Quality Guide for Water Purification

Systems for Pharmaceutical Use

National Agency for Health Surveillance | Anvisa

Copyright © 2013. National Agency for Health Surveillance. Partialor total reproduction of
this work is allowed, provided the source is mentioned. National Agency for Health
Surveillance (Anvisa)

President of the Republic

Dilma Rousseff

Ministry of Health
Alexandre Padilha

Director-president Deputy Diretor-Presidente

Dirceu Brás Aparecido Barbano Luiz Roberto da Silva Klassmann

Directors Deputies
José Agenor Álvares da Silva Neilton Araújo de Oliveira
Jaime César de Moura Oliveira Luciana Shimizu Takara

Chief of Staff
Vera Maria Borralho Bacelar

General Manager of Inspection, Quality Monitoring, Control and Inspection of Raw

Materials, Medicines and Products, Advertising and Publicity
Bruno Gonçalves Araújo Rios

Manager of Inspection and Certification of Medicines, Pharmaceutical Raw Materials

and Health Products
Jacqueline Condack Barcelos

Inspection Coordinator of Medicines

Andréa Renata Cornélio Geyer

Writing
Anderson Vezali Montai

Revision
Jacqueline Condack Barcelos
Lúcia Sciortino Giorgis
Nelio Cezar de
Aquino Roberto dos
Reis

Cover, graphic project and diagramming

Camila Medeiros (Uncom/Ascec/Anvisa)
Quality Guide for Water Purification
Systems for Pharmaceutical Use

National Agency for Health Surveillance | Anvisa

4
1. INTRODUCTION

Purification process of water for pharmaceutical use is based on the

elimination of physical-chemical, biological and microbial impurities until
reach official pre-established compendial levels approved by health
authorities.

Contamination control of the water for pharmaceutical use is fundamental,

since the water has great susceptibility to aggregate several compounds and
suffer recontamination, even after purification steps.

Microbiological quality control is a priority, since sole types of

microorganisms may proliferate in components of treatment and distribution
water systems for pharmaceutical use. Therefore, it is important minimizing
microbiological contamination through appropriate technologies and actions.

Technology to be employed in water purification depends on the type of

water to be obtained. Good Manufacturing Practices (GMP) requirements
applied to them are continuously updated with the aim to reduce the risk of
contamination, whether chemical, biological or microbiological. Generally, it
can be said that the most common and reliable methods for obtaining purified
water (AP or PW) are the ion exchange, reverse osmosis e and ultrafiltration.
To obtain Water for Injections (WFI), distillation process is used or other
method with equal or higher technology.

In Brazil, quality requirements of water for pharmaceutical use are

established by technical rules of Good Manufacturing Practices (GMP) and
also in the Brazilian Pharmacopeia. Current technical rule describing GMP
principles is the RDC nº. 17, of April 2010 and the Brazilian Pharmacopeia,
5th Edition, which was established by RDC nº. 49, of 23 November of 2010.
Although these documents are published by Anvisa, their contents are based
on international recommendations, making that they are in line with
worldwide trends.

Among documents considered by Anvisa as reference for the elaboration of

technical rules are the guides published by World Health Organization
(WHO). WHO guide related to water production for pharmaceutical use was
updated in 2012 and published in the Technical Report Series n° 970. In line
with these changes, Brazilian legislation will be soon updated.

5
Since GMPs are dynamic and are continuously evolving, it is important that
pharmaceutical industries always seek improvements in water purification
processes, aiming to reduce contamination risks.

The main purpose when preparing this document is to describe the minimum
requirements needed for water production systems for pharmaceutical use, as
well as the pharmaceutical market update on Anvisa’s regulatory trends, with
regard to the following topics:

• Construction materials of water purification systems.

• Production technologies of purified water (PW).
• Production technology of water for injections (WFI).
• Distribution and storage of water for pharmaceutical use (purified and for
injection).
• Qualification of PW and WFI systems.
• Revision of PW and WFI systems.
Other objective is also promoting harmonization on the understanding about
the issue during health inspections performed by the National System of
Health Surveillance (Sistema Nacional de Vigilância Sanitária - SNVS).

