GMP Quality Ultra Pure Water for Pharmaceutical Industry Page | 1

GMP Quality Ultra Pure Water for Pharmaceutical Industry

The water used in the pharmaceutical industry, used both in drug synthesis, cleaning, as well as
Water for Injection needs to meet strict quality requirements according to various Pharmacopeia.
Water Treatment Systems and process equipment for the pharmaceutical industry need to be
sanitizeable by steam and for this reason materials are used that can withstand high temperatures.
Highly polished materials (mostly SS) need to be used to prevent the growth of biofilm. Sanitary
pumps are used that minimize particle shedding and no ball valves are allowed because they can
harbor biofilm.

The eight types of water used in the pharmaceutical industry are:

1. Non-potable for cooling

2. Potable (drinkable) water

3. USP purified water

4. USP water for injection (WFI) - Distillation must be used for this type of water according to
European Pharmacopeia

5. USP sterile water for injection

6. USP sterile water for inhalation

7. USP bacteriostatic water for injection (contains an anti-bacterial agent)

8. USP sterile water for irrigation - irrigation in medicine means the washing of a body cavity or
wound by a stream of water

Pure water for various pharma applcations needs to be demineralized, the organics and SS in it
removed and the water disinfected/sterilized to make sure there are no bacteria. Technologies such
sa Micro-Filtration, UF, RO, IEX, EDI, Distillation and UV are used. Stored water is nornally circulated
at a high temperature to prevent biofilm growth. Systems are designed to prevent dead legs and
allow easy drainage for cleaning. The facilities housing the water treatment equipment must be
controlled and prevent cross contamination from outside.
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A- Particle Trap Filtration

B- Carbon Fines Trap

C- Resin Trap

D- RO Prefilter

E- Tank Vent Filter

F- Bioburden Reduction

G- Sterilizing Filter

Quality parameters for Pharma water are: conductivity, various ions, particles (SS), bacteria and
endotoxins. Absence of bacteria is a must for higher quality waters.
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Some of the standards of reference for UPW for Pharma are:

1. FDA Guide to Inspections of High Purity Water Systems, High Purity Water Systems (7/93)

2. USP Monograph <1231> Water For Pharmaceutical Purposes

3. WHO good manufacturing practices: water for pharmaceutical use

When an UPW system for pharma is installed and commissioned, it must undergo Installation
qualification (IQ), Operational qualification (OQ) and Performance qualification (PQ).

Ultra Pure Water systems are validated and qualified to make sure that the water they produce is
consistent with the GMP requirements. For example, periodic tests for leachables are performed to
make sure that the equipment producing the UPW is not leaching TOC. Periodic tests for bacteria
and pyrogens/endo toxins are also made.

Waste water generated by the pharmaceutical industry also needs to be treated to meet strict
discharge limits and Good Environmetnal Practice. High COD waters and active pharmaceutical
ingredients need to me removed. In fact there is published data and investigations that assert that
pharmaceuticals are making it into the environment either through waste water discharge from
pharmaceutical plants, through human sanitary waste and through lanfill waste leachate. Read this
article for more info. Biological treatment is one method that is used, but if the COD is very high,
incineration or Wet Air Oxidation might be needed.

The activated sludge process does not lend itself very well to pharmaceutical waste water treatmant,
the reason being that API's are generally not biodegradable. RBC waste water treatement plants
have shown better results. MBR treatment can concetrate the API's too if the molecules are large
and cannot pass through the MBR membrane and hence reduce the amount of waste water.
UV/H2O2 treatment has also shown good results and is in use for CIP waste water treatment. Note
that two wavelengths of UV light are used, 254 and 185 nm. The higher wavelength water kills
bacteria, the lower one is so strong it even generates Ozone which breaks down organics.

Another very important concept in the pharmaceutical industry is GMP and Validation.

Validation can be defined as process of establishing through documented evidence a high degree of
assurance that a specific process will consistently produce a product that meets its predetermined
specifications and quality attributes. A validated manufacturing process is one that has been proven
to do what it purports or is represented to do. The proof of validation is obtained through collection
and evaluation of data, preferably beginning from the process development phase and continuing
through the production phase. Validation necessarily includes process qualification (the qualification
of materials, equipment, systems, buildings, and personnel), but it also includes th

1. Cleaning Validation
Cleaning validation is carried out to ascertain the procedure and method adapted for cleaning of
equipments , and areas , is capable of giving desired cleanness , cleanliness of equipment can be
ascertained by caring out trace analysis of active ingredient of previous products active ingredient
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trace analysis . By doing rinse water TOC analysis or swab tests, the complete removal of earlier
products residue is ascertained so as to avoid cross contamination. Bioburden is defined as the
number of bacteria living on a surface that has not been sterilized. The term is most often used in
the context of bioburden testing, also known as microbial limit testing, which is performed on
surfaces for quality control purposes.

2. Process Validation
Process validation is carried out on the manufacturing process or steps , which are adapted for
pharmaceutical manufacturing . The process adapted in pharma manufacturing should yield
consistent results with respect to quality of product. The laid down process is crosschecked for
evidence for efficacy, and the results are documented for each step.

3. Method Validation
In Pharma QC labs, only validated methods/qualified instruments are used to analyse for various
API's and only trained personnel are allowed to runs these methods.

FDA guidelines define process validation as follows:

Cleaning Validation proves that the washing of the reactor for example where an API was
manufactured has been cleaned up to spec through Swab TOC tests or Surfactant tests. Some
validation SOP's test for bacteria on surfaces for example using a Swab test.

Process validation: The collection and evaluation of data, from the process design stage through
commercial production, which establishes scientific evidence that a process is capable of consistently
delivering quality products.

For example in manufacturing of tablets a final mixing step is validated by withdrawing samples from
all points in mixer at intermittent intervals , and assay of active ingredients is done, results are
plotted against respective sample points and time intervals , the most efficient time interval at which
there are consistent and satisfactory result for desired content at all sampling points is considered to
be the best for the process of final mixing step, and this best time interval is again validated by
crosschecking and documenting on further three batches. It is one of example of process validation ,
it can extend to other processes adapted in pharma manufacturing i.e control of the entire processes
for repeated batches or runs.

Method Validation is used in labs to prove that a measuring technique is accurate. This involves
calibration using standard reagents.

Key players in the pharmaceutical water treatment industry are:

Siemens Water
Veolia
GE Water
MECO from the USA for Distillation Stills.
Bosch Packaging

Compiled by Rami E. Kremesti M.Sc., CSci, CEnv, CWEM Last updated 23-9-201