3

Validation and Facility Design

J. Robert Adamson
Foster Wheeler, Reading, Berkshire, U.K.

INTRODUCTION This chapter describes an approach that can be used

by the designer to ensure that the design, engineering,
The design, construction, and commissioning of a new and construction process can meet the GMP require-
facility for the pharmaceutical industry is a complex ments. This approach is sometimes referred to as
process that involves the interaction of a wide variety of Validation Master Planning. More commonly, industry
engineering, process and QA, and control disciplines and develops a Validation Master Plan to cover all aspects of
may proceed through a series of different phases from a the validation of an operating unit such as: Process
conceptual, feasibility study, through to the nal detailed Validation, Cleaning Qualication, Automation Vali-
design, construction, commissioning, and nal site vali- dation, and Facility and Equipment Qualication. This
dation activities. The FDAs risk-based approach to GMPs chapter shall refer to it as the Facility and Equipment
for the 21st century has changed the industrys perspec- Qualication or FEQ plan. The key basis to successfully
tive to validation and qualication. This new initiative qualify a facility is to plan the qualication from the
allows the facility designer, constructor and commis- earliest stage of the facility design by the development
sioning group to take a risk-based approach to the of a clear validation strategy that will develop into a plan
qualication of facility and equipment. The basic require- for validation throughout the project. The main focus of
ments for validation of facilities and equipment are this chapter is on new facilities; however, a separate
dened in both the European communitys Guide to section discusses how this approach can be adapted to
Good Manufacturing Practice Vol. IV (Medical Products) meet the needs of revamp or refurbishment projects. A
and the United Statess GMPs CFR Title 21 (1,2). These complete section is devoted to the development of an
documents clearly dene the need for a whole system FEQ Plan. The FEQ section outlines the whole of the
that is based on QA. This is essential for pharmaceutical qualication requirements both in scope and for all stages
companies to ensure that products meet their quality and of the project.
marketing authorization requirements. cGMP is a key
element of an overall QA system and GMP extends
through people, production, premises, and equipment. THE ENGINEERING DESIGN PROCESS
Both the U.S. GMP and the EC Guide emphasize that FOR A FACILITY
premises and equipment should be designed to be
appropriate and t for the purpose. Interpretation of The engineering or feasibility design process typically
this statement implies that it is essential that facilities follows a series of phases.
must be built to standards that meet the requirements of & Conceptual design

the GMPs and be demonstrated to meet these require- & Design development, front-end design or basic/pre-

ments. The process of validation is a key component liminary engineering

within the concept of QA and GMP. The consequence of & Detailed engineering
& Procurement
this for the facility designer is that he or she must use
& Construction
design and engineering methods that will comply with
& Precommissioning
and demonstrate that the facility, when complete, does
& Commissioning
meet the requirements of cGMPs.
Each of these phases has its own engineering
objectives and, consequently, the qualication require-
Abbreviations used in this chapter: cGMP, current good manufacturing ments have both a different scope and extent at each
practice; CIP, clean in place; DQ, design qualication; EC, European phase. The concepts for qualication will be described
Commission; EMEA, European Medicines Evaluation Agency; FAT, for each phase.
factory acceptance test; FDA, Food and Drug Administration; FEQ,
facility and equipment qualication; GMPs, good manufacturing
practices; HVAC, heating, ventilation, and air-conditioning; IOQ, Conceptual Design
installation and operation qualication; IQ, installation qualication;
Introduction
NDA, new drug application; OQ, operational qualication; PID, piping
and instrument diagram; PQ, performance qualication; PV, process
The actual process design commences at a much earlier
validation; QA, quality assurance; SIP, sterilization in place; SOPs, phase than the engineering design. Pharmaceutical drug
standard operating procedures; UK MCA, United Kingdoms discovery, design, and production are key elements of
Medicines Control Agency; URS, user requirements specication; the industry. At a stage during the drug development
USP, United States Pharmacopeia; WFI, water for injection. and clinical trial phases, it will become apparent
12 I: INTRODUCTION

whether the company has a new product that it wishes The typical deliverables of this phase are as follows:
to bring to the market. This is usually the point when & Statement of basis of design
rst considerations for the engineering and manufac- & GMP statement
turing needs for the production of the drug will & Process block ow diagrams or schematics
be addressed. & Major equipment item list
Production of clinical trial material will have moved & Conceptual layout and accommodation schedule
from laboratory facilities to pilot-scale operations. Experi- & Building and HVAC philosophy
ence gained at this pilot-scale production will normally & Outline of utility systems
give sufcient information to enable a process denition to & Outline of control philosophy
be prepared. The marketing organization will also & Safety considerations
have some early projections for demand levels and the & Budget estimate
type of formulations that will be required. These key
elements will give a basis for a conceptual design study. Approach
The collection of process data for subsequent full-scale PV Usually, the conceptual study will be run as a mixed
will also already have begun. Clearly, the current regulat- disciplinary team bringing together research and
ory bodies emphasis on proof of drug equivalence, i.e., development, production, and engineering disciplines
nal production batches must be equivalent in biological led by a study manager. Although QA does not have a
and chemical activity to those used in the clinical trial and major role to play at this stage, it is important that the
any subsequent submissions (typically for the NDA) will team has access to appropriate personnel.
already have some signicant effect on the manufacturing In the design of a pharmaceutical facility, one of the
route, engineering design, and equipment selection. most important aspects of the development is the layout.
The conceptual study must consider all these A typical approach that has been useful is to develop an
aspects and incorporate their requirements into this early accommodation schedule (Fig. 1), which shows a typical
design. Consequently a plan is required to ensure that GMP, example for an aseptic suite.
qualication, and process requirements are incorporated. This shows the ow of personnel, materials, and
products. Figure 2 shows the variety of data that goes
into the development of this schedule, which usually
Purpose brings together specialist disciplines, including an engin-
The main purposes of a conceptual study is to provide: eer who understands layout development. This early
1. An agreed basis for the design philosophy to be able process is an iterative phase during which all disciplines
to proceed to the next phase of development will have their input into the accommodation schedule,
(frequently called Front-End Design by the engin- although it is best if a single individual, skilled in layout
eering contracting organization or sometimes development, coordinates the activities and provides the
known as Design Development or Basic Engineering). preliminary drawings for review by the team. Once a rst
2. To provide an initial capital cost estimate, usually layout is agreed on, it must then be formally reviewed for
for a preliminary budget sanction by senior manage- GMP compliance. Figure 3 shows such a preliminary
ment. Often a conceptual study is used as a feasibility layout. The process may be repeated as the layout is
study (i.e., should we proceed or not?). developed and, consequently, GMP principles are built
3. Deliverables. into the design from an early stage. The whole process

Transfer
to Vials from
Fibreless Warehouse
Trays

Vial
Washer

Stopper
Vial Stoppers from
Washer
Sterilizer Warehouse
Sterilizer

Vial Dry Heat Machine Parts

Product To
Filler Sterilizer
Warehouse

Capping Cartoner
Sterile Caps Inspection Labeling
Machine

Figure 1 Accommodation schedule.

