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Aperçu de la réglementation : USP <645> « Conductivité de l’eau »

rylee.lay@veolia.com — Tue, 17 Mar 2026 03:29:13 +0000

Regulations Overview: USP <645> "Water Conductivity" rylee.lay@veolia.com Mon, 03/16/2026 - 23:29

March 16, 2026

What is USP <645> and why does it matter?

USP <645> is a general chapter in the United States Pharmacopeia (USP) that provides procedures for measuring the conductivity of water. It establishes specific test methods and acceptance criteria for different types of pharmaceutical water including purified water (PW), water for injection (WFI), water for hemodialysis, and other sterile waters.

Electrical conductivity is a measure of a substance's ability to transmit electric charge. Dans les applications de qualité de l’eau, la conductivité résulte de matières ioniques dissoutes. Dans les systèmes d’eau pharmaceutique hautement contrôlés, les changements de conductivité indiquent souvent une contamination, bien que la conductivité serve également à évaluer la composition, la chimie et la consistance de l’eau. Because of the relative speed and ease of measuring conductivity, this parameter has long been regulated in many applications and is widely used as an early indicator of water quality changes.

Salts, dissolved carbon dioxide (CO2) and high pH levels increase ions in solution, thereby increasing conductivity. Fluctuations in this measurement indicate the presence and level of ionic impurities, providing data about contamination in the sample.

USP <645> works in tandem with USP <643> "Total Organic Carbon", which details the monitoring of organic carbon present in a sample. Ensemble, ces tests de contrôle des limites chimiques essentiels déterminent s’il existe un contrôle suffisant dans le système de purification de l’eau. Le COT et la conductivité fournissent des évaluations non spécifiques de la qualité de l’eau, ce qui signifie qu’ils n’identifient pas d’espèces de contaminants spécifiques, mais mesurent plutôt des classes entières de contaminants. This pair of tests quantifies contamination levels that could indicate microbial growth, residues from insufficient cleaning processes, or other impurities.

Conductivity, TOC, endotoxin and bioburden comprise four critical parameters that must be monitored to ensure PW and WFI meet compendial requirements for quality control (QC).

Download Now: Conductivity and TOC Sampling - Standard Operating Procedure (SOP) for Pharmaceutical Grade Ultrapure Water

Conductivity and TOC monitoring provide necessary information to confirm PW and WFI production is free of process by-products. Par exemple, bien que les traitements de pré-conditionnement tels que l’ozone et l’électrodésionisation (EDI) réduisent la contamination, ils peuvent eux-mêmes contribuer à la production de contaminants s’ils ne sont pas correctement gérés. Conversely, while physical processes such as reverse osmosis and ultrafiltration do not introduce substances to the water, monitoring ensures these systems remain functional and effective.

Who is impacted by USP <645>?

USP <645> affects facilities who produce pharmaceutical-grade waters, use these waters as an ingredient, and instrument manufacturers.

Industries and sectors impacted by USP <645> include:

Pharmaceutical and biopharmaceutical manufacturers
Medical device manufacturers Ingredient manufacturers
Research and development facilities and research institutions
Contract testing and quality control laboratories
Water purification system and instrument manufacturers
Some healthcare and veterinary facilities

Additionally, Engineering Design Consultants (EDCs) and Engineering, Procurement, and Construction (EPC) contractors serving life science industries should take these regulations into consideration for point-of-use testing.

Note: This list is not exhaustive.

USP <645> overview and Stage I, II, and III testing

Testing methods detailed in USP chapter 645 follow a staged process of increasing complexity. Ils s’adaptent à la fois aux scénarios de tests en ligne et hors ligne avec des considérations pour déterminer l’adéquation du conteneur d’échantillons. It should be noted that Stage 1 is required for all samples, while Stages 2 and 3 are utilized only when a sample fails to meet Stage 1 test limits.

For pharmaceutical manufacturers, the most desirable state for compliance with USP <645> is Stage 1 conductivity testing. Il s'agit de la méthode la plus simple à exécuter, qui nécessite le moins de temps par échantillon. L’automatisation des tests USP <645> de niveau 1 permet un gain de temps considérable ainsi qu’une intégrité et une sécurité accrues des données. Currently, there is no readily available automation solution for Stage 2 or Stage 3 testing.

Conductivity limits for Stage 1 range from 0.6 µS/cm at 0°C to 3.1 µS/cm at 100°C with specific conductivity requirements detailed in 5° increments. If the measured conductivity exceeds the table value, testing must proceed to Stage 2.

Stage 2 conductivity details testing procedures such as temperature adjustments, agitation, and observation in order to document the change in conductivity due to uptake of atmospheric carbon dioxide. Si la valeur mesurée est inférieure à 0,1 μS/cm par tranche de 5 minutes, la conductivité est notée. La limite de conductivité pour l’étape 2 est de 2,1 μS/cm. Conductivity measurements at this stage may be temperature-compensated to 25°C. If this limit is exceeded, testing must proceed to Stage 3.

Stage 3 is performed within five minutes of the Stage 2 conductivity determination. La température de l’échantillon est maintenue à 25±1 °C avec l'ajout de chlorure de potassium. Le pH est déterminé à l’unité de pH 0,1 la plus proche. The conductivity limit is determined at the measured pH value. pH-dependent conductivity limits range from 4.7 µS/cm at pH 5.0 to 4.6 µS/cm at pH 7.0, with conductivity requirements detailed in increments of 0.1 of pH.

Download Now: Best Practice for Analyzing Compendia Water Samples for USP <643> and <645>

Download Now: Electrical Conductivity, Temperature Dependence and Instrument Methodology

USP <645> sampling methods

As mentioned above, USP <645> regulations accommodate both online and offline (laboratory) testing.

Online testing for USP <645>

Online testing involves measuring samples using an instrument with an integrated conductivity cell. Les échantillons sont automatiquement collectés et analysés, tandis que les données sont enregistrées sans interruption, ce qui permet une surveillance continue. Cela ne s’applique qu’aux tests de l’étape 1. Stage 2 and Stage 3 testing are performed infrequently, and are not online tests.

Download Now: Conductivity and TOC Sampling Standard Operating Procedure (SOP)

Download Now: Low Level Linearity Conductivity Study

Offline or benchtop testing for USP <645>

Offline applications typically rely on portable meters or laboratory-based testing, where a quality control analyst gathers samples to perform periodic measurements. While compliant, the choice of analytical approach or instrument selection can significantly impact efficiency and data integrity.

For example, when conductivity measurements are made using a meter and probe, analysts sample and capture data manually, which increases the potential for transcription errors and reduces lab efficiency. Ces préoccupations peuvent être résolues en utilisant des instruments de laboratoire qui testent simultanément la conductivité et le carbone organique total (COT) à l’aide du même flacon d’échantillon. This approach offers significant efficiency gains, improved data integrity, and fewer opportunities for error.

USP <645> does not make specific recommendations for process development, testing location, testing frequency, or instrument selection. These choices should be based on suitability, manufacturing process, and intended use.

Download Now: Conductivity Bridge Study: From Benchtop Meter and Probe to Automated Analysis

USP <645> Conductivity validation and verification

The regulation is instrument-agnostic, but mandates cell constant verification for all methods. Additionally, the chapter does not explicitly specify verification frequency or concentration levels, but regular verification is compulsory to ensure compliance.

