What changes do you see in pharmaceutical water regulations in the near future?
Improvements in water treatment system design and technologies has lead the European Directorate for the Quality of Medicines & Healthcare (EDQM) to consider changing the current requirement in the European Pharmacopoeia (EP) for the production of WFI by distillation technique only .
Survey data collated by the EDQM has indicated that “A significant reduction of the TOC specification (for WFI) would be in line with actual data presented and also provide further control by reducing nutrients availability”, suggesting that that the new chapter on WFI in the future would contain a lower Total Organic Carbon (TOC) limit than the 500 ppb currently in the EP monograph 0169: Water for injections.
What challenges does this present to users of TOC analysers?
Modern water treatment systems have improved to the point where the quality of the water produced makes it difficult to measure the level of contamination present. For example, it is becoming quite common for modern water systems to generate water with TOC levels <10 ppb, which is beyond the practical limit of quantitation for most general-purpose laboratory TOC analyzers and presents a huge challenge to on-line TOC analyzers, especially those that calculate TOC by using two separate sensors to measure Total Carbon (TC) and Total Inorganic Carbon (TIC) and subtracting one from the other.
Many pharmaceutical facilities still solely rely on general purpose laboratory TOC analysers for batch release. Is this still practical?
Collecting samples for laboratory analysis from a water system with <10ppb TOC provides a challenge in itself. Organic carbon is ubiquitous and avoiding contamination of water during grab sampling is not practically possible.
Organic carbon exists in the air and on our skin. Even using good aseptic sampling technique is not enough because it is very likely that the surface of the grab sample vial will contain more organic carbon than is present in the water itself.
What about TOC analysers designed for general water analysis – will they be suitable for pharmaceutical grade water analysis?
In the very near future it may be no-longer acceptable to state that the TOC level in a water system is ‘below limit of detection’. Regulators are very likely to expect TOC analysis to be able to accurately resolve and trend TOC levels of <10ppb and this will present a huge problem for those people using a general purpose laboratory TOC analyzer that is just not capable of resolving down to those levels.
What techniques for water production are being considered by the EDQM?
One of the techniques for WFI production being considered by the EDQM is the use of reverse osmosis and this brings a challenge to TOC analysis in itself. Reverse osmosis works by filtering the water through a very small pore size osmotic filter which traps a very high percentage of the contaminants in the water and only allows water and gas molecules to pass through.
Because a high level of the water is rejected by this process and yet gases pass through, the RO permeate tends to have increased concentrations of CO2, typically in the low ppm range, i.e. 100 times larger than the TOC levels. TOC analysers that calculate TOC by using two separate sensors to measure Total Carbon (TC) and Total Inorganic Carbon (TIC) and subtracting one from the other. Small percentage errors in the measurement of the TC and TIC can swamp the TOC calculation.
In the ICH Q2 guidance document Validation of Analytical Procedures the International Conference for Harmonization  recognise the need for an analyser to have specificity, i.e. “the ability to assess unequivocally the analyte in the presence of components which may be expected to be present” and TOC analysers that calculate TOC from TIC and TC measurement using two sensors can find this task challenging in pharmaceutical grade waters.
Frequent re-calibration of these instruments can get around this problem and some suppliers offer an automated zero function in an attempt to remove the measurement inaccuracies between the two sensors.
That works well in the laboratory environment where technicians can run frequent calibration verification standards to provide evidence that the auto calibration routine has not adversely affected the TOC analyser’s accuracy, but it does not work well in the on-line environment where a technician would have to make weekly or monthly visits to the water treatment plant room to run calibration verification standards through the TOC analyser to verify its accuracy, which would be very costly and time consuming.
What is different about the Beckman Coulter range of TOC analysers that allows them to overcome these measurement issues?
Beckman Coulter TOC analyzers get around these issues by utilising a single sensor for TOC measurement. In the Beckman analysers, the same sensor is used to measure both TIC and TC or to directly measure TOC.
Any slight baseline drift in the sensor measurement over time does not have an effect on the TOC analysis result as the measurement principle starts with a baseline measurement and then the TOC analysis starts.
Offset caused by sensor drift is eliminated from the TOC analysis by the initial baseline measurement and all TOC measurements are differential related to this initial baseline measurement. By using this technique, we have managed to produce a range of on-line and laboratory TOC analysers that are suitable for today and the future EDQM requirements.
 European Directorate for the Quality of Medicines and HealthCare: Expert Workshop Water For Injections – Potential Use Of Membrane Systems For The Production, 24th March 2011: http://www.ema.europa.eu (PDF) [6th November 2014]
 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Validation Of Analytical Procedures: Text And Methodology Q2(R1), November 2005 [8th August 2014], http://www.ich.org (PDF) [8th August 2014]
About Tony Harrison
Tony held the Convenorship of the ISO Working Group revising ISO 14698-1 & -2 for microbial control in cleanrooms and is the UK subject matter expert to the ISO Working Group currently revising ISO 14644-1 & -2 for airborne particulate contamination control in cleanrooms.
An Electrical & Electronic Engineer by qualification, Tony is employed by Beckman Coulter Life Sciences and currently holds the position of Compliance and Applications Specialist.
An expert in water system TOC, conductivity and ozone analysis and cleanroom monitoring systems, Tony has spent the last twelve years in applied metrology for the pharmaceutical and healthcare manufacturing industries.
Prior to that, he worked for companies providing process control automation solutions for manufacturing industries.
Tony was joint-editor on the ISPE Guide to Ozone Sanitization of Pharmaceutical Water Systems and was also chief editor of the PHSS Best Practice Guide for Cleanroom Monitoring.
Tony is a well-known international speaker and has provided educational seminars on TOC, liquid particle counting, ozone sanitization for water systems and cleanroom monitoring in UK, France, Italy, India, Malaysia, China, USA, Scandinavia, Ireland, Hungary, Switzerland, Indonesia, Hungary, Belgium, Greece, Switzerland and, most recently, Turkey and Denmark.
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