On-Line Exclusive Article

PHARMACEUTICAL ENGINEERING

Risk-Based Equipment Qualification

The Official Magazine of ISPE

May/June 2007, Vol. 27 No. 3

This article presents

an efficient
cooperative
approach to
Commissioning and
Qualification (C&Q)
for manufacturing
equipment and
covers the entire life
cycle for the
specification, design,
manufacture,
installation,
commissioning,
qualification,
operation, and
maintenance of the
equipment in a riskbased approach.
This article reflects
the current status of
the work in progress
conducted by the
GAMP Italia
Equipment Validation
Workgroup. The
main topics covered
in the article are:

Copyright ISPE 2007

holistic risk-based
approach covering
business, safety,
and quality risks
involvement of
the supplier in the
risk management
process and risk
analysis
support from the
supplier in the
C&Q activities
(risk-based)
team building
time savings
trends
good engineering
practice

Risk-Based Equipment Qualification:

A User/Supplier Cooperative Approach
by GAMP Italia - Equipment Validation Workgroup:

Sandro De Caris, Marco Bellentani, Beny Fricano,

Carlo Bestetti, Marco Silvestri, and Barbara Testoni

GAMP Italia and

Equipment Validation Group

AMP Italia is a local Community of

Practice that was introduced to the
ISPE community in December 2005,
during the ISPE Milan Conference.
The mission of GAMP Italia is to improve
the communication among users, suppliers,
consultants, regulatory authorities, and
academia, helping life sciences companies
streamline their validation processes through
a more consistent application of good practices
and the GAMP guidance on both the suppliers
and users side.
GAMP Italia operates in accordance with
the general objectives of the International
GAMP Forum and reports to the GAMP Europe Steering Committee, like other regional
groups (GAMP Nordic, GAMP D-A-CH, and

Figure 1. Standard
equipment development
Life Cycle.
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GAMP Francophone).
The Equipment Validation Group is the first
working group started within GAMP Italia and
is composed of members coming from equipment manufacturers, consultants, end users
(pharmaceutical companies), and academia.
The group is currently preparing document
templates useful for supporting qualification of
different standard and non-standard equipment.

Background
Most equipment currently available on the
market is the result of a very long and uninterrupted improvement process that started many
years ago and brought to the current design.
There is a significant difference between the
purchase of a standard system, as opposed to
the development of a bespoke or custom
made
equipment.
Pharmaceutical users
in most cases are just
buying and installing
standard pieces of
equipment. The design
of new parts or new
functionality is often
negligible, or limited to
a small part of the process. Nonetheless, users are currently spending significant human
efforts and financial
resources in commissioning and qualification activities that are
sometimes excessive
and redundant, quite often including a mere
repetition of verifications already performed
by the manufacturer.

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Risk-Based Equipment Qualification

Inefficiencies also arise from the variable formulation of
different requirements (from different users) for the manufacture of the same standard equipment (from the same
supplier). This may easily lead to different validation approaches and sometimes to very different set of documents on
behalf of the supplier. A more uniform approach and a riskbased definition of the requirements can result in a significant savings in time and effort spent for both parties.
Risk-based qualification can improve quality and
reduce validation efforts. ISPE is actively suggesting this
approach, which is now being used more and more extensively.8,9
Risk management can be significantly enhanced with the
supplier support, because they have a deep knowledge of the
systems they produce. This approach can ensure faster,
cheaper, more complete, and reliable results.
Indeed, C&Q activities can be significantly abbreviated when the supplier is involved since the early
stages of the process and the efforts done during the
product development and subsequent manufacturing are
taken into account.
The main objective of the Equipment Validation Working
Group operating within GAMP Italia is to suggest a more
profitable role of the supplier during the entire equipment
life cycle from specification and purchase, through manufacture and delivery, commissioning and qualification, use,
maintenance, and even retirement.
Considering the current high level of automation in the
industry, it is important to look at computerized systems
and process control software, either embedded or standalone related with the equipment. The importance of computer control systems is emphasized because in some cases,
the equipment is completely dependent on the proper behavior of the software. Computer systems may include PLC or
microcontrollers and Human-Machine Interface (HMI), supervisory PC (e.g., SCADA systems, statistical process control), as well as interfaces with other remote systems like
Manufacturing Execution System (MES).
Therefore, the discussion includes both computer validation and equipment qualification in an integrated approach.
More complex and potentially GxP critical scenarios are
on the horizon due to the emerging Process Analytical
Technology (PAT) applications that may bring new computer systems operating in strict connection with the equipment to ensure product quality. The proper identification and
management of Critical to Quality Attributes and the relevant Critical Process Parameters may significantly help
develop a PAT-ready equipment and extend the ICH Q8
Design Space concept into the equipment process variables.10

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Development Life Cycle

A practical risk-based approach should consider the real life
cycle of the product development (as opposed to the life
cycle in the delivery of a single instance of the standard
equipment). Most manufacturers today have very standard
equipment, designed for a large market and highly modular.
This is quite common for instance with automatic machines
like capsule fillers and tablet presses, and packaging lines,
etc. The design of the equipment for a single customer is
largely a matter of choosing the right model and assembling
together the appropriate optional parts. Practicing good engineering practice is largely sufficient to qualify many elements of standard equipment.

