Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility Part 2

Cleaning procedures should cover every type of equipment to be cleaned. They should specify all critical parameters including water flow, temperature, and pressure as well as washing and rinsing times. Usually these will have been previously set through engineering studies. Cleaning procedures should also include specific details regarding disassembly of equipment, where the small parts should be placed, the quantity of detergent to be prepared and its concentration, and the type of brush or piece of cloth used to apply the detergent. The size (length, and internal diameter) and the type of hose used to perform the cleaning process should also be specified. This is important because, if the hose diameter is small, less water is used and a higher pressure is achieved during the operation. Finally, cleaning procedures should be challenged and validated to demonstrate the reproducibility of results for all cleaned parts.

Validated Analytical Methods

Appropriate validated analytical methods for analyzing cleaning validation samples will be used. A validated method is rugged and robust enough to measure the residue limit established. The method used should be based upon previously established residue limits of the active, cleaning agents, and excipients. The method must be appropriate for measuring the analyte at and below the acceptance limit for residue.

Two important parameters in an analytical method used for cleaning validation are: the Limit of Detection (LOD) and the Limit of Quantitation (LOQ). The LOD is the lowest amount of a compound that can be detected. The LOQ is the lowest amount of a compound that can be quantified. The LOD is usually lower than the LOQ, but is never higher. The LOD should never be used to establish residue acceptance limits. Residue acceptance limit should be established based on LOQ for accurate measurement.

One of the important considerations in choosing an analytical method is the type of residue to be analyzed. Residues can be active drugs, cleaning agents, or organic compounds. The methodologies available are either specific or nonspecific. A specific methodology detects a unique compound in the presence of potential contaminants. Some examples of specific methods are high performance liquid chromatography (HPLC), ion chromatography, atomic absorption, capillary electrophoresis, and other chromatographic methods. Nonspecific methods detect any compound that produces a certain response. Some examples of nonspecific methods include total organic carbon (TOC), titrations, pH, and conductivity. Currently, methods that are complimentary to each other are applied to cleaning validation samples. That is, if a specific method is used for active and cleaning agents, then a nonspecific method, such as TOC can be used as a complementary methodology. Cleaning validation methodology includes other important parameters such as linearity, ruggedness, method precision, and reproducibility.

A method used to analyze cleaning validation samples is properly designed if it identifies possible interferences. Many possible sources of interferences include active drugs and excipients, cleaning agents and compounds, swab materials, and solvents used in performing the cleaning process. Still other sources of interference may be triggered when a sample is not handled properly.

In addition, the method validation must contain sample stability for the reference analyte. Choice of validation methods should guarantee that samples remain stable for the time specified for analysis. This includes the stability of all residues that specifically determine the active and the detergent residues.

Validated Swab Recovery Study

The swab recovery must be validated to determine the amount of analyte that can be recovered from a surface. Previous to validating the equipment cleaning procedure, the types of equipment surfaces for product manufacturing should be identified. This means if four types of surfaces are identified such as glass, stainless steel, Teflon, or rubber; each of the four surfaces must be tested for swab recovery.

The study can be performed on simulated product contact surfaces. The efficiency of the swabbing procedure should be challenged at the acceptance criteria level for active ingredient, excipients, and detergent.

Known amounts of active ingredient, excipients, and detergent will be added to each type of surface. The surface is air-dried and swabbed. The nature of the swab extraction is dictated by the analytical method, which has taken into consideration its dissolution properties as well as the analytical technique used. The amount recovered by the swab is determined using a validated trace level analytical method.

Part 3