1. Total organic carbon TOC measurement history

The TOC test is a test requirement established by the United States Pharmacopoeia (USP) for water for injection WFI and pure water PW in pharmaceutical water since 1998. Prior to this, the USP standard test organics were "hard oxide test", which was carried out using a chemical reaction method in which the color of the KMnO4 solution was changed. Promoting solution test method changes are derived from the development of instrument methods, and improvements in test speed and sensitivity have made it faster and better to measure TOC using analytical instruments. The TOC and refractory tests were selected in the 643 section of the USP in 1996, and later changed from Appendix 5 of the USP version 23 to the prescribed method. It is stipulated that all TOCs complying with USP water should be less than 500 ppb or 0.5 mg/L.

The TOC test is also a requirement for pharmaceutical water use in the European Pharmacopoeia (EP) and the Japanese Pharmacopoeia (JP). EP requires WFI, PW, and HPW to measure TOC, and the result is less than or equal to 0.5 mg / L. The instrument requirements for JP's TOC test are different from USP and EP. USP and EP do not specify TOC for different instrument methods, but Chapter 60 of JP XIV specifies measurement methods and includes different standards such as TOC analyzer type and calibration, system stability test.

All major pharmacopoeias recognize the same TOC limits. Globally consistent TOC limits and measurements will increase the quality of pharmaceutical products worldwide. The Chinese Pharmacopoeia (ChP) and USP have been working on a consistent TOC. It is hoped that the TOC and conductivity testing of all pharmaceutical waters will be agreed within two years. With consistency, Chinese pharmaceutical companies meet a set of standards, and products can be marketed globally without the need for additional drug regulatory investment.

2. Determination of total organic carbon TOC

All TOC testing techniques have at least three steps: baseline determination, oxidation of organic matter, and determination of organic products. Baseline judgments can be performed using computational or mechanical methods. The baseline contains inorganic carbon ICs, which are calculated by subtracting the IC from the total carbon TC after measuring the inorganic carbon, or by isolating the IC as the starting zero. The mechanical establishment of the baseline requires the system to be vacuumed or airborne to produce a low IC background. Once the baseline is determined, it can begin to oxidize.

Oxidation may include heating, UV irradiation, chemical promoters, catalysts or the use of two or more of the above methods. All oxidation processes produce CO2 proportional to the TOC in the water.

Once the oxidation is complete, the test and calculation work can begin. CO2 can be measured in raw water samples, as well as CO2 separated from liquids. Some separation devices include membrane permeation and degassing steps. The CO2 dissolved in water can be detected by conductivity method, and the CO2 in the gas phase can be detected by spectrometry (non-dispersive infrared).

According to the conditions, the TOC can be obtained by subtracting the IC from the TC using a mathematical algorithm. The conductivity method is determined by the CO2 generated after the oxidation of TOC, so that the conductivity of water increases.

3. Different total organic carbon TOC determination techniques

The TOC test method is a method recommended by the FDA for evaluating all carbon-containing organic compounds in water samples, and is widely used in quality control, production, and cleaning verification of related pharmaceutical production equipment. The International Coordination Meeting (ICH), with the assistance of the US FDA (CDER & CBER2), created the guidance document Q2B in 1996: validation of the analysis steps. Specific to the pharmaceutical water system, how to apply these procedures and steps to verify the effectiveness of the TOC method in cleaning validation.

The main differences between TOC measurement techniques are the initial purchase price, consumables cost (UV lamp, carrier gas, reagents), maintenance and labor (preparation of reagents, replacement of catalysts, maintenance of gas generators, calibration time) and experimentation. Adaptability of room or online analysis (in compliance with FDA, LIMS/PLC communication, ambient conditions, etc.). The USP/EP method does not specify a laboratory method or an online method, so users should choose the one that best suits their needs.

The detection limits of different techniques and analytical methods will be different, but they must meet the system suitability and TOC detection accuracy requirements of the appropriate pharmacopoeia. For example, USP requires a minimum detection limit of 50 ppb. The analysis time for each technology can vary from 3 to 30 minutes. The calibration requirements are also different, from daily to yearly, the correction may be done at the user's location, or it may need to be returned to the original factory or completed by trained personnel. The most important differences are operating costs and downtime.

Most of the water samples used for laboratory analysis contain dissolved CO2. In order to accurately measure the TOC, the contribution of the IC in the entire signal is minimized. If the presence of the IC is detrimental to the determination of the sample, the IC can be removed by vacuuming the sample, blowing nitrogen, or adding acid. The above method is not required unless the TOC is low and the IC is high. The initial IC concentration in high-volume pharmaceutical water supplies is generally low, and unless the sample is exposed to air, the TOC can be accurately determined without removing the IC. The FDA has neither approved nor approved the instrument. The FDA simply requires the user to confirm their water purity and continually meets mandatory limits for the purpose of use.

To measure the TOC online (for example, without taking the sample to the laboratory), a clean line can be taken from the water system to direct the flow of water to the inlet of the TOC instrument. When the instrument is no longer in use, it is necessary to properly remove the dead angle of the sample line against the flow. Install a continuous bypass or check valve to prevent backflow.

The online TOC method for most pharmaceutical water applications is performed using UV oxidation and conductivity testing. This is designed for low conductivity water supplies. When the TOC instrument is directly connected to the sample line, there is no total inorganic carbon TIC exposed to the air. Although it is usually necessary to make some corrections to the background, low conductivity water samples do not require removal of the TIC.

When the TOC concentration is 500 ppb or less, an oxidizing agent is not required, and photocatalytic oxidation (with ultraviolet oxidation in the presence of titanium oxide) is sufficiently oxidized. Photocatalytic oxidation is a fixed amount of sample suitable for use in accordance with the USP procedure, and some samples are determined. The important point is that when the TOC is calculated in ppb, the TOC of the sample is required to be completely oxidized. The analyzer can only provide an incorrect reading if it does not completely oxidize the sample. This is one reason why USP requires all organics to be converted to CO2.

The main advantage of on-line measurement of TOC is that it does not require care and continuous measurement. It provides continuous trend monitoring of the water system and has the ability to react immediately to interference, eliminating errors in sample collection, handling and transportation. On-line measurement supports industrial active and pharmaceutical parameters consistent with FDA's PAT (Process Analytical Technology). PAT seeks to ensure the quality of the drug, the quality of the product, the quality of the product in the process, often using online sensors and analyzers, real-time analysis and correction of feedback, and gradually reducing or stopping laboratory measurements after production.