Equipment Categories
To simplify the management of equipment qualification/
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Basic Concepts
Good practices help ensure high quality products.
Properly designed and manufactured products are safe, robust and reliable, well documented; therefore, they should be
easy to qualify and/or validate.
This is true for both pharmaceutical products and the equipment used to manufacture the products.

Commissioning, qualification, and validation activities

are only the final stage of a long process, and can be more
easily and successfully performed if the entire development
life cycle of the equipment is considered, supporting best
practice and the concept of Quality by Design (QbD) when
these are pursued by the manufacturer of the equipment.
This approach closely relates to good engineering practice,
which is endorsed by the ISPE Baseline Guide on Commissioning and Qualification.8
There is a strict similarity between GEP and GMP: in both
cases, quality should be achieved by design, and not just
tested at the end of the process. Embedding quality into an
equipment design is mostly a suppliers responsibility in a
cooperative and trustworthy relationship with the user.
A risk-based approach requires the identification of
critical items, distinguishing them from ordinary items,
and dealing with them in a differentiated manner. Criticality
may refer to different aspects of the product or process:
quality, safety, and business being the most common areas of
interest.
Critical items and key documents should be identified
from the beginning of the project (i.e., explicitly documented
in the User Requirements Specification), properly traced to
standard offerings of the supplier and managed during the
design and manufacture of the equipment, and then carefully
verified during C&Q in a conscious and efficient manner.
C&Q should concentrate on critical items, according to a
sound risk evaluation methodology, and following a structured risk management process.
Standard, non-critical parts (e.g., non contact parts, functionality with no or little impact on product quality) can be
implicitly qualified during manufacturing if the supplier is
capable of demonstrating suitable maturity in the design
and manufacturing. Verifications performed during FAT and
SAT can be used as a proof of the good design and good
manufacture, without the need of repeating the same tests
over and over.
The expertise and knowledge of the supplier and the
activities performed during manufacturing should be used to
avoid redundancy.

Risk-Based Equipment Qualification

validation, it may be useful to distinguish the following main
classes of equipment:
standard equipment with no configurable parts or functions
standard configurable equipment, having two possible
levels of configuration:
- definition of which standard parts are to be included
- setting of parameters for the parts included
custom or bespoke apparatus (prototypes of new equipment, custom built) specifically developed by the supplier
to meet a set of specified user requirements
Standard configurable equipment may contain some custom
parts that should be identified and treated as bespoke apparatus.

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Development vs. Configuration

The development of new products (standard equipment)
follows a complex life cycle, normally defined in the suppliers
Quality Management System. A good reference is the V
model included in GAMP Guide.2
The product is released on the market following an incremental life cycle with many different releases during the
product life span. The entire process, limited to software
portion for simplicity, may be summarized in Figure 1.
The large variety of customer requirements results in a
very high level of modularity within the same equipment.
Different models, different optional units, and a large amount
of variable parameters are normally available in a standard
equipment.
A new version of the equipment and/or its relevant control
software is delivered to the Customer only when the development process has been completed. This includes the management of functional and technical specifications, and the
execution of all defined test cases. New custom (bespoke)
functions may become part of the evolving standard.
Therefore, the standard product development line is orthogonal to the configuration process, needed to tailor the
general product to the customer specific requirements.
Software for a single piece of equipment is quite often
upgraded during the operation period, even long after the
start-up, for instance when new products are to be manufactured. The life cycle for the delivery of a single system from a
combined user and supplier viewpoint can be seen in Figure
2.
The knowledge of the actual product life cycle and the
differentiation between the management of standard parts
vs. bespoke parts is fundamental for an appropriate risk
management.

A Holistic Risk Management Approach

Figure 2. Delivery life cycle for a specific user.

Safety
Business

Product Quality Aspects (GxP)

In this case, what matters in the pharmaceutical industry is
the quality of the final product delivered to the patient. In this
area, all GxP requirements are included. The quality hazard
impact can be evaluated according to:

Risks may arise in different areas:

Quality
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damage to patient (illness, temporary or permanent side

effects, death)
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Risk-Based Equipment Qualification

compliance issues with the authorities

production loss (indirect damage)

Typically, quality aspects are identified by Critical to Quality

Attributes (CQAs) for the product.

