Author: Aden May

Why Pharmaceutical Dissolution Stability Testing Fails: Lessons from Three SAHPRA Recalls

Three products.
Three SAHPRA-approved recalls.
Three dissolution failures that only appeared months after the batches had been released and distributed.

Lasix 80mg failed dissolution at six months. Lumont 10mg failed at twelve months. Cipla-Pioglitazone failed during ongoing stability monitoring. In every case the product passed initial release testing. In every case patients had already received it.

This is the central challenge of pharmaceutical dissolution stability testing: the conditions that cause a product to fail are often invisible at release and only become measurable after months of storage. When the dissolution testing method itself introduces uncontrolled variables, through manual sampling, inconsistent vessel setup or inadequate hydrodynamic control, failures become harder to detect and impossible to defend.

Why do products pass release testing and fail dissolution at stability?

The apparatus controls the dissolution conditions. It does not control what happens to the drug product during storage. That distinction is where most stability failures originate.

Three different storage mechanisms triggered three different failure modes in these recalls. Understanding each one is the starting point for building a dissolution programme sensitive enough to catch them before they become a market withdrawal.

What caused three SAHPRA dissolution stability failures?

Lasix 80mg: furosemide surface passivation

Sanofi Aventis South Africa recalled batch CG022A after dissolution dropped below 80% at 60 minutes at the six-month stability interval. Furosemide is a BCS Class IV drug with dissolution critically dependent on available surface area. During ambient storage, the tablet surface undergoes recrystallisation, converting to a more thermodynamically stable crystalline form that increases hydrophobicity, raises liquid contact angle and progressively retards media penetration. Invisible at release. Measurable at six months.

Lumont 10mg: montelukast excipient matrix hardening

Zydus Healthcare SA recalled Lumont 10mg after out-of-specification dissolution results at the 12-month time point under 30°C and 75% RH long-term conditions. The polymer excipient matrix undergoes cross-linking during extended storage at elevated temperature and humidity. Cross-linking increases structural rigidity, reduces water diffusion rates into the tablet core and creates a denser outer boundary that restricts media penetration. Drug release slows progressively and at month twelve it had slowed below specification.

Cipla-Pioglitazone: particle agglomeration and hydrodynamic dead zones

Pioglitazone is a BCS Class II drug with dissolution dependent on particle size and vessel hydrodynamics. During storage, particles agglomerate, clustering into larger masses that reduce total surface area. In a USP Apparatus 2 vessel those agglomerated masses settle into the near-zero velocity zone beneath the paddle shaft where fluid shear is insufficient to break them apart. Drug release drops. The result is a cone of undissolved material at the vessel base and an out-of-specification stability profile.

 

Why uncontrolled testing variables amplify stability failures

What connects all three recalls is not just the storage mechanism. It is the sensitivity of the dissolution method to detect the developing failure at the earliest possible time point.

Manual sampling introduces timing offsets between vessels. Variable cannula depth changes the concentration gradient at withdrawal. Inconsistent filtration alters the apparent dissolved fraction. Vessel misalignment and imprecise paddle height affect the hydrodynamic pattern within the vessel, including the stagnant zone directly implicated in the pioglitazone failure.

In a formulation where dissolution is already marginal, an uncontrolled testing variable is the difference between catching a failure at six months and missing it entirely until the batch has been on the market for a year.

 

Controlled dissolution testing for pharmaceutical QC: Agilent 708-DS dissolution apparatus

For stability programmes, instrument-level variables must be controlled with the same rigour at month twelve as they are at initial release. The Agilent 708-DS addresses this directly.

TruAlign vessels provide repeatable vessel-to-shaft centering, eliminating the asymmetric hydrodynamic profiles that contribute to stagnant zone formation and cone effect. AutoTemp in-vessel temperature monitoring confirms media temperature is maintained throughout the run. Programmable sampling depth eliminates vessel-to-vessel insertion depth variation. Dissolution Workstation Software provides electronic documentation and audit trail capability for 21 CFR Part 11 compliant environments.

 

Agilent 708-DS

Automated sampling for reproducible stability data: Agilent 850-DS dissolution sampling station

The 850-DS removes the manual variables that amplify dissolution failures in stability testing. Automated withdrawal timing ensures every time point is sampled at the exact programmed interval across all six vessels simultaneously. Automated needle positioning ensures identical sampling depth at every vessel at every time point. Inline filtration at 0.2 or 0.45µm eliminates sample preparation variation from manual filter handling.

For the furosemide, montelukast and pioglitazone dissolution methods specifically, automated sampling is not a convenience. It is a methodological requirement. Detecting a developing stability failure before it becomes a recall requires a testing platform that removes the noise introduced by manual handling.

Practical resource: Agilent 850-DS product page

Speak to a Chemetrix specialist about configuring the 850-DS for your stability sampling volumes, filtration requirements and downstream analytical method.

Agilent 850-DS

📥 Explore the full Agilent dissolution testing portfolio
Agilent dissolution testing resources

Passing release testing is the beginning of compliance, not the end of it

Three recalls. Three different storage mechanisms. One shared failure: a dissolution testing methodology not designed to detect the failure early enough to prevent it.

The analysts who run stability dissolution programmes deserve a workflow that is built to detect what needs to be detected; not a manual sampling process that introduces enough variability to mask a developing failure until it’s too late.

Chemetrix works with pharmaceutical QC labs across Southern and East Africa to design dissolution testing programmes built around the sensitivity and reproducibility that stability monitoring actually requires. The goal is dissolution data that defends the product at every stability time point, not just the first one.

Build your stability dissolution programme around the results you need to defend

Before your next stability pull, work through four questions:

  1. Does your method control vessel centering, paddle height and sampling depth reproducibly across analysts and time points?
  2. Are your stability time points sampled within the required interval across all six vessels simultaneously?
  3. Is your filtration consistent enough to distinguish a genuine dissolution change from a methodological artefact?
  4. Does your audit trail support a SAHPRA inspection or GMP compliance review?

Speak to a Chemetrix specialist about your stability dissolution programme:

  • Pharmaceutical QC labs: apparatus qualification, stability method validation and automated sampling configuration for SAHPRA GMP compliance
  • Generic drug development labs: dissolution method development and bioequivalence stability testing for BCS Class II and IV compounds
  • Contract testing labs: high-throughput stability dissolution workflows with HPLC integration and LIMS connectivity
  • Regulatory affairs and QA teams: dissolution data integrity review and method robustness assessment ahead of SAHPRA submissions

Your dissolution data is only as reliable as the stability programme behind it.

TL;DR

Lasix 80mg, Lumont 10mg and Cipla-Pioglitazone all passed initial release testing. All three were recalled from the South African market after dissolution failures at 6 or 12-month stability intervals. The root causes were different in each case but the pattern is the same: subtle physical changes during storage interact with uncontrolled dissolution testing variables to produce results that passing release testing cannot predict. Automated, end-to-end dissolution workflow control is the primary defence.

Pharmaceutical Dissolution Testing: Why Sampling Causes More Variability than the Apparatus

The dissolution apparatus has been validated. Media temperature is correct. Paddle speed is set. Everything looks right. And yet results from one analyst to the next are not as consistent as they should be.

This is one of the most common and least-discussed problems in pharmaceutical dissolution testing. The problem is almost never the apparatus. It is almost always what happens next: the sampling.

Dissolution testing determines how an active pharmaceutical ingredient is released from a dosage form under defined conditions. A failed or inconsistent result can delay batch release, trigger a data investigation and consume analyst time that could be spent elsewhere. When that variability traces back to sampling rather than the product itself it is a workflow problem, not a formulation problem. And it’s a solvable one.

Why does pharmaceutical dissolution testing produce variable results even when the method
is correct?

The apparatus controls the dissolution conditions. It does not control what happens when the sample leaves the vessel. That distinction is where most labs have a gap.

Manual sampling introduces variability at five distinct points: when the sample is taken, where in the vessel it is withdrawn from, how much is collected, how it is filtered and transferred, and how consistently that process is repeated across multiple vessels and time points. In extended-release products requiring sampling over several hours the opportunity for cumulative variation is significant.

The result is a dissolution profile that reflects the sampling process as much as the drug product itself. Chemetrix consultants see this pattern consistently across pharmaceutical QC labs: unexplained batch-to-batch variation traced back not to formulation but to manual sampling steps that were never formally controlled.

Dissolution testing explained

Every oral dosage form that reaches a patient has been through dissolution testing. The test simulates conditions the drug encounters in the body, exposing the finished product to a defined volume of media at controlled temperature and stirring speed, then measuring API release at defined time points.

Those results determine whether a batch is released for patient use. They underpin bioequivalence decisions in generic drug development and support regulatory submissions across USP, EP and JP pharmacopoeial frameworks. They are used throughout the product life cycle from R&D through to routine QC.

When dissolution data is compromised by sampling variability the consequences extend beyond a failed batch. They reach into data integrity queries, audit findings and regulatory submissions built on data that does not accurately reflect the product. The analytical lab’s responsibility is to produce dissolution data that reflects the drug, not the process of collecting the sample.

