Continued process verification methods in cleaning validation TOC

Abstract

An increasing interest in continued process verification has brought to the spread of on-line assay methods in cleaning processes [1]. This paper deals with two different on-line applications: conductivity sampling and the Total Organic Carbon analysis for washing machines.

Keywords: moist-heat sterilization, steam sterilization of aqueous solutions, sealed containers, headspace
volume, internal pressure, autoclaving, autoclave, superheated water sterilizers, steam/ air mixture sterilizers

INTRODUCTION

The U.S. FDA [1] process validation guidance document released in 2011 increased the emphasis on continued process verification: “ongoing assurance is gained during routine production that the process remains in a state of control”. Until recently, in a washing system, conductivity analysis was the only on-line method used to monitor the quality of the final rinse water. Now, developments in the Total Organic Carbon (TOC) technology allow its integration into washing systems. A general description of these two assay methods is reported in the next section. In closing, the on-line application of conductivity and TOC on Fedegari washing machine will be briefly described.

CONDUCTIVITY AND TOC ON-LINE ASSAY METHODS

Cleaning effectiveness can be determined by visual inspection and analytical methods for measuring removal of manufactured product and cleaning agent [2-3]. Analytical methods must be appropriate because their results determine the efficacy of the cleaning validation cycle.

The analytical methods can be specific or nonspecific. Specific methods measure a certain residue in the presence of expected interferences. Whereas, non-specific analytical methods measure a general property, such as conductivity or TOC, without discriminating the source identity. In order to understand when it is more appropriate to apply a specific assay method or a non-specific one, let us consider the following example: active proteins are commonly denatured by cleaning processes performed with hot, aqueous cleaning solutions. Usually, the protein is degraded into smaller fragments or it is involved in the formation of new molecules. So, residues of the active protein are no longer detectable by specific analytical methods for the native protein. It follows that the cleaning validation protocol must include non-specific assay methods to measure residues of deactivated products [2].