Cleaning validation and verification are based on the premise of risk management. Several regulatory and guidance documents
make this clear. The International Conference on Harmonization's (ICH) guideline on risk management outlines several approaches
to making and documenting risk-based decisions (1). It clearly states that risk management should be based on scientific knowledge
and that personnel should evaluate the effect of potential failures on the patient. In addition, it notes that the levels
of effort, formality (e.g., use of tools), and documentation of the quality risk-management process should be commensurate
with the level of risk.
The US Code of Federal Regulations states that 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 (2). In accordance
with 21 CFR 211.67, ICH issued recommendations on equipment maintenance and cleaning (Q7A, Sections 5.20–5.26) for compliance and safety
that include similar, but more detailed requirements (3).
The US Food and Drug Administration's 1993 guidance on cleaning inspections states that for a swab method, recovery should
be established from the surface (4). The guidance contains no specific requirements about how to establish these recovery
estimates, or the acceptance limits. It is up to the manufacturer to document the cleaning rationale (i.e., process and acceptance
limits) for maintaining the quality and purity of the drug product being manufactured.
Cleaning validation and verification
Cleaning verification consists of routine monitoring (e.g., swab analysis) of equipment-cleaning processes. Cleaning validation
confirms the effectiveness and consistency of a cleaning procedure and eliminates the need for routine testing (5). For example,
cleaning limits are established to determine the maximum allowance of Product A that can carry over to Product B. The calculation
of these limits is well documented and includes factors that increase the margin of safety to protect the patient (6, 7).
Because it is not feasible to swab every square inch of the equipment, swabbing locations are chosen based upon factors such
as how difficult the area is to clean, the size of the equipment, and the areas where product buildup is likely. All product-contact
surfaces must be considered during cleaning verification to demonstrate that equipment is clean, and a recovery value is expected
to be established for each product-contact surface during method validation. The recovery is used to correct the submitted
swab result for incomplete removal from the surface and to compare it with the acceptance limit. This last aspect of risk
management (i.e., establishing the surface recovery) is the focus of this article.
Analysts have many ways to establish the swab-recovery value for a particular product-contact surface. Stainless steel is
the most common material in a manufacturing environment (see Figure 1). Some companies therefore establish a recovery value
for stainless steel and apply that standard to all swab submissions. Other companies attempt to establish a recovery value
for each product-contact surface for every compound. From an analytical standpoint, supporting this activity becomes arduous,
if not impossible to sustain. For example, equipment in a clinical-trial materials (CTM) manufacturing area is used for many
compounds in the company's portfolio. New equipment might have different product-contact surfaces. Each compound in the portfolio
manufactured on a new piece of equipment would require a method revalidation to add a recovery factor for the new product-contact
surface. As the number of materials of construction increases, the difficulty of sustaining that approach also increases.
Grouping materials of construction for analytical-method development in support of cleaning verification and validation activities
is an excellent opportunity to apply a quality risk-management approach, especially when the total product-contact surface
area is considered. Stainless steel accounts for approximately 95% of the surface area in a CTM manufacturing and packaging
environment. Other product-contact surfaces account for only 5% of the total surface area. When polymer surfaces are considered
in a CTM packaging environment, the number of minor product-contact surfaces can grow significantly. A risk-management approach
allows the majority of the time and effort to be spent on activities that ensure the cleanliness of the stainless-steel area
while identifying, analyzing, evaluating, and communicating the risks associated with the small fraction of remaining surfaces.
This strategy does not ignore the surfaces other than stainless steel, but divides them into three recovery groups to support
analytical-method validation. By choosing representative recovery surfaces for those nonstainless-steel materials, the effort
proportionally addresses the risk.
Figure 1: (ALL FIGURES ARE COURTESY OF THE AUTHORS)