Principles of Cleaning Validation
- 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 criteriashould 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
- 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
- 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
- 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