ISO Standard for the Production of Pharmaceutical Water

Recommendation

17-19 September 2024

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GMP Compliance and Technology for the Manufacture of Oral Solid Dosage Forms

ISO 22519 is a new available international standard dealing with the pretreatment and the production of purified water (PW) and water for injection (WFI).

According to the text of the new ISO standard, while there are many guidelines dealing with pharmaceutical water, there is no document that fully describes the different methods of producing PW and WFI. The new document aims to fill this gap and provide guidance on specifying a pretreatment and purification system for pharmaceutical water.

The new 42-page standard contains the following chapters:

• Scope
• Normative references
• Terms, definitions and abbreviated terms
• Design and practices
• Selecting materials, methods and system components
• Sampling
• Instruments
• System design
• Operation
• Maintenance
• Specific GMP requirements
• Control philosophy
• Alarms
• Recommended engineering documentation
• Annex A: Examples of PQ productions systems
• Annex B: Examples of feed water categories
• Annex C: System selection table
• Annex D: Configuration of typical integrity test for polishing UF

Temperature for Sanitization

At first glance, the document appears to contain the essential points that are important for the design and operation of a pharmaceutical water system. Nevertheless, comprehensive works on the subject of pharmaceutical water have already been published. Examples include ISPE's baseline "Water & Steam Systems" and William V. Collentro's book "Pharmaceutical Water: System Design, Operation, and Validation". In addition, not all points in the new document are undisputed. For example, the minimum temperature requirement of 80 °C for sanitization is rather high. The current trend is clearly towards lower temperatures that are sufficient and gentler on the material. Rouging can also be avoided to some extent with lower temperatures. For example, the USP says: "Temperatures of 65°-80° are most commonly used for thermal sanitization". In general, the new ISO standard considers thermal sanitization to be the only appropriate sanitization process. Cold stored and ozonized systems are excluded. All in all, the design criteria described seem to be based on the use of the very special "electrolytical scale reduction" in pre-treatment, at which quite high chlorine values are produced which already have a clearly bacterial-reducing effect during pre-treatment. The use of a UV lamp for chlorine reduction alone is also described. The use of UV systems for destruction in ozonised systems is not mentioned.

Surface Roughness

The surface roughness requirement of 0.6 Ra is also unusual. The current state of the art is still a Ra value of <= 08. It is unclear where the new value comes from. The requirement to inspect 70% of automatically produced welds is also unusually high. Usually, 10-20% is examined using an endoscope. The requirement that PW/WFI contact surfaces should be passivated is also outdated and obsolete. An oxidative protective layer is already formed with the first passage of water.

Particle Filter

Another point of contention is the description of a particle filter after the EDI. The state of the art in the GMP environment is not to install filters in water systems, which is also what GMP inspectors expect. Overall, the GMP content of the new document seems to be quite limited. The chapter "Specific GMP requirements" makes up less than one page, the essential points for the pharmaceutical industry, i.e. qualification and validation, are mentioned, but not explained further. The FDA Guidance for example, which is available for free, contains far more useful information on this topic.

Quality Parameters Conductivity, TOC and total Bacterial Count

The requirement for the quality parameters conductivity, TOC and total bacterial count improving with each treatment step (pretreatment and purification) is also technically questionable. Some processing technologies work in such a way that quality parameters can temporarily be reduced so that the purification process carried out in this step can function at all. Otherwise it would not be possible to use cation exchangers for softening. Calcium and magnesium ions are replaced by sodium ions, which increases the overall conductivity. An increase in the bacterial count is also possible due to the large surface of the ion exchange resins. However, the use of cation exchangers is state of the art and has no negative influence on the quality of the PWs or WFIs produced in pharmaceutical water systems with correct design.

ISO standards usually indicate the state of the art. It can be questioned whether this also applies to the first version of ISO 22519 and its application in the pharmaceutical industry.

The ISO 22519 is available in English from Beuth Verlag.