The cell constant must be known within ±2% accuracy and can be verified through two approaches:

Directly, using solutions of known or traceable conductivity
Indirectly, by comparing instrument readings with conductivity sensors having known or traceable cell constants

When necessary, cell constant adjustments should follow manufacturer protocols, with verification frequency determined by sensor design characteristics.

Several factors can compromise conductivity stability, with atmospheric CO2 being a primary concern. À de faibles niveaux de conductivité, les échantillons sont particulièrement susceptibles de donner des résultats erronés en raison des effets d’absorption et de désorption du CO2, qui peuvent introduire un biais de mesure involontaire. In contrast, higher-level samples are less immune to dissolved CO2 impacts but the compendial acceptance criteria of ±2% from stated values becomes more representative of actual instrument performance when using reference materials at elevated conductivity levels.

Resistance measurement calibration provides additional verification by replacing conductivity sensor electrodes with NIST-traceable precision resistors (accurate to ±0.1%). The measured conductivity with traceable resistors must fall within ±0.1 μS/cm of calculated values, requiring instruments to maintain minimum resolution of 0.1 μS/cm on the lowest range.

System verification ensures proper performance by comparing conductivity readings between the user's system and external calibrated devices. Values should be within ±5% of each other or meet acceptable differences based on water criticality and conductivity ranges, with sensors positioned to measure identical samples under the same temperature and water quality conditions.

Many companies that must comply with USP <645> go beyond basic compendial cell constant verification by implementing method suitability checks using different concentrations and acceptance criteria based on process capabilities. Ces vérifications supplémentaires ne sont pas des exigences réglementaires, mais donnent aux installations une confiance supplémentaire dans l’adéquation de l’instrument à des méthodes spécifiques. These voluntary methods are separate from mandatory compendial verifications and should not be treated as a stand-in for compendial assessments.

Can you test for conductivity at the same time as TOC?

Conductivity and TOC can be tested simultaneously from the same sample vial, but typically they require different analytical methods and instruments. The tests are compatible and do not interfere with each other when performed on the same sample.

Performing simultaneous Stage 1 conductivity and TOC testing from the same vessel requires that the vessel not contribute in any significant way to either conductivity or TOC. Additionally, the vial must minimize ionic and organic contamination for compliance with USP <645> and USP <643>.

Download Now: Lean and Efficient Labs Need Simultaneous Testing for TOC and Conductivity

Download Now: Case Study: Improved Efficiency and Lower Costs Using Simultaneous Testing for TOC and Conductivity

Learn More: Standards and Vials

Download Now: Dual Use Conductivity and TOC (DUCT) Vials

We can support you with USP <645> compliance

Our experts can provide guidance on selecting appropriate instrumentation, applying proper testing procedures, and establishing effective SOPs for documentation and compliance.

After selecting suitable and compliant technology, comprehensive instrument qualification and method validation must be completed before data can be used for making quality decisions. Notre expertise de pointe vous permet de bénéficier d’un soutien approfondi en matière de validation des méthodes et de stratégies de déploiement. With decades of specialized experience, we have refined these processes to meet the most stringent regulatory requirements while maintaining operational efficiency.

Modern efficiency improvements now enable dual testing of conductivity and TOC for compliance with USP <645> and USP <643> from a single sample using specialized vials that prevent ionic leaching and CO2 contamination. This approach enhances sample integrity while reducing analysis time, when compared to traditional methods.

Additionally, many facilities have adopted online water monitoring for real-time release testing (RTRT), eliminating the need for manual sampling and streamlining the QC process. This implementation of process analytical technology (PAT) provides immediate measurement of quality attributes and demonstrates process control in a validated state, particularly when using compatible membrane conductometric technology.

Download Now: Sievers M9: Ensuring Compliance with EP Water Monographs, EP 2.2.38, and USP <645> Conductivity Regulations

Download Now: Sievers M9 Analyzers Offer Simultaneous TOC and Conductivity Compendia Compliance Testing

Download Now: Low-Level Third-Party Conductivity Standards

Tony Saavedra, MBA: Tony Saavedra, MBA is the Life Sciences Product Manager for Veolia's Sievers Analytical Instruments product line, focusing on Sievers total organic carbon (TOC) software and instrumentation. Tony a commencé son mandat dans la gamme de produits Sievers au sein de GE Analytical Instruments en 2011 dans l’organisation des services sur site et a ensuite pris la responsabilité de diriger l’équipe des services techniques en Amérique du Nord où il a supervisé le support technique, le service en usine et les opérations de remise à neuf. Avant d’occuper son poste chez Sievers Products, Tony a servi pendant 10 ans dans l’US Navy où il a supervisé les inspections en vol et effectué des inspections d’assurance qualité et la maintenance de radars électroniques complexes et de suites de communication. Tony holds a BS in Electronic Engineering Technology from ECPI University and an MBA from Colorado State University.
Sydney Jannetta: Sydney Jannetta is a Marketing Manager at Veolia, focusing on Sievers Instruments. Sydney accompagne les clients d’instruments Sievers depuis six ans grâce à son expertise dans les applications de COT et d’endotoxines. Elle a fourni des services de développement de méthodes et d’essais de faisabilité à des fabricants de produits pharmaceutiques et a fait des présentations dans plus de 20 conférences nationales. Sydney holds a Bachelor of Science degree in Chemistry from the University of Northern Colorado..

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Résultats de recherche : Validation de la rCR sur une plateforme de test d’endotoxines microfluidiques sur plusieurs sérotypes bactériens à Gram négatif

rylee.lay@veolia.com — Thu, 15 Jan 2026 03:35:54 +0000

Research findings: Validation of rCR on a microfluidic endotoxin testing platform across multiple Gram-negative bacterial serotypes rylee.lay@veolia.com Wed, 01/14/2026 - 22:35

January 14, 2026

The pharmaceutical industry's transition toward recombinant cascade reagents (rCR) for bacterial endotoxins testing (BET) represents a significant advancement in sustainability and reliability. However, comprehensive validation across diverse endotoxin serotypes and testing platforms remains essential for widespread adoption.

In collaboration with ACC, we conducted a comparative study examining the performance characteristics of microfluidic and traditional plate-based detection methods using recombinant reagents. This research, presented at the PDA Pharmaceutical Microbiology Conference, demonstrates equivalent performance of these platforms in detecting various bacterial endotoxin serotypes, including naturally occurring endotoxins, from multiple Gram-negative bacterial sources.

Our findings provide critical validation data supporting the use of rCR technology with an advanced microfluidic platform, addressing key questions regarding serotype recovery, platform comparability, and analytical performance. Results confirm that recombinant cascade reagents achieve effective recovery and reliability across diverse endotoxins, further validating their suitability as a robust alternative to traditional Limulus Amebocyte Lysate (LAL) reagents for endotoxin testing.

Background: rCR Technology and Endotoxin Detection Methods

Recombinant Cascade Reagents (rCR) represent a sustainable alternative to traditional LAL for bacterial endotoxin testing. En tirant profit de la technologie recombinante, les rCR reproduisent l'ensemble de la cascade LAL, sans jamais dépendre des ressources dérivées de la limule. Ainsi, ils s'alignent sur les objectifs de durabilité du secteur. As adoption of rCR expands, comprehensive validation across naturally occurring endotoxins from diverse Gram-negative bacterial sources becomes increasingly critical.

This study evaluates PyroSmart NextGen® rCR performance across lipopolysaccharides (LPS) from multiple Gram-negative bacterial species using three independent commercial lots. Additionally, the investigation compares two detection platforms - the Sievers Eclipse BET Platform and traditional 96-well microplates - to assess consistency of endotoxin recovery across serotypes and evaluate each platform's performance characteristics.

