10 Questions You Should to Know about pharmaceutical water system

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.  

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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 : 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:

• In the storage tank
• After the UV system
• In the return flow

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:

• Hot water sanitisation
• Sanitisation with steam
• Chemical sanitisation

Thermal sanitisation is most common, but GMP doesn't specify any method.

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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:

• EU GMP 3.38: "Equipment should be installed in such a way as to prevent any risk of error or contamination."
• EU GMP 3.39: "Production equipment should not present any hazard to the products."
• EU GMP 3.36: "Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned."
• EU GMP Annex 1: "Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality."

19. What are the most common issues encountered in the WFI production systems produced under GMP. What should we look for?

1. One common problem is where there is a cold WFI sub-loop off of a heated system with a large shell and tube heat exchangers used for cooling in that sub-loop. When the sub-loop is hot water sanitized, not enough contact time is allowed for the cooling heat exchangers (and their trapped chilled water) to get them thoroughly hot and sanitized. When incompletely sanitized, any surviving biofilm will immediately reinoculate the cold sub-loop after resumed cold operation and be present as detectable micro counts.
2. Other common problems with cold WFI systems are dead legs, sometimes temporary ones that are created by open hard-piped connections to equipment that is not in use and not drawing water. The hot water during sanitization doesn’t mix well with the trapped water in that dead leg, so the dead leg never gets sanitized. If there was any contamination that got into that side leg during previous use, it will grow unabated in the unsanitized dead leg and continuously contaminate the loop water.
3. Another common problem is overwhelming the distillation purification process with a high level of endotoxin in the water going to the still (100+ EU/mL). This can happen with poor maintenance of pretreatment unit ops such as carbon beds, and also when coincident with high endotoxin levels in the city water when they switch over to straight chlorine from chloramine for a part of a year.

False

22. When sampling water ports should we hook up process hoses?  Is this a requirement or a recommendation?

1. If the sampling is for QC “release” of the water for manufacturing use, then the outlet used by manufacturing must be sampled in EXACTLY the same fashion as it is used by manufacturing – same outlet sanitization (if any), same manufacturing hose (no matter how grungy or poorly maintained), same pre-flushing (if any), same everything. The purpose of the sample data is to duplicate the same quality of water that manufacturing is using, so you have to duplicate in sample collection how the water is drawn from the system for use. Those procedures of water use can significantly contaminate pristine water within a water system when it exits, so that “nasty” water is delivered to a manufacturing operation. If you sample the water differently (better) than it is used by manufacturing, you will get lower (better) micro counts that are not representative of the water quality that is actually be used. Sampling like manufacturing water use for QC release is required by FDA to be identical. If it is not, this could earn you an FDA483 observation or worse.
2. If the water is being sampled for process control (PC) for the purpose of water system monitoring and systemic microbial control, it might be done through sampling ports that are not used by manufacturing. Since we know that the outlets themselves can contribute to the bioburden of the collected water, extreme efforts can be used to assure that the outlet does not add to the microbial content of the water as it exits the system (using extreme outlet sanitization, very vigorous and thorough flushing, sterile hoses, etc.). For PC, you are interested in the quality of the water within the system behind the valve and do not want contamination in a sampling port to bias the interpretation of the data.
3. However, water collected from sampling ports (rather than manufacturing use outlets) usually cannot be used for final release (QC) of water since it is not collected in the manner it is actually used. Manufacturing does not generally use water drawn from sampling ports.

False

23. What is your risk in increasing endotoxin levels due to the different sanitization methods?

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1. Endotoxin levels are typically a concern only for WFI systems. Most WFI systems are sanitized by elevated temperatures (hot water is better than steam since no special engineering is needed for hot water sanitization and it is plenty adequate), though more may employ ozone in the coming years as ambient non-distillation purification technologies become more widespread with EP’s relaxation of the methods of preparing WFI in their WFI monograph. Since thermal or ozone sanitization of WFI systems is typically no less frequent than weekly, that is not enough time for biofilm (with its endotoxin) to develop in the system and be released by periodic sanitization.  If the systems are much less frequently sanitized, there is a chance that developing biofilm could release detectable endotoxin when killed by periodic sanitization.
2. If chemical sanitizers other than ozone are used (this would be very atypical for a WFI system or an endotoxin-controlled Purified Water system), the sanitizer would have to be rinsed out, which would also rinse out any released endotoxin.

False