eBook: TOC and Microbial Detection Monitoring - 17

Analytics in Cold Water For Injection

The Hot Topic of Cold WFI
Lower Cost and Higher Production
Pharmaceutical companies across the globe are beginning to investigate the use of Cold
WFI because it has several cost advantages and higher speed of production over
distillation. But what exactly is Cold WFI and what is driving the change?

A move towards Cold WFI
Cold WFI is not truly cold but rather
Water For Injection (WFI) at ambient
temperature produced by a purification
technology other than distillation.
For decades the United States Pharmacopeia (USP) and the Japanese
Pharmacopeia (JP) have permitted the
production of WFI by methods other
than distillation. The USP states WFI
can be produced by "distillation or a
purification process that is equivalent

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2

or superior to distillation in the removal
of chemicals or microorganisms." The
JP approves WFI production with "reverse osmosis (RO) and ultrafiltration
(UF) when fed Purified Water (PW) or
suitably pretreated water." However,
the European Pharmacopeia (EP) has
only permitted the use of distillation to
produce WFI.

EP makes a change
In April 2017, the EP changed the allowed method of production and now
permits "a purification process that is
equivalent to distillation. Reverse osmosis, which may be single-pass or
double-pass, coupled with other
appropriate techniques such as electro-deionisation, ultrafiltration or
nanofiltration, is suitable."
The EP resisted the change for many
years because of a belief that RO water
was susceptible to growth through
biofilm, and the distillation process
when operated properly was not subject to this. As membrane technology
developed and advanced, the EP accepted that RO combined with other
technologies could produce water of
equivalent quality to distillation.
This change by the EP means that the
three major pharmacopeias now permit a method of production for WFI
other than distillation, and this has
initiated a shift in the pharma industry
away from traditional methods of WFI

METTLER TOLEDO Pharmaceutical Waters

17

production. Recognizing this change,
system fabricators are now introducing
Cold WFI production equipment that
integrates reverse osmosis, electrodeionization
and
ultrafiltration
equipment.

The growing need for rapid
microbiological tests
The European Medicines Agency (EMA)
has issued a Q & A document addressing several topics regarding the EP's
change, its concerns and the need for
additional monitoring during Cold WFI
production. The EMA's primary issue
with non-distillation production methods centers on the microbiological
quality of the water as well as the
control and monitoring required to
ensure detection and elimination of
microbes. The EMA states in their Q & A
document that: "Use of alternative / rapid microbiological test methods should be employed as part of the
overall control strategy for the system."

"Additional TOC and conductivity
measurements must be
considered"
Not only does the EMA encourage the
use of rapid microbial technologies for
the control strategy, but it also express
in its Q & A that there should be additional measurement points for conductivity and TOC: "On-line conductivity
measurements and TOC instrumentation must be considered as part of the
control strategy and located at various
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