28/29 April 2021
During our courses and conferences participants quite frequently raise questions on pharmaceutical water preparation and distribution. Therefore following you will find some of these questions and their respective answers.
Question 1: Which concentrations of ozone are required in water systems?
The technical literature delivers different information about the ozone concentrations in water systems: e.g. ISPE Baseline Water and Steam: 0.02 ppm - 0.2 ppm; Collentro, Pharmaceutical Water: 0.2 ppm - 0.5 ppm and W.Setz, Ciba-Geigy 1990: max 0.04 ppm, for sanitisation 0.05 ppm.
The indications provided by the ISPE Baseline refer to the concentration required to prevent microbial growth. One can thus assume that a concentration of 20 ppb ozone can prevent any growth.
If systemic protection is desired i.e. the constant presence of ozone in the water, lower ozone values are sufficient.
In practice, approx. 0.02 to 0.05 ppm should be sufficient for Aqua Purificata. For sanitisation, it naturally depends on the sanitation time intervals - daily or weekly. Finally, the required ozone concentration for the system should be determined within the framework of the validation for the whole system.
Question 2: How many ozone measurement points should be available in the water system?
If ozone is used for the sanitisation of the distribution system, the effect should also be proven by means of - indirectly - the determination of the KBE values on the one hand, and on the second hand through the proof that the ozone concentration is measured at the appropriate points in the water system. For this purpose, the ISPE Baseline mentions at least 3 measurement points:
The measurement in the storage tank shows that the concentration is sufficient during the permanent ozonisation. After the UV system, a measurement is done to assure destruction of the ozone. The post-use point in the return flow of the pipeline system is measured to prove that the ozone concentration is sufficient during sanitisation.
Question 3: Is there - from a GMP point of view - a preferred sanitisation method?
Basically, the following three sanitisation procedures are used today:
Thermal sanitisation is most common, but GMP doesn't specify any method.
Question 4: Is cold storage allowed in WFI systems?
For WFI and purified water, different temperatures are used. WFI is usually stored under heat.
In FDA's Guide to Inspections of High purity Water Systems you can find two indications of temperatures which are actually contradictory. The first temperature interval is described under "System Design". "The fist chapter basically states under "System Design" that it is recognized that hot water systems (here to understand as 65 to 80°C systems) are self sanitizing. Another temperature interval is indicated in the chapter "Piping". This concretely means here that the Guide applies to hot 75 - 80°C circulating systems. These indications are in connection with the 6D rule:
FDA - GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS
"One common problem with piping is that of "dead-legs". The proposed LVP Regulations defined dead-legs as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use. It should be pointed out that this was developed for hot 75 - 80°C circulating systems."
It follows from the above that cold systems for WFI actually don't comply with the requirements. Under these circumstances, it is likely that at least the FDA doesn't accept cold WFI systems.
If appropriate measures (system design and sanitisation measures) can ensure that microbial growth is prevented, cold storage could basically be used. Different limits for cold storage can be found in guidelines and standards (Wallhäuser: 4°C; ISPE: 4° to 10°C). A sanitisation concept for cold storage determined within validation is imperative and should also consider the increased high-risk of bio film formation.
Question 5: Are sterilizing filters permitted in water systems?
The answer to that question requires the examination of the legal provisions and the standards and guidelines on the topic "Water". The EU GMP Guide describes in a few points the requirements for facilities and equipment. Relating to the sterilizing filters, the following indications may be authorised:
In almost all guidelines, references are made to sterilizing filters. As an example, see the following statement from a Japanese guideline: Sterile drug products produced by aseptic processing (Japan 2006)
"As a rule, sterilizing filters should not be placed at water use points since the filters could mask microbiological contamination in the water system. Endotoxins could also be released from dead microorganisms retained in the filters. If the use of filters is unavoidable, the interval of replacement should be based on validation results."
In this Japanese document, the position to filters is obvious: no sterilizing filters should normally be used. Yet, there can definitely be exceptions. The filters shouldn't serve for masking too high CFU values. Finally, one should justify the use of such a filter.