 3: VALIDATION AND FACILITY DESIGN 13

Influences Accommodation Schedule

Guidelines Establish Concepts
Building Regulations Identify Priorities
Process Design Estimate Building Blocks
Basic Equipment List
Architectural Treatment
Existing Site Influences
GMP Material and Personnel Flow Charts
Statement of Fitness for Purpose Conceptual Layout Challenged
Regulatory Authority Requirements with Established Priorities
Containment
and Recycled to Include
Room Data
Identified Improvements

Conceptual Layout
Preliminary Arrangement of Rooms
Adjacency of Areas
Initial Building Concepts
Personnel Access/ Egress
Utility Distribution Concepts Defined
Provisional Constructability Assessment

Front-End Design Figure 2 Conceptual layout

development.

ensures that the nal layout meets GMP and is docu- criteria. The preliminary nature of the study limits the
mented. This is part of the qualication of the design and depth of review. It should address critical issues against
is key DQ documents and must be approved by the the user specication and the GMP requirements.
appropriate team members.

Qualification Activities Qualification Cost

At this stage, the qualication of the facility is in its Clearly if the conceptual phase is to provide a cost
earliest phase and the emphasis must be on the qualica- estimate for the project, then the qualication must be
tion of the design. This can be completed by reviews of similarly estimated at this stage. Some form of qualica-
the proposed design against dened user requirements tion statement and policy is required to at least determine

Figure 3 Preliminary conceptual

layout.
14 I: INTRODUCTION

its future scope. At this stage, this may involve only a Purpose of Design Development
owchart (Fig. 4). Some may prefer to develop a very The main objectives of this design development phase are
preliminary facility and equipment plan (see the section as follows:
entitled Facility Qualication Plans). The decision of 1. To establish a basis for detailed design
which route to take may be determined by the extent of 2. To progress the design to establish the technical,
the study and company policy. Without signicant details capability, and safety aspects of the project
of the facility and its contents, specic costs for the key 3. To provide the necessary design data to evaluate and,
qualication tasks cannot be easily determined unless subsequently, comply with the regulatory, environ-
access to similar projects costs is available. At this stage, mental, and planning requirements of a project with
it is probably more normal to make an allowance based the relevant authorities
on in-house or the design engineers experience. It is 4. To provide an improved cost estimate and so enable
important to have an estimate that reects that of the sanction of the project.
study. If the study is G25%, then it is reasonable for the
qualication estimate to fall within similar limits. Deliverables
Typical design development deliverables are as follows:
& Process ow diagrams
Design Development & Process and equipment specications
Introduction & Utility specications
Usually, by this phase of the project, the pharmaceutical & Control and automation user requirements
company believes that it is highly probable that the project specication
will proceed subject perhaps to certain restrictions, & Preliminary process PID
usually based on schedule and total nal cost. The rst & Floor plans and equipment layouts
key decision is (i) should this phase be done in house? & Facility and equipment qualication plan
(ii) involve an external design construction consultancy? & List of systems
(iii) an Engineering Management Contractor? Frequently, & Building evaluation
the choice is very dependent on organization culture. & Building nishes
Clearly, whatever the choice, some key questions are & HVAC schematics and routings
Can the designer meet and demonstrate that the design & Safety and GMP reviews
complies with GMP? Are you going to use a single & Environmental considerations
engineering organization to manage the project through & Project schedule
design, procurement, construction, commissioning, and & Estimate
qualication? Are the systems in place to aid qualica-
tion? Choosing your contractor is discussed in more Approach
detail elsewhere (3). The answers to these questions have Once the choice of management for the project is made, a
signicant bearing on the route adopted. team must be assembled under a project manager, who

Validation Master Plan

Standard Personnel
Computer Operation Cleaning
Operating Training
Qualification Qualification Qualification
Procedures Experience

Identify Identify Identify Change

Items Systems Systems Control
to be & to be Project
Qualified Subsystems Qualified Engineering
Process
FDA Life Cycle Includes Etc.
Approach Dust Control

Preventative
Design Installation Process
Calibration Maintenance
Qualification Qualification Qualification
Plan
of Products
& Processes
Approved List Items Identify Items
Design to be to be
Documentation Qualified Calibrated
Specification
SOPs
Records

Figure 4 Facility and equipment qualication plan.

