What is Cleaning Validation?

Cleaning validation is a procedure of establishing evidence that cleaning processes for

manufacturing equipment prevents product contamination. Cleaning validation should be
properly documented to demonstrate Current Good Manufacturing Practice (CGMP) for
finished pharmaceuticals.

Why is It Needed?
Cleaning validation is required because Active Pharmaceutical Ingredients (APIs) cross-
contaminated with chemical residues and microbes can compromise patient safety.
Ineffective cleaning processes not only lead to more downtime and batch failures, but it
also result in FDA rejection and costly fines due to drug adulteration.

FDA Guidelines
While the U.S. Food and Drug Administration (FDA) has yet to release cleaning
validation guidelines for pharmaceutical firms, they provide a reference material for the
inspections regularly carried out by investigators and other FDA personnel. In
the document, FDA generally expects:
 Written standard operating procedures (SOPs) for equipment cleaning processes
that address different scenarios (e.g. one process for different batches, different
processes between product changes, etc.)
 Written cleaning validation procedures, including who is responsible for
performing and approving the validation study, the acceptance criteria, and when
re-validation will be required
 Written cleaning validation protocols for the inspection of each equipment that
address common issues (e.g. sampling procedures, analytical methods, etc.),
conducting the validation according to the protocols and documenting its results
 Data-supported, management-approved, and final cleaning validation
report stating whether or not the cleaning process for a specific piece of
equipment or manufacturing system is valid
Types of Sampling Methods
Currently, neither the FDA nor the federal regulation for equipment cleaning and
maintenance (Section 211.67) mention certain types of cleaning validation. However, it is
generally accepted in the pharmaceutical industry that there are two types of sampling
methods for cleaning validation: direct and indirect.
 Direct sampling for cleaning validation is also known as the swab method,
where a sterile material is systematically rubbed across a surface to be analyzed
for the presence of residue.
 Indirect sampling for cleaning validation is often referred to as rinse sampling,
where a solvent like water is rinsed in a specific area of clean surface and tested
for traces of contaminants

Types of Cleaning Methods

While the total number of cleaning methods used in pharmaceutical cleaning validation
has yet to be completely determined, this industry article has listed the most types so far
and it generally includes the following:
 Clean-in-place Method – normally using fixed or rotating spray devices with a
wash tank, recirculation pump, and associated piping
 Clean-out-of-place Method – often used for automated parts washing through
cabinet or tunnel washers with cleaning, rinsing, and drying cycles
 Immersion Method –  either agitated, where a cleaning agent in a process vessel
is mechanically stimulated to achieve a cleaning effect, or static, where the
process vessel is merely soaked with the cleaning agent
 Ultrasonic Washing – typically works better for intricate parts such as filling
needles as it involves a tank equipped with ultrasonic transducers to induce
cavitation
 High-pressure Spraying – serves to dislodge any residues on the surface through
high-pressure, continuous, and directed water or cleaning solution
  Manual Cleaning – usually the most difficult cleaning method to validate;
includes three most common techniques: wiping, sink brushing, and equipment
brushing

Acceptance Criteria
Accurately setting the acceptance criteria for the limit in cleaning validation is crucial to
determine the results of the study. To better evaluate whether or not cleaning methods are
effective, cleaning validation acceptance criteria can be generally categorized into three
various testing parameters:
 Physical Criterion: a visual inspection of the equipment should reveal that there
are no particulate matters or residues
 Chemical Criterion: no more than 10 ppm (parts per million) of a product should
be detected in another product and/or no more than 0.1% of the normal
therapeutic dose of a product should appear in the maximum daily dose of another
product
 Microbial Criterion: no more than 20 CFU (colony-forming units) for bacterial
counts, no more than 2 CFU for molds, and/or no more than 25 CFU/25cm2 of
contaminants in a sample

Pharmaceutical Terms and Their

Definitions
Cleaning validation in the pharmaceutical industry mostly entails certain jargons that
manufacturing personnel should be familiar about. Here are twelve of the most common
abbreviations related to pharmaceutical cleaning validation and what they mean:
 CGMP – Current Good Manufacturing Practice
 API – Active Pharmaceutical Ingredient
 ADE – Acceptable Daily Exposure
 PDE – Permitted Daily Exposure
 MACO – Maximum Allowable Carry Over
 NOEL – No Observed Effect Level
 LOEL – Lowest Observed Effect Level
 NOAEL – No Observed Adverse Effect Level
 LOAEL – Lowest Observed Adverse Effect Level
 LOQ – Quantitation Limit
 LOD – Detection Limit
 LD – Lethal Dose