13

Equipment and
Facility Qualification

Thomas L. Peither
PECON—Peither Consulting, Schopfheim, Germany

I. INTRODUCTION

The importance of the qualification process of technical systems in the pharma-

ceutical industry has been steadily increasing over the last 10 years. It has been
driven primarily by the requirements of regulatory bodies and not by the need
to save money in this part of the industry. If the industry made use of the full
scope of the GMP requirements, the qualification process would be more effi-
cient and the cost of qualification would drop. On the other hand, pharmaceuti-
cal companies want to protect themselves from a less than perfect result during
a regulatory inspection and therefore demand 120% effort from their suppliers
and service companies. New methods and tools must be implemented to reach
the goal of qualifying a technical system while minimizing effort.
Another aspect is the trend for quality assurance departments to evolve
from being mere controllers of product quality to delivering tools and methods
to other departments, thus helping them to design a better production process.
The goal is to improve overall production reliability and availability. In order
to achieve this objective, the quality assurance team must be experienced in
applying and teaching the qualification tools and methods needed. This is a
trend that has not yet started in many companies. It may be seen in other indus-
tries that more instruments and quality tools are necessary than those limited to
qualification and validation. Qualification and validation only appear to be the
beginning of a continuous development process in the quality assurance of the
pharmaceutical industry.

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 To avoid misunderstanding, it is crucial to use the correct terms and ex-
pressions during quality management. A list of definitions can be found in the
appropriate section.
The following describes how the qualification of pharmaceutical equip-
ment and facilities can be efficiently planned and executed.
Figure 1 depicts the most commonly used approach to the qualification
process as used in the pharmaceutical industry. It shows a pyramid, which is
the best way in which to plan a qualification/validation project. Investing more
time in the first phases will save time and money in later and critical phases. If
inadequate investment is made during the start-up of a project, the later phases
of installation qualification (IQ), operational qualification (OQ), and perfor-
mance qualification (PQ) will necessarily require an inordinate amount of time
and money. The project will be a pyramid again, but now it is inverted.
It must be stressed that a good engineering and project process is the best
basis for proper qualification and validation work. It is the current opinion on
qualification in the pharmaceutical industry that the later steps in the qualifica-
tion process need more time and attention than the earlier steps. This may be
totally different in other industry branches; they tend to spend more effort during
the earlier stages to save time and money later on.

Figure 1 Steps of qualification.

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 If the pharmaceutical industry adopted the lessons learned in other
branches (e.g., aircraft industry, automotive industry) it could realize an in-
creased efficiency in the qualification and validation processes. To this end ef-
fort should be made to investigate statistical process control (SPC), house of
quality, Deming circuits, and so on.
At the moment the term design qualification (DQ) is the focus of some
controversy. Performing a DQ is not a legal requirement, but it has been intro-
duced to the qualification process through implementation of Annex 15 to the
EC Guide on Good Manufacturing Practices for Medical Products. It is not a
requirement to implement a DQ, but it seems that regulatory bodies have an
interest in promoting this element of engineering and quality management. It
should be a requirement of a proper engineering process, and in fact although it
is often a part of the engineering process, it is not declared as a separate action.
Nevertheless, the activity itself should be executed in combination with an effi-
cient procedure documented in a standard operating procedure (SOP). (See Sec.
V.) Important aspects that should be taken into consideration before qualifica-
tion aspects start are shown in Figure 2.
It is important to perform these preliminary steps conscientiously. Most
qualification projects fail because these basic activities are not performed ade-
quately.

Figure 2 Preliminary steps.

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 II. PROJECT MANAGEMENT

Good project management is the first step toward organizing the successful
qualification of a technical system. A well-structured and -planned approach to
qualification is the first step toward success.
The tools and methods of project management are mainly used for large
and complex projects. It is equally important to apply these management skills
to smaller projects, however. A good project start is the best way to win the
battle.

A. Project Organization
To start with, the project organization must be defined. The different positions
must be defined and people need to be found with the necessary knowledge to
fill these positions. The most commonly required areas of expertise for a project
leader are organizational know-how, social skills, project management know-
how, time management, validation know-how, and general technical know-how.
A team member should have expertise in communication skills, validation
know-how, and detailed technical know-how.

B. Meeting Management
The communication structure must be defined following the definition of the
best project organization. A lot of projects waste time in meetings. Everybody
is familiar with this scenario. You find yourself sitting in a meeting thinking
that your time is being wasted and that you might not attend another scheduled
meeting. Nobody likes to feel that his or her time is wasted, therefore thorough
planning prior to any meeting is mandatory.
A chairperson heading the meeting must be chosen and a person desig-
nated to take the minutes. Every meeting should have an agenda. People should
be invited based on whether or not they can help with solving the issues on the
agenda. Obviously everyone attending should be well prepared. In order to facil-
itate this process, meetings should be planned 6 months in advance.

