r

Practical guidelines
for qualifying purified
vvjater systems
Purified water (PW) plays a pivotal role in
pharmaceutical processing. This article describes the
steps required to qualify and validate PW systems at
different stages of the project phase.

Annelie Hultqvist urified water (PW) is used in the pharmaceutical industry as a raw
P material in production or to clean equipment. It is, therefore,
important that the water meets the set standards and constantly
provides the specified quality and quantity to ensure there is no
contamination of the product or equipment. Depending on quality, raw
water can be difficult to purify, and can require various processing stages
to obtain PW quality. Raw water quality can also change with the
seasons so conducting regular inspections, tests and samples is
imperative to ensure that the installation complies with regulations and
the user's requirements on a continuing basis.

Requirements for PW installations

A PW installation must meet the following requirements regarding
water quality:
• Pharmacopoeias (e.g., US Pharmacopeia,' European Pharmacopoeia,^
or Japanese Pharmacopeia^).
• cGMP. 21 Code of Federal Regulations.''
• National laws and regulations.
There are also other requirements that do not stem from the product
quality, but concern operator safety, including European directives
98/37/EC (Machinery};^ 89/336/EC (Electromagnetic compatibility);^
73/23/EC (Low voltage);^ PED 97/23/EC (Pressure equipment);^
Underwriters Laboratories (UL) standards^ and American Society of
Mechanical Engineers (ASME) codes and

User requirement specification

The prospective owner of the system creates a user requirement
specification (URS). From a practical perspective, and to obtain good
traceability, it is important that requirements are clear, well-structured,
numbered and testable. A requirement such as'heat exchangers must
be of a high quality'becomes difficult to handle in validation because it
is not a tangible statement. The requirements must also be at the right
level regarding acceptance criteria (e.g., what temperature or hardness
has to be reached or what materials are required?). It is also essential to
avoid setting requirements unnecessarily high during start-up, testing
^ K operation that, on closer inspection, do not need to be met. In fast-
track projects where time is an important factor, changes and updates
take time and it is preferable to assess the installation carefully at the
start in the requirements specification. A risk analysis regarding the end

DECEMBER 2007 PHARMACEUTICAL TECHNOLOGY EUROPE

 Hultqvist
product (e.g., water quality} should be
performed before compiling the URS.
The requirements relating to the safety
of plant operators must be part of the
risk analysis that occurs for CE marking
ofthe installation, according to the
machinery directive.
A well-devised QPR which has been
agreed on and signed by both parties,
saves time and makes it easier to
complete activities such as design,
installations and tests.
it is an advantage to divide the
requirement specification into'C'and
'Q' requirements with the help of the
risk analysis performed. This is
described in the ISPE Baseline Guide
Volume 5, Commissioning &
Qualification.''^ C stands for
commissioning and the requirement
will then be tested under a factory
acceptance test (FAT) or a site
acceptance test (SAT). Q stands for
qualification and the requirement is
Figure 1 V-model: verification of the system according to the design.
Concept and basic design
Consurtancy
URS by Christ
Quality and project
plan
Functional specifications
Mechanical and electrical
hardware design specifications
Software design
specifications
Software module design
specifications
System build — control system programming/code review
24
tested under an installation
qualification (IQ) or an operation
qualification (OQ). To find and select
the typical Q requirements for the
system, the ISPE's Baseline Guide
Volume4, Woter&SteamSystems^^
and FDA's Guide to Inspection of High-
Purity Water Systems^ "^ can provide
assistance.
The easiest way to create
traceability in the project Is to write
the requirement specification in table
format, with the requirements
divided into C and Q requirements,
which can then be given to the
supplier as a Word document for
further processing and completion of
the references to design documents
and tests. The supplier can then
create a traceability matrix from the
file, or copy the requirements to an
Excel table. This avoids having to
write the requirements in the matrix
again, thus eliminating a possible
source of errors and saving time.
Quality and project plan
A quality and project plan (QPP) is
devised at the beginning of a project.
The purpose of this is to establish
parameters for quality control (QC),
OQ
Sysrem acceptance test
Hardware acceptance test
Software iniegration test
Software rnodule test
DECEMBER 2007 PHARMACEUTICAL TECHNOLOGY EUROPE
inspections, approval, project
execution, organization,
responsibility and authorizations. This
guarantees that activities are
performed according to the
requirements set within the agreed
framework, it is also useful to write
down practical details of project
execution that are not dealt with in
the URS. This would define:
• How communication is performed.
• How the information will be
delivered to the project manager,
• Exceptions to the agreed protocols.
• Thedocument approval process.
• The people responsible for
reviewing and approving the
documents.
• The number of days assigned to
the review process.
• in which form comments must be
returned.
• The amount of time allocated for
amendments and updates, and
how the conclusions and approvals
are obtained.
Comments should be specified
in writing and compiled in one
document clarifying who has
commented on what For fast-track
projects, these approval routines are
particularly important and must be
established at the beginning of the
project, it is also recommended that
the number of approving parties is kept
to a minimum. The user should specify
which routine applies to change
requests in the project and from when
it is applicabie. A well-devised QPP,
which has been agreed on and signed
by both parties, saves time and makes
it easier to complete activities such as
design. Installations and tests. An
interface agreement should also be
issued early in the project and wiil
clarify details regarding tie-in points,
control system interfaces and media.
Design
During the design phase ofthe
instaiiation, the focus is on existing
requirements and catering for them
in the design, it is crucial to have an
analysis of the incoming water to
design the system correctly with the
right pretreatment for the
application. There is plenty of
literature regarding the design of
water purifying installations.
Pharmaceutical Water System Design,
Operation, and Validation''^ is
particularly useful, and Baseline
 Hultqvist