Study Design: Comparison of Modern Microfluidic Platforms to Traditional Bacterial Endotoxin Testing

Study objectives:

Evaluate recovery of diverse endotoxin serotypes using ACC's PyroSmart NextGen® rCR on both the Sievers Eclipse BET Platform and 96-well microplates with Molecular Devices SpectraMax® reader
Assess platform comparability between microfluidic and traditional 96-well microplate-based detection methods
Characterize performance parameters across multiple LPS sources

Test materials:

LPS solutions created from Gram-negative microorganism strains (Microbiologics KWIK-STIKs)
Reference Standard Endotoxin (RSE) lot R172R0
PyroSmart NextGen® rCR (ACC)

Methods:

Crude lipopolysaccharide (LPS) solutions were prepared from monocultures of the following Gram-negative microorganisms:

B. cepacia, derived from ATCC® 25416™
E. coli, derived from ATCC® 8739™
P. aeruginosa, derived from ATCC® 10145™
R. pickettii, derived from ATCC® 27511™
S. enterica, derived from ATCC® 51741™
S. maltophilia, derived from ATCC® 13636™

Cultures were suspended in Water for Cell Culture (WFCC), heated, vortexed, and filtered through 0.2µM syringe filters. Les solutions ont été diluées pour atteindre les réponses cibles de 0,5-1,0 UE/mL. Tap water was also collected and diluted to the same target EU/mL.

As a control for the LPS extraction method, WFCC was heated, vortexed, and filtered via the same methodology and tested for interference and contamination. The WFCC control demonstrated equivalent performance characteristics as LAL Reagent Water (LRW) in assays.

Reference Standard Endotoxin (RSE, lot R172R0) was prepared across a concentration range of 50-0.005 EU/mL via serial dilution and tested as a standard curve contemporaneously alongside all samples.

Results and Conclusions:

BET Platform Equivalency and Performance Characteristics of rCR

This investigation confirms equivalent performance between the Sievers Eclipse BET Platform and traditional 96-well plate methodology in detecting various bacterial endotoxin serotypes, including naturally occurring endotoxins. Data validate the Eclipse platform's effective use of recombinant cascade reagents (rCR) for reliable recovery across diverse endotoxins.

The Eclipse's centripetal microfluidic technology provides operational advantages, including reduced assay time and decreased potential for errors. At a sensitivity of 0.005 EU/mL, the average reaction time for RSE on the Eclipse was 1,692 seconds, representing a 37% reduction compared to 2,687 seconds observed with the SpectraMax.

Key findings support the Eclipse platform as a compliant solution for endotoxin testing, offering:

Enhanced analytical efficiency with significant time savings
Decreased variability through automated microfluidic processing
Sustainable testing practices via rCR compatibility
Maintained sensitivity and accuracy across diverse endotoxin sources

These results contribute to the growing body of evidence supporting rCR adoption and advanced microfluidic platforms for pharmaceutical quality control applications.

Authors:

Veronika Wills: Veronika Wills directs Global Technical Service groups at Associates of Cape Cod, Inc. She joined the team in 2007 and has since become a globally recognized subject matter expert and public speaker on endotoxin and glucan testing. Sa grande expertise est vitale pour les clients d'ACC lorsqu'il s'agit d'assistance technique concernant les tests des matrices d'échantillons complexes, la résolution des problèmes, la validation des méthodes, les enquêtes et les aspects réglementaires des TEB. Plus récemment, Veronika a été très impliquée dans l'évaluation et la mise en œuvre des technologies recombinantes et leur automatisation. Veronika holds a Master's Degree in Biochemical Engineering from the Institute of Chemical Technology in Prague, Czech Republic.
Meg Provenzano: Meg Provenzano is the Global Product Manager for Sievers endotoxin instruments at Veolia. Elle possède plus de 10 ans d'expérience dans le secteur des tests d'endotoxines bactériennes et a occupé plusieurs postes liés au contrôle de la qualité, à l'assistance technique et à la gestion des produits. Avant de rejoindre Veolia, Meg était chef de produit chez Charles River Laboratories. Elle est attentive aux besoins des clients et aime résoudre les problèmes sur le terrain, qu’il s’agisse de questions techniques, d’aide à l’analyse ou de logiciels. Meg holds a B.S. in Marine Science and Biology from Coastal Carolina University where she focused on Bottlenose Dolphin population research.
Jake Vincent: Jake Vincent is the Biodetection Specialist and Advanced Lead Researcher for the Sievers R&D group at Veolia, specializing in the development of biodetection analytical instrumentation. Son rôle dans le développement de l'analyseur d'endotoxines Eclipse de Sievers fut déterminant. Jake était responsable de la conception des étalons pré-déposés et intégrés dans le consommable microfluidique. Les recherches de Jake sur la détection des endotoxines microfluidiques, « Miniaturization, Parallelization, and Automation of Endotoxin Detection by Centrifugal Microfluidics », ont été co-écrites et publiées dans Analytical Chemistry. Avant de rejoindre Veolia, Jake a travaillé au développement de méthodes analytiques pour les tests de vaccins contre le flavivirus chez Inviragen et Takeda Vaccines, notamment les essais cliniques du vaccin contre la dengue, Qdenga. He holds a B.S. from Colorado State University.

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Industrial and Environmental

Optimiser les paramètres de puissance EDI pour améliorer la qualité de l’eau extrapure (UPW)

carolynstevens — Mon, 29 Sep 2025 16:25:03 +0000

Optimize EDI Power Settings to Improve Ultrapure Water (UPW) Quality carolynstevens Mon, 09/29/2025 - 12:25

September 29, 2025

How to Optimize EDI Power Settings and Performance to Improve Ultrapure Water (UPW) Quality

Introduction: What is Electrodeionization (EDI)

Electrodeionization (EDI) is a critical process in semiconductor ultrapure water (UPW) systems that combines ion exchange (IX) resins, ion-permeable membranes, and high electric potentials to remove ionic contaminants from water. Le système fonctionne en utilisant des champs électriques pour attirer les ions à travers les résines échangeuses et à travers les membranes, purifiant simultanément l’eau et régénérant les résines. While this continuous process ensures high-quality ultrapure water through real-time monitoring and voltage control, it requires significant electrical power consumption during operation.

The Importance of Continuous Contamination Control in Microelectronics Manufacturing

Ultrapure water (UPW) quality is a critical component to semiconductor fabrication and the purity of this ingredient is directly tied to wafer yield and product quality. Even trace amounts of contaminants in UPW can cause particle deposits, metal contamination, and surface defects on wafers, leading to reduced device performance and overall quality.

Continuous monitoring and control of UPW systems with tools such as total organic carbon (TOC) monitoring and boron monitoring supports high quality fabrication. With immediate process understanding, manufacturers can respond to deviations quickly and with fewer interruptions to production.

The dynamic nature of UPW systems makes ongoing monitoring particularly important. Par exemple, lorsque les tensions du système EDI sont ajustées, il peut s’écouler une semaine ou plus avant que les niveaux de contaminants ne se stabilisent, période pendant laquelle la qualité de l’eau du système peut fluctuer de manière imprévisible. Les fabricants font face à ces périodes de transition grâce à un suivi en temps réel afin d’effectuer des ajustements constants tout en maintenant la production et la qualité des plaquettes. Without this capability, the alternative is pausing production while contamination clears the system - a costly disruption that can significantly impact manufacturing operational efficiency.