This document will cover only the criteria related to the production of
purified water and water for injections for pharmaceutical use. As a
reference, international guidelines, national legislation and the experience of
Anvisa on health inspections were used. Alternatively to the criteria
presented in this document, different procedures may be adopted, provided
they are technically justified.

6
2. CONSTRUCTION MATERIALS OF
WATER PURIFICATION SYSTEMS

Materials that come into contact with the water for pharmaceutical use,
including pipe, valves and assemblies, seals, diaphragms and instruments,
should be selected to meet basic requirements, among which the following
may be mentioned:

Compatibility: all materials used should be compatible with the

temperature and chemical substances used by the system or inside it.
Leak prevention: none of the materials that come into contact with the
water for pharmaceutical use may present leakages within the working
temperature range.
Corrosion resistance: purified water and water for injections are highly
corrosives. To avoid system failure and water contamination, selected
materials should be appropriate, welding process should be carefully
controlled, and all seals and components must be compatible with the
tubing used. System must be submitted to passivation after initial
installation or after modifications. When passivation is performed, the
system must be thoroughly cleaned before use. Passivation process must
be conducted in accordance with a documented procedure clearly defined.
Smooth internal finish: smooth internal surfaces to help prevent roughness
and cracks in the water system must be used.
Welding: selected materials for the system must be of easily welding, in a
controlled manner.
Flanges or joints design: when using flanges or joints, they must be
designed to meet hygiene or sanitary criteria. Checks should be performed
to ensure that correct seals are used and are correctly fitted and adjusted.
Documentation: all information related to system components must be
fully documented.
Materials: appropriate materials must be used in order to be considered as
sanitary elements of the system.

7
For the construction of the Water Systems for Pharmaceutical Use materials
must have appropriate sanitary specifications. Some materials considered
own sanitary elements to a water purification system are stainless steel 316L
(low carbon contents) and polyvinylidene fluoride (PVDF).

Polyvinyl chloride (PVC) is not considered a sanitary material, since, among

other factors, is highly susceptible to microbial contamination (biofilm
formation) is not resistant to certain sanitizing methods and can contaminate
the water with residual chemicals. Thus, from the technical standpoint and
health risk, the use of PVC is not indicated in parts of the systems that come
in contact with water at high purity contents (PW and WFI). PVC can be used
only in the equipment used to obtain water with lower purity degree, such as
deionizers and softeners.

The reservoir used to store water should be suitable for its intended purpose,
i.e., it must be constructed with inert material so that it is not a source of
contamination of its contents. The construction material must have
appropriate characteristics and roughness to difficult waste adherence,
biofilm formation and corrosion by sanitizing agents. Electropolished 316L
stainless steel, with low roughness, is the most common choice to meet these
requirements.

Eventually, the production systems of water for pharmaceutical use may be

made of plastic polymers, such as polyvinylidene fluoride (PVDF), which, if
well designed, meets current GMPs.

Using 304 stainless steel is not recommended, since it does not have adequate
resistance. The 316L stainless steel, in turn, has molybdenum and low carbon
contents in its composition, which greatly increases its resistance against
corrosion, helping to reduce the risk of water contamination.

8
3. PRODUCTION TECHNOLOGIES OF
PURIFIED WATER (PW)

The method chosen for purifying water, that is, the sequence of purification
steps, must be appropriate to the quality of produced water. The
specifications for the water purification equipment and storage and
distribution systems should have configurations that prevent microbial
proliferation.

There are different technologies that can be employed for the production of
PW. Usually PW is produced by deionizers, reverse osmosis, ultrafiltration
and/or electro-deionization. However, the most common is a combination of
these technologies.

Systems kept at room temperature, such as deionizers, reverse osmosis and

ultrafiltration are especially susceptible to microbiological contamination,
particularly when the equipment remains stationary for some time, because of
low or no demand for water use.

Barrier filters are known repositories of microorganisms retained and,

therefore, a critical source for biofilm formation and endotoxins. Filtration
through barrier filters (for example, 0.2 µm; 0.45 µM and 1.0 µM) should not
be used in the distribution rings or in the points of use for controlling
biocontamination. Such filters can hide contamination, increasing formation
risk of eventual biofilms and thus increasing the risk of microbial and
biological contamination of the PW.