 3: VALIDATION AND FACILITY DESIGN 15

will preferably see the project through all the subsequent Three schematic options are shown for aseptic
phases to provide a high degree of continuity. This is an changing facilities (Figs. 57); all have an appropriate
important factor to consider for this key position. use, depending on specic requirements. The designer
The key areas of development during this phase are must be aware of the implications of their choice. The
the following: simplest (Fig. 5) is suitable only for low-trafc-ow areas
1. The layout, to dene and x the building size and may need some form of trafc control to prevent an
2. Dene all major items of equipment exiting operator passing an ingoing operator at a critical
3. Dene piping and instrument requirements, as point. The option in Figure 6 is straightforward and
shown in the PID preferred (i.e., separate in and out), but is more expensive
4. Identify the key process services to equipment (e.g., to build, whereas Figure 7 is a compromise, but reuse of
pure steam, WFI, air, nitrogen, and so on) the garments will require validating. The option in
5. Establish philosophy for process control and auto- Figure 5 requires validation of the trafc ow procedures
mation, containment, and safety and cleanup rates between exit and reentry; perhaps
6. Identify the utility services, HVAC, drainage, elec- automatic systems may be considered to prevent
tricity, and others personnel who are moving in opposite directions from
7. Identify preliminary architectural details and meeting; more normally the rm would rely on
building structure and foundations procedure. The option in Figure 6 clearly eliminates this
8. Identify any long-lead items: usually equipment potential adverse consequence and so makes the sub-
(e.g., major items can be on delivery times as long sequent validation of operations simpler. Each option
as 12 months) presents its specic challenge in design and in sub-
9. Ensure the design meets GMP and can be demon- sequent validation requirements, and an evaluation of
strated (validated) to do so capital cost versus validation costs should be a part of the
10. Develop a cost estimate at a dened accuracy decision process.
(usually 1015% is required at this stage) Again, two options are shown schematically in
Figures 8 and 9, for handling stoppers for an aseptic
Layout Development vial lling process. The designers choice has signicant
From the conceptual design, the materials, personnel effect both on layout and subsequent validation require-
and product ows will have been agreed on, and the ments. The option in Figure 8 may initially appear very
philosophy determined. During this phase, each of these attractive, the use of prewashed and sterilized stoppers
needs to be challenged and developed in detail. Once reduces the need for expensive equipment to be
completed, no further changes should be made during purchased and installed. However, QA must audit the
detailed design other than minor accommodations to supplier, and the designer must devise an aseptic means
permit interfacing with nal equipment installation of transfer to the lling line. The solution is frequently a
requirements. manual transfer by a pass-through hatch and manual
Typically decisions made affect both the DQ and loading into the stopper bowl. Each operation will have
the subsequent validation process. We consider two to be validated. The route shown schematically in
examples: aseptic changing facilities and the options
that might be chosen for sterile stoppers used for vials.

Factory
Change
Outer
Change
Remove Wash
Factory Scrub Up
Clothing
Scrub Up
Step Over Remove Don Clean
Clean Room Room
Garments Garments

Air Air Air

Lock Lock Lock

Clean Corridor
Clean
Corridor

Figure 5 Aseptic changing facilitieslow trafc ow. Figure 6 Aseptic changing facilitiesseparated ow in and out.
16 I: INTRODUCTION

Equipment
Usually, within the scope of this phase, the major equip-
ment specications are developed. These specications
Outer will form part of the DQ and should be related to the user
Change requirements specication. For some major items, with
long-lead times, it may be necessary to develop these into
Remove
requisitions or tender documents to meet the overall
Clean Room Garments STEPOver
Step OVER project schedule. The requirements for validation must
Garments be developed concurrently with these specications and
requisitions. These requirements include identifying all
Air Air types of documentation that will be necessary to execute
Lock Lock the qualication. This documentation will typically
include the following generic topics:
& Equipment suppliers documents and drawings

Clean Corridor & Engineers documents and drawings

& FAT documents
& Delivery and installation documents and drawings
& Protocols IQ, OQ, PQ, and associated documents.
An approach that can be used to assemble the
list of detailed documents and drawings is to develop
Figure 7 Aseptic changing facilitiesseparated ow with
the lists in a matrix form (Fig. 10). It is important
garment reuse.
to incorporate the document drawing requirements
into a requisition, for this can represent a signicant
proportion of the cost. Negotiating for documents post-
Figure 9 shows stoppers being washed and sterilized on delivery of an item can prove costly and, in some
site and then being transferred from the clean side of the circumstances, result in no documentation being
stopper washersterilizer to the vial stopper hopper. This received. The implications of this for the completion of
can be achieved in closed containers minimizing manual qualication are potentially severe. Many of the vendor
contact and operations. Options are available from some documents are also essential to commence and complete
suppliers that make use of isolation technology. Clearly, the IQ and OQ protocols.
this latter route has very signicant inuence of vali- Further details on the protocol contents and asso-
dation requirements and design. ciated documents are found in the section entitled Facility
The two examples demonstrate that the develop- Qualication Plans. Ensuring availability of relevant
ment of the design choices at this stage has implications documents at the correct time in the program is critical
for the layout, the layouts qualication, and the valida- to the validation program. Delays in the supply of, or
tion requirements to be later conducted by the operations inadequate documentation, provided by the equipment
group. These requirements can be covered in the GMP suppliers can signicantly delay the validation and,
review that is a key part of the DQ and can be used as part consequently, adversely affect the nal target dates for
of an evaluation of the options. production of the saleable product.

Clean Area

Stoppers
Validate Supply

Pass
Hatch
Validate Pass Hatch
Procedures

Charge
to Vial
Stoppering Validate Aeseptic
Machine Charging
Aseptic Area
Figure 8 Transfer of prewashed and presterilized
stoppers.
 3: VALIDATION AND FACILITY DESIGN 17

Clean Area

Stoppers
Validate Process

Stopper
Washer
Sterilizer

Charge
to Vial
Filler
Stoppering Validate Transfer
Machine

Aseptic Area
Figure 9 Washing and sterilizing stoppers in situ and
transfer to filling.

Validation Planning Detailed Design and Procurement

If a preliminary plan was not developed at the conceptual Introduction
stage, then qualication planning must commence during The main objectives of this phase are as follows:
this stage, usually toward the completion of this phase or 1. To provide a detailed design for issue to construction
at the commencement of detailed design. 2. To provide a detailed equipment list and specication
Clearly, from the aims of this phase, qualication for each item
planning must be developed to be consistent with that of 3. To place orders for the purchase of major items based
the design development to be able to dene resource on a schedule for delivery to site
requirements, schedule, and costs. A Facility and Equip- 4. To develop a construction strategy and program
ment Plan is a good means of focusing on these elements. 5. To ensure that all aspects of GMP are adhered to in
Developing a preliminary list of systems allows the the design
validation engineer to conduct a preliminary risk and 6. To further develop a strategy for start-up through
impact assessment (4); (see also the section entitled Facility precommissioning, commissioning and validation
Qualication Plans for further details on risk and impact 7. To ensure that all aspects of DQ are met and to set the
assessment). This approach allows the qualication esti- basis for IQ
mate to be more precise by focusing the qualication
activity on those systems that will impact on the process
and product quality. Clearly, the aim is to enable qualica- Approach
tion costs, resources, and planning estimates to be set The project team will grow rapidly during this phase; this
down for management sanction of cost and to give a presents problems of both organization and assurance
basis for the detailed design phase (see the section that all members of the team understand the GMP
entitled Facility Qualication Plans). requirements. This must be addressed by either careful
selection or training, with a particular focus on the
engineering team leaders.
Documentation becomes of key importance,
Documents/ Qualification Phase and documentation management is frequently used as
Activity DQ IQ OQ means of controlling the project and can be used to
Note 1
control the design and its qualication (see documen-
P A E P A E P A E
tation later). A change control procedure should be in
Building & place for the design. It must be a key element of the
Utility
Services DQ to check the design against the original user
Process requirement specication. This should be part of a
Services GMP audit of the design. This can be done in a
Process series of reviews toward the end of design develop-
Equipment ment or early in the detailed design, as appropriate to
Complete the project.
System These planned reviews of key documents should be
done by an independent auditor(s), all of which is part of
the DQ. They should be documented and be a part of the
Figure 10 Validation document matrix. validation record.
18 I: INTRODUCTION