C. Project Planning
After the definition of functions, responsibilities, and communication structures,
the project itself must be planned. Using Gantt charts is often the best way to
schedule the different tasks. This allows you to see quickly which task has to
be done when and by whom. The charts also indicate interdependencies between
different tasks and show what happens if a task takes longer than planned. Dif-

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 ferent software is available to help generate such project plans. An example for
a project plan is shown in Figure 3.
People often ask for an example of a detailed project plan. Working out a
specific project plan requires in-depth knowledge of a technical system, how-
ever. As each system is different, Figure 3 can only show a general overview
of a project plan.

D. Project Reporting
The next important task in the process of project management is the implemen-
tation of efficient project control. A reporting system must be put into place that
describes the current state of the project as well as the progress of the most
important tasks. Additionally, the reporting system must be able to pick up and
highlight problems within the project. A functioning reporting system is the
controlling instrument for the project manager.

E. Tools for Project Management

In order to manage a project efficiently appropriate tools must be applied. There
are several products of project management software on the market. The deci-
sion as to which system is the best suited for a given project should include the
following aspects:

Project focus
Size of a project
Number of team members
Number of tasks in a project
Required functionality

III. VALIDATION/QUALIFICATION MASTER PLAN

It is important to draw up a summarized document that describes the whole

project. It has become common practice in the industry to develop a “validation
master plan” (VMP). This document would usually include the qualification
aspects of a project. Alternatively, a “qualification master plan” (QMP) should
be drafted. In case of a large retrospective qualification project it is beneficial
to write a separate QMP. The main point is to develop a document that includes
the most important information of the project and can be used like a project
handbook.

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 Figure 3 Project plan.

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 Figure 4 Structure of a validation master plan.

A. Structure of a VMP or QMP

The structure of a VMP or QMP is well documented in the PIC/S document PI
006 Recommendation on Validation Master Plan, Installation and Operational
Qualification, Non-Sterile Process Validation and Cleaning Validation. This
document is the basis for Annex 15 to the EC Guide on Good Manufacturing
Practices for Medical Products. Figure 4 displays the most commonly used
topics to be described in a VMP.
The PIC/S-document PI 006 defined the VMP as “A document providing
information on the company’s validation work programme. It should define de-
tails of and time scale for the validation work to be performed. Responsibilities
relating to the plan should be stated.” The EC Guide on Good Manufacturing
Practices for Medical Products, Annex 15, said of the VMP: “All validation
activities should be planned. The key elements of a validation programme
should be clearly defined and documented in a validation master plan (VMP)
or equivalent documents. The VMP should be a summary document which is
brief, concise and clear.” The FDA published another interesting paper in 1995,

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 the Guide to Inspections of Validation Documentation. This guide outlines the
basics in qualification and validation; for example, “Planning documents may
use various formats and styles, and different descriptive terms may be used such
as master validation plan, project plans, study plans, and others. Regardless of
terminology, it is important that suitable documents denote intentions in suffi-
cient detail.” It highlights the benefits of having an overall document such as
VMP.
To summarize, the VMP or QMP should be a brief overview of the proj-
ect, tasks, tools, resources, and methods that are going to be used during the
project. This document should be described at a very early stage of a project by
the engineering or manufacturing department of a pharmaceutical manufacturer
or service provider.
Standard operating procedures are an integral part of any VMP or QMP.
They outline rules that have to be followed during the project and provide proj-
ect members with guidelines as to which rules have to be studied before starting
work.

B. Areas of Interest
Many technical systems in a pharmaceutical production have to be validated or
qualified. The requirement for a system to be validated depends on its impact on
product quality. Whether a system is critical or not may be determined through a
risk analysis. (See Design Qualification.) Following is a list of such different
systems or clusters of systems.

1. Infrastructure and Facilities

High purity water systems (high purity water, water for injection, highly
purified water, etc.)
Clean steam
Gases with product contact (compressed air, nitrogen, oxygen, vacuum,
etc.)
HVAC with rooms (clean area), including lighting

2. Equipment
Closures, tanks, vessels with product contact
Machines with product contact (filling machine, washing machine, closing
machine, granulator, packaging lines, etc.)
Machines with direct impact on product quality (autoclaves, sterilizing
units, labeling system, weighing system, production control system, fa-
cility control system, etc.)

