Quality, safety, and efficacy of finished formulation must be controlled throughout the product life cycle. Cross-contamination by drugs from previous batches, cleaning or sanitizing agents may lead to adulterated product. Cleaning validation protocol follows the Quality risk management process (ICH Q9) with estimation of the criteria for Acceptable Daily Exposure (ADE), Permitted Daily Exposure (PDE), Maximum Acceptable Carry Over (MACO) and No Observed Adverse Effect Level (NOAEL) determination for API in multipurpose equipments. The development and validation of analytical cleaning method follows ICH Q2 (R2) guidelines. Optimization of swab or rinse sampling protocols, bracketing and worst-case ratings, cleaning process qualification and verification on equipment surfaces are some of the challenges that requires careful consideration as per various available regulatory guidelines. The article provides an elaborated overview on various challenges, regulatory and technical requirements for cleaning method validation suggested by various regulatory agencies.