 

How can pharmaceutical QC labs reduce analyst-to-analyst variation in dissolution sampling?

Remove the manual steps. Not because analysts are careless but because repetitive manual sampling across six vessels at five or more time points is an inherently variable process regardless of analyst experience.

The labs that achieve the most consistent dissolution data are not necessarily the ones with the most skilled analysts. They are the ones that have replaced analyst-dependent sampling variables with automated controls. When timing, withdrawal position and filtration are managed by the sampling station the analyst is freed to review data, prepare subsequent runs and apply scientific judgement where it actually matters.

This is what Chemetrix means by treating dissolution as an end-to-end workflow. The apparatus handles dissolution conditions. The sampling station handles the rest. Both need to be
designed together.

Controlled dissolution testing for pharmaceutical QC: Agilent 708-DS dissolution apparatus

The Agilent 708-DS is the established platform for pharmaceutical dissolution testing across oral solid dosage forms, topicals, implants, transdermal patches and medical devices. It conforms to international pharmacopoeial specifications for Apparatus 1, 2, 5 and 6 and accommodates tablets, capsules, transdermal and semisolid formulations.

Key features that directly address variability at the apparatus level include TruAlign vessels for repeatable vessel orientation, motorised lift for integration with automated sampling systems, AutoTemp in-vessel temperature monitoring to confirm media conditions throughout the run and programmable sampling depth to eliminate vessel-to-vessel inconsistency in withdrawal position. The optional Dissolution Workstation Software provides electronic documentation of test parameters and audit trail capability for 21 CFR Part 11 compliant environments.

For labs requiring online UV analysis, the 708-DS pairs with the Agilent Cary 60 UV-Vis Spectrophotometer in multicell and fiber optic configurations enabling real-time dissolution profile monitoring without manual sample withdrawal at each time point.

Speak to a Chemetrix specialist about configuring the 708-DS for your specific dosage form and regulatory requirements.

Agilent 708-DS

Automated dissolution sampling for regulated pharmaceutical labs: Agilent 850-DS dissolution sampling station

The Agilent 850-DS Dissolution Sampling Station automates what the apparatus cannot control. It manages withdrawal timing, sampling position, filtration and sample collection into test tubes, HPLC vials or 96-well plates depending on the downstream analysis method.

For labs running HPLC analysis, samples collected by the 850-DS into Agilent HPLC trays can be placed directly into the HPLC autosampler without manual vial transfer. A validated end-to-end workflow demonstrated with multidrug capsules containing four APIs at different concentration ranges showed that the full sequence from dissolution sampling through LIMS integration to HPLC measurement and result reporting can be completed with minimal manual intervention. Barcoded vials scanned into the LIMS were automatically linked to vessel and time point data, passed to Agilent Sample Scheduler software and submitted to the LC instrument without the analyst managing the sequence manually.

The 850-DS includes an integrated syringe pump, optional filtration module for 0.2 or 0.45 µm filtration, variable pump speeds for different media types including surfactants, automated cleaning cycle and user access level controls to prevent unauthorised method changes.

Speak to a Chemetrix specialist about configuring the 850-DS for your sampling volume, filtration requirements and downstream analytical method.

Agilent 850-DS

📥 Explore the full Agilent dissolution testing portfolio

Dissolution data quality is a workflow decision, not just an instrument decision

There is a mindset Chemetrix consultants encounter regularly: that some variability between analysts or time points is an acceptable part of dissolution testing. That the apparatus is doing its job and the rest is just the nature of manual work.

It is not acceptable. Not when the data produced determines whether a product reaches a patient. The analysts running dissolution tests day after day under time pressure and throughput demands deserve a workflow that sets them up to produce reliable data consistently, not a process that makes accuracy dependent on replicating the previous analyst’s technique.

The labs that consistently produce defensible dissolution data treat sampling as a controlled variable from method design stage. They invest in the workflow that connects the apparatus to the result. Chemetrix works with pharmaceutical QC labs to design and supply that complete workflow, from instrument selection and qualification through to sampling automation and data management. The goal is dissolution data you can defend, not variability you have learned to explain.

How to diagnose dissolution sampling variability in your lab

Before assuming the problem is the product, work through four questions:
  1. Where is variability entering your sampling process? Timing, position, volume or filtration?
  2. Are your sampling time points being hit consistently across all vessels?
  3. How many manual transfer steps exist between the dissolution vessel and your analytical instrument?
  4. Does your current documentation trail support a 21 CFR Part 11 or GMP audit?
Speak to a Chemetrix specialist about your dissolution workflow:
  • Pharmaceutical QC labs: apparatus qualification, automated sampling configuration and Dissolution Workstation Software for 21 CFR Part 11 compliance
  • Contract research and testing labs: high-throughput dissolution workflows with HPLC integration and LIMS connectivity
  • Generic drug development labs: bioequivalence dissolution method development and semi-automated sampling for extended-release formulations
  • Compounding and hospital pharmacy labs: small-volume dissolution testing and method validation support for non-standard dosage forms

TL;DR

Most pharmaceutical labs assume that once the dissolution apparatus is correctly set up the test is essentially controlled. In practice sampling is where the majority of variability enters the workflow. Timing errors, inconsistent withdrawal depth and manual filtration steps all introduce analyst-to-analyst variation that the apparatus itself cannot prevent. The Agilent 708-DS Dissolution Apparatus combined with the 850-DS Dissolution Sampling Station automates these critical steps to produce more consistent reproducible dissolution data with significantly less manual intervention.div

The Crippled Treatment Works

A municipal district in Gauteng plunges into a public health emergency. Dozens of lives lost, hundreds hospitalised, local food producers forced to halt production over unpotable water, and a municipality facing serious legal and compliance liability over a failing utility grid.

This isn’t a hypothetical. It’s the pattern behind real waterborne disease outbreaks linked to wastewater infrastructure failure and at the centre of it is a testing gap that’s entirely preventable.

By the time legacy laboratory methods confirm contamination, the public has often already consumed the water. This matters for every lab and utility responsible for drinking water safety, because the difference between catching contamination in hours versus days is the difference between an isolated incident and a catastrophe.

What happens when a wastewater treatment plant fails?

An over-capacitated, poorly maintained wastewater treatment plant operating far above its design limits doesn’t just underperform, it actively becomes the source of the crisis. Instead of discharging treated, compliant effluent, the dysfunctional plant releases millions of litres of partially treated sewage directly into the river system feeding a downstream drinking water purification plant.

This is rarely a sudden failure. It’s the result of ageing infrastructure, deferred maintenance, and a system running past its intended capacity for years before the consequences become visible at the tap.

 

How does E. coli contamination escalate from “manageable” to “catastrophic”?

The daily reality of this kind of failure isn’t measured in headlines, it’s measured in microbiological density. Upstream of a failing wastewater plant, a river might carry a manageable 5,000 CFU of E. coli per 100ml. Downstream of the same plant, that number can rocket to 1,000,000 CFU per 100ml.

This overwhelming biological load depletes dissolved oxygen in the river ecosystem and introduces highly pathogenic strains that overwhelm standard sand filtration and multi-barrier chlorination at the downstream drinking water plant, allowing coliforms to enter the reticulation network and reach the public.

Why is legacy water testing too slow to prevent an outbreak?

Traditional water testing relies on retrospective culture methods, incubating samples and waiting for bacterial growth to confirm contamination. The problem isn’t the accuracy of this method. It’s the timeline. Culture-based testing can take days to deliver results, and during a wastewater infrastructure failure, days is exactly the window in which the public is already drinking contaminated water.

 

By the time a lab confirms the failure, the exposure has already happened.
The diagnostic gap, not a lack of awareness, is what turns a fixable infrastructure problem into a public health emergency.

How does rapid water quality testing close that gap?

The fix isn’t more frequent legacy testing, it’s a fundamentally faster method. High-throughput enzymatic assays and rapid Quantitative PCR (qPCR) screens detect shifting microbial index markers and indicator spikes within hours rather than days, aligned strictly to SANS 241 drinking water standards.

That speed changes what’s possible operationally. Lab managers can use same-day data to alter chemical dosing, isolate affected reservoirs, and flag a wastewater failure before it cascades into a full-scale contamination event, turning a containable infrastructure problem back into exactly that, instead of a human catastrophe.

 

Should municipal and industrial labs rethink their testing protocols?

For utilities, municipal labs, and the commercial industries that depend on potable water supply, food and beverage producers especially, relying solely on legacy culture testing is a defensible-sounding but operationally risky position. “We tested it” isn’t the same as “we tested it fast enough to act.” Rapid, automated profiling aligned to SANS 241 gives labs the diagnostic speed that legacy methods were never built to provide.

FAQ

How fast can rapid water testing detect contamination compared to traditional methods?

Rapid qPCR and enzymatic assays can detect microbial contamination within hours, compared to days for traditional culture-based testing methods.

What is SANS 241?

SANS 241 is South Africa’s national drinking water quality standard, setting the microbiological, chemical, and aesthetic limits water must meet to be considered safe for public consumption.

Why does E. coli concentration matter for water safety?

High E. coli concentrations indicate faecal contamination and the likely presence of other pathogenic bacteria, signalling a direct health risk to anyone exposed to the water.