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 IV. USER REQUIREMENT SPECIFICATION

The goal of working out user requirement specifications (URS; Fig. 5) is to

document the needs of the manufacturing department. User requirement specifi-
cations are always written for a technical system that should be implemented in
the production process of a pharmaceutical product. The URS is very important
for realizing a project, as many measurements refer to the URS. A well-prepared
URS is the key to a project’s success. Projects without detailed URS have a
tendency to demand lots of change later on, thus increasing cost, start-up times,
or both. Who should evaluate a URS? Best practice is a coordinated approach
among production, quality assurance, and engineering of the pharmaceutical
company. Some companies even use the services of external resources to create
a URS.

A. GMP Requirements
The key aspect of any URS is to generate a document detailing all the GMP
requirements the technical system has to fulfill. The URS is an important docu-
ment for the commissioning phase as well. Often the URS provides the basis
for an offer to the suppliers. A detailed URS will result in a better and more
competitive offer for the technical system. While evaluating a supplier, it is
important to gather as much information as possible. Without a comprehensive
URS, a pharmaceutical company cannot get a clear understanding of the supplier
and may be led to make a wrong decision.

Figure 5 Content user requirement specification (URS) design qualification.

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 B. Technical and Economic Requirements
User requirement specifications cover more aspects than only the GMP require-
ment, because the URS is not written only for the validation procedure; in fact,
a URS is a very important project document covering technical as well as eco-
nomic requirements of the technical system. Pharmaceutical manufacturing de-
partments not only check the GMP aspects of a system; additionally, following
good engineering practice they will review the technical and economic aspects
of a technical system. Obviously, the more experience a company gains, the
more comprehensive a URS become. Past experiences such as project faults,
inefficient technical systems, and bad commissioning can be included in a URS.

V. DESIGN QUALIFICATION (DQ)

Design qualification is more common in Europe than in the United States. There
is no legal requirement to perform a DQ. Sometimes this phase may not be
called DQ, but may instead be referred to as “design review,” “design assess-
ment,” and so on. The intention is important in this phase. The goal is to perform
something similar to a risk analysis and to check the design documents of a
technical system to ensure that they fulfill the user requirements. For this reason
a risk analysis—not yet commonly known in all companies—should be used.

A. Risk Analysis
The overall concept of all of the following tools is that of risk analysis or risk
assessment. Risk analysis helps to decide whether an aspect is GMP-critical or
not. The risk analysis can be performed in a formal or more informal way.
Following are two popular and import types of risk analysis. Another method,
the fault tree analysis (FTA), has recently been used in the area of computer
validation. This method is not described here, as it is a complex form of risk
analysis.

B. FMEA
FMEA is a quantitative risk analysis for complex systems (Fig. 6). As this
approach involves assessment of occurrence probabilities, detection of failures,
and judgment as to the severity of a failure, it should only be chosen if some
practical experience with the technical system is available. Each of the three
values will be assigned a number from 1 to 5. Multiplying these values results
in the “risk priority number.” This number indicates the priority of the assessed
failure. The pure version of the FMEA is seldom practiced in the pharmaceutical
industry.

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 Figure 6 Failure mode and effects analysis (FMEA) overview.

Most common risk analysis forms are mutations of the fundamental

FMEA. It is easier for most companies to start initially with a more practical
way of performing a risk analysis. In the future the fundamental FMEA will be
more commonly applied, as companies will have gained confidence with varia-
tions of the FMEA.
Variations are often made by cutting the detection of failures or severity
of failures. Sometimes the values are decreased to a spread of 1 to 3. In other
cases the risk priority number is not calculated, but the levels are noted in a
matrix to see whether the point is critical or not.

C. Hazard Analysis of Critical Control Points (HACCP)

The second method is the hazard analysis of critical control points (HACCP;
Fig. 7). This method is well known in the food industry. The goal of HACCP
is to reduce the risk of contamination of products and to reduce the effort for
testing products during final tests. The HACCP defines critical control points
(CCPs) in different grades (usually three grades). The HACCP protocols are

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 Figure 7 Hazard analysis of critical control points (HACCP).

worked out and the results are documented in reports. Important steps are the
definition of CCPs and their limits, the implementation of a change control sys-
tem, the execution of corrective actions, and the implementation of a documenta-
tion system. Equally important are regular audits of the concept and the approval
of HACCP protocols using appropriate procedures. As with the FMEA, the
HACCP concept offers the opportunity to rethink all technical and organizational
aspects in an early phase of a project and to find out all critical deficiencies.

