The History of TOC Measurement in Pharmaceutical Processes

Measurement of Total Organic Carbon (TOC) is used daily, across the world, to check the purity of water is suitable for its individual purpose.

TOC is used as a non-specific indicator of water quality – and in some instances cleaning validation (a process for demonstrating cleanliness of vessels and equipment) in the pharmaceutical and biotechnology industries.

But how did we come to rely on TOC in this way, where and when did the practice originate? What is the history of TOC in the pharmaceutical industry specifically? What changes have occurred more recently?

History of TOC Measurement in Pharmaceutical Processes 1900s

1890 introduction into USP of the test for oxidisable substances test
The USP oxidizable substances test was the original was of measuring the suitability of water for pharmaceutical processes. Based on the acidified potassium permanganate method, it was an extremely simple pass / fail test.
  • The water sample was acidified with sulfuric acid.
  • The sample was heated to boiling, and a small amount of potassium permanganate solution was added.
  • The test relied on the colour change of the permanganate solution:
  • If the pink colour of the permanganate persisted after boiling for a specified time (usually 5 minutes), the sample passed the test, indicating an absence of significant oxidizable substances.
  • If the pink colour disappeared completely, it suggested the presence of oxidizable substances that consumed the permanganate, causing the sample to fail the test.
1990 – TOC proposed as a substitute to oxidisable substances testing
 
Godfrey Crane first proposed testing TOC as a substitute for oxidisable substances in ‘Pharmacopeia Forum.’1. There were many reasons for purporting to make the switch, as follows.

Superior Sensitivity:

  • The oxidizable substances test is qualitative, meaning it only indicates the presence or absence of oxidizable substances, not their actual amount.
  • TOC, on the other hand, provides a quantitative measurement of the total organic carbon content in the water. This allows for a much more precise assessment of organic impurities.

Greater Accuracy:

  • The permanganate test can be influenced by various factors like the type and concentration of organic matter present, leading to potential variability in results.
  • TOC analysis is generally considered more accurate and less prone to such interferences.

Improved Detection of Diverse Organic Compounds:

  • The permanganate test primarily reacts with readily oxidizable organic matter.
  • TOC detects a wider range of organic compounds, including those less reactive with permanganate, providing a more comprehensive picture of organic content.

Modernization and Technological Advancement:

  • TOC analysis utilizes advanced instrumentation and analytical techniques, offering a more reliable and efficient method compared to the older permanganate test.
Early 1990s – USP Chapter <643> is written
 
In the United States the Water Quality Committee (WQC) of the Pharmaceutical Manufacturers Association (PhRMA) debated improvements in the testing of purified water (PW) and Water for Injection (WFI) to be included into the United States Pharmacopeia (USP.)
 
Eventually, two new regulations were put into place. Modern techniques replaced old methods, which had, in fact, been in the USP for over 150 years!
  • Chapter <645> on conductivity was a new chapter which replaced a series of individual ion tests.
  • Chapter <643> replaced the Oxidisable Substances tests with Total Organic Carbon (TOC) measurements.
July 1993 – Sucrose and Benzoquinone are decided upon for Standard and System Suitability solutions.
 
After a USP open conference, the system suitability requirements in chapter <643> were refined. A discussion took place to confirm which compounds were to be used to determine if an instrument is suitable for the task of oxidising and measuring organic compounds for in compendia waters.
 
Finally, a WQC sponsored study determined that sucrose and was the best suited for preparing the Standard solution, and 1,4 benzoquinone for the System Suitability solution. Other challenging organics, such as Octoxynol-9 were considered as an alternative to benzoquinone. and subsequently rejected by USP because recovery was inconsistent with some TOC technologies.

A compromise to adopt Benzoquinone was chosen not because it was the most appropriate but because a consensus for early adoption was achieved.

Benzoquinone in our opinion relatively simple to oxidize, is light sensitive and unstable.

Overall, the shift to TOC reflects the need for a more precise and reliable assessment of organic impurities in pharmaceutical water quality control. TOC provides a more accurate and quantitative measure, leading to better assurance of water purity and safety in pharmaceutical applications.

At this point the WQC also specified the TOC detection limit and range of technologies. This created a competitive environment for instrument manufacturers and enabled the pharmaceutical industry to have free choice.

The minimum PW/WFI LOD of 0.05mg/L C was also specified.

TOC for use in cleaning validation

While the US Food and Drug Administration (FDA) didn’t explicitly endorse TOC for cleaning validation until 2002, studies demonstrating its effectiveness were published as early as 1993, suggesting its use prior to this official recognition. It’s important to remember that the adoption of new technologies often occurs gradually, with early adopters paving the way for wider acceptance.

May 1997

The chapter <643> method was enacted in in the USP fifth supplement.

May 1998 The oxidisable substance test was deleted from the eighth supplement

July 1999 – The EP also adopts TOC, albeit with a lower limit for Reagent Water and Blanks
 
The European Pharmacopeia adopted the <643> method and implemented it as its chapter 2.2.44. There were however two minor, but still crucial, changes
  • In USP chapter <643> reagent water blank can have as much as 250 ppb background TOC. In EP <2.2.44> this is 100 ppb
  • In chapter <643> conductivity is as described in USP <661> whereas EP <2.2.44> this is 1.0 μ S cm.
  • USP also states system suitability testing should be done at ‘suitable intervals’, whereas EP states this as ‘periodically.’

History of TOC Measurement in Pharmaceutical Processes 2000s

June 2001 – USP adopts lower limits blank water used in preparation purity (100ppb C), inline with EP

The United States Pharmacopeia also reduced TOC limit to (0.100mg/L C) in the 4th supplement.

2011 – Japanese adoption
 
The Japanese Pharmacopoeia replaced the measurement of oxidisable substances with Total Organic Carbon in its 16th Edition, which was published in 2011.

Key differences in the JP chapter compared to USP and EP are that, in the JP, KHP (Potassium Hydrogen Phthalate) must be used for calibration and a suitability standard from SDBS must be used.

The inclusion of KHP is beneficial because KHP is known to be more stable compared to Sucrose.T.he addition of SDBS adds a test for surfactant which can sometimes be difficult to analyse on some TOC Analysers and can also be challenging to oxidize with some methodologies.

March 2016 – Reverse Osmosis water is now deemed suitable for producing WFI
 
A massive change occurred around the rules for producing water-for-injection (WFI) in 2016. Whilst previously, the chapter had instructed WFI must be made with water from a still, the new chapters instructed that it was permissible to use Reverse Osmosis (RO) water.

Concerns had been raised as to whether RO water was robust enough and that there was potential for biofilm build-up and microbial / microbial bio-product contamination.

Therefore, the importance for monitoring of TOC and conductivity was emphasised. These are indicators of this potential contamination.

May 2021 – TOC limits now related to container size

Further revision was carried out in relation to container size in 2021. Previously, sterile water had a standardised limit and System Suitability concentration of 8.0 mg/L C, regardless of container size. This was now revised to require packaged water to have container volume TOC limits and System Suitability Concentration.

Altus Science produces ISO17025 and ISO17034 Accredited Total Organic Carbon Standards, as well as offering consumables for all major brands of TOC analyser. We strive to offer the highest levels of customer service and support, offering application support and training to ensure you get good, reliable data from your TOC analyser.

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