a major source
of cross-contamination. Regulatory agencies are more concerned about the
cross-contamination of penicillin with non-penicillin products.
A number of warning letters have been issued by the FDA for
deficiencies in cleaning procedures. Residues of the previous product, as well
as the cleaning agent used for equipment cleaning, must be cleaned to prevent
the cross-contamination.
Following are the general requirements of regulatory agencies for
pharmaceutical manufacturing firms regarding cleaning validation.
1. Cleaning Procedures: A written procedure for cleaning processes
for all pieces of equipment used in manufacturing. If there are different
cleaning procedures for a batch to batch change and product to product change
or water-soluble and water-insoluble residues, then conditions to follow the procedures
should be clearly mentioned. Fluid bed dryer bags are difficult to clean so
they should be dedicated to specific products.
2. Cleaning validation protocol should be written and approved
before starting the validation activity. Responsibilities for the validation
activity, sampling procedure, analytical method, acceptance criteria and
revalidation criteria must be clearly defined in validation protocol.
3. Validation must be conducted in accordance with the validation
protocol. Every written step must be followed and each followed step must be written
in the protocol.
4. The final report must be approved by the management with the
result and conclusion of the cleaning validation activity. The conclusion
should state that the residues of the previous product have been reduced to the
acceptance level.
5. During an inspection, the regulatory inspectors need to be
satisfied with the cleaning process and its validation. Validation should answer
their question during evaluation like how the equipment is cleaned, with a
scrubber or just washed with water? Was cleaning batch to batch or product to product?
Which parts of the equipment were cleaned? These steps can help to develop an
effective and easy procedure to clean the equipment because cleaning validation
is not required between two batches of the same product and the equipment
should be only visually clean in that condition.
6. Some clean-in-place systems and equipment are difficult to clean
and the operators must be aware of the cleaning of these difficult to clean
parts of the system and equipment.
7. Microbial aspects of the clean-in-place systems and equipment
should be considered because microbial growth may occur during storage of the equipment
and systems. Equipment should be properly dried after cleaning and application
of 70% IPA solution may help to prevent the microbial
growth during storage. A maximum storage period must be defined
within which the equipment or system can be used for manufacturing.
8. If any residue is found on the cleaned equipment then it is
necessary to review the cleaning procedure and operator who cleaned the
equipment should be trained again for proper cleaning.
9. Specificity and sensitivity of the analytical method must be
determined. HPLC can help to determine the contaminants at a very low level. If
it is not possible to determine the contaminants, it doesn’t prove the absence
of contaminants at all but it indicates the analytical is unable to detect the contaminants
below its detection limit.
10. All contaminants present on the equipment surface cont be
recovered therefore a recovery test must be carried out to get the accurate
results. An inaccurate recovery factor may result in false cleaning validation.
11. Both direct surface sampling and rinse sampling are required
for cleaning validation. Interference of the swab in the analysis should be determined.
Surface sampling is important because water-insoluble residues and dried &
hard to clean area of the equipment can be sampled easily using this technique.
12. By using of rinse sampling technique the inaccessible parts of
equipment and systems can be sampled. A large surface area is sampled by rinse sampling;
therefore, a very low amount of the residue can be sampled and determined.
13. Limits for cleaning validation should be established on the
basis of the therapeutic dose of the product and established limits should be
practical, achievable and justifiable.
14. Detergents used for cleaning must be cleaned completely.
Residues of detergent are also considered as contaminants because detergent is
not a part of the product. To analyze the residues of detergent, all components
of detergent must be known therefore detergent s for cleaning should be selected
carefully.