Layout to as the FAT. This can be an important step in the

Only minor changes should occur at this stage, and these project and the subsequent validation phases. The FAT
should be a part of the developing detail. The nal is not just a physical examination of the item to check that
construction issue drawings are key, and a nal issue of all components are present and to ensure contractual
ows of personnel, raw materials components, and obligations have been fullled, but also a time to ask
products can be completed. These are important docu- the question: does the item meet the agreed specication
ments that conrm good design and are frequently used as and requisition, and is all the documentation in place?
part of a presentation to authorities, typically FDA, EMEA, There are two basic approaches to answering
or UK MHRA to obtain their views before construction the question: who should supply the documentation?
commences. This is not an essential item, but is a rec- One option is to rely on the vendors works checkout
ommended course of action where possible. sheets, or alternatively, to prepare a set of checkout
documents within the project scope. The choice is depen-
Equipment dent on the quality of documents that are normal from the
During this phase most of the equipment is placed on vendor. It would be a good policy to identify the need for
order. A typical activity ow for equipment purchase and and extent of FAT offered when preparing the requisition
procurement is shown in Figure 11. Key to the equipment and in subsequent discussions with potential vendors
qualication is the technical specication that must before order placement. It may be a factor in the choice
initially begin as a URS. This can be developed into an of the vendor. Usually, the documentation and scope of
initial inquiry requisition by the engineers. It is advisable testing offered falls below the requirements. A strategy
in the early phases to develop a list of potential equip- needs to be evolved to determine who will prepare,
ment suppliers and approve them. From an iterative review, approve, and execute each part of the FAT.
process of discussions with potential suppliers and pre- A well-executed FAT can contribute signicantly
liminary evaluations, a preferred supplier can be selected. to the IQ at site and some of the OQ, particularly, for
Before placing an order, it is important to ensure that packaged items (e.g., proving a liquid vial lling line for
any development of the specication and user require- speed and accuracy of ll). If done in the vendors works,
ments are fully discussed and that the supplier is aware of under an approved protocol, this would certainly reduce
all requirements pertaining to the supply of the equip- the work at the site.
ment, necessary documentation, testing procedures,
installation, maintenance, and operation procedures. A
more exhaustive list is given in the matrix in Figure 10. Planning
Procedures must be in place to approve the documents Detailed planning for the installation and construction
and to conduct the necessary supplier inspections during phases commence in this phase. Much of the validation
fabrication. Many of these documents will be key, both to execution will commence toward the middle and end of
the engineering design and to the nal equipment quali- the construction phase.
cation and operation. Validation planning needs to be developed concur-
The nal stage in this process is the predelivery rent with the main project planning to ensure that key
checkout and inspection. This is sometimes referred goals and milestones are met and to identify the resources

Preliminary Enquiry

Select Supplier

Place Order

Receive Supplier
Information Databook

Non-Conformities Review Documents Added

Note (1) to Databook
Approve Fabrication

Non-Conformities Inspections Inspection Reports

Note (1)
Factory Testing Test Reports

Note (1): Equipment Approved Final Databook

Some Non-Conformity for Shipping for Approval
May be Approved Figure 11 Equipment purchase and
procurement flowchart.
 3: VALIDATION AND FACILITY DESIGN 19

that will be required in the execution phases. A typical for senior management approval probably dictates the
overview schedule is shown in Figure 12. latter option. In this case, it is more appropriate to have
As the detailed design progresses, planning for additional but separate support documents (such as sche-
construction commences. Usually this will be done dule, systems lists, templates for protocols, etc.) that will be
by area, using specialist discipline contractors (e.g., civil easier to modify and approve.
and structural, mechanical, and building services; instru- This plan will specify the requirements for the
ment, electrical, and specialist contractors for installation qualication of the facility and equipment and may
of process equipment packages). Many of these have a form part of a series of subplans under a Validation
role to play in the IQ. The approach should be covered in Master Plan. It will dene the requirements for DQ, IQ,
the master plan and follows that developed for equip- OQ, and PQ. It will dene responsibilities and the risk
ment vendors. Again, it is essential to identify the scope and impact assessment process that denes which
of validation services required, particularly documen- systems will be qualied and which will not.
tation, drawings, test procedures, and certicates. The assessment process used most commonly is
In many cases, these will be required to provide key that described in the ISPE Baseline Guide to Commis-
documents in the IQ (e.g., the ductworker installer for a sioning and Qualication. This process considers the
sterile clean room suite will need to have documented facility and equipment as systems and reviews each
installation and test procedures to qualify the critical system for impact on product quality attributes. System
parts of the installation.). are identied as direct, indirect or no impact. Direct
Similarly, the specialist contractor for walls, oors, impact systems are further evaluated to determine
and ceiling will need to provide test procedures and which components are critical. These latter components
certicates to qualify that the nishes meet the standards are those that require qualication. Care needs to be
laid down in the specications and requisitions. This exercised with the indirect impact systems as occasion-
level of detail needs to be considered for each area, and ally there are, for example, cascade control systems that
its appropriateness and relevance to qualication must connect to the adjacent direct impact systems. The impact
be determined. assessment process should form part of an organizations
procedures and be approved and documented. All
Facility and Equipment Qualification Plan systems should be engineered and commissioned using
The FEQ is developed at the start of detailed design to cover good engineering practices. Those system that are direct
all aspects of the design and installation phase. As many of impact are qualied.
the detailed requirements are specied throughout the
detailed design phase, the FEQ has to either become a Design Qualification
document that will undergo change and revision or be at DQ is not a regulatory requirement although the
a level that states only intent. The continued requirement European GMPs refer to DQ in Annex 15 (5) and ICH

