The Application Of Lactose In Process Simulation Testing And Cleaning Validation

Sterile product manufacturing is one of the most difficult process for pharmaceutical products. Since many final products can’t use sterilization to meet the requirement for microbe-free, the manufacturing process of these products must avoid microbial contamination. A sterile validation method is required for these industrial production processes in order to ensure the reliability and suitability.Simulation test (media-fills) as a sterile reliability evaluation is one of the most useful method. Microbial culture medium instead of sterile products is used for the simulation of filling process. At present most manufacturers use trypticase soy broth (TSB) for validation. To reduce the cost and simplicity of validation, this study intends to replace TSB by lactose. Lactose at an appropriate concentration was used in simulation tests for a sterile reliability evaluation. Moreover, the residual cleaning of filled system was explored and validated after successful sterile validation by lactose media. The following main research results were obtained:1.5% lactose instead of TSB culture medium can meet the requirement of the final API in aseptic filling simulation.2. A standard operating procedure of lactose cleaning validation of production equipment is established.① Swab method can be used for the easy-wipe smooth surfaces and equipments for sampling, while the leaching water of not-easy-wipe equipment and pipeline was used for sampling.② Both sampling methods of the allowed residual limits of lactose meet the FDA recommendation.③ The method of total organic carbon (TOC) measurement was adopted to qualify lactose in the cleaning validation. This method effectively solve the problem of lactose quantification by the traditional gas chromatography and liquid chromatography (HPLC) in low concentration (< 10 mg/L) levels of water samples due to insufficient sensitivity.Above research results of the lactose simulation test for sterile product manufacturing and the lactose cleaning validation reduce the cost of aseptic process validation and improve the economic efficiency of our enterprise. Meanwhile, these methods could be useful reference for other domestic sterile API manufacturers.