Business continuity, line efficiency, down time, size change

over, and line set-up are important items in this perspective.
A description of an overall risk management process is
shown in Figure 3.

Safety Aspects (Operator and Environment)

In this case, what matters is the evaluation of the potential
damage to the personnel operating the equipment and/or the
impact on the environment caused by system malfunctions.
The safety hazard impact can be evaluated according to:
damage to personnel (temporary or permanent injury,
death)
damage to the environment (damage to people who live
outside the factory)

Business Aspects
In this case, what matters is the evaluation of the potential
damage for the business caused by system malfunctions or
lack of availability. The business hazard impact can be
evaluated according to:
cost of components to be replaced and workmanship (direct damage)

Risk Analysis
The results of the analysis depends largely on the impact that
the customer assigns to each identified source of risk. The
same function could be potentially critical in a specific application and non-critical in a different one. Cooperation between customer and supplier is essential to properly manage
risks.

User - Supplier Cooperation

The supplier can provide a large number of support activities
and services during the life cycle of a product, under all the
different perspectives, offering a significant contribution in
the risk management process.
A general risk management flow can be adopted. ICH Q9
established a standard approach for Quality Risk Management that is quite general and can be easily adopted for all
three areas.

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Figure 3. Overall risk management flow chart.

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Risk-Based Equipment Qualification

Involvement of the supplier in the process can include a
large part of the risk analysis, provided it is based on the
information supplied by the user.
In more detail, the sequence of operations can be seen in
Figure 4.
The flow of operation also illustrates the embedded Risk
Communication process between user and supplier along the
entire life cycle, and their different role and responsibility in
the risk management process. The following three main
phases can be distinguished:
1. Specification Phase. Its the responsibility of the user to
communicate potential risks and the relevant impact to
the supplier so that important items are properly managed during design and manufacturing of the equipment.
The supplier should be made aware of unwanted issues
impacting the quality of the product, the safety of the
operators and the business, and the relevant impact level.
2. Design and Manufacture Phase. Its the responsibility
of the supplier to identify critical parts (such as mechanical units, components, software functionality, or parameters) and communicate these to the user. The user can
then wisely evaluate the risks and provide additional
controls or countermeasures where necessary, and finally
accept the system design when residual risks are below an
acceptable threshold.

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3. Operation Phase. The operation and maintenance of the

equipment should be performed in cooperation with the
supplier to maintain constant performances over the time
and/or improve the system when necessary.
It should be noted that while the technical part of the risk
analysis can be performed by the supplier, its a responsibility of the user to evaluate the risks, to provide
any required additional controls, and finally to accept
the residual risks. This possible separation of roles has
been clarified in ICH Q9.16
Its important to distinguish between elements criticality and process (residual) risk: an element (system component or function) may be critical because it guarantees the
product quality, nonetheless, the residual risk for the process
can be low due to the high reliability of the element.
However, irrespective of the residual risks, critical parts
should be identified because they need qualification/validation.
Standard parts exhibit less risks than custom parts and
functions. Under a risk perspective, the explanation is in
their improved reliability and lower probability of failure
(while the impact remains unchanged).
When the risk analysis is conducted purely for compliance
purposes (e.g., to define qualification/validation activities), it
can be performed at a high level, without entering into system
details such as analysis at component level.
When the risk analysis is required to investigate on
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specific quality hazards or to cover safety and business risks

(e.g., reliability of the equipment), additional difficulties
arise on the users side: the user doesnt have sufficient
information and knowledge about the system and the analysis can be very labor intensive and time consuming. One of
the difficult items to characterize the system is the probability of occurrence for adverse events since these are quite
often related to system components reliability. The manufacturer on the other hand has the necessary knowledge, can
guarantee an investigation with sufficient level of detail, and
can afford an investment of time and resources on a product
that is intended for a wide market and not only for a single
user.
Its worth observing that risk analysis performed by the
supplier should be somewhat parametric. The results should
in fact be tailored to the specific list of hazards and their
impact level, as communicated by the user during the specification phase.

Validation Life Cycle

Based on the Equipment Validation Group experience, the
following are preliminary recommendations on the entire life
cycle of a generic piece of equipment. Further and more
specific suggestions will be included directly in the dedicated
documents the group will produce in the future for each
equipment type.
The Equipment Validation Group is preparing document
templates useful for reducing the time and efforts in the
entire delivery process, including C&Q. Templates are produced in an industry wide perspective and include suggestions for tailoring the document to the specific application
case.
The group realizes that producing standard documents is
not always possible considering the variety of different mechanical, electrical, and software solutions available on the
market. Where a general template cant be produced, the
group will prepare a guide for the preparation of the document.