Volume4 Water & Steam Systems^^
from ISPE is essential.
Design documents
The following design documents
are consulted for a water treatment
system:
• piping and instrumentation diagram
(P&ID)
• functional specification (FS)
• software design specification
• hardware design specification (HDS)
• electrical schematics
• layout drawing
• component list
• instrument list
• valve list.
The documents illustrate the set
installations and functions of the
system. When the system is built, the
design specifications will be used for
the verification of the system during
commissioning and qualification. At the
end of the project, when all inspections
and tests are performed and possible
deviations are measured, it is important
that the 'as built'design documents are
included into the documentation of the
system (Figure 1).
Design verification
The design is verified in relation to the
user's requirements, ensuring they will
be complied with. This is easily done
by establishing a traceability matrix in
table form from the URS (Table 1).
Design approval
The design approval is an important
milestone in a project as it makes
it possible to progress with
manufacturing and programming.
To reach an approval it is necessary
to review all design documents
and drawings according to the
requirements (Figure 2).
Acceptance tests
With today's tight time schedules,
a FAT is very useful for the new
installation of a plant. The advantage
is that premanufactured units are
checked and tested as much as
possible before they are sent to
site. This is of absolute necessity, for
example, in a turn-key project where
lots of equipment shall be installed
and commissioned in a short time
frame. If the skids/units are at
the factory, it is quick and efficient to
make any changes to eliminate any
deviations.
During FAT and SAT, typical
C-defined requirements will be tested
according to good engineering
practice (GEP) as described in the
ISPE Baseline for Commissioning and
Oualification.^^TheC requirements
do not have a direct impact on the
product quality and it is an advantage
to per-form as many of those tests
as possible in the factory. To get an
impression of process vaiues, product
quality and system capacity, these
values can be recorded in the factory.
The C requirements not tested during
EAT will be performed onsite within
the SAT Protocol. The FAT and SAT
results will be presented in a FAT and
SAT report respectively.
Installation qualification
This is performed by a number
of different verifications, such as
mechanical inspections, instrument
calibrations and documentation
verifications. It is recommended
to include a review of the FAT/SAT

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subscribe at www.ptemagazine.com 25
 Hultqvist

reports at the start ofthe IQ to ensure
that all deviations have been closed.
The sequence of test performances
also needs to be considered. The slope
of the pipes must, for example, be
measured before the distribution pipe
is insulated — in the case of a hot
distribution system — which often
occurs before the IQ is started because
the instaiiation is ready.
Documentation verification is a test
where the status must be checked
Table 1 bility matrix showing in which protocols and tests the reauirements will be met.
Request number QC Description
URS.2301-01 3.2,1 AH instrumental-
mounting sites
(measurements
sites) must be
marked with the
TAG number, indicated
in the P and I diagram.
according to the project schedule on
the iQ precisely, otherwise the IQ test
could be open until both IQ and QQ
are ready and the final
documentation has been copied. A
good way of performing document
inspections is to have a document
schedule clearly indicating which
documents must be completed by
when in the project. When the IQ is
finished and reviewed, the result is
presented in the IQ report and, if no
Protocol
FAT-50303-01 FAT03
SAT-50303-04 SAT02
critical deviations were identified, the
OQ can begin.
Operation qualification
TheQQ will verify the operation of the
system according to the descriptions
in the FS highlighted as critical for
the product. The acceptance criteria,
particularly for the QQ, must be
carefully evaluated — which
conductivity and temperature must be
complied with? Which flow? What are
the actual limits? What is acceptable
for the process and the product? The
product requirements depend on the
water quality that the system has
been designed to achieve.The process
engineer should also have evaluated
suitable alert and action levels for the
process, which form the basis for the
alarms generated by the system. When
all tests are performed and reviewed,
the result of the OQ is presented in
the QQ report. If no critical deviations
were identified, the PQ can start.