In today's competitive semiconductor landscape, continuous UPW quality control has evolved from beneficial to essential for maintaining both product quality and operational profitability.

Real-time Monitoring of EDI Effluent

A study with a semiconductor facility tracked critical contaminant levels and overall UPW quality using the Sievers Boron Online UPW Ultra Analyzer and demonstrated the complex relationship between power settings and water quality parameters. Bien qu’il ait été constaté que des réglages de puissance plus élevés éliminaient plus efficacement les contaminants comme le bore et la silice, ils ont également révélé un inconvénient inattendu : l’augmentation des tensions EDI favorisait la formation de formes ioniques de dioxyde de carbone dissous, ce qui pouvait entraîner une conductivité plus élevée dans l’eau ultrapure. This finding highlighted the delicate balance needed in EDI operations, as excessive power settings could not only increase energy costs but potentially compromise UPW quality.

The research established that EDI effluent quality is determined by three key factors:

Feedwater quality
Resin efficiency
EDI power settings

It yielded data that illustrates the relationship between EDI power and levels of boron, silica, and conductivity in the facility's effluent, and the monitoring helped engineers implement precise control strategies, remove contaminants, and optimize power consumption, ultimately achieving high water quality standards and operational cost efficiency.

Sievers Boron Ultra Online UPW Analyzer

The Sievers Boron Online UPW Ultra Analyzer serves as a critical tool in modern ultrapure water quality management systems. By delivering continuous monitoring and real-time detection, plants are able to prevent ionic contamination events before they become problematic.

Read the full details of the study here.

Learn more about UPW, the Sievers Boron Online UPW Ultra Analyzer, and the microelectronics industry on our applications page.

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Trucs et astuces : Revenir aux bases de l’analyse de la charge biologique

carolynstevens — Tue, 16 Sep 2025 17:41:14 +0000

Tips and Tricks: Going Back to the Basics of Bioburden Testing carolynstevens Tue, 09/16/2025 - 13:41

September 4, 2025

Bioburden Testing: Traditional vs Modern

What is bioburden?

Bioburden is a measurement that refers to the total number of viable microorganisms, including bacteria and fungi, present in or on products, materials, or objects. It's particularly crucial in pharmaceuticals, medical devices, raw materials, and cosmetics, since these industries must adhere to strict acceptable limits set by regulatory agencies.

Monitoring bioburden is vital. La contamination microbienne peut entraîner des risques tels qu'une efficacité moindre, des rappels de produits coûteux et, surtout, des risques pour la santé des consommateurs. Les niveaux de biocontamination sont un indicateur clé de la qualité des procédés de fabrication. They are influenced by various factors including the manufacturing environment and equipment cleanliness and condition.

How do you test for bioburden?

Bioburden testing has traditionally relied on cultivation methods that measure Total Viable Count (TVC), combining Total Microbial Count (TMC) and Total Yeast and Mold Count (TYMC), and are reported in Colony Forming Units (CFU/mL or CFU/gram). Traditional approaches include membrane filtration, direct plating (pour plate and spread plate), and Most Probable Number (MPN).

Dating back to 1905, these traditional methods provide acceptable accuracy, but their long wait times (2-7 days) make them ineffective for real-time process monitoring and timely product release. This creates a significant gap between testing and actionable results, leading to retrospective, rather than proactive, process controls.

Rapid Microbial Methods (RMMs) offer a modern solution to this gap, delivering results in hours - or even less than an hour with specific RMMs - rather than the days required by traditional methods. Toutes les MRM ne sont pas égales. Toutefois, certaines technologies de détection microbienne rapide sont bien corrélées avec le comptage sur plaques classiques. Ce choix est donc idéal pour les fabricants à la recherche de fiabilité et de rapidité. By maintaining the accuracy technicians are accustomed to while dramatically reducing wait times, these select RMMs not only accelerate the testing process but also enhance overall operational efficiency.

With near real-time data for monitoring ultrapure water and manufacturing processes, RMMs deliver substantial improvements over traditional bioburden testing, including significant time-savings for quality control labs, faster product release cycles, reduced operational costs, and enhanced overall productivity.

The combination of speed and accuracy makes switching to RMMs suitable for both laboratory and at-line applications, offering life sciences customers a way to modernize their bioburden testing without sacrificing reliability.

How fast are rapid microbial methods?

Rapid Microbial Methods (RMMs) deliver results in hours rather than days, with speeds varying by technology. Many RMMs provide results within 8 hours, while advanced systems can deliver data in under 45 minutes - compared to traditional methods that require 2-7 days.

The fastest RMM technologies, such as flow cytometry-based systems, enable precise analysis of single cells, offering near real-time results, and in certain cases, distinguishing between viable cells and abiotic particles. This represents a dramatic improvement over traditional plate-counting methods, enabling same-day decision-making instead of multi-day waiting periods for product release and quality control decisions.

What are the benefits of modern bioburden testing methods / rapid microbial methods (RMMs)?

Speed and Efficiency
- Dramatically Faster Results - Obtain bioburden data in under 45 minutes with certain RMMs, compared to 2-7 days with traditional methods
- Near Real-Time Monitoring - Enable immediate decision-making with actionable results using RMMs that correlate to conventional plate counts
- Faster Product Release - Reduce the time products are held up waiting for test results
Operational Improvements and Cost Savings
- Enhanced Lab Efficiency - Automated systems reduce manual plate counting, minimizing human error
- Improved Decision-Making - Make fast, confident decisions about manufacturing processes to reduce risk
- Remove Testing Bottlenecks - Eliminate the bioburden testing bottleneck that delays product release
- Significant Cost Savings - Reduce costly waste from process inefficiencies or discarded products
Risk Management and Quality Control
- Better Risk Management - Make faster decisions to prevent contamination issues and reduce manufacturing risks
- Enhanced Data Integrity - Certain RMMs can provide electronic records that are easily retrievable and tamper-proof, reducing transcription errors while offering comprehensive audit trails for accuracy and regulatory compliance
- Comprehensive Monitoring - Monitor critical control points in your water system with faster, automated testing that provides real-time contamination detection

Utilizing RMMs with the Sievers Soleil

The Sievers Soleil Rapid Bioburden Analyzer is a transformative rapid microbial detection system for bioburden testing in pharmaceutical manufacturing. Il fonctionne en combinant la cytométrie de flux à haut débit avec des colorants de viabilité exclusifs pour fournir des résultats de biocontamination en temps quasi réel, en corrélation avec le comptage sur plaque. Fonctionnant à 8 mL/min (bien plus rapide que les μL/min de la cytométrie en flux classique), l'analyseur fournit des résultats en moins de 45 minutes, avec une sensibilité inférieure à 10 cellules viables/100 mL, par rapport aux méthodes classiques qui nécessitent 2 à 7 jours. Le système s'appuie sur des algorithmes sophistiqués pour distinguer avec précision les particules vivantes des particules non vivantes. Ainsi, les fabricants de produits pharmaceutiques peuvent passer d'un contrôle de processus rétrospectif à un contrôle de processus proactif. This facilitates same-day actions to minimize production delays and costly operational shutdowns while improving overall risk management strategies.