What should your lab do before the next wastewater failure?

When wastewater infrastructure fails, the difference between a contained incident and a public health catastrophe often comes down to testing speed. Legacy culture methods confirm contamination days too late. Rapid, SANS 241-aligned qPCR and enzymatic screening close that gap to hours — giving lab managers and utilities the window they need to act.

TL;DR

A failing municipal wastewater plant can push E. coli levels from 5,000 to 1,000,000 CFU/100ml downstream, overwhelming drinking water filtration and triggering public health crises. Legacy culture-based testing detects this days after exposure. Rapid qPCR and enzymatic assays, aligned to SANS 241, flag contamination within hours, giving labs the window to act before a wastewater failure becomes a human catastrophe.

Beyond the Quartz Waterline: The True Cost of Chemical Attack in High-TDS ICP–OES Analysis

It’s 4:30pm on a Friday, and your calibration standards have started drifting. Not failing outright, just enough to make you squint at the screen and wonder if it’s the method, the standards, or something else entirely. You’ve run high-TDS samples all week. You already know what you’ll find when you pull the torch: a faint haze of devitrification creeping up the quartz, the first sign that your “reliable” consumable has quietly started lying to you.

This is one of the most common, and most under-discussed, failure points in ICP-OES analysis. Standard quartz torches are excellent components, but they were never built to survive sustained exposure to high total dissolved solids (TDS), complex organic matrices, or heavy alkaline-earth and alkali metal loads (Li, Na, K, Ca, Mg, Rb, Cs). When labs run these matrices routinely, the torch becomes the silent variable behind drifting baselines, unexplained reruns and consumable budgets that never seem to add up.

This matters because most labs are still buying consumables on sticker price, not on cost per sample and that one decision is quietly driving the downtime, rework and accuracy issues everyone blames on “the instrument.”

Why does my ICP-OES torch keep failing on high-matrix samples?

Every analyst who’s run high-matrix samples for any length of time has lived this story. You start the week with a torch that performs beautifully. By Wednesday, you’re seeing slightly elevated background noise. By Friday, the quartz has started to devitrify, that cloudy, crystalline degradation that happens when alkaline-earth salts attack the silica structure under plasma heat. The glass becomes structurally weaker, more porous, and less optically clean, and your results start drifting in ways that don’t show up until you’ve already reported a few batches.

The instinctive response in most labs is to try to revive it: scrub it, soak it, polish it, swap in a “spare” that’s already half-degraded. Chemetrix consultants see this pattern across hundreds of labs in the region, teams spending real hours trying to nurse a structurally compromised torch back to usable condition, when the real fix has nothing to do with cleaning technique and everything to do with material selection. It’s not a bad habit. It’s a consumable mismatched to the matrix.

 

Why does quartz fail but ceramic doesn’t?

It’s easy to think of a torch as just a piece of glassware sitting inside an instrument. But every high-TDS or alkaline-earth-rich sample that runs through a degraded torch is, somewhere downstream, a decision that affects someone outside the lab. A mining company relies on accurate trace metal data to prove environmental compliance. A food producer relies on it to confirm a batch is safe to ship. A water utility relies on it to confirm a community’s tap water meets safety limits. None of those decisions are better than the data behind them, and that data is only as good as the consumable it passed through.

This is the part of analytical chemistry that rarely gets discussed outside the lab: the instrument doesn’t make the result trustworthy, the entire chain does, right down to whether the torch was chemically stable enough to deliver a clean, repeatable plasma. When a torch is quietly devitrifying, the risk isn’t just rework for the analyst, it’s a small crack in the chain of trust between a lab result and the public decision built on top of it.

That’s exactly why Chemetrix exists in this conversation, not to sell glassware, but to make sure the science underneath these decisions is as solid as the stakes riding on it.

Is a cheaper ICP-OES torch actually cheaper?

Quartz wins on the quote. But the real cost shows up later, in reruns, manual cleaning hours, replacement downtime, and accuracy risk from consumables run past their usable life. Compare cost per sample instead of cost per torch, and silicon nitride ceramic outer tubes, lasting up to 10x longer than quartz, win decisively.

How do you streamline a high-matrix ICP-OES workflow?

Most labs set their torch configuration once at installation and never revisit it as sample types change. Chemetrix’s solution design experience points to a simple fix: match outer tube and injector material to the matrix before degradation starts, and use demountable platforms so only the stressed component needs replacing.

Best torch setup for mining and environmental labs

Mining and environmental labs run heavy alkaline-earth, high-TDS matrices that strip standard quartz fastest. The Agilent 5800/5900 Series ICP-OES with demountable torches and silicon nitride ceramic outer tubes lets labs replace only the stressed component. See the 5000 Series Quick Reference Guide or watch the demountable torch video.

Agilent 5900 ICP-OES

Preventing injector damage in food, beverage, and petrochemical testing

Complex organic matrices attack injector material rather than the outer tube, causing drift and blockages. Agilent’s full-range alumina injectors let labs configure a torch matched to organic-heavy samples without sacrificing durability. See the vertical torch technical overview, or talk to a Chemetrix specialist.

 

Should labs just “cope” with outdated systems?

Frequent torch failure isn’t just part of the job, it’s a symptom of consumable choices built around short-term cost. Chemetrix exists to challenge that: helping labs build a culture of integrity, accuracy, and respect for the people doing the work, starting with the right consumable, chosen properly.

What should you do next to protect your ICP-OES accuracy and uptime?

Recurring drift, frequent torch replacement, and hours lost to manual cleaning point to one culprit: the consumable, not the method. Silicon nitride ceramic and full-range alumina injectors offer up to 10x the lifespan of quartz, with less downtime and better accuracy.

TL;DR:

Standard quartz ICP-OES torches degrade quickly under high-TDS, alkaline-earth, or complex organic matrices, driving baseline drift, reruns, and downtime. Agilent’s silicon nitride ceramic outer tubes last up to 10x longer than quartz and full-range alumina injectors resist chemical attack; together lowering true cost per sample and protecting accuracy.

How to Get Reliable FTIR Identification Every Time with the Agilent Cary 630

Your raw material just failed its FTIR identity check. The match score came back at 87%, the batch is on hold and three people are standing around a spectrometer debating whether to reject a container of perfectly good excipient.

Here is the hard truth: in most cases, the material is fine. The instrument is fine. The problem is a misunderstanding of what FTIR matching actually measures, and it is costing pharmaceutical QC labs hours of unnecessary retesting, false rejections and eroded confidence in a technology that is genuinely excellent at its job.

This article unpacks the three real causes of low match scores, what FTIR can and cannot tell you, and how to build a workflow that turns your spectrometer into the trusted identification workhorse it was designed to be.

 

Why does my FTIR keep giving me low match scores?

Walk into most pharmaceutical QC labs and you will see some version of the same frustration. A technician places a powder loosely on the diamond crystal, presses the plunger halfway down, gets a poor match score and logs it as a suspected material failure. After years of working alongside QC teams across hundreds of laboratories, the Chemetrix team can tell you that this scenario almost always comes down to one of three things.

Poor ATR crystal contact: Infrared light only penetrates a few micrometres into the sample surface. Air gaps or inconsistent pressure mean the evanescent wave never reaches the material properly, producing a weak and noisy spectrum that will not match any reference cleanly.

Generic reference libraries: Most labs rely on commercial libraries built from a single reference sample under ideal conditions. When your actual material arrives with slight batch variation, a different particle size or minor additives, it will not match that idealised reference, even if it is exactly the right material.

Misplaced expectations: A match score measures similarity under the conditions of measurement. It is not an absolute verdict on material identity. Even a correct material from the correct supplier can return a score well below 100% if technique or library quality is off.

The good news is that all three of these problems are fixable.

What is FTIR actually measuring?

FTIR spectroscopy works by focussing on infrared light at a sample and measuring which wavelengths the material absorbs. Every compound has a unique pattern of absorption peaks, its molecular fingerprint. The ATR (attenuated total reflectance) method makes this fast and practical by bouncing the infrared beam off a diamond crystal in contact with the sample, requiring no preparation beyond placing the material on the sensor.

Library matching then compares your sample’s fingerprint to a reference spectrum using a mathematical correlation algorithm. The result is a match score, not a binary yes or no,
but a measure of how similar the two spectra are under the conditions of that measurement. Importantly, standard library search methods are designed to detect differences in the 5 to 10% range between a sample and its reference, which means some variation is expected
and entirely normal.

This is a critical distinction. Natural spectral variation occurs between batches of the same material due to:

  • Moisture content and surface effects
  • Particle size differences between suppliers or manufacturing runs
  • Trace additives or stabilisers that are entirely acceptable within specification

None of these make the material wrong. But all of them will affect your match score if your reference library was not built to account for them.

Here is the insight that changes everything:

FTIR is an identification tool, not a purity tool. It will tell you what something is. It will not tell you how pure it is or quantify trace impurities. That is the job of HPLC. Stop asking your FTIR to do HPLC’s work and start letting it be the world-class ID workhorse it was built to be.

How do you improve ATR sample preparation?

