Execution Phase

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7.1 Visual Examination

After the cleaning, both product contact and nonproduct contact surfaces of the equipment are to be visually inspected for the presence of drug product traces. Verification of equipment cleanliness has to be done before sampling of product contact surfaces can commence. Surrounding areas (floor, walls, etc.) should also be visibly cleaned of product and detergent residue.

7.1.1 Sampling

Depending on the contamination or the residue that is being tested for and the analytical method used, it is very important to determine the type of sampling material to be used and its impact on the test results, as the material may interfere with the analysis of the samples.

It is also important to ensure that the solvent used for extraction purposes is satisfactory. The solvent must be nontoxic and is usually ethanol, water or an ethanol-water combination.

Several different sampling methods can be used, but the direct surface sampling method is preferred.

The validation officer of the company will execute the protocol.

Sample site selection will be based on areas that are deemed hardest to clean. Criteria include

• Equipment complexities (areas of different geometry that are likely to be difficult to clean)

• Areas of different materials of construction

• Ability to access and reproducibility of the sample

The number of sites to sample will be based on the above considerations as well as on the overall dimensions of the equipment. If there is an area that is deemed more "difficult to clean" during a cleaning validation, it will be included in that specific validation program.

7.1.2 Swab Sampling

To ensure that current equipment cleaning procedures are effective in reducing the residual concentrations of active ingredients to acceptable levels, swabs will be used to collect samples from production equipment after cleaning. These swabs will be used to determine both microbial and chemical contaminants.

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Samples of the internal surfaces are then taken by moistening the swab with a suitable solvent, sampling a 5-cm2 area (or the entire area if small), and then placing the swab in a test tube containing 10 mL of the solvent (specified for each active material from the analytical test method available in the laboratory or from pharmacopeias). For walls and plane surfaces, a minimum area of 5 cm2 will be covered.

It is important to take a representative sample of the area, as the results will be calculated for the entire surface area at a later stage.

Swabbing will occur after the equipment has been cleaned and in accordance with SOPs. Swabbing has been deemed an advantageous method because it comes in direct contact with the sampling surface, allowing for the detection of substances that are not easily rinsed off or soluble.

Swab samples will be collected from maximum contact areas and areas that are difficult to clean. Both major and minor pieces of equipment, as well as different surfaces, will be assessed where possible (if applicable to the manufacturing process).

7.1.3 Rinse Sampling

It is important to have both kinds of sampling, that is, swabs and rinses. The inclusion of rinse water sampling ensures that contaminants that may not be attainable or that may have been missed through swab sampling/analysis are detected from the surface of the equipment. This sampling technique is especially advantageous when a CIP system is utilized.

Samples of machine rinses are collected in a 500-mL volumetric flask after final rinsing of the machine with purified water, as described in the individual equipment cleaning SOP. The residues in water may be determined by TOC, spectrophotometry, TLC, or conductivity comparison with purified water/water for injection or the HPLC method or any other suitable method described.

Details of samples taken by the validation team are recorded on a sampling sheet for ease of reference. This includes all the information required to ensure that the necessary samples are taken properly as well as any information required to calculate the results.

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