Laboratory vs Online TOC Analysis for Pharmaceutical Water

Amscorp Scientific

Laboratory, at-line or online TOC? A practical guide for AU and NZ pharmaceutical teams on matching TOC measurement to sampling points, release decisions and workload.

Sievers M9 laboratory and M500 online TOC analysers with TOC sample vials

Most pharmaceutical sites measure total organic carbon (TOC) for the same reason: to show that Purified Water and Water for Injection are under control. Where they differ is how they measure it. Some rely on grab samples tested in the QC laboratory. Others install analysers directly on the water loop. Many end up using a mix of both.

In our introduction to what TOC tells you about pharmaceutical water, we touched on this choice briefly. This article goes further, with the practical questions that usually decide it.

What the pharmacopoeia allows

USP <643> describes a test that can be performed using on-line or off-line instrumentation, as long as the apparatus meets the chapter's requirements and the sample suitably reflects the quality of the water being used. In other words, the chapter does not prefer one approach over the other. Both need a suitable instrument, a documented procedure and periodic system suitability testing. [1][2]

That means the decision is really about your water system, your workflow and the decisions you need the data to support.

Check which pharmacopoeia you need to meet

USP <643> is not the only TOC method that may apply. European Pharmacopoeia 2.2.44 and the Japanese Pharmacopoeia also set requirements for TOC in pharmaceutical water, and they are not identical. The differences that usually matter are the calibration standard and the system suitability test. For example, the Japanese Pharmacopoeia expects the analyser to be calibrated with potassium hydrogen phthalate (KHP) and uses its own system suitability test.

USP and Ph. Eur. have long been closely aligned, and one system suitability set used to cover both. That is changing. The revised Ph. Eur. 2.2.44 (Supplement 12.3, effective 1 July 2026) requires system suitability standards made from European Pharmacopoeia Chemical Reference Substances (CRS), replacing sucrose R and 1,4-benzoquinone R. For sites that need both USP and EP compliance, the straightforward approach is to run separate system suitability sets made from the respective official reference standards. Using an alternative requires documented validation demonstrating equivalence and traceability to the applicable reference standards. [7][8]

If your site supplies more than one market, or may do so in future, confirm which pharmacopoeias apply before you finalise methods, standards and instrument qualification, and review how often these standards need to be run within your quality system. We will cover the USP, EP and JP differences in more detail in an upcoming article.

Laboratory analysis: flexible and familiar

A laboratory TOC analyser measures samples collected in vials from points of use, loops and other locations, then brought to the QC lab. An autosampler can run larger batches with less hands-on time. [3]

Laboratory analysis tends to suit sites that:

test many different sampling points on a schedule, rather than one fixed location
need TOC for more than water, for example cleaning validation rinse or swab samples
want one instrument to serve several water systems or buildings
already have established QC workflows and review processes for grab sample data

The trade-off is time and handling. Each result depends on someone collecting a clean, representative sample, getting it to the lab and analysing it within the site's approved hold time. Sampling and handling can also affect results, so clean containers, representative sampling and controlled handling procedures are essential.

Online analysis: continuous visibility at a fixed point

An online TOC analyser is plumbed into the water system and measures continuously at a chosen point, typically on the distribution loop. Veolia's Sievers M500 online analyser, for example, can provide a TOC measurement every three minutes during continuous online monitoring and can also measure conductivity. [4]

Online monitoring tends to suit sites that:

want to see trends and short-lived changes between routine grab samples
want earlier warning of a developing problem, so it can be investigated before it becomes a deviation
want to reduce routine point-of-use grab sampling for TOC, where their quality system supports it
are working towards real-time release of water, where online TOC and conductivity data support releasing water into production without waiting for laboratory results [5]

The trade-off is that an online analyser sees one location. Where it is installed matters, and it needs the same attention to calibration, system suitability, maintenance and data review as a laboratory instrument.

At-line analysis: the middle ground

There is a third option that is easy to overlook. A portable TOC analyser can be taken to the process and used close to where the sample is collected. This is often called at-line analysis. It is particularly useful for time-critical work such as cleaning validation, where waiting for a QC lab result can leave equipment sitting idle. [6]

Some portable analysers can also be connected to a sample line for a period of online monitoring, then moved back to the bench, which can help when a site wants to trial online data before committing to a permanent installation.

Five questions to ask before you choose

How many sampling points do you need to cover, and do they change? Many varied points usually favour laboratory or portable analysis. A small number of critical, fixed points may justify online monitoring.
What decision does the result support? Routine compliance testing, trending and early warning, release of water into production, or cleaning verification each place different demands on turnaround time.
How quickly do you need to know? If a delay of hours or days between sampling and result creates risk or downtime, online or at-line measurement is worth considering.
Who will run and maintain it? Consider QC lab capacity, engineering support for an on-loop installation, and who reviews alarms and trends.
What does your quality system need? Think about qualification, method transfer if you move from laboratory to online testing, system suitability, data integrity and audit trails. Using the same measurement technology online as in the laboratory can simplify method transfer. [6]

Why many sites use both

Laboratory and online TOC are not competitors. A common pattern is online analysers on the main loop for continuous visibility, with laboratory analysis for points of use, investigations, cleaning validation and periodic confirmation. When an online trend moves, a grab sample from nearby points can help work out where the change is coming from.

Whichever approach you choose, the result is only as good as the standards and consumables behind it. Certified TOC standards support calibration and system suitability, and certified low TOC vials help keep contamination out of grab samples.

Talk it through with Amscorp

Amscorp Scientific is the exclusive Australian and New Zealand distributor for the products we supply, including laboratory, online and portable TOC analysers, certified TOC standards with a Certificate of Analysis and full traceability, and certified TOC vials. Our analyser software is designed to support FDA 21 CFR Part 11 compliance.

If you are weighing up laboratory, online or both, book a free product demo and we can talk through your sampling points, workload and release decisions.