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A variety of analytical methods are used to detect active ingredients, degradation or byproducts, bioburden, endotoxin level, and cleaning agent residues. The selection may be based on multiple factors including the analyte of interest, analytical resources available, rinsability, and carry-over risk. The rinsability of a cleaning agent is crucial in demonstrating that the components within the formulation rinse freely from the surface with water. If the components within the formulation rinse at similar rates, then either non-specific methods, such as conductivity or TOC, or specific methods, such as ultra high-performance liquid chromatography UHPLC , can be used 13, If the components do not rinse at similar rates, then it is important to identify and set residual limits based on the last-to- rinse component.

Figure 4. Monitoring of cleaning agent residues on surface. TOC is total organic carbon. Cleaning agents used for product contact surfaces must have toxicity information available, which is important in determining safe levels of cleaning agent residues. The toxicity of components is important, especially if they are the last to rinse from the surface or if they display mutagenic, reproductive, carcinogenic, developmental, or chronic toxicity. In the case of cleaning agents, the sum of components may have increased or decreased toxicity compared to individual components, and toxicity of the cleaning agent should be available from the suppliers.

The ability to sample the surface for cleanliness is the preferred technique to demonstrate the equipment is ready to manufacture the next batch of product, a new product, or to proceed with the next manufacturing process step. Surface testing, however, requires a significant amount of time to: In addition to the amount of time required for sampling and testing, there is allocation of labor for sampling and testing, often scheduling between multiple departments, and more importantly lost time that could be used for manufacturing or sampling and testing critical steps within the manufacturing process.

The selection of sampling sites and test methods and performing surface sampling recovery will help in significantly reducing or even eliminating routine surface sampling to demonstrate surface cleanliness. A documented sampling and testing plan must be prepared describing: They also aid in understanding the rationale behind the sampling site selection. Figure 5 , for example, shows the interior of a vessel with multiple accessories that reduce the coverage provided through the spray device top circumference in a CIP system.

The shaded area in the vessel represents the normal process air-to-liquid interface, which is often an area where solids settle onto the surface and form a scum-like ring on the walls. Figure 5. Sampling site selections. Sampling sites should be defined based upon the geometry and design of the equipment, materials of construction, hard-to-clean areas, and locations that may have a higher risk to product contamination i. The riboflavin testing used for spray device qualification in CIP systems also helps in identifying areas that must be sampled due to limited coverage.

Risk-based surface sampling locations and testing performed. A risk assessment should be performed to minimize the number of sampling sites.

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A risk assessment should also be performed to minimize the number of tests performed, such as microbial, detergent, or active ingredient testing. For example, a TOC swab may be able to demonstrate removal of the large molecule API as well as the cleaning agent used. A single UHPLC swab may be able to demonstrate the removal of multiple detergents that are used in separate wash steps of the cleaning procedure Applying a scientific, risk-based rationale can drastically reduce the number of samples taken as well as testing performed.

Table II. Risk assessment of surface sampling locations. MOC is material of construction. Surface sampling recovery studies using swabs, wipes, or direct sampling techniques should be performed as part of the design stage to ensure that testing of the surface can meet predefined acceptance criteria. Surface sampling should define the swab or wipe used, surface location sampled, surface area sampled, material of construction of the surface, number and condition of the swab s or wipe s , sample storage and stability conditions, swab or wipe diluent, and sampling accessories; qualified analysts should perform the testing.

The surface sampling recovery study should also consider, if applicable, the swab or wipe wetting solution and various spiked amounts on the surface. The spiked amount and design of the surface sampling recovery test should challenge the sampling and analytical procedure.

The analysis of swab recovery from various active pharmaceutical ingredients as well as cleaning agent residues from a single site using various materials of constructions including metals, plastics, and elastomers supported that stainless steel could be used as a representative surface for swab recovery Forsyth, et.

Visual inspection is important to ensure that the equipment looks sufficiently clean to proceed with analytical testing. There are limitations, similar to surface sampling, with routine visual inspections, such as large equipment or lengths of piping, as well as the time and resources required for proper visual inspection. Visual inspection can be defined as the process of using the unaided eye as the sensing mechanism from which judgments can be made about the condition of a unit to be inspected. A visual non-uniformity on equipment surfaces may present as an interruption of the normal pattern or grain either by residue or discoloration in amount as perceived by the unaided eye.

This non-uniformity could be on the surface, such as visible residue, particulate matter, pooling of liquid, or rouge oxides or within the surface, such as scratches, corrosion, or etching. During the design and qualification stages of the lifecycle model, a correlation between visual inspection, surface sampling, and rinse sampling should be performed, so that a visual inspection or rinse sample can be scientifically justified to determine that the equipment, piping, or parts are cleaned.

Visual inspection as the method to assess for cleanliness is ideal for small parts or open process equipment that are easy to inspect. Several published articles have evaluated the use of visual inspection procedures and the role of visible cleanliness in control of critical variables, as well as establishing visible residue limits of select analytes. Forsyth et al. A large biopharmaceutical manufacturer was designing a new facility for the final compounding and filling of their product. This standard parenteral facility consists of an automated parts washer, steam sterilizer, automated vial washer, depyrogenation tunnel, filling machine, closure machine to insert stoppers, capping machine, and product labeler.

