EU Legislation - Eudralex (EU Guide to GMP)

CLEANING VALIDATION

36. Cleaning validation should be perIormed in order to conIirm the eIIectiveness
oI a cleaning procedure. The rationale Ior selecting limits oI carry over
oI product residues, cleaning agents and microbial contamination should be
logically based on the materials involved. The limits should be achievable
and veriIiable.
37. Validated analytical methods having sensitivity to detect residues or contaminants
should be used. The detection limit Ior each analytical method
should be suIIiciently sensitive to detect the established acceptable level oI
the residue or contaminant.
38. Normally only cleaning procedures Ior product contact surIaces oI the
equipment need to be validated. Consideration should be given to noncontact
parts. The intervals between use and cleaning as well as cleaning and
reuse should be validated. Cleaning intervals and methods should be determined.
39. For cleaning procedures Ior products and processes which are similar, it is
considered acceptable to select a representative range oI similar products and
processes. A single validation study utilising a 'worst case approach can
be carried out which takes account oI the critical issues.
40. Typically three consecutive applications oI the cleaning procedure should be
perIormed and shown to be successIul in order to prove that the method is
validated.
41. "Test until clean". is not considered an appropriate alternative to cleaning
validation.
42. Products which simulate the physicochemical properties oI the substances to
be removed may exceptionally be used instead oI the substances themselves,
where such substances are either toxic or hazardous.

5.2 Equipment Maintenance and Cleaning
5.20 Schedules and procedures (including assignment oI responsibility) should be
established Ior the preventative maintenance oI equipment.
5.21 Written procedures should be established Ior cleaning oI equipment and its
subsequent release Ior use in the manuIacture oI intermediates and APIs. Cleaning
procedures should contain suIIicient details to enable operators to clean each type oI
equipment in a reproducible and eIIective manner. These procedures should include:
-Assignment oI responsibility Ior cleaning oI equipment;
-Cleaning schedules, including, where appropriate, sanitizing schedules;

-A complete description oI the methods and materials, including dilution oI cleaning

agents used to clean equipment;
-When appropriate, instructions Ior disassembling and reassembling each article oI
equipment to ensure proper cleaning;
-Instructions Ior the removal or obliteration oI previous batch identiIication;
-Instructions Ior the protection oI clean equipment Irom contamination prior to use;
-Inspection oI equipment Ior cleanliness immediately beIore use, iI practical; and
-Establishing the maximum time that may elapse between the completion oI
processing and equipment cleaning, when appropriate.
5.22 Equipment and utensils should be cleaned, stored, and, where appropriate,
sanitized or sterilized to prevent contamination or carry-over oI a material that would
alter the quality oI the intermediate or API beyond the oIIicial or other established
speciIications.
5.23 Where equipment is assigned to continuous production or campaign production oI
successive batches oI the same intermediate or API, equipment should be cleaned at
appropriate intervals to prevent build-up and carry-over oI contaminants (e.g.
degradants
or objectionable levels oI micro-organisms).
5.24 Non-dedicated equipment should be cleaned between production oI diIIerent
materials to prevent cross-contamination.
5.25 Acceptance criteria Ior residues and the choice oI cleaning procedures and
cleaning agents should be deIined and justiIied.
5.26 Equipment should be identiIied as to its contents and its cleanliness status by
appropriate means.

12.7 Cleaning Validation
12.70 Cleaning procedures should normally be validated. In general, cleaning validation
should be directed to situations or process steps where contamination or carryover oI
materials poses the greatest risk to API quality. For example, in early production it may
be unnecessary to validate equipment cleaning procedures where residues are removed
by subsequent puriIication steps.
12.71 Validation oI cleaning procedures should reIlect actual equipment usage patterns.
II various APIs or intermediates are manuIactured in the same equipment and the
equipment is cleaned by the same process, a representative intermediate or API can be
selected Ior cleaning validation. This selection should be based on the solubility and
diIIiculty oI cleaning and the calculation oI residue limits based on potency, toxicity,
and
stability.
12.72 The cleaning validation protocol should describe the equipment to be cleaned,
procedures, materials, acceptable cleaning levels, parameters to be monitored and
controlled, and analytical methods. The protocol should also indicate the type oI
samples
to be obtained and how they are collected and labelled.
12.73 Sampling should include swabbing, rinsing, or alternative methods (e.g., direct
extraction), as appropriate, to detect both insoluble and soluble residues. The sampling
methods used should be capable oI quantitatively measuring levels oI residues
remaining
on the equipment surIaces aIter cleaning. Swab sampling may be impractical when

product contact surIaces are not easily accessible due to equipment design and/or
process
limitations (e.g., inner surIaces oI hoses, transIer pipes, reactor tanks with small ports or
handling toxic materials, and small intricate equipment such as micronizers and
microIluidizers).
12.74 Validated analytical methods having sensitivity to detect residues or contaminants
should be used. The detection limit Ior each analytical method should be suIIiciently
sensitive to detect the established acceptable level oI the residue or contaminant. The
method`s attainable recovery level should be established. Residue limits should be
practical, achievable, veriIiable and based on the most deleterious residue. Limits can be
established based on the minimum known pharmacological, toxicological, or
physiological activity oI the API or its most deleterious component.
12.75 Equipment cleaning/sanitization studies should address microbiological and
endotoxin contamination Ior those processes where there is a need to reduce total
microbiological count or endotoxins in the API, or other processes where such
contamination could be oI concern (e.g., non-sterile APIs used to manuIacture sterile
products).
12.76 Cleaning procedures should be monitored at appropriate intervals aIter validation
to ensure that these procedures are eIIective when used during routine production.
Equipment cleanliness can be monitored by analytical testing and visual examination,
where Ieasible. Visual inspection can allow detection oI gross contamination
concentrated in small areas that could otherwise go undetected by sampling and/or
analysis.
Cleaning of equipment and environmental control
To differentiate efforts and decisions based on the intended use (e.g., multi- versus single-
purpose,
batch versus continuous production)
To determine acceptable (specified) cleaning validation limits