Water gener­a­tion process & micro­bial cont­a­m­i­na­tion

The preven­tion of a micro­bial cont­a­m­i­na­tion is crucial within the water gener­a­tion for the phar­ma­ceu­tical industry. But how can we persis­tently prevent such? By under­standing the process and thus being able to esti­mate the contri­bu­tion of the risk for a micro­bial cont­a­m­i­na­tion for each indi­vidual process step. The design of the plant and the main­te­nance proce­dures are the two crucial aspects. We need to under­stand where the germs come from, there­fore it is crucial to know how the entire water gener­a­tion process is struc­tured.

As the EU GMP Annex I states: "... The sterility test applied to the finished product should only be regarded as the last in a series of critical control measures by which sterility is assured. It cannot be used to assure sterility of a product that does not meet its design, procedural or validation parameters. The test should be validated for the product concerned..."

The water gener­a­tion process in 3 steps

For every step, the contri­bu­tion to the risk of micro­bial cont­a­m­i­na­tion must be iden­ti­fied. This also applies to main­te­nance and repair activ­i­ties. BWT has designed their instru­ments consid­ering all aspects like mini­mized dead volumes, sani­ti­z­able compo­nents, and e.g. special regen­er­a­tion proce­dures for the soft­ener to avoid dead zones.

Learn more about the individual water generation steps and their contribution to the risk of microbial contamination. With a deeper understanding of water generation, your CCS becomes all-​encompassing. Thus, the respective contributions to the risk of microbial contamination can also be identified. This also includes maintenance and repair activities. So the actual question is...

Where do germs come from?

Water Generation Process Flow 2


Microorgansims can enter through poorly sanitized sampling points of use.


Microorganisms can enter through ventilation system. Vent filter is crucial for microbial contamination.


The seal-free spiral design of the septron is the ideal protection against microbial contamination.


Due to the large surface, the filters (which still have high level of nutrients present) are prone to increase the microbial load.

Reverse Osmosis permeate side

A contamination only occurs here if reverse osmosis membrane is damaged.

Reverse Osmosis concentrate side

Here, high level of nutrient and minerals are present which are good growth conditions for microorganisms.


Due to its design (enormous resin surface and high level of nutrients), softeners are prone to increase the microbial load.


The main source of bioburden with up to 1'000'000 microorgansims / ml

To guarantee highest microbial safety, regular preventive or better predictive maintenance is recommended. BWT helps you with this.


Various water para­me­ters influ­ence the effec­tive­ness and effi­ciency of a PW and WFI gener­a­tion system. Factors such as parti­cles, hard­ness, chlo­ri­na­tion, and other char­ac­ter­is­tics of the raw water need to be consid­ered when designing a phar­ma­ceu­tical water gener­ator.

There are several pre-​treat­ment proce­dures avail­able, such as Soft­ener, Filtering, Anti­s­calant, and Bisul­fite. The soft­ener is broadly used in the pre-​treat­ment process to reduce the concen­tra­tion of hard­ness minerals (such as calcium and magne­sium) to guar­antee that the down­stream water treat­ment processes, in partic­ular the reverse osmosis can operate effi­ciently. As an alter­na­tive anti­s­calant dosing may replace the soft­ener by increasing the solu­bility of crit­ical minerals.


Impor­tant to consider is the fact that due to the design of a soft­ener or filters, it is obvious that the level of bioburden rather increases than decreases in this process step. The growth condi­tions for microor­gan­isms are very good with high nutrient and large surface areas of the resin or filters. 

Even if the level of microor­gan­isms before the RO membrane does not neces­sarily have a huge impact on the final product since the RO is a very effec­tive barrier for bacteria, micro­bial load may influ­ence all further process steps and may cause high endo­toxin or TOC values. The only way to combat the micro­bial load is frequent sani­ti­za­tion of the softener, short regeneration intervals and/or filter replace­ment.

Water Purifi­ca­tion

The water purifi­ca­tion process in cold systems is based on 3 main steps:

1. Reverse Osmosis (RO)

RO is the first process step towards puri­fied water (PW) or water for injec­tion (WFI) that changes the release rele­vant para­me­ters like conduc­tivity, total organic carbon (TOC) and bioburden. RO can either be applied as single or double pass, depending on the system setup and raw water compo­si­tion. However, due to the design and func­tion­ality of the RO the concen­tra­tion side of the RO always shows a very high bioburden and mineral concen­tra­tion. Even if the RO is a very effec­tive barrier, it’s not a 100% barrier. Membrane degassing and NaOH dosage are methods used to get rid of CO2 since it will increase the conduc­tivity and influ­ence the effi­ciency of the EDI.
Reverse Osmosis Bilder

2. Elec­trodeion­i­sa­tion (EDI)

EDI is used as a further purifi­ca­tion step. It is a combi­na­tion of sepa­ra­tion of ions by applying an elec­tric field, ion exchange resin and membrane sepa­ra­tion. The ions pass through a semi-​perme­able membrane under the influ­ence of an elec­trical field. The SEPTRON is not a mechan­ical barrier for microor­gan­isms but due to the chem­ical condi­tions (pH –Gradient) it further reduces micro­bial burden.
EDI Schematic Picture

3. Ultrafiltration (UF)

UF is the final step of the water purifi­ca­tion process. It holds back parti­cles, microor­gan­isms or endo­toxins.
Ultrafiltration Bild


Each purifi­ca­tion step bears a risk for micro­bial cont­a­m­i­na­tion by either malfunc­tion or insuf­fi­cient main­te­nance proce­dures. Moni­toring of the func­tion can be done by measuring phys­ical, chem­ical or micro­bial para­me­ters. E.g. integrity of membrane systems can be moni­tored by measuring differ­en­tial pres­sure or conduc­tivity. Integrity moni­toring in terms of micro­bial cont­a­m­i­na­tion risk is not suffi­ci­aent since minimal “leak­ages” in membranes may have a minimum effect on phys­ical or chem­ical para­me­ters but are kind of an open door for microor­gan­isms. Conse­quently, a comprehensive concept for sanitization and monitoring is crucial for process control.

storage and distri­b­u­tion

PW or WFI must be distrib­uted from the water gener­ator to the point of use. For storage and distri­b­u­tion, there are several strate­gies to ensure and main­tain the quality.

  • Hot storage
  • Continuous Electrolytic Ozoniza­tion


The main cont­a­m­i­na­tion risks in storage and distri­b­u­tion are the storage tanks (ventilation, stagnant water) and the point of use itself. Filter quality and main­te­nance as well as proce­dures (SOP’s) for sampling is extremely impor­tant. The majority of cont­a­m­i­na­tion cases are due to inad­e­quate SOP’s for sampling or handling fail­ures.

Usually, the risk of cont­a­m­i­na­tion is small either by hot storage or perma­nent appli­ca­tion of ozone. Anyway, author­i­ties require proof of the micro­bial load by frequent sampling and analyzing.

Want to know more?

Learn more about Cont­a­m­i­na­tion Control Strategy and the 4 elements of it...


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