Consistent results require consistent technique.
These are the four rules that make the biggest difference:

Powders: Spread the sample evenly across the full crystal surface before pressing. Apply firm and consistent downward pressure using the sample press. If the signal is weak, press harder and recollect the background.

Hard solids: Press a flat face directly onto the crystal or grind a small portion to a fine powder first. A smooth surface fragment beats a large irregular chunk every time.

Pastes and semi-solids: Apply a thin even layer onto the ATR surface with a spatula. These conform naturally to the crystal and are the easiest sample type to handle well.

Crystal hygiene: Clean the crystal between every sample with an appropriate solvent and a lint-free cloth. A contaminated crystal from the previous sample is an invisible source of error that will affect match scores across multiple runs.

Standardising these steps into a written SOP, what Chemetrix calls the “SOP of the Squeeze”, is the single fastest way to improve reproducibility across your team.

How can you build a pharmaceutical FTIR library that actually works?

The solution to false rejections in pharmaceutical raw material identification is not to lower your acceptance thresholds. It is to build a smarter library. A site-specific library collects reference spectra from your own approved batches of each material, across multiple suppliers and multiple delivery lots, so that the natural variation of your actual materials is built into the reference from the start. When a new batch arrives with slightly different moisture content or particle size, your library recognises it as the correct material because it has seen that variation before.

The instrument that makes this possible: the Agilent Cary 630 FTIR

The Cary 630 is purpose-built for pharmaceutical QC applications. Its instrument configuration delivers energy throughput up to 30% greater than comparable routine FTIR systems, which means faster data collection, lower noise and more reliable spectra even when sample variation is present. Its diamond ATR crystal is impervious to abrasion, requires very small amounts of sample and is easy to clean between samples. Modular sampling accessories click in and out in seconds with no alignment required, and at just 20 x 20 cm on the bench and 3.8 kg, it lives where the work happens rather than in a centralised lab.

 

 

Most importantly, the Cary 630 runs Agilent MicroLab software, a method-driven and pictorial interface that makes building site-specific libraries an intuitive task rather than a data science project. MicroLab supports advanced classification methods including PLS-DA (partial least squares discriminant analysis). In published testing using the Cary 630 with MicroLab, a PLS-DA method achieved 100% correct classification of pharmaceutical samples and detected contaminants at levels as low as 0.5%. Results are displayed as colour-coded pass/fail indicators and automatically logged in 21 CFR Part 11 compliant audit trails.

This is what Chemetrix calls the Golden Reference Library: a site-specific and validated collection of spectra that reflects your materials, your suppliers and your real-world conditions. Not a generic database. Yours.

 

Practical resources:

What does a validated FTIR library mean for regulatory compliance?

For pharmaceutical manufacturers operating in a regulated environment, a site-specific library is not just a practical improvement. It is a compliance asset. The Cary 630 meets or exceeds the performance specifications of the US, European, Japanese, Chinese, Indian and International Pharmacopoeia. Its automated IQ/OQ qualification software generates documented and auditable performance reports covering wavenumber accuracy, spectral resolution and signal-to-noise ratio. MicroLab OQ handles qualification for the US, European and Indian Pharmacopoeia directly, while MicroLab PC can be configured for additional requirements including the Japanese Pharmacopoeia. The optional MicroLab Pharma software package adds full 21 CFR Part 11 and EU Annex 11 support including electronic signatures and data integrity controls.

 

But instrument qualification is only one part of the compliance picture. A validated reference library, with documented collection conditions, approved batch traceability and defined acceptance criteria, is what gives your QA team the scientific and regulatory confidence to act on FTIR results without
second-guessing every match score.

Chemetrix supports clients through the full validation process, from initial library design through to IQ/OQ documentation and method verification against pharmacopoeial requirements.

Practical resources:

📌 Contact Chemetrix to discuss validation support for your FTIR workflow.

There is a better way to run your QC lab

Too many pharmaceutical QC labs have quietly accepted that FTIR is unreliable. They have added extra retesting steps. They have lowered thresholds without understanding why. They have learned to work around the instrument rather than with it. That is not good science. And it is not a sustainable way to run a quality control operation. Chemetrix believes that every lab, regardless of its size, its budget or its current frustrations, deserves instrumentation that works, workflows that are documented and a team that understands what their results actually mean.

The Cary 630 is not just sold and installed. Chemetrix partners with your team through three practical engagement points:

  • Workflow audit: Identifying exactly why your current match scores are low and where the process is breaking down
  • Method development Assistance: Building and documenting the SOP of the Squeeze that standardises ATR technique across your team
  • Validation support: Ensuring your custom library meets the compliance requirements of your QC environment

When your library is right and your technique is standardised, FTIR stops being a source of anxiety. It becomes what it was always supposed to be: fast, reliable and auditable identification, every time.

 

Low FTIR match scores are almost never an instrument problem.
They are a library problem or a technique problem, and both are fixable.

The three things to take away from this article:

    • A match score measures similarity under the conditions of measurement. Natural batch variation, particle size differences and trace additives will affect it even when the
      material is correct.
    • ATR sample preparation technique has a bigger impact on match scores than most labs realise. Standardising your approach with a documented SOP is the fastest win available.
    • A site-specific library built from your own approved batches will outperform any generic commercial database for your materials, in your lab and from your suppliers.

The Agilent Cary 630 FTIR makes the instrument side of this straightforward. Chemetrix makes the rest straightforward too.

Ready to stop second-guessing your FTIR results?

📩 Contact the Chemetrix team to book a workflow audit, arrange a Cary 630 demonstration or discuss building your Golden Reference Library: chemetrix.co.za

The Method Validation Wall: Why Elemental Impurity Compliance Stalls and How to Break Through It

There is a particular kind of silence in a pharmaceutical audit that every QA manager knows. It is not the silence of a clean room or an empty corridor. It is the silence after an inspector closes a data file, looks up and says nothing because everything is in order. That silence is the goal. And in elemental impurity testing, it is harder to achieve than most labs expect.

ICH Q3D and USP chapters 232 and 233 set mandatory limits for elemental impurities in pharmaceutical products. Compliance is not discretionary. It is not a best practice recommendation. It is a regulatory requirement that applies to every oral and parenteral drug product on the market. The question is not whether your lab will comply, but whether your workflow can prove it, consistently, at trace levels, across every batch, under inspection.

This article explains where most labs stall, why the problem is almost always a process issue rather than a hardware issue, and how a validated ICP-MS workflow built on the right instrumentation and partnership gives you the audit confidence you need.

What is the real cost of getting elemental impurity testing wrong?

Elemental impurities are unwanted inorganic elements that enter pharmaceutical products through raw materials, metal catalysts used in synthesis, manufacturing equipment or packaging. They include Class 1 elements such as arsenic, cadmium, lead and mercury, which carry the highest toxicological risk, through to Class 2 and Class 3 elements with route-specific exposure limits. None of them belong in a finished drug product above their permissible daily exposure levels, and none of them are detectable by visual inspection, smell or conventional wet chemistry.

This is what makes a compliance failure in this category so damaging. By the time a contamination event is discovered, product has often already been distributed. The financial cost of a recall is significant. The cost to patient trust is permanent. And because elemental impurities at toxic concentrations produce no visible sign of product degradation, the only defence is a validated analytical method that catches them before the product leaves the facility.

The pressure is continuous. Batch testing is not a one-time validation exercise. It is a routine, recurring obligation that runs for the entire commercial life of the product. Every batch. Every route of administration. Every manufacturing site change. The workflow that handles this cannot be fragile, analyst-dependent or difficult to defend under scrutiny.

What do ICH Q3D and USP 232/233 actually require?

ICH Q3D is the international harmonised guideline for elemental impurities in pharmaceutical products. It is adopted by the US Food and Drug Administration, the European Medicines Agency, Japan’s Pharmaceuticals and Medical Devices Agency and other global regulatory bodies. It establishes permissible daily exposure limits for a defined set of elemental impurities across oral and parenteral administration routes.

USP chapter 232 sets the acceptance criteria, defining the specific concentration limits for each element by route of administration. USP chapter 233 defines the analytical procedures required to demonstrate compliance, including the method validation parameters of specificity, linearity, accuracy, precision and detection limits.

The analytical techniques specified under USP 233 for elemental impurity analysis are ICP-MS and ICP-OES. These are the techniques that provide the ideal capabilities for determining inorganic contaminants to ICH Q3D and USP 233 requirements. Between the two, ICP-MS is the instrument of choice for most pharmaceutical laboratories, offering superior sensitivity at trace and ultra-trace concentration levels across the full range of regulated elements. ICP-OES is well suited to elements present at higher concentrations and to laboratories where the breadth of the ICP-MS dynamic range is not required for every element in scope.

Together, ICH Q3D, USP 232 and USP 233 define not just what must be measured, but how the measurement must be proven to work and on which platform. The regulatory framework is specific. The instrumentation it points to is equally specific.

Where does the ICP-MS workflow actually break down?

The Chemetrix team consistently identifies method validation as the point where pharmaceutical labs stall. Not instrument performance.
Not detection capability. Method validation.

