Questions and Answers on the Topic “Pharmaceutical Water”


In the following News, you will find questions on pharmaceutical water preparation and distribution frequently asked during our courses, as well as their respective answers. Read more here.,8427,8428,8526,Z-PEM_n.html

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:

  • 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

The FDA, as well as the ISPE in its Baseline – are in favour of thermal sanitisation with steam. The Guidance for Industry: Sterile drug products produced by aseptic processing Prepared by Task Force (Japan) contains the following note:
Since water for injection needs to be microbiologically pure, the equipment used for its production should be capable of withstanding periodic sterilization with pure steam at temperatures over 121°C for a given length of time. If steam sterilization is not possible because of low heat tolerance, an alternative sterilization or sanitization procedure (e.g., hot water or chemical agents) should be used for the equipment.”
GMP doesn’t specify any method. According to the state of the art, one should prefer sanitisation with steam.

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:
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.”

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 KBE values. Finally, one should justify the use of such a filter.



DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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