Think the Sievers Soleil Rapid Bioburden Analyzer might be a good fit for your lab? Learn more about it here:

Download now: Sievers Soleil Rapid Bioburden Analyzer Infographic

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Trucs et astuces : Revenir aux fondamentaux du carbone organique total et de la conductivité

carolynstevens — Tue, 16 Sep 2025 16:02:12 +0000

Tips and Tricks: Going Back to the Basics of Total Organic Carbon and Conductivity carolynstevens Tue, 09/16/2025 - 12:02

September 4, 2025

The Fundamentals of Total Organic Carbon and Conductivity

What is Total Organic Carbon?

Total Organic Carbon (TOC) is an analytical measurement that indicates the amount of carbon found in organic compounds present in a sample, serving as a key indicator of water quality and purity in pharmaceutical and environmental testing. Le COT est essentiel, car même une contamination organique minime peut compromettre la qualité du produit et la sécurité des consommateurs. Le COT provient de sources naturelles (les plantes et les animaux) et de matériaux synthétiques (comme les produits de nettoyage, les plastiques et les pesticides). It's characterized by carbon-hydrogen bonds that can be oxidized to CO₂.

A common way to determine the amount of organic carbon in a sample is by subtracting results for Total Carbon (TC) and Inorganic Carbon (IC):

Total Carbon - Inorganic Carbon = Total Organic Carbon, or

TC - IC = TOC, where:

TC (Total Carbon): All carbon present in a sample, including organic inorganic forms.
IC (Inorganic Carbon): Carbon present in inorganic compounds (CO₂ , HCO₃ - and CO₃²-)
TOC (Total Organic Carbon): Amount of organic carbon remaining after the inorganic carbon has been removed.

USP <643> establishes standards and procedures for TOC testing in pharmaceutical grade water, specifying technology requirements, system suitability analysis, method validation parameters, and acceptance criteria to ensure water quality and purity.

What is Conductivity?

Conductivity measures a substance's ability to conduct an electrical current, indicating the presence of inorganic chemicals and salts. In pharmaceutical water testing, conductivity serves as a critical quality attribute to detect the presence of ionic species and ensure water purity.

Per USP <645>, conductivity levels must be below 1.3 μS/cm at 25 °C. Conductivity testing detects both intrinsic ions (from dissolved CO2) and extrinsic ions (such as chloride and ammonia), which can harm equipment and human health. Testing is crucial for monitoring salt and inorganic contamination.

Who tests for TOC and Conductivity?

TOC and conductivity testing applications by industry:

Pharmaceutical: Cleaning validation, Water for Injection (WFI), sterile water, and clean steam.
Microelectronics: Ultrapure water monitoring and process control
Municipalities: Drinking water quality, wastewater treatment, and stormwater management
Food & Beverage: Cleaning processes, wastewater monitoring, release water, and product consistency
Oil & Gas: Water contamination assessment and process monitoring

How do you measure and test for TOC and Conductivity?

TOC testing involves two critical steps: oxidation and detection. During oxidation, organic compounds in the sample are converted to carbon dioxide (CO₂) through established methods including high-temperature catalytic combustion or UV / persulfate oxidation (wet chemical oxidation). Different oxidation techniques are selected depending on application needs, sample matrices, or testing requirements.

The detection phase is where analytical precision becomes crucial, as CO₂ measurement accuracy directly determines TOC result reliability. Three primary detection methods include:

Non-Dispersive Infrared (NDIR) - Measures CO₂ through infrared light absorption but suffers from water vapor interference that compromises accuracy
Direct Conductivity - Measures sample conductivity before and after oxidation but is prone to various interferences
Membrane Conductometric Detection - Offers robust CO_² measurement while effectively minimizing interferences, providing the most reliable results

When accuracy and precision are non-negotiable, Membrane Conductometric technology enables confident water quality assessment and process control.

For conductivity, common testing methods include two-electrode (contacting) conductivity cells, four-electrode cells, toroidal (inductive) conductivity sensors, and in-line continuous monitoring systems, with measurements typically performed using conductivity meters that apply an A/C voltage across electrodes.

In pharmaceutical water testing, conductivity measurements are governed by USP <645>, which describes three stages of conductivity testing to ensure water meets stringent purity requirements. These measurements are captured temperature-compensated, or non-temperature-compensated conductivity, per the staged requirements in USP <645> to provide a complete assessment of water quality.

TOC and conductivity testing provide complementary measurements of water quality; TOC detects organic contamination while conductivity measures ionic and inorganic impurities, together ensuring comprehensive water purity assessment for pharmaceutical and industrial applications.

TOC and Conductivity with Sievers Analytical Instruments

To meet diverse customer needs, Veolia offers a wide variety of analyzers as part of its Sievers portfolio with different analytical ranges and suitability for specific applications, enabling comprehensive solutions across multiple industries. The Sievers Analytical Instruments product line includes advanced solutions for both TOC and conductivity testing.

For TOC and conductivity testing, the Sievers M500, M9, and M5310 C TOC Analyzers deploy membrane conductometric technology to measure both TOC and conductivity. The Sievers technology uses a proprietary gas-permeable membrane to filter CO₂ from samples into ultra-pure deionized water. Ce procédé permet une analyse sans interférence d’autres composants. The CO₂ transfer creates measurable conductivity changes that correlate to IC and TC levels, which allows users to calculate TOC levels.

The Sievers InnovOx TOC Analyzer uses innovative Supercritical Water Oxidation (SCWO), technology that combines heat, pressure, and chemical oxidizers to handle complex samples including oils and fats and other challenging substances.

Direct conductivity, employed by the Sievers CheckPoint TOC Sensor, measures samples before and after UV oxidation.

All of these methods, excluding the Sievers CheckPoint TOC Sensor, follow the fundamental principle of oxidizing organic compounds to CO2, measuring the resultant CO₂, and calculating TOC as the difference between total carbon and inorganic carbon. This approach ensures compliance with USP <643> requirements while providing accurate, interference-free detection.

Veolia has established itself as a leader in TOC analysis with its Sievers Analytical Instruments product line. To learn more about implementing TOC and conductivity testing in your operations, watch our on-demand webinar: https://www.watertechnologies.com/lp-ai-online-toc-for-cv-webinar

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Trucs et astuces : Revenir aux bases des tests d’endotoxines

carolynstevens — Tue, 16 Sep 2025 13:18:13 +0000

Tips and Tricks: Going Back to the Basics of Endotoxin Testing carolynstevens Tue, 09/16/2025 - 09:18

September 4, 2025

The Fundamentals of Endotoxin Testing

What are endotoxins?

Endotoxins are biocontaminants derived from gram-negative bacteria's outer cell membrane. Bien qu’elles ne soient pas des organismes vivants en soi, elles sont essentielles à la survie des bactéries et remplissent de multiples fonctions, notamment l’intégrité structurelle et le transport des nutriments. Endotoxins are:

Present naturally in food and water
Dangerous if entering the bloodstream
Common in raw materials and products

Endotoxins should not be confused with bacteria themselves - they are components that become harmful when separated from a bacterial cell.

Why do we test for endotoxins?

Bacterial Endotoxins Testing (BET) is crucial because endotoxins pose serious health risks when entering the bloodstream directly, bypassing normal digestive defenses. As pyrogens (substances that produce fever when introduced or released into the blood), they can cause potentially fatal drops in blood pressure, leading to organ failure, septic shock, or even death, when introduced into the bloodstream or spinal fluid.

Particularly concerning is that endotoxins persist even after sanitization; killing bacteria doesn't eliminate the toxic threat. For these reasons, testing is essential in these key areas of pharmaceutical and medical device manufacturing:

Drug production and formulation
Cleaning validation (equipment and container sanitization)
Buffer preparation
Drug reconstitution

Given endotoxins' ubiquitous nature and resistance to standard sanitization methods, rigorous BET is vital for ensuring patient safety in medical and pharmaceutical applications.