The leap from early-stage R&D profiling, where the goal is elemental detection and characterisation, to validated routine QC, where the goal is defensible batch release data, is significant. In R&D, an analyst runs a method, gets a result and moves on. In QC, that same method must be formally validated, transferred to a different instrument or operator, proven robust across variations in sample matrix and demonstrated to remain fit for purpose over time.

This is where the human and process variables multiply. Instrument-to-instrument method transfer introduces drift. Analyst-to-analyst variability in sample preparation introduces inconsistency. Calibration standard preparation from single-element solutions introduces calculation errors and traceability gaps. Any one of these variables can generate an audit finding, not because the underlying science was wrong, but because the documentation did not adequately capture what was done and why.

The calibration standard problem deserves particular attention. Preparing ICP-MS calibration solutions for a multi-element elemental impurity method from individual single-element stock solutions is time-consuming, error-prone and difficult to trace. A single pipetting error, an incorrect dilution factor or a matrix mismatch between the standard and the sample can compromise the entire run. In a routine QC environment running batch after batch, these risks compound over time.

Chemetrix Insight: “In ICP-MS-based elemental impurity testing, the strongest flagship is not the data. It is the defensibility of that data.”

How do you build a validated ICP-MS elemental impurity workflow that holds up under inspection?

The answer is to remove as many human variables as possible before the method reaches routine QC. For ICP-MS elemental impurity workflows, this starts with the reference materials.

Use pre-formulated, certified reference material kits designed specifically for USP 232/233

Agilent’s ICH Q3D/USP 233 Elemental Impurities Portfolio does exactly this. The portfolio includes certified reference material kits for both oral and parenteral routes, with elements sorted by ICH and USP class, chemical compatibility and relative mandated concentrations.

This design eliminates the need for analysts to prepare their own calibration standards from single-element solutions, removing the most significant source of human error in the ICP-MS calibration workflow. Instead of calculating and preparing multi-element mixes from scratch, analysts work from pre-formulated, ready-to-use solutions that are already matched to the permissible daily exposure levels required by the method.

The kits are manufactured in an ISO 17034-accredited facility and certified in an ISO/IEC 17025 testing laboratory. Each kit is supplied with a Certificate of Analysis confirming actual concentrations, measurement uncertainty and NIST traceability. A dedicated Pharma Internal Standard Solution is included, optimised specifically for ICP-MS and ICP-OES results with common pharmaceutical sample types, which is critical for accurate internal standardisation across the wide mass range covered by a full USP 232/233 elemental panel.

Agilent has also updated these kits to reflect the most recent USP 232 guideline changes, which increased the permissible limits for gold and silver. Using current, regulatory-aligned certified reference materials is a fundamental audit requirement and one that is easily overlooked when laboratories are managing their own standard preparation programmes.

Build on preset ICP-MS methods designed for USP 232/233 compliance

Agilent ICP-MS and ICP-OES platforms include preset methods built specifically for ICH Q3D and USP 232/233 compliance. This reduces the configuration burden during method transfer from R&D to QC and provides a validated starting point that is consistent across instruments, reducing the risk of method drift between sites
or between analysts.

What makes the ICP-MS the right platform
for pharmaceutical elemental impurity compliance?

The ICP-MS is the primary instrument for pharmaceutical elemental impurity testing because the regulatory requirements demand it. USP 233 specifies trace-level multi-element analysis across a wide range of elemental classes with strict accuracy and precision requirements.
ICP-MS is uniquely suited to this task, offering the sensitivity, selectivity and multi-element capability that the method demands.

For pharmaceutical applications specifically, the combination of the Agilent ICP-MS platform with the ICH Q3D/USP 233 certified reference material kits creates a complete, traceable, regulation-aligned solution. The oral kit covers the full panel of elements required for oral drug product release. The parenteral kit addresses the tighter permissible daily exposure limits applicable to injectable and infusion products, where the regulatory scrutiny is highest.

The Agilent ICP-OES platform extends this capability to elements present at higher concentration ranges, and provides a complementary option for laboratories where the full sensitivity range of ICP-MS is not required for every element in scope. For many pharmaceutical laboratories, ICP-MS and ICP-OES are used together to cover the complete elemental panel efficiently.

Agilent’s OpenLAB Software Suite supports data management and analysis across the ICP-MS and ICP-OES platforms, maintaining the data integrity and audit trail controls required in a regulated pharmaceutical environment. Analytical Instrument Qualification and Functional Verification services are available from Agilent to support regulatory submissions and inspection readiness, ensuring that the instrument performing the analysis is as well-documented as the method itself.

📌 Ask Chemetrix about configuring a complete ICP-MS elemental impurity compliance workflow, including reference materials, method setup and instrument qualification.

Audit-ready is not a feature, it is a service

Supplying an Agilent ICP-MS system is the beginning of the story, not the end. The instrument is capable. Whether the workflow built around it is defensible under inspection is a different question entirely, and it is the question that Chemetrix answers.

Too many labs reach the method validation wall and stall there. They have the instrument. They have the regulatory guidance. But the gap between a working ICP-MS method and a validated, documented, transferable method that survives an audit is wider than most labs anticipate when they start the project.

Chemetrix closes that gap through three specific services:

  • Method Development and Transfer: Chemetrix does the heavy lifting of trace-level ICP-MS method development, building validated elemental impurity procedures that are designed from the start to transfer cleanly from R&D to routine QC without drift. This includes worst-case element selection, matrix-matched calibration design and the full validation parameter set required by USP 233.
  • Routine Batch Reliability: Long-term instrument stability for recurring batch testing does not happen automatically. Chemetrix provides the service framework that keeps ICP-MS instruments qualified, certified reference materials current and data trails complete, so that the programme running today is still audit-ready in three years.
  • Audit-Ready Documentation: From instrument qualification records through to method validation reports and standard operating procedures, Chemetrix helps build the documentation package that turns a technically sound ICP-MS workflow into a regulatorily defensible one.

Compliance is mandatory. The data alone is not enough.
It is the documented, traceable, reproducible system behind the data that gives regulators confidence and gives patients the protection they are owed.

Conclusion

Elemental impurity compliance under ICH Q3D and USP 232/233 is one of the most technically demanding and most consequential analytical obligations in pharmaceutical manufacturing. The stakes are patient safety. The standard is mandatory. And the challenge is not the sensitivity of the ICP-MS. It is the defensibility of the workflow built around it.

The three things to take away from this article:

  • ICP-MS is the primary analytical platform specified for USP 232/233 compliance. Building your elemental impurity workflow around a purpose-designed, regulation-aligned ICP-MS configuration is the most direct path to audit readiness.
  • Pre-formulated certified reference material kits remove the single biggest human variable in the ICP-MS calibration workflow. Agilent’s ICH Q3D/USP 233 portfolio is manufactured to ISO 17034 and certified to ISO/IEC 17025, with NIST-traceable Certificates of Analysis for every kit.
  • The silence of a successful audit is earned, not assumed. It comes from a validated ICP-MS system, traceable reference materials, consistent sample preparation and documentation that tells a complete and accurate story.

The Agilent ICP-MS platform and certified reference material portfolio provide the instrumentation and standards. Chemetrix provides the validated workflow, the ongoing support and the audit-ready confidence that makes elemental impurity compliance continuous rather than periodic.

Ready to move from compliance pressure to compliance confidence?

📩 Contact the Chemetrix team to discuss ICP-MS configuration, reference material selection or audit preparation for your elemental impurity programme: chemetrix.co.za

How to Get Consistent, Defensible Cleaning Validation Results with the Veolia Sievers M9

The batch is ready. The vessel looks clean. But the documentation is not done, the QC queue is backed up and the equipment has been sitting idle waiting on analytical results.

This is the real cost of a slow or uncertain cleaning validation programme. Not the cost of the instrument. Not the complexity of the method. The cost is measured in hours of lost production, delayed releases and the quiet anxiety of knowing that if an inspector walked in right now, your data trail would not tell a clear and convincing story.

Total organic carbon (TOC) analysis exists precisely to eliminate that anxiety. When implemented correctly, it is one of the fastest, most regulator-friendly, and most operationally practical cleaning verification methods available. This article explains why so many labs are not using it that way and what it takes to change that.

What does a failed clean actually cost?

Most cleaning validation conversations start with the method. They should start with the consequence. A single failed clean in a pharmaceutical or food manufacturing facility does not just mean re-cleaning the vessel. It means halting production, quarantining potentially affected batches, initiating a deviation investigation, documenting the root cause, re-validating the cleaning cycle and demonstrating to QA that it will not happen again. In a worst-case scenario, that is days of downtime on a critical piece of manufacturing equipment.

The Chemetrix team has seen this play out in facilities relying on product-specific methods like HPLC for cleaning verification. When an unknown degradant or cleaning agent residue slips through undetected, the specific method offers no warning. TOC does. Because it measures the total organic carbon in a rinse or swab sample, it catches APIs, degradants, excipients and cleaning agents in a single analysis. There is no invisible contamination with a properly implemented TOC method.

