Chapter 6 in the new Annex 1: Supply and media systems

News from Annex 1:

A very interesting statement comes from Annex 1, which in the opinion of gmp-experts should be treated with caution and above all with good GMP expertise:

WFI systems

The new Annex 1 is listed under Chapter 6 – Supply and media systems in subsection 6.15:

“WFI systems should include the use of continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, as these can give a better indication of biofilm formation that individual samples would not always detect. The placement of sensors should be based on qualification.” (Translation from English by gmp-experts)

Distribution system

To this end:

If a TOC measuring device determines that there is a biofilm in the distribution system, all other GMP systems from the planning, installation, qualification, operating mode and monitoring of ultrapure water systems carried out under the keyword “hygienic design” have categorically failed.

TOC meter

If there is an increase in the values on the TOC device, there must be an extremely high (continuous) bacterial load in the distribution system. In order to detect a ppb of TOC content in the water, a much higher bacterial load in the water is required than the specification requirements according to Pharm.-Eur. allow. If, on the other hand, a single biofilm floc were to find its way into the minimum volume flow of a TOC measurement, this would have to be described as an extremely high random factor.

Biofilms are generally very stationary systems that are more likely to be found in the regions of a water system where things tend to be calm, i.e. without much turbulence. This is therefore more likely to be found in the area of valves (if they are not used / decontaminated for a long time), in narrow gaps where the capillary force with high suction pressure (approx. 0.3 bar at 10µm gap size) allows water to enter, for example, tri-clamp connections or the clamping area of membranes on valves, where a biofilm can form very locally and become firmly established in the long term after the appearance of a germ.

GMP conformity for ultrapure water systems

In principle, GMP conformity for ultrapure water systems is subject to the conditions of a suitable design (hygienic design) and operating mode (production / decontamination) in conjunction with comprehensive, risk-based monitoring. This is the only way to ensure that biofilms can be avoided, eliminated and, above all, detected.

The TOC measuring device detects the total content of organic carbons, which can have many causes, e.g. the presence of_CO2 as a non-condensable gas. Therefore indispensable measuring principle, but not suitable for the intention of Annex 1.

Conclusion

For further discussion of the topic, please refer to the detailed explanations EMA/INS/GMP/443117/2017GMP/GDP Inspectors Working Group: Questionsandanswersonproductionofwaterforinjectionbynon-distillationmethods-reverseosmosisandbiofilmsandcontrolstrategies

Dipl. Ing. Wolfgang Rudloff

Vita

• 30 Jahre Erfahrung in der pharamzeutischen Industrie

Expertise:

• Geprüfter Sachverständiger für Reinraumtechnik und GMP-Management
• Lead Auditor und Gutachter

Stationen:

• Technischer Leiter
• COO / Gesamt-Herstellungsleiter
• Remidiation-Manager
• Projektleiter Neubau/GMP-Upgrade
• Management-GMP-Beratung
• Fachautor, GMP-Trainer, Mediator