Cleaning Validation Protocol


1. Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products.

2. Pharmaceutical products can be contaminated by other pharmaceutical products. The objective of cleaning validation is the confirmation of a reliable cleaning procedure so that contamination is reduced to predetermined levels.

3. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts.

4. Cleaning procedures for product formulation changeover should be validated.

5. Generally in case of batch-to-batch production of the same product, it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined as appropriate.

6. Cleaning procedures for products and processes which are very similar do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation program which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria. This practice is termed "Bracketing".

7. Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. Control of change to validated cleaning procedures is required. “Testing until clean” is unacceptable.

8. Operators carrying out manual cleaning procedures should be adequately supervised Dedicated equipment may be necessary for products which are difficult to remove, for equipment which is difficult to clean, or for products with a high safety risk.

9. The existence of conditions favorable to microorganisms and the time of storage should be considered. The period and, when appropriate, the conditions of storage of equipment before and after cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.

10. Samples should be taken according to the cleaning validation protocol. The choice of sampling methods should be demonstrated to provide accurate information about the effectiveness of the cleaning process.

11. Two methods of sampling considered to be acceptable are direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods may be desirable in circumstances where accessibility of equipment can mitigate against direct surface sampling.

12. The suitability of the material to be used for sampling and of the sampling medium should be determined to assure predetermined levels of recovery.

13. Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples. A direct or indirect measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.

14. Other techniques which may be used include coupon sampling, solvent sampling, product sampling, placebo sampling and direct surface monitoring.

15. If cleaning agents are used, acceptable limits should be defined for residue of the agent after cleaning.

16. Analytical methods should be validated.

17. Analytical methods used to detect residuals or contaminants should be appropriate for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable.

18. The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery.

19. The rationale for selecting limits for product residues should be based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.

20. One cannot ensure that the contaminant will be uniformly distributed throughout the system. It is also invalid to assume that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch.

21. In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.

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