Swab Sampling for Cleaning Validation of a Residual Active Pharmaceutical Ingredient

A swab-sampling method was developed for cleaning validation of a residual active pharmaceutical ingredient in samples collected after cleaning the sampling suite. A summary of the strategies and results of the method development is presented. The developed extraction method produced an acceptable level of recovery and precision. ross contamination with active ingredients is a real concern. The Code of Federal Regulations (CFR) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official, or other established requirements” (1). Cleaning validation is required in the pharmaceutical field to avoid potential clinically significant synergistic interactions between pharmacologically active chemicals (2). Since the issuance of the US Food and Drug Administration’s “Guide to Inspection of Validation of Cleaning Process” in July 1993 (3), cleaning validations have received increasing attention. Validation is required not only for manufacturing sites, but also for the sampling– filling suite in research and development. To ensure that the sampling techniques chosen meet the established acceptance criteria, prevalidation feasibility studies and method development must be performed. The two main sampling techniques available for cleaning validation are rinse and swab sampling. FDA prefers swab sampling to rinse sampling (4, 5). In many pharmaceutical manufacturing sites, a hood is used to sample and aliquot multiple active pharmaceutical ingredients (APIs) on site. After sampling a given lot of API, the sampling or filling suite is cleaned. In the suite where this study was conducted, cleaning is performed by swabbing with water and then 70% isopropyl alcohol (IPA). In many cases, it is also necessary to prove by appropriate analytical testing that the solvent residue is removed from the equipment after cleaning (6). Validation is not required for volatile cleaning agents such as IPA that do not leave a residue (7). Typically, to verify the effectiveness of API removal, the socalled “worst case” representative API must be determined (8). Therefore, if multiple APIs are used at the manufacturing site, we must demonstrate that the cleaning method effectively removes the API that is the least-soluble in the cleaning solution (in this case, 70% IPA). For this study, all the APIs used at the site were tested, and Compound A was the least soluble in 70% IPA under ambient conditions. Compound A also has chemical features that are typical of a small molecule drug candidate. A well-conceived recovery study is the keystone of a good C