The three most common operational pain points the Chemetrix team identifies in cleaning validation programmes are:

  • Poor worst-case selection. Labs test the wrong compound or the wrong surface area, which means their validation does not reflect real-world cleaning challenges.
  • Weak limit translation. There is a well-defined ppm requirement on paper, but nobody has converted it into an actionable TOC concentration limit for the instrument.
  • Inconsistent sampling. Swab technique varies between analysts, water baseline is not controlled and grab samples represent a single timepoint rather than a continuous view of the cleaning cycle.

These are workflow problems. Not instrument problems.

Why is TOC considered the gold standard for cleaning validation?

TOC analysis works by oxidising all organic residues in a sample and measuring the carbon dioxide produced. The result is a single, quantitative carbon concentration value that tells you, objectively, how much organic material remains on the equipment surface or in the final rinse.

This matters enormously in a regulated environment because it removes operator subjectivity from the result. There is no peak integration to argue about, no ghost peaks to investigate and no ambiguity about whether a signal is real or an artefact. The FDA has issued numerous warning letters specifically for HPLC data integrity failures, including failure to integrate peaks and inadequate investigation of unknown peaks. These problems are structurally unavoidable in product-specific methods because cleaning processes generate degradants and unexpected compounds that the specific method was never designed to detect.

TOC does not have this problem. It detects everything organic. That is not a liability. That is a feature. The regulatory acceptance of TOC for cleaning validation is well established. The US Pharmacopoeia, the US Food and Drug Administration and the European Medicines Agency all recognise TOC as an appropriate and compliant method for demonstrating equipment cleanliness. The FDA’s 2011 process validation guidance is particularly significant: the traditional practice of measuring a single API with a specific method is no longer considered compliant with FDA best practice, because it does not provide the process understanding the life cycle approach requires. TOC, as a non-specific method, measures both product-related and process-related residues as a function of carbon content, making it compliant with that guidance and giving a comprehensive view of cleanliness at every phase of the validation life cycle.

When sensitivity becomes a concern, it is worth reframing the question:

A TOC analyser is not too sensitive. It is appropriately sensitive. Sensitivity is exactly what guarantees that equipment is genuinely clean, not just clea

n enough to pass a method that was not looking for everything.

Is TOC actually cheaper than HPLC for cleaning validation?

The short answer is yes – in most cases, TOC is more cost-effective than HPLC, often delivering noticeable savings within the first year of implementation.

Here is what a realistic comparison looks like across the two approaches:

HPLC for cleaning validation requires a separate, validated method for each product. Method development is time-consuming and assumes that all potential interferents are fully understood. It cannot detect degradants or cleaning agent residues that fall outside the target compound. Laboratory workflow typically means grab samples are transported to the QC lab, queued for analysis and results returned hours later. Equipment sits idle during this time.

TOC for cleaning validation requires a single method that covers APIs, excipients, degradants and cleaning agents simultaneously. The Sievers M9 delivers results in two minutes in standard mode, or four seconds with the optional Turbo mode. The M9 Portable model can be taken directly to the manufacturing floor, samples can be analysed almost immediately after collection and equipment can be released faster.

The economic gains compound over time. Fewer out-of-specification investigations due to environmental or transcription errors, faster analyst throughput, reduced re-testing and the elimination of mobile phase preparation all contribute to a meaningfully lower total cost of running a cleaning validation programme.

Chemetrix Insight: “TOC almost always reduces total validation costs within the first year by accelerating batch release and reducing the frequency of re-testing. The instrument cost is recovered faster than most labs expect.”

How do you troubleshoot a TOC cleaning validation workflow that is not performing?

When TOC results are inconsistent or a cleaning validation programme is not delivering the confidence it should, the problem is almost never the analyser. Here is the hierarchy of where to look first.

Step 1: Check the water baseline. The carbon contribution of the rinse water itself must be established and controlled. If the water baseline is elevated or variable, every subsequent result will be unreliable. Low-TOC water and appropriate Sievers certified vials are the foundation of reproducible results.

Step 2: Review the swab technique. Analyst-to-analyst variability in swabbing is one of the most common sources of inconsistency in cleaning validation data. In published validation data using the Sievers M9, two different analysts achieved recovery values of 100% to 105.8% with RSD values below 2.1% for the same CIP-100 cleaning agent at multiple concentration levels, demonstrating that a well-standardised method is highly reproducible across operators. If your res

ults do not look like this, the method has not been standardised, not the instrument.

Step 3: Confirm the worst-case compound is correctly identified. Many facilities test the easiest-to-detect compound rather than the hardest-to-clean one. Worst-case selection should be based on solubility, toxicity and difficulty of removal, not analytical convenience.

Step 4: Verify the limit is correctly translated. A product limit expressed in ppm of compound is not directly equivalent to a TOC limit. The conversion requires multiplying by the percentage carbon in the chemical formula of the compound. For example, if a specific API limit is 10 ppm and the percentage carbon is 50%, the TOC limit is 5 ppm. This step is frequently skipped or done incorrectly.

Step 5: Consider the deployment. If equipment turnaround is the primary constraint, laboratory-based grab sample analysis may simply not be fast enough. At-line analysis with the M9 Portable or online analysis with the M9 On-Line can eliminate the QC queue entirely and enable real-time equipment release.

Practical resources:

  • Veolia Application Note: Validating the TOC Method for Cleaning Validation Applications in the Pharmaceutical Industry
  • Veolia Fact Sheet: Top 5 Secrets to a Successful Cleaning Validation Program
  • Veolia eBook: Total Organic Carbon for Cleaning Validation Programs
📌 Contact Chemetrix to request a workflow review of your current cleaning validation programme.

What makes the Veolia Sievers M9 the right instrument for pharmaceutical cleaning validation?

The Sievers M9 was not designed for a research scientist with unlimited time. It was designed for the QC technician who needs to verify that a vessel is clean, release the equipment and get back to supporting production. That distinction matters.

The Sievers Membrane Conductometric Detection method is what sets the M9 apart technically. Unlike instruments that use non-dispersive infrared (NDIR) detection, the Sievers gas-permeable membrane selectively passes only the CO₂ produced from the oxidation of organics. Acids, bases and halogenated compounds, which are frequently present in pharmaceutical cleaning processes, are prevented from interfering with the measurement. This delivers selectivity and precision in exactly the sample matrices where cleaning validation is performed.

The M9 comes in three configurations to match any deployment need:

  • M9 Laboratory: For QC labs running high volumes of rinse and swab samples, with optional Autosampler for 24-plus hours of unattended analysis
  • M9 On-Line: Attached directly to a CIP skid for continuous real-time monitoring and automated equipment release without any manual sampling
  • M9 Portable: Lightweight and IP-21 rated for at-line use on the manufacturing floor, supporting both rinse and swab samples with optional Turbo mode

Across all three configurations, the M9 delivers a measurement range of 0.03 ppb to 50 ppm with precision below 1% RSD and accuracy of plus or minus 2% or plus or minus 0.5 ppb, whichever is greater. Calibration is typically stable for 12 months. Maintenance requires just a few hours per year. The instrument comes pre-calibrated from the factory and can be prepared for analysis in under one hour.

For regulated environments, the optional DataGuard software provides full 21 CFR Part 11 and Annex 11 compliance, with a secured audit trail, user-level access controls and data that cannot be modified or deleted. The M9 also simultaneously reports TOC, inorganic carbon and conductivity from a single sample, giving three discrete data points that can be used together to identify root cause, optimise cleaning cycles and support OOS investigations.

Practical resources:

  • Veolia Application Note: Validating the TOC Method for Cleaning Validation Applications in the Pharmaceutical Industry
  • Veolia Fact Sheet: Top 5 Secrets to a Successful Cleaning Validation Program
  • Veolia eBook: Total Organic Carbon for Cleaning Validation Programs
📌 Contact Chemetrix to request a workflow review of your current cleaning validation programme.

Stop blaming the instrument and fix the workflow

The most common story Chemetrix hears is some version of this: “We tried TOC. It did not work for us.” After closer investigation, the story is almost always the same. The water baseline was not controlled. The worst-case compound had not been properly identified. The limit had not been correctly translated from ppm of compound to a TOC concentration. The sampling was inconsistent between analysts.

The instrument was fine. The workflow was not.

Chemetrix does not just supply a Sievers M9 and move on. The partnership Chemetrix offers is built around making sure the workflow is right before the instrument is even switched on, and that the team running it has the knowledge to trust the results it produces.

This means three specific things in practice:

  • Worst-Case Selection Support: Helping your team identify which compound, which equipment surface and which cleaning cycle represents the genuine worst case for your process, so your validation is defensible under inspection.
  • Limit Translation: Converting your existing acceptance criteria into actionable TOC concentration limits, accounting for the percentage carbon in the chemical formula and the sampling method used.
  • Sampling Standardisation: Establishing consistent swab technique, water baseline controls and vial selection across your team so that analyst-to-analyst variability is eliminated as a source of OOS investigations.

When results are consistent, compliance follows. That is not a slogan. It is the operating principle of a cleaning validation programme that works.

Conclusion

Cleaning validation does not have to be the bottleneck it has become in many facilities. The science is straightforward. The regulatory acceptance is well established. The instrument is reliable, automated and designed for QC technicians rather than research scientists.