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This product was being filled by a contract manufacturing organization CMO , which was using only water for cleaning. During the design phase of the cleaning program, coupon testing was performed by coating the finished product onto stainless-steel coupons and evaluating the cleaning with water and a formulated alkaline cleaning agent to remove the finished product. Water-only cleaning at ambient to 80 oC was not sufficient to yield a visual clean and water-break free surface.

In support of a visual inspection program of the items being washed in the parts washer, a visible residue limit VRL study was performed on the final drug product as well as on a formulated alkaline cleaning agent on stainless-steel and glass surfaces. The VRL study procedure consisted of precleaning and drying stainless-steel coupons with a 2B finish as well as borosilicate-glass coupons. The roughness of the stainless coupons was comparable to the L stainless-steel specifications for the filling parts.

The formulated acid and alkaline cleaning agents as well as the finished product were compatible with stainless steel, so the use of these coupons as a test substrate versus L was justified. The test samples were serially diluted, and 1 mcl of diluted sample and 20 mcl of low TOC de-ionized DI water were applied over a 1-cm2 area. The sample was then allowed to air-dry at ambient temperature for at least 16 hours.

After drying, the coupons were inspected by two analysts, in duplicate, at one of the following distances 0. A light meter Cooke Corporation Cal-Light lux , digital protractor, and 1—5 mcl syringe Hamilton were used in the study. The borosilicate glass surface was used in the construction of the viewing endcap on the final formulation compounding tank, so the higher VRL observed was not critical. The visual inspection procedure as well as the inspector qualification study consisted of precleaning and visual inspection of the coupons before spiking.

Cleaning validation sampling methods...

This procedure is used to try to eliminate phantom residues or false positives. The coupons were placed flat on a table in front of a fume hood in groups of three, and the inspector stood back approximately 0. The lighting in the room was between and lux. Rinse sampling is commonly used to evaluate surface cleanliness of closed production equipment, hoses, and piping commonly cleaned by CIP systems 23— The advantages of rinse sampling are that the entire surface can be sampled, with no disassembly of equipment and no direct sampling of the surface, and that rinse sample analysis via conductivity, TOC, UV, and other methods in-line or on-line can be adapted to PAT technologies.

The disadvantages of rinse sampling are that the analyte measured may not be soluble in the rinse solution, rinsing may not pick up the residue due to poor coverage during rinsing, and the analyte may be too diluted in the rinse solution volume.


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Rinse recovery studies can be used in addition to assessing the solubility of the active ingredient in the rinse solution. The studies are performed by adding a specified concentration, around the acceptable limit, of the residue on the surface. The selection of the residue, conditioning of the residue, surface material, roughness of the surface, rinse solution, volume of rinse solution per surface area, rinse solution temperature, and flow rate should all be considered in setting up a rinse solution recovery study.

Two rinse recovery studies are discussed as examples. Figure 6. First rinse recovery study; linearity between conductivity to concentration of a formulated alkaline cleaning agent. Figure 7. Second rinse recovery study; linearity between total organic carbon TOC and concentration of a formulated alkaline cleaning agent.


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  8. Conductivity and pH results, hour air-dried samples. Total organic carbon TOC results, hour air-dried samples. Three lots of the formulated alkaline cleaning agent were diluted at various concentrations between 1 and ppm by volume using DI water and tested at ambient temperature. Temperature compensation was not used for this testing. Three lots of the formulated alkaline cleaning agent were diluted at various concentrations between 0.

    Solution was applied in drops to provide a uniform coverage.

    Samples were air-dried on the coupons in a horizontal position. After drying, mL of DI water at ambient temperature was poured from a squeeze bottle over the coupon so that the flow cascades down the face of the coupon for approximately 30 seconds. Surface cleanliness is crucial in ensuring that process residue, cleaning agent residue, and bioburden do not adversely affect the safety, quality, and potency of the drug manufactured.

    Evaluating Surface Cleanliness Using a Risk-Based Approach

    For glass, go to the next hardware store and buy a sheet of ordinary window glass, for polypropylene and teflon, there are plenty of suppliers of virgin teflon and polypropylene in the US, the first one that comes out of Google is. Normally you will get them for free as a customer service from the supplier.

    The only coupons that are somewhat complicated to get are coupons from materials that are proprietary to the manufacturer e. The point is that if you ask for a quote for cleaning validation coupons for the pharmaceutical industry, the price rises instantaneously at least ten times. Once you got the coupons, clean them with a good degreaser, then with the cleaning agent you use to clean your equipment, and take a blank swab before spiking them for recovery, to get a background and see potential interferences. For the stainless steel coupons, what size, grade and finish did you want?

    Aren,t the coupons supposed to comme with a certificate of material? I thought that since we have to get a certificate of material for each surface in contact with product for the prodcution equipment, we would need it too for the coupons?