When the company uses a barrier filter immediately before the storage tank,
there must exist a sampling point before this filter and a periodic sampling to
ensure that the water before the filter is not a source of microbiological
contamination.

Continuous deionization and electrodeionization are technologies effective

for removal of dissolved inorganic salts. Deionization systems, also known
as conventional deionization systems, produce deionized water for routine
use, through ion exchange resins specific for cations and anions. These resins
are organic polymers, generally sulfonated in the form of small particles.
Cationic resins capture ions, releasing H+ ion in water, since anionic resins
release OH-.

9
These processes are renewable, respectively, with acids and bases. This
process alone does not produce high purity water because the process releases
small fragments of resin, facilitates microbial growth and promotes low
removal of organic wastes.

Deionization through resins is very useful as pre-treatment of water, as is

very efficient in the removal of ions. Deionization technique with resins
when used as a single-step purification of PW is not appropriate because it
does not meet GMP and presents a high risk of promoting contamination,
both microbial and physical-chemical.

Considering that deionizer beds are potential sources of microbial growth and
biofilm formation due to its working principle and the constitution of the
resins, according with current GMP concepts, the existence of systems where
terminal steps of purification consist of deionization followed by a barrier
filter is not appropriate.

The most used technique as the final treatment step in the production of PW
is reverse osmosis, because it is able to greatly reduce the risk of microbial
contamination of the water, besides being of easy operation and maintenance.
Ultrafiltration and distillation can also be used for this purpose.

10
4. PRODUCTIO TECHNOLOGT Y OF
WATER FOR INJECTIONS (WFI)

In the planning to construct a water for injection production system

appropriate technology involved in the process should be considered; the
quality of the feeding water; the required specification for water quality; the
optimization of the water generator size in order to avoid frequent stops and
restarts of the system; and the functions of discharge and emptying.

Some pharmacopoeias prescribe or limit the final stage of purification in the

production of water for injection. Distillation is the preferred technique since
it is considered a more robust technique, due to the phase change of water,
and in some cases, because of the equipment which is operated at very high
temperatures.

The water coming from the public network supply can contain contaminants,
such as chlorides and volatile organic substances. Because these
contaminants have a physical size smaller than water, the semipermeable
membranes used in reverse osmosis are not able to retain them. Moreover,
currently there are no effective methods for the identification of all possible
toxic contaminants present in water.

The apparatus of reverse osmosis, if used in the production of WFI, must be

validated to ensure that the water quality produced is equivalent to that
prepared by distillation. It should be noted that many commercially available
devices are not designed for such use.

Among the inconvenient related to reverse osmosis membranes the high

probability of biofilm formation is highlighted. In comparison with
distillation, the only use of reverse osmosis technology for producing WFI
increases the risk of microbiological contamination, mainly due to the
following factors:

Biofilm formation on both sides of the reverse osmosis membrane begins

within minutes after the unit starts its operation.
The biofilm on the anterior side of the membrane has a large variety of
metabolic byproducts. The concentration is sufficient for them to pass
through the membrane.

11
 A biofilm consists of a large variety of gram-positive and gram-negative
bacteria.
Pathogenic bacteria are frequently found in biofilms, particularly
mycobacteria.
Biofilms are very difficult to be eliminated. Any attempt to use biocides
results in a rapid increase in the growth of biofilms after treatment.
Biofilms may be formed on the permeate side of the membrane, among
others, by the following manners: when there are microscopic holes and
fissures in the membrane or when the permeate side of the membrane is
not sterile.
Biofilm will grow and become very resistant to sanitization due to
glycocalyx.
The reverse osmosis is a percentage removal system: due to the high
concentration of microorganisms, metabolic byproducts, exotoxins,
among others, can pass through the membrane.
Many types of reverse osmosis membranes do not support sanitization at
high temperatures.
In other words, the reverse osmosis membranes will become, in practice,
in a point of great microbial growth. Since bacteria in the biofilm grow
and metabolize several metabolic byproducts are secreted, which include
proteins and carbohydrates, some of which may be biologically active.
These contaminants are not easily identifiable and quantifiable.

