By: Michelle Neumeyer - Life Sciences Product Applications Specialist for the Sievers line of analytical instruments - SUEZ Water Technologies & Solutions
The United States Pharmacopeia (USP) specifies regulations for pharmaceutical manufacturing and testing to ensure safe and effective drug products. USP Total Organic Carbon (TOC) pertains to requirements for testing pharmaceutical grade water. TOC is an important quality attribute that contributes to understanding water quality before use in critical applications. TOC is central to process control and patient safety and therefore stringent testing requirements are enforced by regulatory bodies around the world. USP <643> was revised effective May 2021 to require packaged water to have container volume-dependent TOC limits and system suitability concentrations. Whether using the Sievers M9, or another instrument for TOC analysis, now is the time to scrutinize technology and processes used to test TOC. Below are a few frequently asked questions regarding the recent USP <643> changes.
What is Changing?
Previously, sterile water had a standardized limit and system suitability concentration of 8 ppm. This concentration was applied regardless of container size. The limit of TOC has changed from a defined value of 8.0 mg/L C (8 ppm) to a variable limit determined by container volume as shown in the table below. USP requirements for sterile water still require the instrument to have a specified range from 0.10 mg/L up to the highest range for TOC limit for container size. While concentrations for packaged water system suitability have changed, determining system suitability pass/fail maintains the same calculations. The procedure section of USP outlines testing of samples. This testing procedure has changed from a pass/fail limit test to a staged testing procedure described in more detail below.
Why Were the Changes Implemented? If Bulk Water Meets TOC Conductivity Requirements, Why Would It Have to Be Tested After Packaging?
Controlling organic impurities in water becomes difficult when water is packaged. Once water is packaged, there is potential for leaching of organic impurities from the packaging to the water. Different container size brackets help address the surface area-to-volume ratio differences. For example, low volume containers falling in the <5mL container bracket have higher surface area-to-volume than that of larger containers, leading to increased opportunity for leaching of organic impurities. The USP has determined limits based on the maximum allowable leachable for a specific package volume. Although bulk waters may have met acceptance criteria per section 1 of USP <643>, this does not represent water quality following manufacturing of packaged water. The risk of leachables in the packaged water must be mitigated by testing for TOC per section 2 of USP <643>.
Is the Testing Procedure the Same?
As noted in the next question, the TOC methodology has not changed. However, the testing procedure has changed to a staged testing format.
When testing water samples against limits for the defined container size:
- If sample is less than Limit 1, then sample passes, and test is complete.
- If sample is greater than Limit 1 and less than Limit 2, then proceed to step 2.9(6.) to identify and quantify organic impurities exceeding 0.20 mg/L of Carbon. This is where additional methodology will be required for identification and quantification as TOC is a non-specific test.
- If sample is greater than Limit 2, then sample fails, and test is complete.
Is the Methodology or Technology Required Different?
The methodology for analyzing total organic carbon has not changed. Most technologies oxidize organic molecules in the water samples, resulting in CO2. Resultant CO2 is measured to determine the amount of carbon in the water sample. All technologies must be able to discriminate between CO2 generated from oxidation and inorganic carbon that can be present in water samples prior to analysis. The procedure section has changed to be a staged test as mentioned in the previous question. In the case of samples exceeding Limit 1 but within Limit 2, additional methodology will be required to quantify and identify organic impurities. These organic impurities need to be evaluated for safety. As TOC is a non-specific method, alternative methodology will need to be used in the event samples are between Limit 1 and Limit 2.
Are New Standards Needed? Are There New System Suitability Requirements?
USP revisions for sterile packaged water require system suitability and acceptance criteria to be contingent on container volumes. Benzoquinone and Sucrose are still the required compounds; however, the concentrations have changed to reflect container volume size. SUEZ has provided standard concentrations and procedures to align with required concentrations defined in USP. The concentrations included in each set will be based on the nominal container volume. The standards included in these sets will be used to determine Limit 1, Limit 2, and response efficiency. Limit 1 and 2 are determined by subtracting the response of the reagent water from the response of the standard solutions. Response efficiency is calculated as in the past, using the Limit 2 standard solution. Pass/fail criteria maintains the same calculation as the previous USP version, as shown below.
- rSS = Instrument response to the System Suitability Solution (1,4-Benzoquinone)
- rW = Instrument response to the Reagent Water Control
- rs = Instrument response to the Standard Solution, Limit 2 (Sucrose)
- Re = 100 x [(rss – rw)/(rs-rw)]
To pass suitability, response efficiency (re) must be no less than 85% and no more than 115%.
Summary
Testing quality of pharmaceutical grade water is not only important for quality and safety, but it is strictly enforced by regulatory bodies around the world such as USP. In the case of TOC testing, USP prescribes instrumentation, testing, and acceptance limit criteria that must be adhered to for compliant TOC analysis. USP requirements are living documents and can be revised to better fit industry needs or improve safety of products. USP revisions for sterile packaged water require system suitability and acceptance criteria to be contingent on container volumes. These changes are specific to packaged water, which breaks volumes into three brackets. The Sievers M9 can fully support these changes with analytical range, accuracy, precision, and data integrity. With these changes, it is important to examine technology and procedures to make sure TOC testing is up to regulatory expectations. In addition to instrumentation, standards, and consumables, SUEZ’s team of experts is ready to address questions and concerns.
About the Author
Michelle Neumeyer is the Life Sciences Product Applications Specialist for the Sievers line of analytical instruments at SUEZ – Water Technologies & Solutions. Previously, Michelle worked in Quality at Novartis and AstraZeneca, ensuring compliant water systems, test methods and instrumentation. Michelle has a B.A. from the University of Colorado, Boulder in Molecular, Cellular and Developmental Biology.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from American Pharmaceutical Review – all delivered right to your inbox! Sign up now!