In general, what are some current issues facing pharmaceutical companies in regards to cleaning process verification?
Demonstrating process understanding is a key issue facing pharmaceutical cleaning validation (CV) and verification programs. By improving process understanding, companies can decrease risks and increase efficiency. The onus is on the manufacturer to demonstrate that they have control of their cleaning process through constant monitoring and investigation of Out-of-Specification (OOS) results. Industry best practices are shifting from using specific analytical methods for cleaning to nonspecific methods, such as Total Organic Carbon (TOC) analysis, in order to demonstrate process control and understanding, as well as adherence to validation lifecycle guidance. Whereas product-specific analytical methods may be less useful for detecting uncharacterized degradants, difficult-to-clean compounds, or detergent residues, TOC analysis provides a more complete measure of total cleanliness with simpler method development. In the continuous verification phase of a CV program, manufacturing concerns include product changeover, equipment turnover, and a desire for automated monitoring. Using analytical equipment such as TOC and conductivity to provide realtime data on cleaning processes in the production environment is the means by which companies can address these concerns and achieve their goals.
Up to the present, what has been the standard procedure for cleaning verification? What are its shortcomings?
Cleaning verification procedures have evolved from the use of specific methods, such as High Performance Liquid Chromatography (HPLC), to now nonspecific methods such as TOC as the preferred analytical tool. The motivation for this change comes from many benefits achieved from switching to TOC, including time savings, process understanding, decreased consumables costs, and reduced waste streams. While techniques such as HPLC can identify the presence of a particular residual compound or API, the method development is much more complex, setup and analysis times are longer, and the tests may not identify all residual compounds. Uncertainty associated with ghost peaks during HPLC analysis can result in lengthy troubleshooting and failed validations. Together, these factors can contribute to production downtime before processing equipment can be certified for cleanliness. In addition to TOC being a faster and simpler method, the benefits realized through better process control and understanding (see Question 1) ultimately enable companies to achieve greater efficiencies and productivity.
Can you describe the latest technologies for cleaning process verification? What benefits do these technologies offer?
One of the challenges in addressing cleaning process verification with nonspecific methods such as TOC is avoiding interferences from oxidation byproducts that artificially shift the end measurement high or low. The solution to this challenge is to have selectivity and specificity for the intended oxidation product, in this case carbon dioxide. Our Sievers* proprietary membrane conductometric technology achieves this by selectively measuring CO2 to offer superior accuracy and specificity. This makes the Sievers M9 TOC Analyzer the most appropriate analytical instrument for the intended use of cleaning validation and verification to establish process control and understanding. The added benefit of Sievers membrane conductometric technology is that it enables seamless integration from the lab to the production floor with like-for-like instrument qualification and method validation transfer protocols. This enables compliance with the FDA’s Process Analytical Technology (PAT) guidance. With Sievers products, there is no sacrifice in quality when moving to a PAT environment. In fact, the ease of use and robustness of Sievers technology lends itself perfectly to these initiatives.
What product(s) has SUEZ introduced that implements the latest technologies in cleaning process verification? Can you provide us with details? Benefits?
When a method is transferred from the lab to the production floor, challenges may arise related to sample acquisition, sample volume, and rinse timing as it applies to CIP cleaning cycles and configuration. SUEZ’s Sievers M9 TOC Analyzers leverage membrane conductometric technology and provide features such as simultaneous Stage 1 Conductivity and real-time measurements with Turbo mode. The combination of these features empowers the end user to acquire real-time cleaning profiles for both TOC and conductivity, providing quantitative data manufacturers can use to optimize cleaning cycles and methods. With the new addition of a low flow sampling block for the M9 Analyzer, real-time TOC and conductivity soil profiling can now be accomplished at flow rates as low as 3 mL/min.
In addition to the instruments, does SUEZ offer other services/expertise to assist pharmaceutical companies with cleaning process verification? Can you describe them?
We are committed to the success of our customers and have a long history of providing technical expertise and specialized services for the pharmaceutical industry through the Sievers brand. These include validation support packages for cleaning validation, onsite service and maintenance, and contract services through our application lab to assist with preliminary method development work to support seamless deployment at customer sites. In addition to technical support and application training, we can provide Failure Analysis Reports (FAR) to help close OOS investigations more efficiently, when needed. For customers that prefer a fixed total cost of ownership for their system, Sievers comprehensive service plans cover support, service, reference materials, and consumables.
Looking ahead, how will SUEZ continue to offer its current and future customers the best available technology and expertise for cleaning process verification?
We will continue to develop innovative methods for our current and future customer application needs, leveraging Sievers technology and deep domain expertise. These include methodologies in harsh matrices such as concentrated acid or base, low flow applications, and many other new and emerging application needs. Having quantitative, real-time data at their fingertips allows customers to capture previously unrealized opportunities to implement advanced process control and efficiency.
*Trademark of SUEZ; may be registered in one or more countries.