Is endotoxin testing mandatory?

Regulatory agencies like the FDA, EMA, and others require endotoxin testing to ensure products meet safety standards and do not cause pyrogenic reactions. It is mandatory for:

Pharmaceutical manufacturers producing parenteral drugs, including:
- Intravenous (IV)
- Intramuscular (IM)
- Intrathecal (IT)
Medical device manufacturers whose products contact blood
Veterinary/animal health product manufacturers producing blood-contacting items

The specific testing requirements depend on the product type, intended use, and regulatory jurisdiction.

How do you test for endotoxins?

Bacterial Endotoxins Testing (BET) primarily uses LAL (Limulus Amebocyte Lysate), derived from horseshoe crab blood. This remarkable discovery from the 1950s was standardized in the 1960s, creating a reliable endotoxins detection method.

There are three common testing approaches used today:

Deciding which method is best to use depends on several factors, including product characteristics, sensitivity requirements, and regulatory requirements.

The newest method for endotoxins testing: Microfluidic technology

The Sievers Eclipse Bacterial Endotoxins Testing (BET) Platform is a game-changing method for endotoxin testing due to its microfluidic technology that delivers significant time savings and efficiency improvements over traditional methods. Les principaux avantages comprennent une réduction de 89 % des étapes de pipetage et un temps de configuration de seulement 5 à 10 minutes. La plateforme Eclipse utilise une plaque microfluidique permettant de mélanger les échantillons avec le réactif LAL, en utilisant uniquement 1 mL de réactif LAL, soit 90 % de moins que les méthodes conventionnelles, tout en conservant la précision. The unique microplate contains embedded endotoxin standards and positive product controls (PPCs) and remains stable at room temperature for up to 25 months, eliminating expensive cold storage requirements.

Other unique capabilities of the Eclipse Platform include remote data review, minimal laboratory space and training requirements, and reduced failure rates. Les résultats sont mesurés en unités d’endotoxine (EU), 1 EU équivalent approximativement à 1 partie par billion (ppt). While LAL's biological nature typically requires users to prepare standard curves, PPCs, negative controls, and samples for each assay, the Sievers Eclipse significantly simplifies this process - users only need to add water and samples to the appropriate segments, as the standards and controls are already embedded in the microplate.

While traditional testing approaches work, newer microfluidic technology offers a more efficient, reliable, and cost-effective method for endotoxin testing while still ensuring regulatory compliance. La technologie microfluidique offre également aux utilisateurs une grande flexibilité dans le choix des réactifs, qu’ils choisissent le LAL traditionnel ou le réactif en cascade recombinant (rCR). This modern technology, combined with recombinant reagents, represents a key opportunity to achieve both efficiency gains and sustainability goals in endotoxin testing.

Learn more about bacterial endotoxins testing, LAL, rCR and the Sievers Eclipse BET Platform by watching a quick on-demand webinar: https://www.watertechnologies.com/lp-ai-usp-86-webinar

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Industrial and Environmental

Optimiser les performances des chaudières grâce à la surveillance du COT : comment la surveillance des matières organiques protège l’équipement et la rentabilité tout en augmentant l’efficacité des chaudières

carolynstevens — Thu, 04 Sep 2025 15:49:01 +0000

Maximizing Boiler Performance with TOC Monitoring: How Organics Monitoring Protects Equipment and Profitability While Increasing Boiler Efficiency carolynstevens Thu, 09/04/2025 - 11:49

September 4, 2025

Boiler systems are an integral part of countless industrial facilities across the world, from power plants and refineries to food & beverage operations and chemical processing facilities. Qu’il s’agisse de produire de l’électricité pour les communautés ou de soutenir des processus de fabrication essentiels, ces systèmes de production de vapeur ont besoin d’une eau extrapure exempte de contaminants organiques pour fonctionner efficacement et en toute sécurité. However, maintaining equipment uptime and preventing unplanned costs are critical to preserving profitability and operational control in these competitive industries.

Water chemistry and boiler system performance

Proper boiler water chemistry is essential for preventing scale formation and corrosion, which can lead to costly equipment failure and unplanned shutdowns. Avec les températures et les pressions élevées inhérentes aux cycles eau-vapeur, même des traces de composés organiques peuvent se dégrader en acides organiques et accélérer les dégâts. Contaminants such as sugars, cleaning agents, cooling fluids, or organic acids are often present at low levels and remain undetected by traditional monitoring methods, creating hidden risks that can result in catastrophic failures.

Contamination: Sources and real-world incidents

These contaminants can originate from various sources - CO2 corrosion typically stems from issues within the boiler feedwater system itself, while glycol contamination often results from external leaks in associated heat exchangers or chiller systems. For example, CO2 entering through feedwater leads to generalized metal loss, while glycol leaks from cooling systems can contaminate steam condensate and cause severe fouling.

Recent incidents at major facilities underscore these risks. Des fuites de glycol ont forcé la fermeture de plusieurs installations, tandis qu’une importante raffinerie du Texas a subi une contamination par les condensats de vapeur et un encrassement de la chaudière qui ont entraîné des arrêts imprévus et des pertes financières importantes. For plant managers across these industries, implementing robust contamination detection systems isn't just about maintenance - it's about protecting profits, preventing shutdowns, and ensuring reliable operations.

Traditional monitoring techniques including pH and conductivity often fail to detect many common contaminants. Les fuites de glycol, par exemple, ne sont pas détectées en raison de leur état non ionique à température et pression ambiantes. Unfortunately, these methods don't alert operators to organic acid degradation until damage has already occurred.

Monitoring total organic carbon (TOC) in boiler water provides a proactive solution for detecting contamination and optimizing processes. Le COT sert de mesure de premier plan pour indiquer les problèmes potentiels de corrosion et d’intégrité du système avant que des conséquences néfastes ne se produisent, ce à quoi les méthodes de surveillance traditionnelles échouent souvent. La surveillance du COT a permis d’identifier la contamination au glycol dans les centrales électriques, entrainant une maintenance proactive qui ont évité des arrêts coûteux. Similarly, continuous TOC monitoring at industrial facilities enables real-time detection of contamination events, protecting capital equipment and enhancing production uptime.

Maximizing condensate reuse through effective monitoring

Reusing condensate from industrial processes carries inherent contamination risks, but these risks and their financial implications can be effectively mitigated with online organics monitoring. Accurate assessment of condensate quality not only provides opportunities to detect leaks and prevent fouling, but also impacts operational decisions - enabling maximum reuse while reducing costs associated with producing additional make-up water and wastewater treatment.

The Sievers InnovOx TOC Analyzer addresses these critical monitoring needs with reliable online organics detection using advanced supercritical water oxidation technology. Cette méthode d’oxydation éprouvée permet d’atteindre une efficacité d’oxydation de plus de 99 %. Le COT peut ainsi être mesuré avec une exactitude et une précision supérieures sur l’ensemble des contaminants potentiels. En offrant une visibilité en temps réel sur la qualité de l’eau de chaudière, l’InnovOx permet d’optimiser les performances, de réduire les maintenances non planifiées et d’augmenter la rentabilité. To learn more about how the Sievers InnovOx TOC Analyzer can help your boiler water system needs, read our application note.

