Most pharmaceutical companies in the United States and Europe use laboratory Total Organic Carbon (TOC) analyzers to control the TOC quality attribute for the compendial release of the Purified Water (PW) and/or Water for Injection (WFI) used in drug manufacturing. Recent FDA documents encourage the application of scientifically and risk based approaches to the development of automated process control systems in the pharmaceutical industry. To save on operational costs a large number of companies are converting from laboratory TOC analysis to automated on-line TOC analysis-based water release systems.

We surveyed and interviewed pharmaceutical companies with real-time TOC water release systems. To understand and explain successful and unsuccessful real time TOC release system implementations we performed a scientific comparison study of on-line TOC technologies. The evaluation results and company interviews are used to derive the important considerations and characteristics of successful on-line TOC implementation strategies. Additionally, the on-line TOC technology evaluation suggested the currently approved United States Pharmacopoeia (USP) TOC “system suitability test” does not ensure the suitability of a TOC analyzer for real-time TOC release applications. The importance of the interaction between the raw water, the water purification system, and the type of on-line TOC technology will be reviewed in light of creating a successful real-time TOC water release system design.