The three things to take away from this article:

  • TOC catches what specific methods miss. APIs, degradants, excipients and cleaning agents are all detected in a single analysis, making it inherently more comprehensive than HPLC for cleaning verification.
  • Most TOC problems are sampling and workflow problems. Controlling the water baseline, standardising swab technique and correctly translating limits will resolve the vast majority of analytical inconsistencies.
  • The Sievers M9 is built for production environments. With two-minute analysis time, optional Turbo mode at four seconds, three simultaneous data outputs and 21 CFR Part 11 compliance, it is designed to release equipment and get out of the way.

The Sievers M9 delivers consistent, defensible proof that cleaning works. Chemetrix makes sure your workflow does too.

Ready to stop guessing and start releasing?

📩 Contact the Chemetrix team to book a cleaning validation workflow audit or arrange a Sievers M9 demonstration: chemetrix.co.za

The Intelligent Lab: How AI and Advanced Metabolomics are Redefining Scientific Discovery

The pace of scientific discovery is no longer governed solely by the physical limits of manual experimentation. We are currently witnessing a shift that is as transformative as the invention of the microscope itself. Artificial Intelligence (AI) and advanced metabolomics are reshaping how science is conducted, moving research from a “trial-and-error” model to a predictive, data-driven discipline. By combining high-resolution analytical hardware with machine learning, laboratories can now solve complex biological challenges – such as developing animal-free culture media – with unprecedented speed.

The complexity of the modern workflow

In the fast-evolving landscape of biopharmaceuticals and cell biology, the reliance on traditional methods often leads to significant hurdles. For decades, the industry has relied on fetal bovine serum (FBS) to supplement cell culture media, despite its high costs, ethical concerns, and inherent inconsistency.

Many lab teams find themselves buried under mountains of raw data from complex matrices, struggling to identify which specific molecular components actually drive performance.

When dealing with undefined raw ingredients, such as plant and microbial extracts, understanding chemical composition is critical to ensuring batch-to-batch reproducibility and process continuity when scaling.

From raw peaks to actionable insights

The challenge in modern labs isn’t a lack of data; it is the complexity of interpreting high-dimensional datasets. Manual analysis of thousands of formulations is no longer feasible. As regulatory requirements for biologics become more stringent, the demand for defined, reproducible, and regulatory-compliant media has grown.

Advanced metabolomics provides the molecular profiling required to qualify raw materials, while AI handles the broad combinatorial screening. This synergy allows researchers to tailor media composition to specific cell lines, improving yield and efficiency across the drug development lifecycle.

Optimising media with LC/Q-TOF

To solve the media development challenge, Chemetrix supports the implementation of untargeted metabolomic workflows. By utilising the Agilent 6545 LC/Q-TOF, labs can perform detailed molecular characterisation of both raw materials and finished formulations.

How Chemetrix assists:

Our specialists help your team establish metabolomic workflows that provide detailed molecular information for R&D. We assist in identifying “critical component targets” – biomarkers of performance – that become your QC benchmarks. By linking these molecular features to cellular outcomes, we help you replace inconsistent serums with precise, scalable,
animal-free alternatives.

Agilent 6545 LC/Q-TOF

Predictive productivity

Efficiency in the modern lab is increasingly driven by smart automation. The Agilent Infinity III LC Series is designed to address the operational risks that lead to downtime and lost samples through integrated AI-powered solutions.

How Chemetrix assists:

Chemetrix provides the technical expertise to integrate these platforms into your existing regulatory-ready environment. The Infinity III offers predictive analytics and real-time alerts to pre-empt operational failures. We assist in configuring these advanced informatics platforms so that your lab can handle complex workflows with greater precision. This shift to an automated, AI-enabled system allows your staff to focus on high-value data interpretation rather than routine manual monitoring.

Compressing development from years to months

The shift toward AI-guided development marks a new paradigm in biological optimisation. By continuously training algorithms with high-quality experimental data, each project makes the platform more intelligent. This iterative process has the power to compress development cycles that once took years into just a few months. When molecular characterisation is linked directly to cellular performance, the result is a more resilient supply chain and a faster time-to-market for novel therapies.

Optimising the path to discovery

The integration of AI and separation science is no longer a luxury; it is the foundation for the next generation of bioprocess innovation. At Chemetrix, we provide the local application expertise and technical support required to navigate these digital transformations.

Your action plan

Identify a workflow in your lab that currently relies on undefined ingredients or manual screening. Contact a Chemetrix specialist today for a workflow audit. We will help you leverage advanced metabolomics and AI-powered instrumentation to ensure your processes are reproducible, compliant, and ready for the future of biomanufacturing.

Beyond the Bench: Why Partnership is the Critical Component in Pharmaceutical Analysis

In the pharmaceutical industry, the most valuable asset isn’t the active ingredient or the patented molecule – it is the integrity of the data that proves it works. In a sector governed by uncompromising regulatory standards, a laboratory’s reputation is built on its ability to produce consistent, compliant, and accurate results. However, as drug formulations grow more complex and detection limits move lower, many laboratories find that having the right equipment is only half the battle. The real challenge lies in the support system that keeps that equipment performing within the narrowest of margins.

At Chemetrix, we have been an authorised Agilent distributor in Southern and East Africa for decades. While our heritage is diverse, our commitment to the pharmaceutical sector is foundational. We don’t just supply instruments; we provide the technical scaffolding that allows pharmaceutical analysts to move from a raw sample to a validated report with total confidence.

Why great hardware isn’t enough

One of the most persistent challenges in the pharmaceutical workflow is the transition from a concept to a robust, validated method. It is a common misconception that high-end instrumentation automatically guarantees ease of use. In reality, pharmaceutical analysts often struggle with the “blank space” between unboxing an instrument and running their first compliant sample.

Whether you are identifying trace impurities, performing stability testing, or conducting complex bioanalysis, the method development phase is often where projects stall. A method that works in a controlled environment can fail in a high-throughput production setting if it hasn’t been stress-tested for robustness. This leads to a reactive cycle of troubleshooting and re-validation, which drains resources and delays time-to-market.

Navigating a shifting regulatory landscape

Data integrity is the non-negotiable cornerstone of the pharmaceutical industry. Global research shows that 90% of pharmaceutical professionals agree that reliable instruments are the single most important factor for a successful workflow. This is because, in this sector, a failure in reliability is a failure in compliance.

The pressure to process more samples while maintaining absolute adherence to 21 CFR Part 11 and EudraLex Annex 11 is immense. Without a partner who understands the nuances of IQ/OQ (Installation and Operational Qualification) and ongoing maintenance, labs risk falling into the “efficiency gap.” This is where sophisticated instruments sit underutilised because the method is too temperamental or the staff lack the specific training required to navigate the software’s compliance features.

Mastery of complex matrices with Agilent LC/MS

For laboratories tackling the most demanding pharmaceutical applications – such as nitrosamine analysis or impurity profiling– Agilent’s LC/MS solutions are globally recognised as the definitive standard. These systems provide the sensitivity and specificity required to detect analytes at levels that were previously unimaginable.

However, the “Chemetrix Edge” lies in how we support this technology. We recognise that method development for LC/MS is a specialised skill. Our support department acts as an extension of your own team, providing on-site assistance to help you develop, optimise, and troubleshoot your pharmaceutical methods. By leveraging our local application expertise, you can reduce the time spent in method development and ensure that your LC/MS system is performing at its peak from day one.

Driving throughput with the Agilent 1290 Infinity III LC

The workhorse of any modern pharmaceutical lab is the Liquid Chromatograph, and the Agilent 1290 Infinity III LC is engineered specifically for high-throughput environments. It is designed to handle the everyday pressures of pharmaceutical analysis with ultra-low carryover and exceptional pressure stability.

Chemetrix supports this hardware through a comprehensive service programme that goes beyond simple repairs. We offer tailored preventive maintenance and rapid-response technical support to ensure your 1290 Infinity III stays in a qualified state. By integrating our service expertise with this robust hardware, we help labs eliminate the “time traps” of manual intervention. Our goal is to ensure your staff spend less time worrying about baseline
drift and more time focusing on high-value data interpretation.

Agilent 1290 Infinity III LC

The reward of proactive support

The transition from a reactive laboratory to a proactive one is transformative. When you partner with a specialist who understands pharmaceutical applications, the results are measured in more than just uptime. You gain the peace of mind that comes from knowing your methods are robust, your instruments are qualified, and your data is defensible.

Our most successful pharmaceutical partners are those who have moved away from viewing instrumentation as a commodity and have embraced it as a collaborative workflow. This partnership leads to faster validation cycles, fewer “Out of Specification” (OOS) investigations, and a laboratory team that is empowered by their technology rather than frustrated by it.

 

Take the next step in laboratory excellence

The road to an optimised pharmaceutical workflow doesn’t have to be a solitary one. Whether you are looking to expand your LC/MS capabilities or need to refine the efficiency of your current chromatography setup, the expertise you need is available locally.

Your Action Plan:

Identify your most temperamental method – the one that requires the most manual intervention or frequent re-runs. Contact a Chemetrix specialist today for a workflow audit. Let’s work together to resolve your method development challenges and ensure your lab is equipped for the future of pharmaceutical discovery.