Currently it is not possible to assume that the quality of the water for
injection prepared by reverse osmosis is as safe as the water prepared by
distillation. Technically the reverse osmosis technology is inferior to
distillation due to a higher risk of physical chemical, biological and
microbiological contamination of the water.

Another problem related to reverse osmosis membranes is in the process of

sanitization, which is usually performed by chemical agents. In order to
perform this type of sanitization, the membranes must necessarily be
removed for cleaning, which favors the possibility of system contamination.
There is also to consider that the chemical processes of sanitization are less
effective than thermal sanitization. However, with the availability of new
materials for technologies such as reverse osmosis and ultrafiltration, which
allow operating and sanitizing at higher temperatures, new applications arise,
possibly validate for the production of water for injection.

12
Considering these factors, it is evident that the process of first choice for
obtaining WFI is distillation, in equipment whose internal walls are
manufactured of suitable metal, such as stainless steel AISI 316L, the neutral
glass or quartz. Alternatively, the WFI obtained by an equivalent or superior
process to distillation for removal of chemical contaminants and
microorganisms, since it is validated and monitored for parameters
established.

Currently regulatory agencies have charged efforts of pharmaceutical

companies to mitigate any risk to the production process, in order to ensure
the quality and efficacy of medicines that will be consumed by the
population. Thus, the final unit operation for obtaining water for injection
should be limited to distillation or other process equivalent or superior. The
distillation technology is consecrated by its long history of reliability and can
be validated for production of water for injection.

13
5. DISTRIBUTION AND STORAGE OF
WATER FOR PHARMACEUTICAL USE
(PW AND WFI)

Water for pharmaceutical use must be produced, stored and distributed in

order to avoid microbiological, physico-chemical or biological
contamination. The storage and distribution systems should be considered a
critical part of the entire system.

Purification, storage and distribution systems of PW and WFI should be

designed to prevent microbial contamination and proliferation.

The storage and distribution system must be configured to avoid

recontamination of the water after treatment and should be subjected to a
combination of on-line and laboratory monitoring, to ensure that appropriate
specification of the water is maintained. The proliferation of contaminants
within the storage tank and the distribution ring must be controlled.

The capacity of the storage tank should be sufficient to provide short term
reserve in case of failures in the equipment of water treatment or production
incapacity because of sanitization or regeneration cycle. The distribution of
PW and WFI should be performed with continuous circulation ring, since a
water system without recirculation ring can be considered basically a “dead-
point”. The proliferation of contaminants inside the storage tank and in the
circulation ring must be controlled.

The water treatment equipment must operate continuously for significant

periods of time to avoid inefficiency, and wear, which occurs when the
equipment is switched on and off frequently.

Mechanisms shall be employed for microbial control and sanitization of

purified water systems kept at room temperature, as these are particularly
susceptible to microbial contamination, especially when the equipment
remains static during periods of little or no water demand. Maintenance of a
turbulent circulating flow in the water distribution system reduces the
likelihood of biofilms formation. Thus, systems should promote constant
recirculation of water.

14
Conditions with no flow or low flow can cause microbial proliferation and
development of biofilms, especially in pipelines for water distribution.
Considering the importance of the flow of water to control microbial load,
this parameter must be constantly monitored.

The configuration of the distribution systems should allow a continuous and

turbulent flow of water in pipes by recirculation. The use of non-recirculating
systems, without circulation ring or “single-way” should be avoided
whenever possible. The industry experience has shown that continuous
recirculation systems are easily operated.

Systems equipped with circulation rings, besides reducing significantly the

possibility of microbial contamination of the water, are easier to undergo to
continuous and periodic sanitizing. Exceptionally some systems without
storage tank and without circulation ring might be accepted depending on the
purpose of the PW, such as for example, a company that uses water only for
washing equipment. In this exceptionality could also be fitted companies that
use water only sporadically, as for example, once a week. In this situation
would be apparent that the volume of water used associated to the frequency
would not justify a water system with storage and distribution. However,
technical justifications and procedures are necessary to ensure the safety of
operations, mitigating the inherent risk.