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Construction

1 External Works and Building

2 Site Preparation
3 Foundations/ Underground
4 Reinforced Concrete Frame/ Floors
5 Structural Steelwork Roof Plantroom
6 Structural Steelwork Internal
7 Cladding (Incl. Cladding Rails to Frame)
8 Building Finishes
9 Building Services and HVAC Testing
10 Install Equipment
11 Pipe Fabrication
12 Pipe Erection/Testing
13 Electrical
14 Instrumentation and Calibration
15 Paint and Insulation
17 Mechanical Completion Process Building

Precommissioning IQ/ OQ

18 Installation Qualification
19 Operation Qualification
20 Process Qualification

Figure 12 Qualication schedule from concept to validated facility.

20 I: INTRODUCTION

Q7A (6) would normally be conducted during this phase. completed against specications approved during
It essentially conrms that the design meets the user detailed design. Changes must be evaluated to check
requirements with particular reference to those require- whether there are any implications that impinge on
ments that impact on product quality attributes and GMPs or nal product quality. Those impacting on
process controls that impact on critical parameters. quality or GMP aspects would require quality approval.
Once changes are agreed to, they can then be executed
Construction IQ and approved. This process is normally controlled using
As discussed earlier in the section entitled Detailed Design an approved change control procedure.
and Procurement construction will normally commence Change control would be the normal practice in
part way through detailed design, with site clearance, construction management, but it is particularly important
foundations, and drainage being laid down in the early for a facility intended for the manufacture of medicinal
phases. The building will be erected and the t out will products. For example, changes to room nishes that may
commence as soon as the facility is weatherproof. impact on the cleaning of critical surfaces in a suite of
Construction will normally proceed on an area a trade clean rooms for sterile product manufacture would need
(civil, piping, mechanical electrical and instruments) basis to be reviewed and approved.
while the commissioning group requires completed Delivery and installation of equipment at site is
systems to be able to commence precommissioning activi- again all part of the IQ and should have had all its
ties such as walkdowns to ascertain completeness prior to groundwork of documentation completed in advance.
commencement of the commissioning activities. At some The completion of a FAT before shipment will
stage construction will need to complete systems in order often simplify the IQ and some of the OQ activities.
that commissioning can commence. Initial commissioning Frequently, nal documentation is not available from
activities involve start-up to conrm basic functionality of vendors until the FAT is complete. This tends to delay
the systems for by more extensive testing and set up to the preparation of OQ documents. However, the need
adjust and regulate the system such that it performs as to complete as much before this stage is essential. The
intended. The IQ can be completed once the system is speed of execution activities and schedules set for com-
conrmed as construction complete and the precommis- pletion and commencement of production draw near at an
sioning activities are complete. The OQ can be executed alarming pace. The more of this work completed during
once the system has been commissioned. A typical the detailed design phase, the easier the task at site will be.
construction program is shown in Figure 13.
The construction group will offer systems as
completed to the commissioning engineers for checkout. Site OQ
The engineer will check the system against the design The site OQ phase has two key objectives:
and construction drawings and provide a punch list. 1. To ensure that the system or subsystem works and
The list will identify where there are anomalies that performs as intended
require rectication. The importance of change control 2. To ensure that Operations personnel receive the
at this phase becomes evident. The checking should be relevant training and experience.

Construction Systems Complete

Mechanical Civils Piping E&I

Walkdown
Rectify

Punch
List

Note (1) Note (1)

Commissioning Punch Items Impact Next Step.
Step 1 Commissioning Step 1, Basic
Rectify
Testing. Commissioning Step 2,
Full Functionality Testing
Punch Note (2)
list Commences Once Plant is
Physically Complete, Usually
Note (1) Post Basic Testing.
Installation Commissioning
Qualification Step 2
Note (2)

Operational
Qualification
Figure 13 Schedule of qualification
activities during site construction phase.
 3: VALIDATION AND FACILITY DESIGN 21

The protocols and procedures prepared are now & Personnel and responsibilities
used in the execution of this phase. This execution will & Schedule
be a joint exercise, conducted by the engineers, operations & Preventative maintenance