User Requirements
To properly implement a holistic risk-based approach, it is
necessary to start defining critical items from the beginning
of the process. The user should provide the supplier with the
identification of different hazards (quality, safety, and business) and the relevant impact evaluation.
The following are some specific suggestions:
The User Requirements Specification (URS) should be
treated as a contractual document, avoiding conflicts with
other technical specification documents. The URS should
not be considered a mere part of the validation documentation, but rather the main - and possibly only - specification document for the equipment.
Ideally, the requirements should be independent from the
suppliers product and express customer needs without
addressing specific design solutions.
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Risk-Based Equipment Qualification

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Figure 4. User-supplier cooperation scheme.

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Risk-Based Equipment Qualification

The URS should, as a minimum, cover all mandatory
parts, including those necessary to guarantee the final
product quality and achieve compliance with the rules.
One often neglected part is the definition of the expected
quality of the product and the level of allowance for
unwanted defects.
Requirements on equipment safety and business performances also should be included.
Figure 6. Standard vs. specific documentation.

Detailed technical requirements which are typically produced by the user may be included if appropriate in an
annex of the URS, as this document usually specifies
design solutions rather than equipment performances.
Ideally, all requirements should be identified with a unique
code for easy and unambiguous traceability and classified
according to the impact. If possible, impact should be
defined in more than one level (e.g., high/medium/low).
Business requirements should be classified according to
their priority (e.g., mandatory or nice to have.)
Generic requirements like the software shall be 21 CFR
Part 11 compliant should be avoided. High level identification of GxP critical data which are expected to be
handled by the system should be done at this stage of the
process.
The main issue for the customer during the requirement
phase is to identify the most appropriate supplier and the
most appropriate equipment model that can satisfy all the
requirements.

Validation Plan
The Validation Plan should be developed by the user considering the actual life cycle of the manufacturer that changes
significantly depending on the amount of design activities

required to deliver the equipment. Efforts should be based on

the overall risk scenario, thus, considering on a global level,
aspects related to standard components, supplier, and product maturity.

Overall Risk Scenario

Product and supplier maturity should be evaluated. A good
guide is provided in the GAMP Good Practice Guide: Testing
of GxP Systems;6 - Figure 5.

Supplier Maturity
The supplier maturity should be evaluated with a detailed
analysis of the design, manufacturing, and support processes
of the supplier. The supplier audit is the best tool to achieve
this goal and its an important part of the process. To facilitate sharing and comparison of information, the use of standard checklists is highly recommended, such as the one
proposed in the Appendix M2 of the GAMP Guide.3
Re-use of previously performed supplier audits is encouraged, especially within large organizations, thus, avoiding
repetitions and redundancy. A secrecy agreement with the
supplier may be necessary.

Product Maturity
Product maturity should be carefully evaluated, considering
the level of standardization achieved for the specific equipment. This may require an investigation with the supplier,
and a standard survey may prove useful when selecting
among different suppliers. Standard and robust products
should be preferred to custom solutions, unless strictly necessary. Custom (bespoke) systems normally exhibit much
higher risks and should be handled with extra care.

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Functional Specifications

Figure 5. GAMP GPG: Testing of GxP Systems (Figure C1.1:

Supplier and Product Maturity Model - Chapter. 1: Minimizing User
Testing).
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Functional Specifications (FS) are documents commonly produced by the manufacturer. FS for a standard equipment can
be structured in a standardized validation package that
often includes Design Specification (DS), plus Installation
Qualification (IQ) and Operational Qualification (OQ) protocols - Figure 6.
The main issue here is to map variable User Requirements with standard elements (components or functionalities)
of the equipment. This is normally done by the supplier
during the User Requirements evaluation phase. Different
situations may arise when analyzing each User Requirement:

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Risk-Based Equipment Qualification

1. The requirement can be satisfied with a standard basic
element.
2. The requirement can be satisfied with an optional element.
3. The requirements involves the re-design of an existing
element.
4. The requirement involves the design of a new element.
Cases 1 and 2 are very similar: the main difference is
generally only at the commercial level, and both can be
considered as standard equipment.
Case 3: The re-design should be managed by the supplier
under strict change control and the decision should be made
to include the change in the standard product or consider this
as a customer specific (bespoke) difference. Bespoke components are highly discouraged in the development of standard
equipment, but this may be the only way forward.
Case 4: New parts can be designed on demand and still be
included in the standard product life cycle, but the risk may
be higher for the first installations. Software is normally
managed as a standard product, typically highly configurable
with many parameters.
To ensure traceability with the User Requirements, each
single Functional Specification should be identified with a
unique code.

