Residue assays are a critical quality attribute in establishing a validated cleaning program. They are essential for accurately determining amounts of residual active pharmaceutical ingredient (API) or formulation component in comparison with the acceptable residue limit (ARL) for a given process or equipment train (1). The residue assays are validated for several parameters: linearity, precision, sensitivity, specificity, and recovery. From an analytical standpoint, recovery is from the cleaning-test sample or the swab. From the cleaning-program standpoint, the concern is the recovery of the residue from the manufacturing equipment (1, 2), which is determined through experiments in which sample equipment materials spiked with known amounts of the substance of interest are swabbed and tested. The swab and the swabbing solvent must be capable of recovering a sufficient amount of material to allow an accurate and precise measurement of the spiked component.
It is a common practice to set baseline limits for a minimum acceptable recovery (e.g., a minimum product recovery of 70%). These limits, however, are sometimes set without scientific justification. The most important aspects for product-recovery factors are that the data be consistent, reproducible, and provide an adjusted ARL that is within the method limit of quantitation. ARLs must be achievable and practical. If recoveries are too low, either the methods will need to be optimized or equipment dedicated for the process.
Although reducing the amount of testing for a cleaning-validation program is desirable, efficiencies must have technical merit and be scientifically justified. For each new drug product manufactured, quantitative studies determine acceptable swab recoveries from each material of construction that requires surface sampling. One way to reduce the amount of testing is to test a new substance on only a subset of materials. A justification based on low risk for product carryover would include testing representative materials and excluding materials that have limited product contact (i.e., <5% of total surface area). An alternative justification groups materials based on similarity in composition (e.g., metals, plastics, and glass). The former justification ignores potential residue buildup, and the latter discounts individual material characteristics.Several parameters affect the recovery of residue from equipment surfaces (3). Residue solubility, swab and solvent type, and material of construction are the three most influential parameters. These three parameters are interrelated. Each residue has an inherent cleanability, which may be related to its solubility (4). The cleanability of the residue affects the choice of cleaning procedure. The harder a residue is to clean, the higher the anticipated amount of residue to be swabbed. The amount of anticipated residue affects the choice of swab and solvent and the validation of the analytical testing method.
The materials used to recover the residue also affect recovery. The swab material must be able to absorb sufficient residue and solvent to remove the residue from the equipment material surface. The type and amount of recovery solvent must solvate the residue sufficiently for removal without leaving residue or solvent behind. The swabbing technique should be standardized to minimize subjectivity and should recover enough residue consistently so that a precise measurement is ensured. The combination of swab material and recovery solvent should not interfere with the subsequent sample assay.
Finally, the material of construction of the manufacturing equipment needs to be considered. Most equipment in the pharmaceutical industry with drug-product contact is composed of stainless steel. Component parts of equipment, however, may be made from other materials such as Teflon and rubber. The swab recovery of residue from each material of construction should be determined to accurately quantify residue levels and assess material cleanliness.
The goals for this study were to gather and statistically analyze all available historical data to achieve the following:
The result of this analysis may reduce the number of studies required for new substances in a cleaning-validation program.
Multiple manufacturing sites conducted recovery studies based on site manufacturing equipment and the current product manufacturing matrix. For this study, 16 sites manufacturing drug products accumulated a significantly diverse database during several years. The data set consisted of 1262 recovery-factor (RF) values for 48 different drug substances, formulations, or detergents on 29 different materials of construction.
The swab material and solvents were defined for each residue. The analytical methods were validated for the specific residue of interest. The swabbing technique at each site was consistent, but there were differences in procedures from site to site.