Are Your Drug Tests Predicting Clinical Reality?

A promising drug candidate passes every 2D cell culture test. The data looks perfect. Then it fails in clinical trials because it behaves completely differently in actual human tissue. This scenario plays out in pharmaceutical labs every day. The problem isn’t the science or the scientists. It’s the fundamental limitation of using 2D cell models to determine drug efficacy and toxicity when those models don’t adequately address the complexity of real world 3D tissues.

Ex vivo models and 3D samples like tumouroids and clinical biopsies are more biologically relevant than traditional 2D cell assays. But moving beyond traditional cell models requires tools designed specifically for cellular phenotyping of ex vivo samples.

When 2D models stop being enough

Every drug discovery researcher knows the frustration. Your 2D cell assay is optimised. The results are reproducible. But then the compound behaves differently in more complex models or clinical settings.

The quiet truth heard across pharmaceutical labs: using 2D cell models to determine drug efficacy and toxicity does not adequately address the complexity of real world 3D tissues. Cells growing in a monolayer on plastic experience conditions that simply don’t exist in actual organs or tumours. When researchers try to move beyond 2D cultures, they face a critical challenge: lack of tools for cellular phenotyping of ex vivo samples. Clinical biopsies are precious material that can’t be wasted on methods not designed for them. Tumouroids and organoids have thickness and complexity that traditional tools struggle to analyse. The very characteristics that make these models valuable also make them harder to work with.

The result? Many labs continue using 2D assays not because they provide better data, but because the alternatives seem too difficult. Experiments stall. Toxicity data remains unclear. The gap between laboratory findings and clinical outcomes persists.This isn’t a problem researchers can solve through better technique alone. It requires instrumentation designed for the realities of three-dimensional biology.

Why 3D samples provide more useful data

Biologically relevant 3D cell models provide more useful data than traditional 2D cultures. But why does dimension matter so much?

Ex vivo models help researchers gain insight into a drug’s mechanism of action and safety within a more physiologically relevant context than cell cultures. When you test a drug on cells growing flat on plastic, you’re studying biology that doesn’t exist in patients. When you test the same drug in ex vivo samples like clinical biopsies or tumouroids, you’re studying biology that actually resembles the tissue the drug will encounter.

3D samples like tumouroids and ex vivo clinical biopsies are more biologically relevant than traditional 2D cell assays because they retain structural complexity, cell-to-cell interactions and tissue architecture that influence how drugs actually work. A compound that appears effective in a monolayer might fail to penetrate a 3D structure. A drug that seems safe in 2D might trigger unexpected responses when cells interact in three dimensions.This isn’t just about making experiments more complicated. It’s about making data more predictive. The goal of drug development is to understand how compounds will behave in patients. Ex vivo systems move researchers closer to that reality. The challenge has been measuring these complex samples reliably. That’s where tool selection becomes critical.

Making ex vivo workflows work

Ex vivo workflows can actually improve efficiency when paired with the right tools, even though they appear more complex at first glance. The key is choosing instruments designed specifically for the samples you’re studying rather than trying to adapt tools built for 2D cultures. When you lack tools for cellular phenotyping of ex vivo samples, every experiment becomes trial and error. You spend time troubleshooting methods that were never designed for thick, irregular, three-dimensional samples. You waste precious clinical material on approaches that can’t capture the biology you need to see.

The right tools eliminate this friction. Instruments designed for ex vivo analysis accommodate sample complexity from the start. They’re built to handle the thickness, irregularity and physiological relevance that make 3D models valuable. This reduces the experimental iterations needed to generate meaningful data. Efficiency isn’t about shortcuts. It’s about matching tool capabilities to sample reality so researchers spend less time fighting their instruments and more time understanding biology.

Metabolic analysis in physiologically relevant context

Analysing drug efficacy and toxicity in ex vivo samples requires understanding how drugs affect cellular function in samples that retain three-dimensional structure. Traditional methods often require destroying the very architecture that makes ex vivo models valuable. The Agilent Seahorse XF Flex Analyser is designed for the analysis of ex vivo samples so researchers can gain insight into a drug’s mechanism of action and safety within a more physiologically relevant context than cell cultures. The system works with clinical biopsies, tumouroids and organoids without requiring tissue dissociation.

This matters because ex vivo models help researchers gain insight into drug mechanism of action and safety within a more physiologically relevant context than 2D cell cultures. By analysing intact tissue samples, researchers can assess how drugs affect cellular metabolism in conditions that actually resemble patient biology. The Seahorse XF Flex addresses the lack of tools for cellular phenotyping of ex vivo samples by providing metabolic profiling capabilities specifically designed for these challenging sample types.

24-well metabolic analyzer, Seahorse XF Flex Analyzer | Agilent

Practical applications:

Analysis of clinical biopsies using the Agilent Seahorse XF Flex Analyser
YouTubeAgilent Seahorse XF Flex Tissue Workflow: A Simple, Optimized Method for Your 3D Metabolic Analyses

Imaging of cell invasion and migration during cancer drug research
iconAgilentagilent.com/en/solutions/cell-analysis/cell-migration-invasion

General imaging
iconAgilentagilent.com/en/product/cell-analysis/cell-imaging-microscopy/cell-imaging-microscopy-software/biotek-gen5-software-for-imaging-microscopy-1623226/gen5-image-analysis-capabilities

Imaging deeper into 3D biology

Understanding cellular responses in ex vivo samples requires seeing into thick, complex structures. Traditional imaging approaches struggle with samples that extend beyond a few cell layers, forcing researchers to either section valuable material or accept surface-level data that misses critical biology.

The Agilent BioTek Cytation C10 Confocal Imaging Reader allows researchers to look deeper into thick sample biology with improved clarity and detail. The confocal imaging system addresses the lack of tools for cellular phenotyping of ex vivo samples by providing the depth resolution needed for three-dimensional structures.

This capability matters for drug development because biologically relevant 3D cell models provide more useful data when you can actually see what’s happening throughout the structure, not just on the surface. Cell migration, invasion and drug responses often vary by location within a tumouroid or tissue sample. Without appropriate imaging tools, researchers miss spatial information critical to understanding efficacy and toxicity.

The Cytation C10 enables cellular phenotyping of the ex vivo samples that provide physiologically relevant data for drug discovery.

Practical applications:

  • Image cell migration and invasion in 3D cancer models
  • Visualise drug distribution in thick tissue samples
  • Phenotype cellular responses throughout tumouroids and organoids
  • Analyse ex vivo clinical biopsies with depth resolution

Confocal High Content Imaging Microscope, BioTek Cytation C10 | Agilent

Science that respects biological reality

There’s a common mindset in drug discovery that researchers must accept the limitations of 2D models because ex vivo systems are too difficult. That working with clinical biopsies isn’t practical. That 3D cultures are too complex for routine use.

Chemetrix rejects this narrative.Researchers shouldn’t settle for models that don’t adequately address the complexity of real world 3D tissues. They shouldn’t compromise scientific rigour because tools weren’t designed for physiologically relevant samples. And they absolutely shouldn’t accept that predicting clinical outcomes requires choosing between feasibility and accuracy.

This is where partnership matters. Chemetrix doesn’t just supply instruments. We advocate for a scientific culture grounded in integrity, accuracy and respect for the complexity of living systems. When we say ex vivo models provide more useful data, we’re affirming that good science requires data that reflect real biology. The lack of tools for cellular phenotyping of ex vivo samples has been a barrier for too long. The Seahorse XF Flex and Cytation C10 aren’t just instruments. They’re commitments to removing barriers between researchers and the capabilities they need.

Chemetrix partners with researchers because they deserve solutions designed with biological reality in mind. Ex vivo systems that work reliably. Analysis that captures what matters. Support that helps labs implement physiologically relevant models confidently. This is how drug development advances: not through researchers heroically overcoming inadequate tools, but through systems that make biological relevance routine.

Better models, better medicines

Drug development doesn’t have to rely on models that don’t adequately address the complexity of real world 3D tissues. Biologically relevant 3D cell models provide more useful data. But only when you have tools designed for cellular phenotyping of ex vivo samples.

Ready to move beyond 2D limitations?

Discover how the Agilent Seahorse XF Flex enables analysis of clinical biopsies and 3D cultures. Explore how the Agilent BioTek Cytation C10 allows researchers to look deeper into thick sample biology with improved clarity and detail.

Contact Chemetrix to discuss how ex vivo workflows can improve the predictive value of your drug discovery research. Better models lead to better medicines. With the right partnership and the right tools, your lab can generate the clinically relevant data that truly matters.

✅ TL;DR – Key Takeaways

  • Using 2D cell models to determine drug efficacy and toxicity does not adequately address the complexity of real world 3D tissues
  • Ex vivo models help researchers gain insight into drug mechanism of action and safety within a more physiologically relevant context than cell cultures
  • 3D samples like tumouroids and ex vivo clinical biopsies are more biologically relevant than traditional 2D cell assays
  • The Seahorse XF Flex and Cytation C10 address the lack of tools for cellular phenotyping of ex vivo samples