Traceability Matrix
Producing a Traceability Matrix (TM) is very important for
C&Q activities. It can help to trace all user requirements,
thus, ensuring both complete coverage of URS and test
coverage of the critical functions.
Following the GAMP suggestions, TM should report the
criticality level of each function. This can help the quick
identification of critical functions. Safety and/or business
critical functions also should be properly identified in the TM
to achieve a holistic system criticality understanding.
In addition to the recommendations from the GAMP
Guide,4 additional information should be included in the TM
regarding the level of standardization of the function. Higher
risk non-standard functionality can be quickly located in this
way.

Design Specifications

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Risk Analysis (and/or Risk Management Plan)

The supplier may play a very important role in the risk
management process. This has already been covered in the
discussion A Holistic Risk Management Approach.
Under the modern approach of ICH Q9, the risk management concepts along the entire life cycle should replace the
pure risk analysis performed in a single phase. Therefore, it
is recommended to prepare and follow a Risk Management
Plan, rather than a single Risk Analysis document.
It should be remembered that according to the spirit of
ICH Q9, risks should be carefully evaluated by the user and
residual risks formally accepted.
Before starting the risk analysis process, it is essential to
establish the scope: to either evaluate only the quality aspects and define the validation approach, or also to cover
safety and business aspects.
In the first case, the risk analysis can be efficiently
performed by the user, adopting a top-down technique like
Fault Tree Analysis (FTA) to cover specific product quality
related risks.
In the latter case, risk analysis should be more detailed
and cover system components. This is in general a complex
and time consuming exercise that can be effectively performed by the supplier using a bottom-up technique like
Failure Mode and Effects Analysis (FMEA). This approach
also helps with preparing the list of critical items (GxP,
safety, business). Making this information available to the
user is an important part of the risk communication process.

Equipment Construction, Commissioning and

Qualification
Significant savings can be achieved if efforts are focused on
critical items of the equipment and the results of previous
testing phases - Figure 7.

Check-Out Testing
Consolidated software versions installed on each equipment
are tested by the manufacturer according to the development
life cycle.
The check-out internal testing phase at the suppliers
premises has the purpose to ensure that the equipment is
properly built and functioning in all of its components (mechanical, electrical, electronic, and software) and that it
satisfies the specific user requirements provided by the
customer. The focus of testing activities before the delivery of
a standard equipment to a specific user is the proper configuration (selection of items and parameters that satisfy the
user requirements), and proper integration in the equipment. These testing activities can be optimized. For instance,
if a software algorithm has already been tested during the
development process, it is not always necessary to include it
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Design specifications for standard equipment should describe the equipment, rather than fit specific User Requirements. The main purpose of the documentation is to provide
the user with useful information for the operation and maintenance of the equipment. Normally, the supplier is able to
demonstrate traceability between standard DS and the relevant standard FS. This traceability also may be included in
the standard Qualification/Validation Package.
However, design solutions that are arranged specifically
for the user should be identified. Non-standard solutions
should be managed with additional care and specific details,
especially when they cover critical aspects of the system.
The supplier should provide all the required documents
for the parts included in the final equipment. As-built docu-

mentation (such as electrical, lubrication, and pneumatic

diagrams) is commonly available from the supplier.
Additional documents may be contractually agreed between the user and the supplier in the technical annex of the
URS.

Risk-Based Equipment Qualification

already produced during the FAT, focusing on parts and
functions that may be compromised by the disassembling,
transport, and reassembling process. The supplier may help
with indicating which tests are to be repeated at the final
destination. Testing of non critical parts or functionality may
adequately be covered by the SAT, without any need for a
formal qualification. Additional suggestions about the management of commissioning activities can be found in the ISPE
Baseline Guide on Commissioning and Qualification.8
The supplier supports the customer with plenty of documentation that can be used to develop the specific preventative maintenance plan and the calibration plan. Additional
suggestions can be found in the GAMP Good Practice Guide:
Calibration Management.7
Information from the supplier may be useful to prepare:

Figure 7. Testing activities.

in the check-out.
Quite often the equipment check-out is ignored during the
subsequent steps of the commissioning and qualification,
while the evidence of these tests could provide sufficient
information and avoid test redundancy.

FAT
A Factory Acceptance Testing (FAT) phase can be executed to
check congruence of the system to the purchase order and its
proper functioning with the actual customer products. FATs
are mainly intended to allow the customer to verify proper
construction and operation of the equipment at the suppliers
premises; therefore, authorizing delivery to the users plant.
The documentation produced during the FAT may be in part
re-used during the subsequent Site Acceptance Test (SAT).
When the supplier has been properly qualified, a significant reduction in testing activities can be done. FAT should
concentrate on critical items identified in the previous steps
of the process. Testing of standard parts can be evidenced by
the internal test results of the supplier, including the final
check-out documents.
The execution of FAT may be skipped for standard equipment produced by well-known suppliers, while the user may
require the testing documentation (e.g., final checkout results) before authorizing delivery.