personnel, and quality control colleagues. The systems & Change control

will be tested using the approved protocols, and this & Procedures

serves as a means of training. It is essential that a & Documentation

system and procedures for this are in place and that it is & Appendices

fully documented. Commissioning should be complete The foregoing list may vary depending on the
and the system should be fully functional. Critical instru- project phase for which an FEQ is written. At the
ments will have been calibrated and control loops conceptual stage, it will be very preliminary, whereas at
regulated such that they perform as intended. The OQ the detailed engineering phase it needs to have substan-
will then ensure that those Operations personnel who will tial detail and address all aspects of the qualication. It
conduct the process qualication are themselves qualied may be high-level document with supporting documen-
for this later exercise. Without this, it would be reasonable tation. How this is applied at each of the project phases is
to question whether the subsequent process qualication discussed in the following.
was itself valid if conducted by untrained personnel.
Introduction
FACILITY QUALIFICATION PLANS This section should be written primarily as an introduc-
Validation and qualication have been dened many tion to the qualication process, the facility and
times and typical examples are as follows: equipment and is intended to set the scene. Awareness
The EC denition: Action of proving, in accordance of the potential audience is very important, because the
with the principles of Good Manufacturing Practice, that plan may be used for various purposes (e.g., as a
any procedure, process, equipment, material, activity or corporate document or an introduction to the qualica-
system leads to the expected results (see also Qualica- tion for the inspection and regulatory bodies). The latter
tion) (1). Note EC Guide (1) denes qualication as use is probably more typical. It should include a descrip-
Action of proving that any equipment works correctly tion of the facility, its premises and equipment, and its
and actually leads to the expected results. The word purpose. The intention and scope of the qualication
VALIDATION is frequently widened to incorporate the should be set down. It is in this section that other relevant
concept of qualication (1). site policies and plans should be referred to and how this
The U.S. denition: Process Validation is estab- particular plan relates to these. These will probably
lishing documented evidence which provides a high include factory or corporate policy statements on, for
degree of assurance that a specic process will consist- example, GMP, QA, and such.
ently produce a product meeting its predetermined
specications and quality attributes (7).
Each of these denitions emphasizes the need to Methodology
demonstrate that a system does what it purports to do. To The plan needs to be developed and to focus on those
be able to execute this, a plan is essential. For a single standards that must be met including regulatory require-
system, this is achieved through a protocol, which in simple ments. This section of the plan should address these
terms is a plan, followed by its execution. For a whole requirements by identifying the standards that are to be
facility and its operation, we require a plan that encom- applied to the facility. These will subsequently be used in
passes all aspects of validation and qualication and this is the development of the acceptance criteria that are used
usually termed a Validation Master Plan. It would cover to judge the validation.
facility and equipment, automation, cleaning, process and The standards will normally comprise the following
laboratory and analytical systems. These would often have three elements:
& Regulatory and guidance documents
their own subplan and in the case of our facility we have
& National standards (or equivalent)
termed this the facility and equipment qualication or
& Company standards
FEQ plan. Qualication normally pertains to systems and
not processes as dened on the EC guide (1). The actual Regulatory and guidance documents would encom-
choice of name validation master plan or FEQ is very much pass, for example,
& FDA CFR Title 21 specic sections
an individual or corporate preference, what is important is
& EC Guide to Good Manufacturing Practice vol. IV
that the scope is clearly dened in any such plan. This
section describes the controls of a typical facility and Medicinal Products Guide to the Manufacture of Drugs
equipment qualication plan or FEQ. by Aseptic Processing
& GMP regulations of Japan
& Pharmaceutical Inspection Convention GMPs
Contents
The typical contents of an FEQ are as follows: International and national standards could include
& Introduction the following examples:
& Methodology
& Qualication ISO 13408, 14644
& DQ British standards BS5950, BS5750
& IQ
U.S. military standards AFM 84-4 to TO 25-203
Engineering standards Company or contractor
& OQ
standards, IEEE
& PQ
22 I: INTRODUCTION

Some organizations (operating rms, A&Es, equip- delivered to site). Others have linked some areas together
ment manufacturers and contractors) have developed (e.g., IOQ), and produced unied protocols, or have even
their own internal standards, for example: called this phase engineering or equipment qualica-
& Surface of equipment nish for sterile products tion. Clearly a exible, but formalized, approach is
& Valves and piping for use in USP and WFI systems required, and it may be appropriate to adapt the
& Finishes for walls and oors in clean rooms approach to the specic projects needs. The important
It is normal during the planning phase of any issue is to ensure that denitions in the organization and
project to set standards that will apply to the engineering for a specic project are consistent and cover all aspects
design; these are usually referred to as the basic engin- of the qualication process, and that the validation
eering design data. This phase of the FEQ identies those structure and organization is clear to any inspecting
standards that will be critical to the validation and its authority.
implementation. They are applied through the project to
ensure compliance with the GMPs. Design Qualication
It is also important to develop clear policies on DQ covers all aspects of the design and procurement of
documentation standards that will be applied. These facility and equipment. It is intended to encompass all
may be planning and execution documents, such as those activities that might take place in the design phase,
protocols, records, reports, or construction and commis- detailed and development, including activities associated
sioning documents that will or may be used in support of with procurement of equipment and checkout at the
qualication. Many organizations have developed suppliers works. DQ is a verication that the design
procedures and standards for these types of documents. meets user requirements with a particular focus on those
This section should either refer to these procedures or, requirements that relate to GMP and product quality. The
when necessary, either augment or provide new, as extent of DQ may depend on the contract arrangements.
required. These procedures should include: Design may be subcontracted to suppliers or subcontrac-
& Layouts for each type of document
tors and how this is covered should be dened in the
& Authorization procedures for review and approval
plan. DQ is not a regulatory requirement but is a smart
These procedures and formats, if not already in activity to include in the qualication process. Where DQ
existing corporate documents, for completeness can be is not identied as a specic step, it is still essential that
appended to the FEQ, or be in supporting documentation. aspects of design are demonstrated in the qualication
All systems will be commissioned using good
process as the existing regulations require that facility
engineering practices (GEP). There should be a commis-
and equipment are of suitable design and appropriate
sioning plan and schedule of activities that is integrated
to purpose.
with the construction schedule. GEP requires commis-
sioning documentation and records. Part of the process of
Installation Qualication
documentation is to develop a Turnover Plan and docu-
The IQ element of the FEQ should clearly dene those
mentation known as ETOP for equipment. Much of the
areas and items of equipment systems that are to be
testing and records if executed using GEP will be used in
qualied. The lists will vary depending on the nature of
support of the qualication.
a facility. A sterile lling unit might include the following.
Qualification
Premises Layout
The phases of qualication have included, for example, Flow of personnel, product, raw materials,
design, installation, operational, and performance. For and such
the purposes of this chapter, the elements of qualication Finishes of walls, ceilings and oors
and their scope are dened as follows: Utility services Drains
DQ is dened as Providing documented verication that Water systems (e.g., cooling, hot and cold)
all key aspects of the design, procurement and Services gases (e.g., instrument air)
installation adhere to the approved design intention Electrics
and that all the manufacturers recommendations HVAC class 100 systems
have been suitably considered. Class 10,000 systems
IQ is dened as Providing documented verication that Class 100,000 systems
Process services USP and WFI
all key aspects of the design, procurement and
Process gases: nitrogen, propane, and
installation adhere to the approved design intention others
and that all the manufacturers recommendations Clean steam
have been suitably considered. Equipment Steam sterilizer
OQ is dened as Providing documented certication Stopper washersterilizer
that the system and subsystems operate as intended Tray washerautoclave
throughout all anticipated operating ranges. Dry heat sterilizer
PQ is dened as Providing documented verication Vessels
that the system performs and does what it purports Hot air tunnel sterilizer
to do. Ampoule or vial washing machine
The foregoing denitions are so written that they Filling and capping machines
encompass all aspects of the design, procurement, instal- Lyophilizer
lation, and commissioning process. Some authorities Inspection line
Labeler
have dened other phases of qualication (e.g., receipt,
Packing (primary)
this being a checkout of equipment band systems as
 3: VALIDATION AND FACILITY DESIGN 23

