Cleaning validation should be performed in order to confirm the effectiveness of
any cleaning procedure for all product contact equipment. Simulating agents may
be used with appropriate scientific justification. Where similar types of equipment are grouped together, a justification of the specific equipment selected for cleaning validation is expected.
A visual check for cleanliness is an important part of the acceptance criteria for cleaning validation. It is not generally acceptable for this criterion alone to be used. Repeated cleaning and retesting until acceptable residue results are obtained is not considered an acceptable approach.
It is recognised that a cleaning validation programme may take some time to complete and validation with verification after each batch may be required for some products, e.g. investigational medicinal products. There should be sufficient data from the verification to support a conclusion that the equipment is clean and available for further use.
Validation should consider the level of automation in the cleaning process. Where an automatic process is used, the specified normal operating range of the utilities and equipment should be validated.
For all cleaning processes an assessment should be performed to determine the variable factors which influence cleaning effectiveness and performance, e.g. operators, the level of detail in procedures such as rinsing times etc. If variable factors have been identified, the worst case situations should be used as the basis for cleaning validation studies.
Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train.
Therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances.
If it is not feasible to test for specific product residues, other representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity. The risk presented by microbial and endotoxin contamination should be considered during the development of cleaning validation protocols.
The influence of the time between manufacture and cleaning and the time between cleaning and use should be taken into account to define dirty and clean hold times for the cleaning process.
Where campaign manufacture is carried out, the impact on the ease of cleaning at the end of the campaign should be considered and the maximum length of a campaign (in time and/or number of batches) should be the basis for cleaning validation exercises.
Where a worst case product approach is used as a cleaning validation model, a scientific rationale should be provided for the selection of the worst case product
and the impact of new products to the site assessed. Criteria for determining the worst case may include solubility, cleanability, toxicity and potency.
Cleaning validation protocols should specify or reference the locations to be sampled, the rationale for the selection of these locations and define the acceptance criteria.
Sampling should be carried out by swabbing and/or rinsing or by other means depending on the production equipment. The sampling materials and method should not influence the result. Recovery should be shown to be possible from all product contact materials sampled in the equipment with all the sampling methods used.
The cleaning procedure should be performed an appropriate number of times based on a risk assessment and meet the acceptance criteria in order to prove that the cleaning method is validated.
Where a cleaning process is ineffective or is not appropriate for some equipment, dedicated equipment or other appropriate measures should be used for each product as indicated in chapters 3 and 5 of EudraLex, Volume 4, Part I.
Where manual cleaning of equipment is performed, it is especially important that the effectiveness of the manual process should be confirmed at a justified frequency.
EU Guidelines for
Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use
Annex 15: Qualification and Validation