Water quality is a common thread among pharmaceutical manufacturers striving to meet minimum standards for different applications. Whether used as a raw material or for processing, formulation, reagents, intermediates, and/or cleaning, water is fundamental to GMP processes and must be monitored as such. USP Water for Pharmaceutical Purposes defines different types of water alongside minimum water quality requirements for those waters. USPalso introduces design, installation, operation, performance, maintenance, and monitoring requirements that support validation and qualification of a water system.
Once a water system is validated, routine monitoring must occur on a designated frequency to ensure control of the system and acceptable water for intended use. Sampling locations, frequency, and attributes being sampled and tested should be based on the validation as well as criticality of the water. These tests may include microbial analysis, endotoxin, total organic carbon (TOC), conductivity, nitrates (EP), and pH. Unlike microbial testing, some chemical tests can be conducted online to avoid sampling, such as TOC and conductivity analysis.
TOC and conductivity are critical quality attributes that must be monitored to ensure appropriate water for use in GMP manufacturing. While the requirement for monitoring these quality attributes is discussed in USP <1231>, USP <643> Total Organic Carbon and USP <645> Conductivity mandate the explicit testing and sample acceptance criteria. When choosing technology for water monitoring of TOC and conductivity, it is compulsory to meet the requirements outlined in the compendia. For example, USP <643> requires that TOC technology must have a specified limit of detection of 0.05mg/L C or lower, must be able to demonstrate system suitability, and must be able to discriminate between the inorganic carbon resulting from atmospheric CO2 that could be present in a given sample and the CO2 generated from oxidation of the sample itself.
An important consideration to make when choosing technology is how the TOC is actually measured and reported from a sample. The vast majority of online TOC instruments employ conductivity as a means to measure carbon. Sievers TOC Analyzers, such as the Sievers M500, are carbon analyzers, wherein a gas-permeable membrane separates interfering compounds from CO2 to allow for accurate measurement of carbon. This technology instills confidence in the accuracy and precision of the measurement. Whereas sensors work by measuring conductivity pre-oxidation and post-oxidation without a conductometric membrane. While many TOC instruments measure conductivity pre- and post-oxidation in some manner, sensors measure the resultant conductivity without any level of discrimination against interfering ions. The difference in conductivity is attributed to TOC, even though other species (not carbon) may be contributing to the measurement. This can lead to over- or underreporting when interfering substances are in the sample.
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!
Once suitable and compliant technology is chosen, appropriate instrument qualification and method validation are required before data is considered valid for making quality decisions. Part of method validation and method deployment is determining how the methodology will be used in practice. In other words, will measurement take place online or in the laboratory? Traditionally, this testing has been done by taking grab samples from identified points of use (POU) and taking those sample back to the QC lab for analysis. Benchtop TOC analyzers and software are available that allow users to stack protocols, run system protocols, run large volumes of samples at a time, manage data, and electronically sign and export data. Whether the TOC analyzer is being used for cleaning samples or water monitoring, efficiency is an important factor for most laboratories.
One example of increasing efficiency is the ability to test for two attributes from a single sample. Companies can now implement a “lean lab” solution that allows for simultaneous TOC and conductivity analysis from a single vial. Specialty vials are used to prevent ionic leaching from the vial surface and to prevent atmospheric CO2 from dissolving into the sample, causing over-reporting. This solution greatly increases sample integrity and time savings over traditional meter and probe analysis.
For even further time and efficiency gains, many manufacturers have deployed online water monitoring as a solution for Real-Time Testing (RTT). This type of method deployment not only saves time associated with grab sampling and the QC workflow but can be easily implemented if already using like-for-like membrane conductometric technology in the QC laboratory.
Online analysis is considered Process Analytical Technology (PAT) and is a way manufacturers can increase quality, efficiency, process control, and process understanding. In 2004 the FDA published a guidance document on how to best implement PAT in GMP processes. This document contains non-binding recommendations and serves to encourage GMP manufacturers to deploy PAT to achieve process understanding, process control, and continuous demonstration of a validated state. PAT allows for real-time measurements of desired quality attributes such as TOC and conductivity. Using real-time data enables process understanding and demonstration of a validated state without manual sampling or laboratory analysis.
Online water monitoring achieves RTT for TOC and conductivity, greatly increasing efficiency while reducing sampling and laboratory errors. Additionally, online monitoring allows for Out- Of-Specification (OOS) and Out-Of-Trend results (OOT) to be highly detectable and detectable in real-time. Rather than waiting hours or even days for an OOS or OOT to be detected by the lab, they can be detected and further investigated in real time. To properly test water in real time, detect OOS/OOT results, and achieve processes control, the data must be accurate, quantitative, validated, and secure. To fully apply these quality and efficiency gains, manufacturers must ensure the technology used is accurate, efficient, and meets the highest degree of data integrity. With the correct technology in place, online analysis will provide great insight and understanding into a water system while maintaining the highest degree of compliance to compendial requirements.
Every pharmaceutical manufacturer relies on water in some form. Water is central to cleaning GMP equipment, manufacturing drug products, and for laboratory analysis. The United States Pharmacopeia outlines critical quality attributes that must be monitored for water to be acceptable for use. Included in those is total organic carbon and conductivity analysis. While TOC and conductivity aren’t new, there are new ways of deploying these analyses online to increase efficiency, save analyst resource, and release accurate, quantitative data from a validated analyzer in real time. To see what online TOC and conductivity analysis can do for your water monitoring program, visit https://www.suezwatertechnologies.com/products/analyzersinstruments/sievers-m500-online-analyzer
Author Biography
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 University of Colorado, Boulder in Molecular, Cellular and Developmental Biology.