After identifying the systems that will be qualied, and Quality Control departments. It is not the intention of
the next stage is then to develop a qualication plan. This this chapter to cover this in detail, but to suggest that the
is the protocol. A protocol will contain the following: approach already proposed for IQ, OQ, and PQ is valid
& A clear denition of purpose for PV. The processes and process systems are to be
& A plan for execution identied. Protocols can then be prepared and executed.
& Who will compile the execution It would be normal to draw up a matrix identifying
& How it will be conducted all the systems and whether they require validation and
& What procedures are required to what extent (Fig. 14).
& Acceptance criteria
& Dened methods for recording the results
Personnel
& A nal acceptance review
People are the key to success of any validation exercise.
& Means of certication of the qualication
The CFR 21 [see Sec. 211.21(2)] states Each person
engaged in and each person responsible for supervising
Operational Qualication the manufacture, processing, packaging or holding of a
The pattern established for IQ is followed in OQ. The key drug product shall have the education, training, and
approach in OQ is to identify and dene those systems experience, or a combination thereof, to enable that
that are to be qualied. The facility should be split into person to perform the assigned functions. It is reason-
system with clearly dened boundaries. This should able to imply from this that persons involved in the PV,
cover the whole of the facility, and it is usually appro- which is part of the GMP and QA process, must also
priate to be consistent with those developed for IQ. The fulll this requirement. Hence, if the process is executed
types of systems identied will be dependent on the with inappropriately qualied and trained personnel,
nature of the facility, but a typical example list a for a then the validation could be deemed invalid.
secondary sterile facility are given as follows: The FEQ should lay down the principles for
& Facility
personnel requirements. It must address these aspects
& HVAC class 100, 10,000, 100,000
for each phase of the validation process. Personnel will
& WFI water
change throughout the engineering design, construction,
& Process gases: air, nitrogen, CO2
and commissioning program. The task of ensuring each is
& Propane
appropriately qualied and trained and has relevant
& SIP systems
& CIP systems
experience may fall on different organizations (e.g., the
& Vial washer
engineering contractor of the pharmaceutical manufac-
& Vial tunnel sterilizer
turing company). The experience can be demonstrated
& Vial ller and stopper machine
by written biographies or curriculum vitae. The extent of
& Lyophilizer
detail will vary with the phase of the project. When
& Vial capper
training is required to augment experience and qualica-
& Vial inspection tion, it can be provided in-house or externally. Courses
& Vial primary packing should be run by specialists or equipment suppliers.
& Autoclave A combination of these is probably most desirable.
& Dry heat sterilizer Documenting the training is essential and is a requisite
& Stopper washerautoclave of the GMPs (1,2).
& Solution preparation system
Once all the systems have been dened, then Schedule
specic protocols for each can be prepared. These have A work program is essential and should be prepared at an
a form similar to that described for IQ. The information early stage. It sets out the milestones for the validation
for the IQ and OQ is frequently presented in a matrix process and incorporates them into the overall project
form identifying those systems to be qualied. OQ tests schedule. This will normally be in the form of bar charts
the systems throughout their normal operating range. and critical path networks, and it needs to be planned to
the same depth as the overall project.
Performance Qualication The importance of a plan becomes evident as the
This is generally applicable to those systems that require complexity grows. A good plan will contain all the
extended testing over a period of time such as water necessary features to identify when various activities
systems, heating, and ventilation systems such as those are due for execution and demonstrates to the outside
applicable to clean rooms and the actual performance of that the project is under control. This enables resources to
the clean room to meet the dened standards of operation be allocated at an appropriate time to achieve the activity.
over periods of time. Some organizations may include A typical example would be the completion of process
this type of testing in the OQ. specications to enable requisition placement, with the
subsequent delivery of documentation from the vendor to
Process Validation allow the design and protocol preparations to proceed
Process qualication is the phase during which the (Fig. 10). It ensures that all parties with an interest in the
manufacturing process and procedures are qualied. It project are aware of not just the engineering targets, but
would not normally be an area for which the engineering of the validation targets, and it has a tendency to assist in
organizationeither internal or externalwould be gaining commitment from all who are involved, from
involved. It is a primary responsibility of the Production those conducting the execution, to top management. It
24 I: INTRODUCTION

VALIDATION MATRIX

Validation SOP SOP SOP SOP Computer

Equipment Description URS DQ FAT IQ Calibration OQ Operation Cleaning
Required Training Maintenance Validation
Vial Washer
Stopper/Capper Washer
Vessels
Filters And Integrity Test
Oinment/Cream Homogeniser
Tube Filling Machine
Filling Machine
Depyrogenation Oven
Label Printers
WFI
Pure Steam Generator
Monobloc Filler/Capper
Freeze Drier
Vial Filler
Ampoule/Vial Inspection
Capping Unit
Laundry Equipment
Balances
PH Meter

Figure 14 System qualication matrix.