Moreover, for production and distribution of water for injection (WFI) the
absence of a storage and distribution system is unacceptable because of the
high risk involved in the process.

The sanitization procedures and technologies are of utmost importance for

the microbial control of production systems, storage and distribution of PW
and WFI. The temperature of the system is a very important parameter to be
considered in the design. It is recognized that systems kept heated at
temperatures between 65 and 80°C are self-sanitizing and therefore less
susceptible to microbial contamination than systems that are kept at lower
temperatures. Because they are considered self-sanitizing, well designed
systems and maintained at elevated temperatures usually dispense frequent
chemical sanitization. In systems kept at high temperatures, chemical agents
are used more for the purpose of cleaning, during factory shutdowns.

The growth of microorganisms may be inhibited by ultraviolet radiation,

maintenance of the system at high temperature (temperatures higher than
65°C); periodic sanitization of the system using hot water (temperature
greater than 70ºC for a suitable time), system sanitization periodically using
superheated water or pure steam and routine chemical sanitization using
ozone or other effective chemical agent. The material of construction of the
system must be resistant to sanitization methods employed.

15
In systems kept warm, temperature reduction, when required by the process,
should occur for the shortest time possible. The cooling cycle and its duration
must be considered during system qualification and must provide satisfactory
results. In hot systems water reservoirs should be jacketed to assist in
maintaining the water temperature.

In systems maintained and/or sanitized with high temperatures is important to

note that the temperature sensors must be located in the most critical points of
the system. These sensors must register and show that the thermal
distribution is homogeneous throughout the system, as defined in the project.

Considering the current concepts of GMP and the mitigation of the risk
inherent to the process of production, storage and distribution of water for
pharmaceutical use, as well as the technical concepts involved in chemical
and thermal sanitization technologies, it is possible to infer that the thermal
sanitization of the system must be always the first choice. Thermal
sanitization is performed by sanitary heat exchangers installed in the system.
In this process there is no opening in the system, no need to shutdown the
system and also there is no need to perform washing with consequent
disposal of water to eliminate chemical agents required in the chemical
sanitization.

PW has a microbiological specification softer than for WFI, allowing easier

maintenance of a PW system at room temperature. In general we believe that
purification systems of PW kept at room temperature exhibit much lower risk
than WFI systems kept under the same conditions. PW systems kept at room
temperature are easier to be controlled by chemical sanitizations (e.g.
ozonation) than WFI systems. Furthermore, we must consider that
microbiological deviations in PW system, in most cases, result in a level of
criticality and risk much lower than a deviation for WFI. However, even for
the PW systems that are kept at room temperature, it is highly recommended
that there must exist heat exchangers that are capable of performing periodic
thermal sanitizations.

Considering the stringent quality requirements of water for injection and the
inherent risk in the production process, it is difficult to maintain a WFI
system operating properly at room temperature and performing only periodic
chemical sanitizations. Furthermore, systems maintained at room temperature
are susceptible to contamination, which is contrary to the principles of risk
management of current GMP.

16
Storage and distribution WFI systems must primarily be maintained at
elevated temperatures for as long as possible, as well as undergo periodic
thermal sanitizations. When there is the need for using water at a lower
temperature, for process reasons, it is recommended that the time in which
water is maintained at low temperatures is the lowest possible, i.e., when
there is no demand for use of this water (for example, in periods during the
night or weekends) it must remain heated. Therefore, it is important the
correct design and installation of sanitary heat exchangers with capability to
quickly heat and cool the water.

17
6. QUALIFICAFION OF PW AND WFI
SYSTEMS

Although this section only focus on Performance Qualification (PQ), it is

important reinforce that any water purification system must be submitted to
installation qualification and operational qualification, regardless of when the
system has been installed. In the case of new systems or significant
modifications to existing systems, the design qualification should also be
considered.

All systems of water for pharmaceutical use are considered critical systems of
quality and of direct impact on the quality and safety of medicines, so they
must be qualified. The qualifications must follow procedures previously
written and approved. The data obtained must be duly recorded and reviewed
for approval. In the qualification process, possible seasonal variations that
may affect the quality of water for pharmaceutical use should be considered.
Sanitization or sterilization techniques employed should be considered during
planning the system design and its performance must be demonstrated during
qualification activities.