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Learn more about the Sievers Eclipse

Principales conclusions : tests d’endotoxines bactériennes à l’aide de réactifs recombinants et d’une technologie microfluidique innovante

rylee.lay@veolia.com — Fri, 15 Aug 2025 18:29:29 +0000

Key Findings: Bacterial Endotoxins Testing Using Recombinant Reagents and Innovative Microfluidic Technology rylee.lay@veolia.com Fri, 08/15/2025 - 14:29

August 13, 2025

We collaborated with Eli Lilly to present research on recombinant reagents and microfluidic technology for Bacterial Endotoxins Testing (BET) at the Parenteral Drug Association (PDA) Pharmaceutical Microbiology Conference.

Our findings, based on real-world sample data, demonstrate the accuracy and reliability of recombinant agents on modern microbiological detection platforms. Jay Bolden and Hayden Skalski present research at PDA Microbiology Conference.

Jay Bolden and Hayden Skalski present research at PDA Microbiology Conference

Background: Limulus Amebocyte Lysate (LAL) vs. recombinant cascade reagents (rCR) in microfluidic BET assays

Pharmaceutical companies are increasingly adopting innovative technologies to meet evolving regulatory expectations while building more sustainable operations. Les tests d’endotoxines sont un excellent exemple de ce changement, car les pressions réglementaires et de durabilité transforment le paysage des TEB. Annex 1 encourages technological advancement to streamline manufacturing processes, and the recent publication of USP <86> on recombinant reagents for endotoxin testing represents a key opportunity to achieve both regulatory compliance and sustainability goals.

For these reasons, Veolia, in partnership with Eli Lilly, conducted a comparison study using the Sievers Eclipse Bacterial Endotoxins Testing (BET) Platform to compare results between traditional Limulus Amebocyte Lysate (LAL) and newer recombinant cascade reagents (rCR). La plateforme utilise la microfluidique et la force centripète ; elle permet de configurer les tests en 85 % du temps nécessaire à la configuration d'une microplaque traditionnelle à 96 puits ; elle utilise jusqu'à 90 % moins de LAL ou de rCR ; et elle automatise l'administration du LAL aux échantillons. Beyond increasing efficiency, it assures precise and accurate results, allowing manufacturers to meet Annex 1 and sustainability goals while remaining in full compliance with regulations to assure patient safety.

This research outlines the results of the endotoxin tests with data obtained from real-world samples, providing a practical comparison between the two reagent types.

Comparison Study: Detecting naturally occurring endotoxins (NOE) and Reference Standard Endotoxin (RSE)

The purpose of this study was driven by two objectives. L’objectif principal était d’évaluer la détection et la récupération des endotoxines naturelles (NOE) et de l’eau purifiée dopée avec de l’endotoxine standard de référence (RSE). This evaluation was conducted using two different testing methods: traditional Limulus Amebocyte Lysate (LAL) and recombinant Cascade Reagent (rCR), with the goal of demonstrating reliable endotoxin recovery across both testing platforms.

Secondly, these capabilities were validated on the Sievers Eclipse BET platform by challenging it with both types of reagents. This validation was particularly significant as it aimed to demonstrate the system's suitability for real-world sample testing while offering two substantial benefits: a 90% reduction in reagent consumption and the option to use recombinant reagents, thereby promoting more sustainable testing practices in the industry.

Samples: rCR comparison study of 12 sample types

The following samples were used in the comparison study between Limulus Amebocyte Lysate (LAL) and recombinant Cascade Reagents (rCR):

Two monoclonal antibodies
Insulin
Peptide
NOE (see Figure 1)
Histidine and Sodium Acetate
LRW
Purified Waters
Purified Waters with RSE spikes
Polysorbate 80
Counterfeit products
Components (stopper, cartridge)
Yeastolate

Figure 1: Comparison of Naturally Occurring Endotoxins (NOE)

Results: LAL vs rCR - Performance and testing results

The following figure details Positive Product Control (PPC) recovery rates of sample and reagents.

Figure 2: Percent Recovery Comparison of Sample and Reagent

Conclusion: rCR performance in microfluidic platforms

This study showed equivalent performance between LAL and rCR using the Sievers Eclipse for the detection of bacterial endotoxins in real-world samples, as well as naturally occurring endotoxins. Based on the evidence, it can be determined that the Sievers Eclipse Bacterial Endotoxins Testing Platform is able to successfully utilize recombinant Cascade Reagents, provided that the sample's compatibility has been verified.

Automation via the Eclipse's centripetal microfluidic platform offers the simplest form of BET microfluidics available, providing significant time savings and reducing opportunities for error. With the availability of this innovative technology, BET assays can be streamlined while remaining fully compliant with compendia.

Benefits include:

USP <85> and <86> compliant
Proven to work with both LAL and rCR reagents
Up to 90% less reagent needed; aids in sustainability initiatives
27 total pipetting steps for 21 samples for increased efficiency
Innovative technology aligned with Annex 1 guidelines

Authors:

Jay Bolden: Jay Bolden is a Senior Director in the Eli Lilly and Company global Analytical Quality Control Organization. Il est un expert en endotoxines bactériennes et dirige une équipe chargée de superviser le contrôle qualité mondial des méthodes de test des endotoxines, de la microbiologie et de la virologie. Jay est titulaire d’une licence en biologie et d’un certificat en études environnementales de l’Université de l’Indiana et possède plus de 25 ans d’expérience dans l’industrie dans les domaines du développement, de la microbiologie des procédés et des laboratoires, ainsi que de la direction de laboratoires de microbiologie. Jay est membre du comité d’experts en microbiologie de la pharmacopée des États-Unis et est l’auteur d’un chapitre de livre et de plusieurs articles évalués par des pairs sur les endotoxines. Accordion content 1.
Meg Provenzano: Meg Provenzano is the Global Product Manager for Sievers bio-detection instruments at Veolia. Elle possède plus de 10 ans d'expérience dans le secteur des tests d'endotoxines bactériennes et a occupé plusieurs postes liés au contrôle de la qualité, à l'assistance technique et à la gestion des produits. Avant de rejoindre Veolia, Meg était chef de produit chez Charles River Laboratories. Elle est centrée sur le client et aime résoudre les problèmes de manière pratique, qu'il s'agisse de questions techniques, d'assistance pour les analyses ou de logiciels. Meg holds a B.S. in Marine Science and Biology from Coastal Carolina University, where she focused on Bottlenose Dolphin population research.
Brian Short: Brian Short is a Global Pharmaceutical Application Specialist at Veolia, providing strategic pharmaceutical biodetection and TOC application support for the life science industry. Avec 20 ans d’expérience de travail dans et avec des laboratoires de contrôle de la qualité pharmaceutique, Brian a supervisé et soutenu de grands volumes d’essais en cours de fabrication et de produits finis. Ayant précédemment occupé des postes chez Wyeth et Lonza, et fort de neuf ans d’expérience dans le soutien de la gamme de produits Sievers au sein de GE Analytical Instruments, SUEZ et maintenant Veolia, Brian possède une expertise approfondie des instruments et des logiciels de détection des endotoxines, y compris l’installation, la qualification et la formation. Brian holds a Bachelor of Science degree in Biological Sciences from York College of Pennsylvania.
Hayden Skalski: Hayden Skalski is the Life Sciences Product Application Specialist for Veolia, specializing in bacterial endotoxins testing (BET). Hayden a plus de 10 ans d’expérience dans l’industrie pharmaceutique et le contrôle de la qualité microbiologique et a fait des présentations sur de nombreux sujets entourant les tests d’endotoxines. Auparavant, Hayden a occupé des postes chez Charles River Laboratories, Regeneron et Novartis, où il a validé et exécuté des protocoles de développement de méthodes pour les tests d’endotoxines, en assurant l'assistance à la clientèle, le dépannage et la prise en charge des tests de produits en grand volume. Hayden est titulaire d’un B.S. de l’Université d’Albany (SUNY) en biologie. Kelly Smith est biologiste principal au sein de l’organisation mondiale de contrôle de la qualité analytique d’Eli Lilly and Company. He is a bacterial endotoxins subject matter expert with over 25 years of industry experience and has a B.S. in chemistry from Butler University.
Kelly Smith: Kelly Smith is a Senior Principal Biologist in the Eli Lilly and Company global Analytical Quality Control Organization. He is a bacterial endotoxins subject matter expert with over 25 years of industry experience and has a B.S. in chemistry from Butler University.