D. Documentation of DQ
The results of any risk analysis should be well documented as they become the
key input into the qualification and validation process. They are the basis for
defining tests in the IQ, OQ, and PQ phases. It is often impossible to say prior
to a risk analysis what steps of qualification need to be performed. It depends
on the risks and measurements defined during the risk analysis. Equally impor-
tant, this procedure increases the efficiency of the qualification process. In the
past, the decision on which qualification tests to perform was outlined by writ-
ing qualification protocols. These usually prompted long and expensive discus-

Copyright © 2003 Marcel Dekker, Inc.

 sions. One of the challenges is to determine which parts of a system to devise
tests for. It is easy to imagine that companies and people who have experience
with risk analysis are in a better position, as they will have developed standard
tests for a list of critical elements, leaving only a few additional tests to be
designed for a particular system. The result is that the longer the qualification
system is in place the more effective it becomes. This is a great advantage and
helps to repay the investments of starting a risk analysis system quickly.

VI. INSTALLATION QUALIFICATION

The decision as to which system needs to be qualified should result directly

from the risk analysis process and should be described in the VMP or QMP. In
any case, it would be a technical system that impacts on the quality of a pharma-
ceutical product. Installation qualification aims to check documentation against
reality. The result is “as-built documentation.” The other task in the IQ is to
ensure that the GMP requirements are fulfilled. The generally accepted way to
perform an IQ is to

Develop an IQ protocol (Fig. 8)

Approve the IQ protocols (by the quality assurance, production, and tech-
nical departments)
Perform the IQ
Work out the IQ report
Approve the IQ report (by the quality assurance, production, and technical
departments)

Installation qualification is defined in the PIC/S document PI 006 as “The

performance and documentation of tests to ensure that equipment (such as ma-
chines, measuring equipment) used in a manufacturing process, are appropri-
ately selected, correctly installed and work in accordance with established speci-
fications.”
The OQ phase relies on valid calibration of all quality-relevant instru-
ments. The best way to guarantee this is to perform the calibration at the end of
the IQ phase. Sometimes it is performed at the beginning of the OQ. This proce-
dure is acceptable as well.
The IQ phase will be executed with personnel of the supplier of a techni-
cal system or with technical personnel of the pharmaceutical company. It will
follow the procedures set out in the IQ protocols. After performing the IQ, the
results are summarized and documented in an IQ report.
The qualification of the control unit of a technical system is very similar
to that of the mechanical equipment of a system. This does not apply to compu-

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 Figure 8 Example of an IQ protocol.

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 Figure 8 Continued.

terized systems, however. These are described in detail in another part of this
book.
The most important aspects to consider during IQ are
Provide as-built documentation (e.g., P&ID check).
Check training reports.
Check that documentation is complete.
Check calibration reports.
Identify piping and instrumentation

VII. OPERATIONAL QUALIFICATIONS

Operational qualification is defined in the PIC/S document PI 006 as “Docu-

mented verification that the system or sub-system performs as intended through-
out all anticipated operating ranges.”
Operational qualification tests whether or not the system works as ex-
pected. The approach to a successful OQ is the same as described for IQ [de-
velop OQ protocols (Fig. 9)], approve OQ protocols (by the quality assurance,
production, and technical departments), perform OQ, work out OQ report, and
approve OQ report (by the quality assurance, production, and technical depart-
ments).
The OQ phase normally involves personnel from the supplier of a techni-
cal system or technical personnel from the pharmaceutical company. It is prefer-

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 Figure 9 Example of an OQ protocol.

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 able to include customer employees, as they are going to be the users of the
system. This facilitates a better know-how transfer between supplier and cus-
tomer. Again, this process follows the rules outlined in the OQ protocols. The
results of OQ are summarized and documented in an OQ report. It is commonly
accepted practice in the industry to produce one report for both IQ and OQ
results. This saves money and time for approval.
Operational qualification of the control unit of a technical system is one
of the most important steps during the OQ phase. It tests all critical functions
and alarms of the technical system. There are no different procedures for me-
chanical OQ and control unit OQ.
The result of the OQ is a documented approval that the technical system
fulfills the user requirements and all GMP-related functions of the technical
system.
Typical tests in the OQ include the following:
Alarm tests
Behavior of the system after energy breakdown
Accuracy of filling lines
Transportation speed in a sterilization tunnel
Temperature distribution in an autoclave
Performance of a washing machine
Accuracy of a weighing system