The first principle that must be considered in qualifying performance of the

water system is that this study aims to provide a logical understanding of the
whole system, as well as generate technical inputs to the correct
implementation of operational procedures, especially those of sanitation,
cleaning, maintenance and sampling.

A three-phase approach must be used to satisfy the objective of verifying the

reliability and robustness of the operational system during a prolonged
period. Generally these phases are called Phase 1, Phase 2 and Phase 3.

Phase 1 is the first step of the study and precedes the use of water by the
pharmaceutical industry. It should be performed whenever a system is
starting productive activities or when undergoes changes that impact the
process. The initial concept for Phase 1 is that there is an intensive
monitoring of all sampling points of the system for all parameters specified
for water, all consecutive days for at least two weeks. An important
observation to be made is that this phase is just used to verify that the system
is robust and has capability to reliably produce, store and distribute PW or
WFI.

18
It is also during this phase that the company must adjust its key operational
procedures according to technology and reality of the respective system of
purification, storage and distribution. Therefore, in Phase 1 is not justifiable
to approve a qualification study that has out of specification results, or even
technical problems. In such a situation the company must open a deviation,
properly investigate the causes of the deviation, implement corrective actions,
and finally perform again the Phase 1.

In the execution of Phase 1, daily sampling or continuous monitoring of the

feeding water should be performed to check its quality. A test period of two
weeks must be conducted to intensively monitor the system. The following
approach should be adopted:

Perform chemical and microbiological tests according with a previously

defined program.
Daily sample or monitor feeding water to verify its quality.
Continuously sample or monitor the quality of the water after each step of
the purification process.
Continuously sample or monitor each point of use and other defined
sampling points.
Develop appropriate operational specifications.
Develop and finalize procedures of operation, cleaning, sanitization and
maintenance.
Demonstrate the production and distribution of water in the required
quality and amount.
Use and improve procedures of operation, maintenance, sanitization and
solution of problems.
Check provisionally alert levels.
In Phase 2, for an additional period of two weeks, intensive monitoring
should be performed during the implementation of all procedures enhanced
upon satisfactory completion of Phase 1. The sampling plan shall be the same
as Phase 1. Water use for the manufacture of finished pharmaceutical product
during this phase may be acceptable, provided that Phase 1 is satisfactorily
completed and approved and the Phase 2 data demonstrates appropriate water
quality and this practice is approved by the Quality Assurance area.
Occasional deviations that occur during this phase should be properly
investigated and considered in the conclusion of the study.

19
Generally it is expected that Phase 2 will also be completed without
significant deviations in the process of production, storage and distribution of
water. The approach should also:

Demonstrate consistent operation within the established specifications.

Demonstrate consistent production and distribution according with
standard operational procedures.

In Phase 3, operational procedures must now be reviewed, adjusted and

implemented. The periodicity typically is one year after the satisfactory
completion of Phase 2. During this phase the water can be used to
manufacture the finished pharmaceutical product. The objectives of this step
of qualification are:

Demonstrate reliable performance during a long period of production.

Ensure that seasonal variations are evaluated.
The sampling points, frequency and Phase 3 tests must be reduced to the
standard routine established in the procedures developed and reviewed during
Phases 1 and 2.

Upon completion of the water system qualification, a review of the data

obtained should be performed, corrective actions taken and adequacy of
operational procedures, if necessary. After review, a routine monitoring plan
must be established.

The performance requalification should be performed whenever there is a

change that has direct or indirect impact on production, storage and
distribution of PW or WFI. The analysis of the need for requalification must
be correctly performed, through the control of changes procedure. The
sampling plan for requalification of Phases 1 and 2 can be equal or lower
than the initial qualification, provided that it is duly justified by risk analysis
of the change.

20
7. REVISION OF WATER SYSTEMS
(PW E WFI)

The systems and results obtained in the monitoring of water quality must be
reviewed at appropriate regular intervals. The review team should include
representatives from engineering, quality assurance, operations and
maintenance areas.