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USP <643> « Carbone organique total »

rylee.lay@veolia.com — Tue, 12 Aug 2025 04:32:46 +0000

USP <643> "Total Organic Carbon" rylee.lay@veolia.com Tue, 08/12/2025 - 00:32

August 11, 2025

What is USP <643> and why does it matter?

USP <643> is a general chapter in the United States Pharmacopeia that provides guidance on measuring total organic carbon (TOC) in pharmaceutical waters. Il fournit une méthode normalisée pour mesurer le COT, garantissant que l’eau pharmaceutique répond aux normes de pureté requises. By measuring TOC, pharmaceutical manufacturers can detect contamination or determine quality and purity of the water used in the manufacturing process, all of which can impact product quality and safety.

TOC serves as one of a pair of essential chemical limit tests for validating chemical control in water purification systems. It is used in conjunction with USP <645> Water Conductivity testing, which specifically measures ionic contaminants, to ensure water quality standards are met.

Who is impacted by USP <643>?

Some of the industries and sectors impacted by USP <643> are:

Pharmaceutical and biopharmaceutical manufacturers, including research and development and ingredient manufacturers
Medical device manufacturers
Contract testing and quality control laboratories
Water purification system and instrument manufacturers
Some healthcare and veterinary facilities

Note: This list is not exhaustive.

USP <643> guidance and regulation overview

The chapter provides guidance on TOC measurement technologies and methodologies. Bien qu’il n’approuve pas de processus ou de technologies spécifiques, il exige que les méthodes soient capables de faire la distinction entre le carbone inorganique et le carbone organique. Cette distinction peut être réalisée soit par mesure indirecte - en déterminant le carbone inorganique et en le soustrayant du carbone total - soit par mesure directe - en purgeant le carbone inorganique avant l’oxydation. TOC testing can be performed either online or as an off-line laboratory test.

The guidance also clarifies that TOC measurements, while capable of detecting organic materials that could support microbial growth, cannot substitute for endotoxin testing or microbiological control methods. Although organic carbon may function as a potential nutrient source for microorganisms, TOC levels do not directly correlate with microbiological activity in a quantifiable way.

USP <643> for bulk purified water

For bulk purified water, the chapter outlines requirements that include:

Instrumentation with detection limit of ≤ 0.05 mg/L (0.05 ppm)
Use of reagent water with TOC level of ≤ 0.10 mg/L
Preparation procedures for containers and labware to reduce or prevent contamination

System suitability testing is used to demonstrate the suitability of the instrument for TOC monitoring. Les utilisateurs doivent déterminer la fréquence d’adéquation du système en fonction de la criticité de l’évaluation des risques liés aux applications et aux processus. Le règlement définit une solution facile à oxyder (USP Saccharose Rs) et une solution difficile à oxyder (USP 1,4-Benzoquinone Rss) afin de démontrer l’adéquation de l’instrument avec une gamme de composés. It should be noted, good manufacturing practices (GMP) are important for accuracy of solution preparation, as improperly prepared solutions could contribute to suitability failures and lead to additional investigations.

USP <643> for sterile waters derived from bulk purified water

For sterile water, USP <643> establishes more stringent limits and testing requirements, such as water for injection (WFI) or ingredient water as part of inhalation or irrigation products. Étant donné que ces produits ont un accès direct à la circulation sanguine ou au système respiratoire, les risques associés à la contamination sont nettement plus élevés. Les contaminants organiques contenus dans ces produits peuvent entraîner des réactions indésirables graves, des infections ou des réactions toxiques. De plus, les composés organiques présents dans ces eaux pourraient interagir avec les produits pharmaceutiques, ce qui pourrait nuire à leur stabilité, à leur efficacité ou à leur innocuité. Le chapitre détaille des limites de détection d’instruments plus strictes pour les eaux stériles et comprend des procédures spécifiques pour la manipulation et l’analyse des échantillons. It also provides guidance for preparing system suitability and standard solutions for each category of container volume.

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Download now: USP <643> Sterile Water Testing Protocols: Implementing TOC Analysis for USP Compliance

USP <643> for sampling, instrumentation, procedures, and system suitability

The chapter details requirements for sampling, including proper container preparation, procedures for collecting representative samples, and sample handling.

Instrumentation requirements include regular demonstration of instrument suitability, specific detection limit requirements for both bulk and sterile water, and options for both online and off-line testing.

Procedures must be detailed and documented to include step-by-step testing and calculations for calibration, system suitability and sample analysis.

System suitability requirements include the use of specified reference standards, calculation of response efficiency, acceptance criteria as well as requirements for periodic verification of system performance.

Download Now: Comparison of TOC Analyzers and Sensors for Pharmaceutical TOC Applications

USP <643> and process verification

Process verification involves:

Demonstration of system suitability testing with an 85-115% response efficiency
Use specified reference standards (USP 1,4-Benzoquinone RS, and USP Sucrose RS)
Periodic demonstration of instrument suitability
Reagent water control must use water with TOC level ≤ 0.10 mg/L for bulk water testing and may require conductivity testing to ensure method reliability
Sample container choice and preparation must document cleaning procedures and verification so as not to introduce contamination

Download now: Selecting the Best TOC Sample Vial for Your Application

USP <643> does not make specific recommendations for the following:

Process development: Organizations must ensure that sampling is truly representative of water quality
Location: Testing can be performed either online, at-line, or in a laboratory
Instrumentation: The choice should be based on suitability, manufacturing process, and intended use

Facilities must balance efficiency and other operational demands when implementing USP <643> guidelines, making compliance uniquely challenging for every organization.

Download now: Best Practice for Analyzing Compendia Water Samples for USP <643> and <645>

We can support you with USP <643> compliance

Working with experienced partners who specialize in TOC testing and water system monitoring can help address any challenges you have when implementing USP <643>, as well as USP <645> Conductivity Testing. Our experts can provide guidance on selecting appropriate instrumentation, applying proper testing procedures, and establishing effective SOPs for documentation and compliance.

Modern efficiency improvements now enable dual testing of TOC and conductivity for compliance with USP <643> and <645> from a single sample using specialized vials that prevent ionic leaching and CO2 contamination. This approach enhances sample integrity while reducing analysis time compared to traditional methods.

Additionally, many facilities have adopted online water monitoring for real-time testing (RTT), eliminating the need for manual sampling and streamlining the QC process. This implementation of process analytical technology (PAT) provides immediate measurement of quality attributes and demonstrates process control in a validated state, particularly when using compatible membrane conductometric technology.

For more information about TOC compliance, transitioning to real-time testing, or improving efficiency of USP <643> TOC testing.

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