Currently, there are multiple publications, as well as guidelines from regulatory agencies that make the critical process
of equipment cleaning validation easier. These sources provide in-depth information for the validation specialist, making
the development and implementation of a robust cleaning validation program possible within any particular facility developing
or manufacturing parenteral, biological, or sterile ophthalmic products.
José A. Morales Sánchez
Extremely important, specific, and above all, mandatory, are the requirements established by regulatory agencies such as the
US Food and Drug Administration (FDA), the European Medicinal Evaluation Agency (EMEA), Australia's Therapeutic Goods Administration
(TGA), etc. For example, the 2004 Code of Federal Regulations (CFR) Title 21, Volume 4, Section 211.67, states:
"Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination
that would alter the safety, identity, strength, quality or purity of the drug product beyond the official or other established
Additionally, Section 211.182 requires that cleaning procedures must be documented appropriately, and that a cleaning and
use log should be established.
This article provides the reader with cleaning validation information enhanced by the author's thirteen years of hands-on
experience working in equipment cleaning validation.
This article focuses on manual cleaning procedures because these are considered the worst-case scenario. It applies to parenterals,
ophthalmic, and biologic presentations and is intended to cover equipment validation for raw materials, contaminants, cleaning
agents, as well as the control of potential microbial contaminants associated with those products.
The flowchart in Figure 1 graphically shows the different aspects that should be considered when developing a cleaning validation
program. Understanding each aspect of the process, the relationships among these actions, and the sequence in which they should
take place will make the development of a cleaning validation program a successful experience.
Figure 1. Depiction of Different Aspects for Consideration When Developing a Cleaning Validation Program
After all applicable cleaning information sources and regulatory guidelines have been consulted, the first item to consider
when establishing a cleaning validation program is the raw material and final product flow. By following the flow of the product,
one can identify the equipment that comes in contact with it, such as utensils (scoops, spatulas, funnels, pipettes, etc.),
tanks, filter housings, pressure vessels, syringes, and others. Equipment such as this is considered critical equipment because
it comes in direct contact with the product.
Other areas where raw materials or products are processed, which might be considered non-critical because they are not in
direct contact with the product, should also be considered. From the point of view of microbial load, inappropriate cleaning
and sanitation of these areas may contribute to cross-contamination. Some examples of these areas include: sampling and weighing
rooms, as well as formulation and filling rooms.
Typical steps to follow in process flow are as follows:
Raw Materials Sampling: Raw materials include both active and inactive ingredients. Many active ingredients are potent compounds, such as steroids,
cortisone, antibiotics, proteins, and therefore it is important to demonstrate their removal. But be aware that some inactive
ingredients have poor solubility in water and their residues may be more difficult to remove than those of an active drug.
Utensils used during the sampling process of raw materials require cleaning validation unless they are disposable. Typically,
use of disposable utensils is the preferred practice for parenteral and biological products. The sampling of raw materials
should be performed within a controlled environment (classified as 1,000, 10,000, 100,000, etc.,) in order to reduce the introduction
of non-intrinsic contamination to the process.