The revision must considerate the following topics:

changes performed since last revision;
system performance;
reliability;
quality trends;
failures;
investigations;
out-of-specification results obtained during monitoring;
changes in the facilities;
updating of facilities documentation;
logbooks;
status of the current list of operational procedures.
The report of the periodic review of water system should not be restricted to
the results to analyze whether physical-chemical, microbiological and
biological results are within specification. The only analysis of the results of
quality control does not provide a dynamic view of the system and also not
allow concluding whether the system is actually under control.

The main objectives of the periodic review of the water system are the trend
analysis of the data of quality control, deviations, corrective actions, out of
specification results, among others, just to conclude if there is any trend,
either positive or negative, when appropriate, to establish a change plan.
Examples of values that can be set right after a correct periodic review are the
specifications of alert limits.

21
It is noteworthy that in the periodic review of monitoring data obtained with
the equipment installed in line and also the results of tests performed in the
laboratory should be considered.

Periodic review activities of production, storage and distribution systems

should be properly described in approved procedure. The reports must be
periodic, usually annual, and must be evaluated and approved by the Quality
Assurance department in conjunction with other sectors involved.

The elaboration of a correct periodic review of the water system must provide
subsidies and technical evidence that the system is robust and operates
without negative trends to the process, or requires corrective actions. The
conclusion of the report should be clear about the need for corrective actions
and the need for a new requalification of the installation, operation or
performance (Phases 1, 2 and 3).

22
8. FINAL CONSIDERATIONS

The technical guidelines in this document, extracted from technical rules and
national and international pharmacopoeias, seek to guide companies for
occasional needs of adequacy to the current law. These guidelines indicate
the need to seek continuous improvements in production systems of purified
water and water for injection. Meeting the current Good Manufacturing
Practices, companies reduce the risk to the quality of manufactured products.
Thus, they are contributing to the improvement of the quality, safety and
efficacy of medicines consumed by the population.

23
9. LITERATURE REFERENCES

BRASIL. Resolução da Diretoria Colegiada - RDC N.º 17, de 16 de abril de

2010, dispõem sobre as Boas Práticas de Fabricação. Diário Oficial da União,
Brasília-DF, 19 de abril de 2010.

BRASIL. Resolução da Diretoria Colegiada - RDC N.º 49, de 23 de

novembro de 2010, aprova a Farmacopéia brasileira, 5a Edição. Diário Oficial
da União, Brasília- DF, 24 de novembro de 2010.

FOOD AND DRUG ADMINISTRATION. Guide to inspections of high

purity water systems. Estados Unidos da América, 1993. Disponível em:
<http://www. fda.gov/ICECI/Inspections/InspectionGuides/ucm074905.htm>
Acesso em 27/12/2012.

WORLD HEALTH ORGANIZATION. WHO Good Manufacturing Practices:

Water for pharmaceutical use. Report. Geneva, 2005. (WHO Technical
Report Series, nº. 929, 2005) Disponível em:
<http://whqlibdoc.who.int/trs/WHO_ TRS_929_eng.pdf#page=49>. Acesso
em 27/12/2012.

WORLD HEALTH ORGANIZATION . WHO Good Manufacturing

Practices: Water for pharmaceutical use. Report. Geneva, 2012. (WHO
Technical Report Series, nº. 970, 2012) Disponível
em:<http://www.who.int/medicines/areas/
quality_safety/quality_assurance/expert_committee/TRS-970-pdf1.pdf>.
Acesso em 27/12/2012.

HEALTH SCIENCES AUTHORITY. Regulatory Guidance: Water systems

for manufacturers of non-sterile products. Singapura, 2008. Disponível em
:<http:// www.hsa.gov.sg/publish/etc/medialib/hsa_librar
y/health_products_regulation/ gmp/files_1.Par.87527.File.dat/GUIDE-MQA-
010-006-web.pdf> Acesso em 27/12/2012.

THE EUROPEAN AGENCY FOR THE EVALUATION OS

MEDICINAL PRODUCTS. Note for guidance on quality of water for
pharmaceutical use. London, 2002. (EMEA CPMP/QWP/158/01,
EMEA/CVMP/115/01). disponível
em:<http://www.emea.europa.eu/docs/en_GB/document_library/Scientific
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24
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