Swabbing is the preferred method to validate critical cleaning within pharmaceutical manufacturing environments. The 1993 FDA Guide to Inspections states that direct surface sampling (e.g., with swabs) is the “most desirable” technique. Potential contaminants eluted from the swab are tested down to trace levels. As a result, the selection of a quality swab and a validated swabbing method is critical to producing sensitive, accurate, and repeatable results.

The purpose of swabbing is to prove that the cleaning process served its purpose. The cleaning process must successfully remove any active pharmaceutical ingredients (API) used in previous batch runs while not leaving any residues behind from the cleaner itself.

Measurement of the Residual Acceptable Limit (RAL) can be accomplished with High Performance Liquid Chromatography (HPLC) or Total Organic Carbon (TOC) tests. HPLC-UV is a specific analysis technique that identifies and quantifies the residues found within the sample. TOC is a non-specific conductometric assay that is a catch-all for quantifying oxidizable carbon compounds within the sample.

Cleaning validation employing
These analytical methods is a complex activity requiring a careful selection of the procedure and materials involved. Establishing a capable method begins with the selection of the swab. The swab must offer:

Minimal extractable interferences
Ultra-low particles and fibers
Solvent compatibility
High recovery rates

Huachenyang’s Cleaning Validation Swabs

CY-761

CY-715A

are engineered to meet this demand. As an example, the CY715 swab offers a low absorbance spectrum in the 190-235 nm range for HPLC analysis. This range is significant as it is the detection range typical of common residues. Swabs with a high UV absorbance background in this range interfere with the result by concealing residue contamination.

TOC measurements are extremely sensitive. They are reported in part per billion (ppb) (equivalent to micrograms per liter (µg/L)). Any particles from the swab head material or sample container can contribute to the TOC value. The lower the contribution and variance of these particles, the less interference from this TOC background.

Huachenyang offers TOC kits with swabs and vials specifically manufactured to low TOC tolerances. Low TOC swabs within the CY3340 and CY3342 kits are certified to <50 ppb TOC while their vials are treated to ensure a <10 ppb TOC background. The swabs are pre-scored with notches to allow the head to break off easily and cleanly. The swab head can be snapped off by aligning its handle on edge, with the notch placed on the top edge of the vial and pulling down to snap the handle. This method eliminates the use of scissors, thereby eliminating an action that could contribute to more particulates (i.e., a higher TOC background).

In addition to having minimal analytical interferences, high quality cleaning validation swabs must allow for high recovery rates. Recovery rates are a function of swabbing method as well as material absorption and residue-releasing of the swab.

The swabbing pattern used is critical to ensure an accurate and reproducible collection of residues.
The first side of the first swab is swiped horizontally ten times.
The swab head is flipped over and the second side is swiped vertically ten times over the same surface.
The swab is deposited in the vial.
The first side of the second swab is swiped diagonally upwards ten times.
The swab is flipped over and the second side is swiped diagonally downward ten times.
The second swab head is deposited in the vial.

Huachenyang’s Cleaning Validation Series swabs all use polyester fibers in their head material which offers a wide solvent compatibility. This compatibility is essential for recovering the residue off the surface and depositing it into the preselected diluent for testing.

Cleaning validation usually employs two sampling methods: rinse sampling and wipe sampling.

Rinse sampling is typically used to collect samples from large surfaces such as floors or walls. A liquid solution is poured onto the surface and then collected and measured for TOC levels to determine the quantity of organic matter on the surface.

Wipe sampling is typically used to collect samples from smaller surfaces such as equipment or tools. A specialized TOC cleaning validation swab is used to wipe the surface and then placed in a <10 ppb sample bottle for subsequent testing.

When conducting swab sampling, there are two critical steps that must be considered to optimize the sampling material and residue, in addition to the analysis itself:

Step 1: Use a specialized TOC cleaning verification swab to take a sample from the surface in contact with the product.

Step 2: Transfer the residues from the swab to the extraction solution (usually low TOC water)

The material of the sampling swab can affect the sampling efficiency. Conventional cotton swabs used in the past may release particles or fail to release the sample into the extraction solution. Special TOC cleaning validation swabs have good abrasion resistance and are compatible with most solvents, including acetone. They have excellent absorption and locking ability to solvents, and their sampling efficiency is outstanding.

To ensure that the sampling point represents the ‘worst case’ scenario of the equipment, use TOC cleaning validation swabs to repeat the sampling process within a specific rectangular area. After wiping, the extraction solution on the swab should be left as little as possible on the surface. In addition, after the cleaning process involving high temperature drying, the equipment surface needs to be cooled to room temperature before sampling.

After sampling, the sampling recovery rate can be improved by optimizing the extraction method, such as using a vibration table or ultrasonic bath to enhance the release rate of residues/samples in the sampling cotton swabs, which mainly depends on the type and condition of the residues.

Total Organic Carbon (TOC) is measured by a special instrument called “Total Organic Carbon Analyzer,” which oxidizes the TOC in aqueous solution to carbon dioxide and measures its content. The correspondence of carbon content between carbon dioxide and total organic carbon is used so that the total organic carbon in aqueous solution can be quantitatively determined.
The TOC method consists of two processes: the oxidation of carbon and the detection of the carbon dioxide generated. Various oxidation techniques are available, including photocatalytic oxidation, chemical oxidation, and high-temperature cautery.

What is Cleaning Verification?

The operable cleaning method is determined according to the specific situation of the equipment. For equipment that can be easily wiped and the surface is flat, the cotton swab wiping method can be used. For the equipment and pipelines that are not easy to wipe to take samples should use the drenching method. To determine the limits of residual contaminants by measuring microbial limits and total organic carbon according to different cleaning methods.

The systematic applicability, linearity, accuracy, and repeatability of the analytical method were verified to confirm that the method is suitable for the testing requirements of equipment cleaning validation, and the sampling recovery rate verified the validity of the sampling method.

Application of TOC Cleaning Verification Method

It applies to validating the TOC determination method for samples collected after cleaning the equipment related to the common line production of the medicine extraction workshop, medicine preparation workshop, etc.

Advantages of the TOC Method

For the TOC method, when organic substances are set as exclusive substances, it is possible to determine the presence of any residual substances, regardless of their source, whether they are products, cleaning agents, chemicals, solvents, or by-products or microbial contamination, and to perform this task well. As long as the molecular structure contains carbon, any active pharmaceutical ingredient or residual substance for cleaning can be detected. The detection result must be below the limit of the target compound, which improves the stringency of the cleaning verification.

The pharmaceutical industry has gradually accepted the TOC method, and the stringency of cleaning validation has been significantly improved throughout the industry and is increasingly in line with the overall requirements of the industry. The universality of the TOC method saves time and labor costs for pharmaceutical companies. The scientific, rational, and feasible cleaning validation process ensures the cleanliness required for the safe production of pharmaceuticals.