VIII. PERFORMANCE QUALIFICATION

The PQ is the phase in which either a technical system is tested over a long
period of time (e.g., water system), or a complex technical system is tested
overall (connected filling line). For many systems OQ is the last phase per-
formed during qualification. If there are only a few performance tests needed,
it might be more practical to include them during OQ or process validation.
Combining OQ and PQ decreases the number of documents (less documentation
work in the future) and cuts approval time and effort. Again, the procedure for
PQ is the same as for IQ and OQ ([develop PQ protocols, approve PQ protocols
(by the quality assurance, production, and technical departments), perform PQ,
work out the PQ report, and approve the PQ report (by the quality assurance,
production, and technical departments)]. The documentation and test description
are identical to those in the OQ phase.
Performance qualification should be executed by customer personnel. It is
a great disadvantage if it has to be performed by the supplier. Ideally this phase
allows know-how to be established at the pharmaceutical company.
The following technical systems need to be performance-tested and quali-
fied:

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 High purity water systems (monitoring of the quality parameters: pH,
TOC, conductivity, CPU, temperature)
HVAC systems (temperature, pressure, humidity)
Complex connected systems (e.g., filling line, BPI production line; perfor-
mance parameters)

IX. DOCUMENTATION SYSTEM

To quickly locate any given document, it is mandatory to have implemented an

appropriate documentation system. In case of a fault in production or inspection,
it becomes necessary to find a document within 15 to 20 min. All companies
should test the reliability of their documentation system using internal audits.
One aspect of a working documentation system is a standardized docu-
mentation structure. If every system is documented using the same document
structure, everyone can gain access to the necessary information quickly. Figure
10 shows an example of a documentation structure.
Documents do not need to be delivered to the customer in paper format.
Electronic media documents such as CDs are equally acceptable. Obviously, an
appropriate reading system must be in place to access the documents at a later
date (e.g., for an inspection). Such a system must remain in place until the

Figure 10 Documentation structure.

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 documentation is destroyed. In case of a complete electronic documentation
system the whole system needs to be validated by computer validation.

X. CHANGE CONTROL

Change control is defined in the PIC/S document PI 006 as follows: “A formal

system by which qualified representatives of appropriate disciplines review pro-
posed or actual changes that might affect a validated status. The intent is to
determine the need for action that would ensure and document that the system
is maintained in a validated state.”
Change control is a lifetime monitoring approach. Planning for well-
executed change control procedures (Fig. 11) includes the following aspects:

Figure 11 Change control procedure flowchart.

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 Workable documentation system
Defined responsibilities and job descriptions
Defined review procedures
Well-trained staff
The implementation of a change control system is an important and neces-
sary step in the validation approach for equipment and facilities. Vital to any
change control system is its efficiency in that it does not require too much time
and effort to handle changes. In order to design an efficient change control
system, the following aspects need to be taken into consideration:
Early categorization of a change as major or minor change (i.e., cata-
logue). This should speed up the decision and approval time of a
change.
Easy and logical way of document flow (production engineering, quality
assurance, production).
Easy and logical decision tree for major or minor changes or planned or
emergency changes.
It is not only good practice but also essential that a requested change is
only implemented after the appropriate change control procedures and approvals
have been followed. Time and money are often wasted because a change was
not correctly evaluated (major or minor) or personnel was not familiar with the
best practice for change control procedures. It is crucial for an efficient change
control process that the production, engineering, and validation departments are
working together very closely.
Clear change control procedures have to be in place for all eventualities.
This must include instructions for situations in which the supervisory or man-
agement personnel is not present when the problem occurs. In such a case, for
example, a change or correction might be implemented quickly by the mainte-
nance or operational personnel that must then be reviewed and approved by
management within 24 hr.

REFERENCES

1. U.S. Food and Drug Administration. 21 CFR 210/211 Good Manufacturing Practice.
Fed Reg (2001).
2. U.S. Food and Drug Administration. Guide to Inspection of Validation Documenta-
tion (1995).
3. Recommendation on Validation Master Plan, Installation and Operational Qualifi-
cation, Non-Sterile Process Validation and Cleaning Validation, Pharmaceutical In-
spection Co-Operation Scheme PIC/S PI 006 (2002).

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 4. EC. Guide on Good Manufacturing Practices for Medical Products. EU (2001).
5. U.S. Food and Drug Administration. Guide to Inspection of Process Validation
(1987).
6. The gold sheet. F-D-C Rep 34 (2000).
7. Vina, B. GMP Compliance, Productivity, and Quality. Interpharm Press (1998).
8. ISPE. Baseline Pharmaceutical engineering guide series: Introduction of commis-
sioning and qualification. ISPE 2000 European seminar, Amsterdam, 2000.

Copyright © 2003 Marcel Dekker, Inc.