Figure 2 ing and instrumentation diagran^ distillation unit

26 DECEMBER 2007 PHARMACEUTICAL TECHNOLOGY EUROPE

General
Test procedures should be written in a
way that is complete, understandable
and possible to repeat. With all
qualifications. It is important to collect
all relevant data, make clear references
to documents used, mark attachments
and review performed tests regarding
completeness, traceability and
signatures.
Complete documentation for
the water treatment system
It is fundamental that the structure of
the documentation must be:
• logical
• trackable
• simple
• clear.
Simplicity and user-friendliness
are key, and cannot be emphasized
enough. It has to be possible to find
specific sections/documents several
years later and the supplier must
consider whether the structure is
logical. If it seems compiicated it
should be changed until it can be
explained and defined in a logical
manner. The supplier may also
consider whether there are
groups/departments that need
different parts of the documentation.
It may be advantageous to have
certificates for instruments, valves and
components in separate binders, and
data sheets, technical specifications
and manuals in others. Certificates are
often stored by the quaiity department
whiie technical documentation is
needed by the users.
Decisions must be justified and
followed to obtain consistency in the
documentation. The system owner
should understand the train of
thought and how the tests were
performed at a latter stage. Good
documentation practice (GDP) must
be followed. Nothing must be left
incomplete and empty — unused
fields in tables, for example, should be
crossed-out. The execution must be
followed by a review to detect
whether anything is incomplete, or
has not been described or referred
to in a logical way.
Summary
The main focus when validating water
treatment systems should be on the
requirements the water must comply
with. This relates to parameters that
controi the current water quality,
subscribe at www.ptemagazine.com
such as: conductivity, total oxidizable of the LawiL^vlember States Relating to
carbon (TOC), microbiological values Electrical Equipment Designed fof Use
and the presence of contaminants, Within Certain Voltage Limits.
including endotoxins, nitrates and www.europa.com
heavy metals. 8- Directive 97/23/EC of the European
A risk assessment for the system Pariiarnent and of the Council of 29 May 1997
should be created based on these on the Approximation of the Laws of the
parameters, and the process steps and Member States Concerning Pressure
components required to produce the Equipment.
desired quality need to be evaluated. www.europa.eu
The design of the water purification 9. UL Standards for Safety (Underwriters
system should then be assessed and Laboratories Inc.)
the appropriate inspections and tests www.uLcom
developed. A thorough knowledge 10. ASME Codes and Standards. ASME Boiler and
of the process is required to perform Pressure Vessei Code, {ASMS, 2004) Section B,
optimum qualification. Good Division 1.
communication and a comprehensive 11. ASME Codei and Standards. ASME
understanding of the requirements Bioprocessing Equipment [ASME, 2'
at the planning phase will guarantee 12. Baseline Guide, Volume 5. Com
a successful project — and a water and Qualification (ISPE, 2001) p 1
treatment system that performs 13. Baseline Guide. Volume 4, Water
well. SS SyjtemsdSPE, 2001) p 228.
14. Qulde to Inspections of High Purl
Annelie Hultqvist Systems (US FDA, 1993],
is the QA/validation manager at Christ www.fda.com
Nishotech Water Systems Pvt. Ltd in Navi yS.'^N.CoWerwto, Pharmaceutical Water System
Mumbai (India). She began her career at a Design. Operation, and Validation (Informa
fermentation company in Sweden and became Healthcare USA, 1998) p 694.
a validation engineer in 1998. She was a
member of the team which staned Christ
Nordic AB in 2000 where she was responsibie
for quality and validation. She has worked on
projects across Europe, as well as In the US.
References
1. US Pharmacopeia Edition 29, (12601
Twinbrook Parkway, Rockeville, MD, USA
20852, 2006),
2. European Pharmacopoeia Edition 5
(EDQM,226. avenue de Colmar BP 907,
F-67029 Strasbourg, France, 2005).
3. Japanese Pharmacopeia Edition J4 (National
Institute of Health Sciences, Kamiyoga
1-18-1, Setagaya-ku, Tokyo 158, Japan,
2001).
4. 21 CodeofFederal Regulations —Part 210
Current Good Manufarturing Practice in
Manufacturing, Processing, Packing, or
Holding of Drugs; Generai, 2005.
www.fda.gov
5. Directive ^S/ST/EC of the European
Pariiament and of the Councii of 22 June 1998
on the Approximation of the Laws of the
Member States Reiating to Machinery.
www.europa.eu
6. Directive 89/336/EC on the Approximation
of the Laws of the Member States Relating
to Electromagnetic Compatibility, 2004.
www.europa.eu
7. Directive 2006/95/EC of the European
Parliament and of the Councii of
12 December 2006 on the Harmonisation