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Key-Words: Cleaning validation, Acceptance Criteria, Residue, Swab Sampling, Rinse Sampling
Introduction
Cleaning Validation Definition: Manufacturing It is advisable to perform at least three
processes have to be designed and carried out in a consecutive and successful applications of the
way that prevent cross-contamination as much as cleaning procedure in order to prove that the
(4)
possible. Since most pieces of equipment are method is validated .
being used to manufacture different products, In case of detecting variable residue, following
cleaning procedure must be able to remove cleaning (especially an acceptable cleaning),
residues from equipment to an acceptable level (4). enough attention must be given to effectiveness of
Importance and purpose of cleaning validation: the process and operators performance (7).
Not only it is required to comply with Equipment cleaning validation maybe performed
regulations, but also it is necessary to concurrently with actual production steps during
fulfill customers' requirements. process development and clinical manufacturing.
It ensures the safety, identity, strength, Validation programs should be continued through
and purity of the product which are the full scale commercial production (1, 7). For new
basic requirements of cGMP (Current chemical entities it is essential to perform a risk
Good Manufacturing Practice). assessment analysis before any operation in GMP
It provides manufacturer with enough plants (8).
confidence that internal control is When cleaning validation is necessary according
established properly (5, 6) to guidelines of WHO:
Product-contact surfaces (Consideration
* Corresponding Author should be given to non-contact parts into
E.mail: ramin3205@gmail.com which product may migrate for example,
Tel: 00989122168569 seals, flanges, mixing shaft, fans of ovens,
Fax: 00982126212319 heating elements etc.)
( ) BSs ( kg )
practical (5, 22).
For Non-Therapeutic materials the Residue Acceptance MA CO ( mg ) = 10 ppm mg
Limit is based on toxicity (23).
kg
For particular situation justifiable acceptance criteria BSs = Batch Size of the Subsequent product
should be determined according to each company's Advantages of this criterion: Since there is no need to
requirement (33). calculate the limit for each previous product/
subsequent product combination, calculation is easier.
The worst condition can be considered if the smallest
Table 8: Advantages and Disadvantages of Rinse Sampling (4, 5, 9, 11, 13, 16, 17, 37)
Advantages Disadvantages
Adaptable to online monitoring Limited information about actual surface cleanliness in
Easy to sample some cases
Non- intrusive Very low amount of residues may not be
Less technique dependent than swabs homogeneously distributed
Applicable for actives, cleaning agents and excipients Rinse volume is critical to ensure accurate interpretation
Allows sampling of a large surface area of results, since the sensitivity of the assay may be
Allows sampling of a unique (e.g. porous) surfaces greatly reduced by dilution of the contaminant
and inaccessible areas of equipment that cannot be Sampling methodology must be defined since rinse
routinely disassembled sampling method can influence results
May be difficult to accurately detect location of residues
and control the areas sampled, therefore, usually used
for rinsing an entire piece of equipment, such as vessel
Reduced physical sampling of the surface especially for
dried out residues
Solubility of the contaminant in the relevant solvent
should be considered which may result in lower amount
Table 11: Different methods of analysis for cleaning validation (9, 38, 39, 42, 45, 46)
Method Advantages Disadvantages Additional information Applications
HPLC Separation of multiple Generation of Possible interference such as HPLC coupled with
compounds, Several correct results cleaning agent residues UV/ Visible is an
extraction solution can depends on the interference with the assay must be accurate, precise and
be used, Producing use of a suitable evaluated. Interferences may lead robust method for
specific peaks of reference to changes in retention time, peak quantitative analysis
interest , Different standard, It takes height or peak shape, Large of pharmaceutical
swab types can be more time to amounts of solvent waste has to be products. Used for
employed because of validate this disposed. It is essential to extract both swab and rinse
high separation power, method drugs from their formulations prior samples,
Selective method due compared to the to analysis. Quantitation of any
to use of variable others, More material produced
columns and detectors expensive, not by degradation
suitable for
products lack a
chromophore
Atomic A specific method for Limited to Cations such as sodium and/ or Only applicable to
Absorption both anions and residues potassium that may be present in metal ions.
cations in cleaning containing ions. cleaning formulations and also
formulations, anions, such as the anions from
Determination of acidic detergents (phosphates,
metal residues in drug citrates, glycolates) or builders
remaining from the (carbonates, glyconates, silicates,
manufacturing process and EDTA
(ethylenediamminetetraacetic acid)
Sakun Publishing House (SPH): IJPLS
3363
Review Article [Asgharian et al., 5(3): March, 2014:3345-3366]
CODEN (USA): IJPLCP ISSN: 0976-7126
can be measured by this method
GC and MS Capable of separation, Limited to Some detergent residues are not as Mainly used for
identification, and volatile volatile as other compounds (such detection of
quantitation of results, compounds as some solvents). So these agents detergents or solvent
providing an require to be removed off. The residues.
acceptable reference mobile phase does not require
standard is used. disposal.
Provision of improved
peak shape and greater
separating power
compared to HPLC
due to capillary
columns usage
TOC TOC analyzers are TOC analyzers It theoretically measures all the It is specific to
very sensitive are not specific covalently bonded carbon in water organic compounds.
enough, based on this assumption that an It is commonly used
therefore should organic residue contains carbon in the biotechnology
be used with pH that can be oxidized under TOC industry for cleaning
and conductivity. test conditions. Then it measures validation. This can
Since all of the carbon dioxide. It is typically also be used for the
measured carbon reported at the part per billion analysis of
is theoretically (PPB), or (g/ml). To reach detergents,
attributed to the enough sensitivity quality of water endotoxins, and
target substance, utilized should be high. polyethylene glycol.
the measured
amount is the
maximum
amount of the
target calculated
according to this
assumption.
Samples must be
water soluble.
Swab selection is
important due to
interference with
TOC analysis.
pH Very sensitive to The Significant changes in the pH of Trace levels of acids
hydrogen ions. measurement of system can be monitored. and alkalies used in
pH in unbuffered However, this technique is not the cleaning process
systems around sufficiently capable of measuring can be measured by
neutral is actual levels of alkaline or acidic this method.
unreliable. There residues.
is no linear
relationship
between the level
of cleaning agent
and pH.
Conductivity It can be used as an It is not specific Linear behavior is observed in It can be used for
upper limit estimate of to an ion. dilute solutions. cleaning validation
Table 12: Limits for the microbial status of product contact surfaces (18)
EU GMP Guideline Proposal for
contact plates implantation Table/
Class d=55 (mm) (CFU/plate) machine (CFU/ 25 cm2)
A <1 G: <1, W: 2, A:3
B 5 G: 5, W:2, A:5
C 25 G:25, W:25, A: 50