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Commissioning and SAT

The supplier normally supports the customer during the
installation of the equipment, connecting utilities, and performing initial installation tests. The usage of standard
check-lists is highly recommended in this stage.
When the installation has been completed, a Site Acceptance Testing (SAT) phase can be executed to verify proper
operation of the equipment at the users premises, including
local interfaces with other systems. SAT efforts may efficiently be reduced re-using the experience and documents
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training
SOPs
business continuity/disaster recovery planning
maintenance planning and action procedures

Qualification: IQ, OQ, and PQ

IQ, OQ, and PQ activities should be limited to systems and
components with Direct Impact on the product quality. All of
the rest of the system may be simply commissioned and
managed according to good engineering practice. The identification of critical parts is an outcome of the Risk Analysis.
IQ and OQ may be easily conducted using the standard
Qualification/Validation Package normally available from
the supplier, covering the majority of physical and functional
features of the equipment. This documentation should be
produced in accordance with a sound risk-based approach.
The execution of IQ and OQ tests may be accelerated with the
support of the supplier, especially when using its document
set. However, specific URS and relevant Critical Process
Parameters also should be addressed by IQ and OQ with
additional tests to be integrated into or enclosed to the
supplier standard package. The responsibility of the qualification testing is still with the user who should review and
approve the documents and witness the execution of the tests.
Repetition of tests already performed during equipment
check-out, FAT or SAT is normally redundant and should be
performed only when the previous tests can be compromised
by other activities.
PQ is more specific for the customer application and some
level of tailoring from a standard template is quite often
necessary. The supplier may optionally contribute in the
preparation of this document as well as support the execution
of the relevant tests.

Training
Training is another important part of the commissioning and
qualification phases. Specific sessions for the different roles
involved in the usage of the equipment should be designed by
the supplier in order to explain the right things to the right
people. The supplier should prepare a suitable risk-based
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Risk-Based Equipment Qualification

agement of GxP and safety risks.

On-Going System Operation

Once the equipment is in production, there are still several
opportunities for the customer and supplier to keep on the
positive cooperative relationship created during the start-up.
The supplier may support the user to perform most critical
and complex maintenance checks and operations with specific frequencies.
In addition to these maintenance interventions, the user
should periodically review and evaluate the system performances.
As a result of this analysis, the user may decide to perform
a periodic revalidation repeating a subset of IQ/OQ tests
covering the components and features with higher criticality
level in order to demonstrate that the system maintains its
validated state. The supplier can still support the customer to
identify appropriate tests and execute them more rapidly.
Other services that the supplier can provide during the
life-time of the equipment cover the following aspects:
specific training sessions to new people involved in the
equipment operation
software and/or hardware upgrade and relevant qualification activities (typically performed to comply with updated regulations, to renew obsolete components, or to
adopt improvements applied to the product installed on
different equipments)
warranty services
extraordinary maintenance interventions
support for equipment relocation from one site to another

Decommissioning
The supplier may support the user even in the final stage of
the equipments life. At system retirement, it may be necessary to safeguard important information that is kept in the
system, because the mere backup or recovery procedures
could not fit for data migration to a new, different, equipment.
The supplier role, in the case, may be helpful in many aspects,
including managing obsolete mass storage devices or coding
specific software filters.

Quality Audits

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Conclusions
To save time and money in the commissioning and qualification activities still guaranteeing the final proper quality level
of the equipment and the relevant production, it is basilar to
use a risk-based approach that focuses on critical items of the
equipment and critical activities of the life-cycle.
The knowledge of the actual manufacturing life cycle may
aid in the identification of critical steps in the process,
distinguishing the production and assembling of standard
parts from the design of custom parts.
Supplier involvement from the early stages of the process
can further improve savings. Building a trustworthy relationship between the user and supplier can reduce redundancies and provide significant advantages for both parties.
C&Q efforts can be significantly reduced using mature
products and mature suppliers. Using best practices in the
design and manufacturing bring the mature supplier closer
to the sphere of Quality by Design, improving their products
and services.

Glossary
C&Q
CQA
DS
FAT
FMEA
FS
FTA
GAMP
GEP
GMP
GPG
HMI
IQ
MES
OQ
PAT
PLC
PQ
QbD
SAT
SCADA
SOP
TM
URS

Commissioning and Qualification

Critical to Quality Attribute
Design Specification
Factory Acceptance Test
Failure Mode and Effects Analysis
Functional Specifications
Fault Tree Analysis
Good Automated Manufacturing Practice
Good Engineering Practice
Good Manufacturing Practice
Good Practice Guide
Human Machine Interface
Installation Qualification
Manufacturing Execution System
Operational Qualification
Process Analytical Technology
Programmable Logic Controller
Performance Qualification
Quality by Design
Site Acceptance Test
Supervisory, Control, and Data Acquisition
Standard Operating Procedure
Traceability Matrix
User Requirements Specification

References
1. GAMP 4 Good Automated Manufacturing Practice
(GAMP) Guide for Validation of Automated Systems,
International Society for Pharmaceutical Engineering
(ISPE), Fourth Edition, December 2001.