can also show due dates for that all-important nal and its designthrough construction to operationand
inspection. should be addressed in the FEQ.
This section of the FEQ should then lay down the
Preventive Maintenance requirements for a set of procedures for change control
This element is frequently considered to be the responsi- that cover:
bility of the Site Maintenance and Operations department 1. The project through design, construction, and
and often is given a low priority within an engineering commissioning
design team. There is a clear requirement to keep a facility 2. The ongoing change that will inevitably occur in both
in a state of qualication. A preventative maintenance the process, the equipment, and the engineering
program is an essential component of a schedule of work aspects
to achieve this objective. The Validation Master Plan must 3. Identifying how to determine which changes require
identify the need for this program and, hence, to ag its QA approval and which require only Engineering
importance to the designers. The role of vendors and approval
suppliers is very important in this area. Operation and The link between this section and previous is very
maintenance manuals should be considered as a key part strong. Both preventive maintenance plans and change
of the specication program. This activity should be control are intimately linked.
conducted during the design phase, and the documen-
tation required should be included in the requisition. The Procedures
execution of a preventive maintenance program can take Procedures are an essential part of any system of vali-
on greater relevance within the precommissioning and dation. These cover engineering standards used in the
commissioning phases demonstrating that, once quali- project design, through to commissioning phases, and
ed, a unit has been maintained both in a proper manner the facilitys SOPs. Usually, the FEQ will identify the
and in accordance with the suppliers instructions. commitment to written procedures and identify an
approval procedure for formats, preparation, and author-
Change Control ization of these procedures.
The frequently asked question is When is qualication/
validation complete? The process is never nished; it is Documentation
an ongoing exercise as the facility, its services, equipment, The documentation section of the FEQ is usually used to
and processes must always be in a state of validation identify the documentation that will be produced.
to comply with the regulatory requirements. Change Depending on the stage in a project when the plan is
control applies not only to the ongoing manufacturing produced, the detail will vary. A preliminary plan may
processes but also throughout the whole of the project. identify only the broad areas of documents that will be
Change control should address all aspects of the facility produced; for example:
 3: VALIDATION AND FACILITY DESIGN 25
& Engineering drawings Services
& Equipment supplier drawings and documents Are you proposing new services or reuse of existing
& Factory acceptance documents (works qualication) services? Do the existing services have adequate vali-
& IQ documents dation documentation, IQ, OQ, and PQ? Are the existing
& OQ documents services adequate for their new role?
& PQ documents Some of the common areas of concern do revolve
around reuse of equipment. Frequently, this equipment
Appendices does not have adequate validation records, and obtaining
Much of the outcome of the execution will be written documentation to support its qualication is difcult,
documents. The appendix section is commonly used in especially if it is being considered for a new use.
more detailed master plans to hold examples of the types Suppliers often no longer support that specic model
of documents and formats that will be used in the range. All of these factors increase the validation effort.
execution stage. Similarly, existing services may not meet current stan-
dards (e.g., a USP water system running for many years
requires extension to the ring main). What standards do
REVAMP OR EXPANSION PROJECTS
we apply to the new section, and what strategy should be
Introduction taken to the validation?
Projects of this nature usually take the form of upgrades
of exiting facilities and can include the following:
1. Environmental upgrades to ne chemical, pharma- Validation Aspects
ceutical, and microbiological facilities The approach should be similar to other projects, as
2. Expansion of existing pharmaceutical operations discussed earlier. A Qualication Plan is essential, and
and facilities it is important that it encompasses all aspects of the
3. Infrastructure work in ne chemical and pharma- project and its effect on other systems. It should involve
ceutical businesses, such as waste management all parties, Engineering, Production, and QA. The Vali-
and utilities dation Steering group should consider all the key factors
4. Plant and buildings demolition and disinvestment and ensure that these are addressed in the plan.
5. Plant and buildings maintenance and repair Reviews and audits of both the design and
6. Facilities replacement, retting, and redevelopment execution strategy are important to the services of a
7. Safety and GMP upgrades revamp or an upgrade project. Changes to either of
8. Decommissioning of plant, equipment, buildings, these must be examined for effect on quality, not only
or facilities just in the project and its intended scope, but also on
It is important at an early stage to have a clear surrounding activities. It is not uncommon for changes to
denition of both the purpose and scope of the upgrade, affect adjacent processes. Clear strategies for evaluation
and an understanding of where the project is coming must be incorporated into the Validation Master Plan and
from and what are the main drivers. Frequently, the major then be executed. Reviews should consider additional
factors driving the project will be a need to provide a requirements.
modern facility to meet the latest GMP standards, an & Decontamination

upgrade in capacity, improvements in working methods & Cross-contamination

and technology, or a reorganization to take a new product & Operation and process protection during decommis-

line. A knowledge and understanding of these drivers sioning and construction phase
helps and enables a validation plan to be developed. & Any breach to GMP integrity of the system
& Any effect on existing procedures or protocols

Approach The foregoing consideration should be in addition

Once a scope and purpose are set, the methodology is to those already discussed in previous sections of this
very similar to that for detailed design and construction chapter (The Engineering Design Process for a Facility
(see the section entitled Detailed Design and Procure- and Facility Qualication Plans).
ment). Some additional points need to be considered.

Location SUMMARY
It is important to review the location of the project and Validation is an essential part of GMP (8) and as a key
evaluate its effects on the surrounding operations. element must be incorporated into the design and
How will you manage interruptions in services? building of pharmaceutical facilities for the manufacture
Or segregation to avoid contamination to adjoining of pharmaceutical products. It should be considered from
operations? What if decontamination is necessary if the earliest phase (i.e., conceptual study) and be a key
changing products? feature of the project.
The extent of the validation or qualication require-
Equipment ments will vary with the project phase. The responsibility
Is new equipment to be used or will it be reuse of existing for its execution should be clearly dened and allocated
equipment? What is the current state of validation IQ, to the appropriate discipline functions of engineering,
OQ, and PQ? Will it need upgrading, and do you need to production, and QA. Its execution is best achieved by
involve the original vendor? Is the model still manufac- having a fully dened scope that is then incorporated
tured; what is the current spares situation? into the project plan and schedule. This is best achieved
26 I: INTRODUCTION

by an FEQ that may become a subset of plans linked to 2. Code of Federal 21 (CFR 21) Parts 200299. Ofce of
a validation master plan. This can become a living the Federal Register National Archives, and Records
document and identify the qualication/validation Administration.
3. Simmons PL. The design construction and commissioning
requirements at each of the project phases. This plan
of a new facility in accordance with GMP regulations. Pharm
can then become a vehicle for demonstrating a structured Engin 1992; 12(5).
and organized approach to the regulatory and inspecting 4. Baseline Guide to Commissioning and Qualication ISPE
bodies. 2001.
5. European GMP Annex No Validation.
6. ICH Q7A.
7. Center for Drugs and Biologics, and Center for Devices and
REFERENCES Radiological Health. Guideline on General Principles of
1. The governing of medicinal products in the European Process Validation. Rockville, MD: Food and Drug Admin-
Community. Good Manufacturing Practice for Medicinal istration, 1987.
Products. Vol. IV. Luxembourg Ofce for Ofcial Publi- 8. Adamson JR. An approach to validation. Pharm Technol
1992; 12(5).
cations of the European Communities, 1992.