Suez Total Organic Carbon - March 2020 - 4

application note

analytical methods in
cleaning validation
the challenge

common product-specific analytical methods

A typical cleaning validation (CV) program consists of three phases:

The following product-specific analytical methods have historically
been used in cleaning applications. All are designed to determine if a
specific compound is present in its original form.

1) Design
2) Validation
3) Continued Verification
A key industry challenge is how to select the most appropriate
analytical method(s) for evaluating known and potential residues
throughout the different phases of a CV program.
For example, in early design-phase work, adequate information on
the cleanability of the worst-case compounds or their degradants

High Performance Liquid Chromatography (HPLC)
HPLC involves the separation of a unique compound from a matrix by
chromatography, followed by measurement of the compound with a
UV or other detector.
*

Advantages: Ability to identify the presence of a particular
residual compound, may provide data on the nature of a
cleaning failure

*

Challenges: Assumes compounds have not degraded in the
cleaning process, that all potential interfering or residual
compounds are fully understood, and may require extensive
method development

may not be known. This may create challenges in developing productspecific analytical methods as these tests assume that all potential
interferences are known. Similarly, in the validation phase, productspecific analytical methods may be less useful as common residuals
may include uncharacterized degradants or more difficult to clean
compounds rather than a target active pharmaceutical ingredient
(API). Lastly in the continued verification phase, manufacturing
concerns including product change-over, equipment turnover, cost,
and a desire for continuous or automated monitoring may influence
the methods used.

cleaning process method selection
In many situations, cleaning process-specific methods such as
total organic carbon (TOC) analysis (in contrast to product-specific
methods) may give a very accurate picture of the overall effectiveness
of the cleaning process at every phase of a cleaning validation
program. A key point is that selection of one or more methods will
depend on the nature of the residue as it exists after the cleaning
process. If an active ingredient is not degraded or dissolved during a

Enzyme Linked Immunosorbent Assay (ELISA)
ELISA is an antigen or antibody type reaction using specific chemicals
and standards. If the specific protein is intact and present in the test
solution it will bind to the enzyme. This binding is then detected.
However, if the protein is denatured but still present in the solution,
the ELISA test will not detect the denatured content. ELISA has many
of the same advantages and challenges as HPLC, but applied to
biopharmaceutical manufacturing.

Ultraviolet/Visible Spectrophotometry (UV/Vis)
UV/Vis involves the measurement or absorbance of a specified
wavelength of light by a solvent solution of the residue.
*

Advantages: Simplicity, does not require separation of a
residual from a matrix

*

Challenges: Not applicable to all compounds, potential
interferences from other light adsorbing compounds

validated cleaning process and all interferents are well understood,
then more product-specific methods including HPLC, UV/Vis, or
ELISA may be appropriate.1,2

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Suez Total Organic Carbon - March 2020

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