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Copyright ISPE 2007

The customer may increase his confidence in the supplier

during the life cycle: by means of quality audits performed on
the development process, periodically inspecting the supplier
during the construction phases, controlling check-out results
during FAT, and finally during the installation and qualification phases.
The mature supplier uses the results of audits,
verifications, and inspections in a pro-active philosophy as drivers for continuous improvement.
Developing standard products, both the supplier and the
equipment progressively increase their maturity level, going
toward the preferred solution where customer verifications
may be reduced in terms of frequency and rigour - Figure 5.

Trust is based on the confidence on the supplier quality

system and the overall design and manufacturing processes
that bring to the final equipment.

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Risk-Based Equipment Qualification

2. GAMP 4 Good Automated Manufacturing Practice
(GAMP) Guide for Validation of Automated Systems,
International Society for Pharmaceutical Engineering
(ISPE), Fourth Edition, December 2001, Chapter 6 Validation Overview.
3. GAMP 4 Good Automated Manufacturing Practice
(GAMP) Guide for Validation of Automated Systems,
International Society for Pharmaceutical Engineering
(ISPE), Fourth Edition, December 2001, Appendix M2
Guideline for Supplier Audit.
4. GAMP 4 Good Automated Manufacturing Practice
(GAMP) Guide for Validation of Automated Systems,
International Society for Pharmaceutical Engineering
(ISPE), Fourth Edition, December 2001, Appendix M5
Guideline for Design Review and Requirements Traceability Matrix.
5. GAMP Good Practice Guide: A Risk Based Approach to
Compliant Records and Signatures International Society
for Pharmaceutical Engineering (ISPE), First Edition,
April 2005.
6. GAMP Good Practice Guide: Testing of GxP Systems,
International Society for Pharmaceutical Engineering
(ISPE), First Edition, December 2005.
7. GAMP Good Practice Guide: Calibration Management,
International Society for Pharmaceutical Engineering
(ISPE), First Edition, December 2001.
8. ISPE Baseline Pharmaceutical Engineering Guide, Volume 5 - Commissioning and Qualification, International
Society for Pharmaceutical Engineering (ISPE), First
Edition, March 2001.
9. A White Paper on Risk-Based Qualification for the 21st
Century, ISPE, 9 March 2005.
10. Branning, R., et al., Quality by Design, Validation, and
PAT: Operational, Statistical and Engineering Perspectives, Pharmaceutical Engineering, Vol. 26, No. 6, 2006,
pp.
11. US FDA - Code of Federal Regulations, Title 21, part 210:
Current Good Manufacturing Practice in Manufacturing,
Processing, Packaging, or Holding of Drugs; General.
12. US FDA - Code of Federal Regulations, Title 21, part 211:
Current Good Manufacturing Practice for Finished Pharmaceuticals.
13. US FDA - 21 CFR Part 11: Electronic Records; Electronic
Signatures - Final Rule.
14. European Commission, The Rules Governing Medicinal
Products in the European Union Volume 4: Good Manufacturing Practices Medicinal Products for Human and
Veterinary Use, Annex 11 Computerised Systems; Annex 15.
15. PIC/S Guidance: Good Practices for Computerised System in Regulated GxP Environment, Document PI 011-2
(July 2004).
16. ICH Q9 - Quality Risk Management (step 4, approved Nov
2005).

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About the Authors

GAMP Italia Equipment Validation Workgroup

The working group has a Steering Committee, active members, and associate members. The following list includes only
the members of the group who authored the article.
Sandro De Caris is an IT Compliance Consultant for the life sciences industry, supporting both manufacturers and suppliers.
His expertise covers computer systems validation, GxP compliance, risk management,
and PAT. He graduated in electronics engineering and has more than 20 years of experience in the pharmaceutical industry at the
international level, operating in hardware and software
design, software quality assurance, computer validation,
project management, and company management. Before
moving into a freelance profession, his last role was managing director of a leading Italian company specialized in
compliance and validation; a subsidiary of an international
IT company based in the UK. De Caris is currently chairman
of GAMP Italia and coordinates the Equipment Validation
Workgroup. He can be contacted by telephone at: +39 051
6516945 or by e-mail at: [email protected].
IT Compliance and Validation Consultant, Via Giardino,
60, 40065 Pianoro, Bologna, Italy.
Marco Bellentani graduated in computer
science at the University of Bologna, joined
MG2 in 1993 as a software engineer, and for
11 years has held a position of Software
Projects Leader and Product Manager with
particular focus on quality assurance, validation, standards, and methodologies definition. GAMP, GxP, risk management, electronic records and signatures have been some of the quality
and regulatory aspects experienced during these years. In
2005, Bellentani joined the Quality Assurance Department
as Validation Manager and Software Quality Assurance
Manager. In this role, he defines validation, training and
documentation policies and software development standards,
conducts Supplier quality audits required by customers, and
follows internal projects for process optimization. He also is
the coordinator and project quality assurance of MG2 PAT
Team, a group of experts supporting customers in the implementation of practical PAT solutions, and in this role, he
attends to pharmaceutical meetings both as a speaker and as
an attendee. Since the beginning of 2006, he has been a
member of MG2 Executive Board involved in the definition
and supervision of MG2 strategies for the future. He can be
contacted by telephone at: +39 051 4694 111 or by e-mail at:
[email protected].
MG2 S.r.l., via del Savena, 18, I-40065 Pian di Macina di
Pianoro, Bologna, Italy.

