Quality control of ultra pure water in pharmaceutical manufacturing

Two TOC instruments offering different oxidation methods

TOC-L mit ASI-L

Ultra pure water is one of the most widely used reagents in industry and its quality is therefore of utmost importance in all industrial processes. Quality control has, for many years, been carried out and documented via conductivity measurements, which provide an assessment of the concentration of all inorganic species present in water. This detection method does not take organic pollutants into account as they typically do not contribute to conductivity. However, organic pollutants can tremendously influence further industrial processes and it has become increasingly more important to include quantitative determination of all organic species in quality control of water samples.

The TOC value (Total Organic Carbon) can be used as sum parameter for organic compounds. Similar to conductivity signals that are composed of ionic compounds, the TOC value is a measure of the contribution of many organic compounds present in a water sample.

Different areas of application therefore require different grades of pure water. The European Pharmacopoeia (EP) defines several grades of quality including ‘Purified Water’, ‘Highly Purified Water’ and ‘Water for Injection.’

Clarifying the Terminology

Water for Injection is ultra-pure water used in the preparation of injection solutions. Ultra-pure water is produced via distillation. Its TOC content may not exceed 0.5 mg/L (water for injection in bulk).

Highly Purified Water is sterile water for the production of drugs not requiring ‘Water for Injection.’ It is often used for the final rinse during cleaning as well. Highly purified water is produced via reversed osmosis. Its TOC content may not exceed 0.5 mg/L. However, the United States Pharmacopoeia does not apply this classification.

Purified Water is used for the production of drugs not requiring a separate standard. Organic content is determined via TOC value (0.5 mg/L) or the permanganate test for purified water in bulk.

TOC determination according to EP 2.2.44

The EP 2.2.44 guidelines do not prescribe any particular oxidation technique for TOC determination. But the TOC systems must differentiate between inorganic and organic carbon. This can be utilized via removal of the inorganic carbon species (NPOC method), or a separate determination (difference method). The limit of detection for TOC should be at least 0.05 mg carbon/L. Applicability of the method must be determined via a system suitability test.

To carry out a system suitability test, a standard solution consisting of sucrose with a carbon content of 0.5 mg/L is prepared as well as a control solution of 1,4-benzoquinone with the same carbon content. The blank water reference solution (ultra-pure water) used for this purpose may not exceed a TOC content of 0.1 mg/L. For the system suitability test, all solutions including the blank water reference are subsequently measured and the resulting signals are recorded.

Blank water reference: r_w
Standard solution (sucrose): r_s
Control solution (benzoquinone): r_ss

The signal of the blank water reference is subtracted from the response signals of both standard solutions. Then, the recovery of the benzoquinone standard is subsequently calculated with respect to the sucrose standard.

Recovery in %:

Results between 85 – 115 % are acceptable. The ultra-pure water sample corresponds to the guidelines when its response signal (r_u) does not exceed r_s – r_w.

TOC determination in ultra-pure water

Two oxidation methods are routinely being used in TOC analysis:

Catalytic combustion where carbon compounds are converted into CO₂ using a catalyst under high temperatures with subsequent detection of the CO₂ using a NDIR detector.

Wet chemical oxidation which uses a combination of UV irradiation and persulphate for oxidation.

Both methods can be applied for ultra-pure water TOC determination. Which of the two methods will offer the best solution for different applications can not be answered in general, but requires closer examination of the particular application.

TOC series

Shimadzu’s TOC series covers all water quality analysis requirements. Two systems are particularly suitable for ultra-pure water TOC analysis. Both offer a wide measuring range of 0.5 µg/L up to 25,000 mg/L and support a broad range of applications – from ultra-pure water up to highly polluted wastewater (or cleaning validation). Both systems are available as a PC as well as a standalone version and are easily adjustable to any laboratory environment.

The two TOC instruments for ultra-pure water analysis differ in their methodology. The TOC-V_WP/WS uses wet-chemical oxidation whereas the TOC-L uses the catalytic oxidation method at 680 °C.

TOC-L: Oxidation via catalytic combustion

The TOC-L applies the proven catalytic oxidation at 680 °C. The integrated ISP sample preparation unit (an 8-position switching valve with syringe and sparging gas connection) considerably reduces analysis time and complexity, as dilution, acidification and sparging are fully automated by the instrument. Automatic dilution increases the measuring range up to 25,000 ppm (detection limit: 4 µg/L).

In addition, the combustion technique can be used in combination with the TNM-1 module, whereby a single injection is sufficient for simultaneous TOC/TN_b (total bound nitrogen) determination. This is carried out in accordance with EN guidelines for TN_b determination via chemiluminescence detection.

In this case catalytic combustion happens at 720 °C. Simultaneous TOC/TN_b determination is highly suitable for cleaning validation, as this makes differential determination between cleaning agent and product possible.

Wet-chemical oxidation using the TOC-V_WP

The key technique of the TOC-V_WP analyzer is the powerful oxidation via the combination of sodium persulphate and UV-oxidation at 80 °C.

A persulphate solution is needed for the determination. Therefore, it is important that this solution does not contain any contaminants affecting the measuring value negatively. The TOC-V_WP contains an automatic reagent preparation function that eliminates possible contamination of the persulphate solution in order to assure that the average TOC value truly originates from the sample – and not from the reagent solution used.

Combined with the large injection volume (up to 20.4 mL) and the highly sensitive NDIR detector, this leads to an extremely low detection limit (0.5 µg/L) and excellent reproducibility in the lower ppb range. The TOC-V_WP/WS is therefore highly suitable for TOC determination in the ultra-trace range.

Conclusions

Both types of instruments with their different oxidation methods can be used for TOC determination according to EP 2.2.44 guidelines. The advantage of the combustion method is its high oxidation potential, especially for samples containing particulate matter. Moreover, simultaneous TOC/ TN_b measurements can be carried out using this instrument.

The advantage of wet-chemical oxidation is its high injection volume, which leads to higher sensitivity and therefore enables high precision measurements in the lower ppb range.