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Risk-Based Equipment Qualification

Beny Fricano graduated in electronics engineering at the University of Ferrara. Since
2001, he has been involved in software quality assurance and qualification and computer system validation at I.M.A., a company
engaged in the design and manufacture of
packaging machinery and Systems for both
pharmaceutical and alimentary products.
Fricano has been an ISPE member since 2005. He is involved
as active member of the Gamp Italia (Equipment Validation
Workgroup). He can be contacted by telephone at: +39 051
6514999 or by e-mail at: [email protected].
IMA SpA, I.M.A. Industria Macchine Automatiche, Via
Emilia 428/442, 40064 Ozzano dellEmilia, Bologna, Italy.
Carlo Bestetti is a consultant in computer
system validation and compliance. With an
educational background in classical studies
and a degree in mechanical engineering c/o
Politecnico di Milano, his working life has
been spent in application fields such as mechanics, electronics, petrochemistry, energy
in engineering companies, production companies, plant maintenance, and validation services touching
every aspect of automation engineering. Bestetti shares his
experience by tutoring on the job, publishing articles, presenting papers at international congresses, and has obtained
patents. He is an active member of Gruppo Imprese
Strumentazione Italia (GISI) and Associazione Italiana per
lAutomazione (Anipla). He joined ISPE in 1995 as member of
the Italian Affiliate Steering Committee, and in 1996, he
received an ISPE special Award. Bestetti is now active in the
GAMP COP. He can be contacted by telephone at: (+39) 039
24 96 855 or by e-mail at: [email protected].
Compliance and Automation Validation Consultant, Via
Ramazzotti, 11, I-20052 Monza, Milano, Italy.

mechatronics at the mechanical engineering laurea magistrale

degree, and Packaging mechanics at Food Industry Mechanical Engineering laurea magistrale degree. He can be contacted by telephone at: +39 0521 90 5700 or by e-mail at:
[email protected].
Universita degli Studi di Parma, Dipartimento di
Ingegneria Industriale Pal., 8 Viale G.P. Usberti 181/A 43100,
Parma, Italy.
Guerrina Barbara Testoni is a Project
Manager and Executive Consultant with
Adeodata, Italy. She has a degree in math.
Prior to join Adeodata, she was the R&D IT
Development Area Manager with Chiesi
Farmaceutici. Testoni has more than 16 years
of experience in the pharmaceutical industry
specializing in computer system validation,
information system implementation and management, system integration, and business process reengineering of various systems such as: LIMS, EDMS, eSubmission, CDMS,
Drug Safety, Clinical Database, ERP. She can be contacted by
telephone at: +39-338-8426687 or by e-mail at: barbara.
[email protected].
Adeodata, Via Grigne, 5, I-20020 Lazzate, Milano, Italy.

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Copyright ISPE 2007

Marco Silvestri received the Laurea Degree in mechanical engineering from the
University of Parma, Italy in 1999. After
collaborating with the Industrial Engineering Department of the same university, he
was employed as researcher by Computes
s.r.l. (Niviano di Rivergaro, PC), a software
house that produces CAD/CAM for mechanical industry. During 2001-2002, he was head of research and
development of Tecnomec s.r.l. (Vignola, MO), a manufacturer of machines and plants for the meat industry. In this
role, he developed innovative solutions for plants of Campofrio
(Burgos, Spain) and Rovagnati (Biassono, Italia). Silvestri
also was involved in vision system projects for industrial
automation, collaborating with Vicivision s.r.l. (Fidenza, PR)
on developing automated control machines for pharmaceutical (GlaxoSmithKline) and medical device (B.Braun) industries. Since October 2002, he has held the position of Assistant Professor at University of Parma, lecturing on actuators
mechanics at the mechanical engineering laurea degree, on
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