The Industry’s Authoritative Source
Essentials of Validation
Project Management
Part I
William Garvey
T
VECTOR CORPORATION
To qualify and validate a pharmaceutical
manufacturing facility, one must carefully review
the facility design for compliance with good
manufacturing practices and manage project
scope definition, labor and cost estimating, and
master-plan development. These activities,
properly implemented, help deliver a validated
facility on schedule, at the estimated cost, and
with expected quality.
William Garvey is Validation Consultant at
Millipore Corporation (Billerica, MA).
Phone: (781) 533-2407.
Email: William_garvey@millipore.com
Submitted: Aug. 16, 2005. Accepted: Sept. 9, 2005.
he qualification and validation of complex pharmaceutical
manufacturing facilities requires the careful coordination
of multiple activities. Conceptual, preliminary, and detailed
designs must be reviewed to ensure compliance with cur-
rent good manufacturing practices (CGMPs); protocol and stan-
dard operating procedure (SOP) formats must be developed; and
project resources must be identified and obtained. A validation
schedule must be created and integrated with the facility construc-
tion schedule. The Quality Assurance and Calibration–Metrology
departments must be notified of impending increased workloads.
And finally, the manufacturer should alert the local US Food and
Drug Administration district office that a new facility is planned.
Considering all these activities, careful planning and cautious man-
agement will increase the likelihood of a successful project out-
come, no matter how difficult or complicated the project. Success-
ful project completion is never guaranteed, but by implementing
proven techniques and the programs described in this article, a fa-
vorable end-result is much more likely.
Parts 1 and 2 of this article will examine seven critical compo-
nents of a comprehensive validation program for new and reno-
vated manufacturing facilities. The programs and procedures ex-
plained are appropriate for all commonly manufactured dosage
forms (e.g., tablets and capsules, active pharmaceutical ingredients
[APIs], parenterals). Given that the design, construction, and qual-
ification and validation of a major facility are relatively infrequent
events in most corporate life cycles, some of these project compo-
nents are not well known or understood. For this reason, Part 1 of
DATA AND REVIEW
this article examines the following areas:
• facility- and equipment-design review to en-
sure compliance with CGMP regulations;
• project scope definition, organization, and
planning;
• project labor requirements and budget;
• validation master plan development.
Part 2 will continue with a discussion of the
following validation-related subjects:
• protocol and SOP development, scheduling,
and implementation;
• design- and construction-document collec-
tion (turnover package);
• evaluation of deviations and discrepancies.

Facility- and equipment-design review

By definition, the construction of a new or ren-
ovated facility and the purchase and installation Figure 1: Valve orientation (45
above Figure 2: Fluidized bed dryer showing
of mechanical equipment and process systems horizontal) and nonchloride insulation mechanical components requiring maintenance
constitute a project. All projects have basic, com- in purified water, USP system. located outside the process space (photo
mon features: a logical start, a logical end, and courtesy of Vector Corporation).
little or no possibility of recurrence (i.e., the proj-
ect will not repeat at some future time). In addition, the design understanding of GMP-compliant design often exceeds that of
process is common to all facility projects. All facilities start with a the owner and engineer combined (2). Design reviews should
design, about which engineers, owners, scientists, and other stake- be performed using a structured and systematic approach. For
holders confer to determine how the facility will appear and op- mechanical systems such as HVAC, the evaluation of drawing
erate and what equipment and systems are needed. The usual se- sets takes precedence over most other documents. Vendor sub-
quence starts with the development of a conceptual design by an mittals always should be reviewed. Although less beneficial, Di-
engineering firm, from which preliminary decisions are made about vision 15, 22, and 23 type construction specifications (3) also
facility layout and size, utilities required, and equipment capacity should be examined, even though these are often standard with
and material of construction. The process then continues into the little customization. Checklists and other reviewing aids may
preliminary and detailed engineering stages, in which costs are fi- be valuable because they prove that the designs were evaluated
nalized and designs are completed and approved. It is at this point and they may be used again for subsequent projects.
when the conceptual design transitions to preliminary engineer- Three critical steps must be taken in a design review:
ing that formal review to verify GMP compliance begins. • identify and evaluate any potential areas or items of noncom-
In general, process equipment and utility systems affecting prod- pliance;
uct quality or contacting product are the subject of design review. • ensure that designs are modified to eliminate noncompliant fea-
Typical reviewed utilities include heating, ventilation, and air-con- tures;
ditioning (HVAC), compendial waters (e.g., water-for-injection, • prepare a brief report that summarizes the design-review process
purified water, clean steam), and compressed gases such as nitro- and obtain appropriate approvals, including quality assurance.
gen and compressed air. At present, regulatory expectations for Much of the current content in both domestic and foreign GMP
other utilities such as chilled water or plant steam are minimal, regulations is limited and nonspecific. The owner is obligated to
and these may be omitted. Design review is mandatory for highly review all designs and verify conformance with industry standards
customized or unique process equipment, particularly when the and regulatory guidelines. In the absence of standard equipment
unit is custom manufactured. Equipment for critical processes specifications within the GMPs, logic dictates that process equip-
such as aseptic filling and packaging, lyophilization, and final pu- ment and utilities must be designed to be:
rification also requires rigorous evaluation. Because the GMP reg- Nonreactive. Materials of construction must be inert and non-
ulations are interpretive and nonspecific for equipment design and additive. Type 304 and Type 316 stainless steel are commonly
construction, the design engineer and owner are responsible for used. Hastelloy C frequently is used in reactor systems and con-
assessing compliance (1). densers. Wood should be avoided, even for utensils, because it
During the design review stage, the engineer and owner can generate unwanted particulates and is porous and difficult
should evaluate all critical specifications and drawings to en- to clean. Gaskets must withstand attack by process fluids and
sure that regulatory compliance is achieved. In general, experi- be dimensionally stable under expected temperature conditions.
enced vendors understand the requirements imposed by GMP Chloride-containing insulation should not be used with stain-
regulations and design and construct their equipment and sys- less steel components (see Figure 1).
tems accordingly. Rarely are serious design and construction Cleanable. Equipment surfaces must be smooth and free of voids
errors uncovered because a reputable vendor’s knowledge and and crevices in which material can accumulate. Welds must be
2
polished smooth, although mirror polishing is not always recom-
mended where glare is a concern. Short-radius corners are pre-
ferred at joined surfaces. Threaded fittings usually are not permit-
ted on sanitary systems. Diaphragm valves must be installed on
horizontal lines at 45
angles to ensure complete drainage (see
Figure 1). Labeling and packaging equipment must be designed
to permit thorough inspection. If cut labels are used, equipment
should permit stray labels to fall to the floor unimpeded. Seam-
less floor coverings should be installed where practical because
they prevent the infiltration and exfiltration of water and con-
taminants from and to sublayers. Valves and flanges should be
minimized in concealed-piping runs over critical process areas
where leakage or failure could be problematic.
Maintainable. Through-the-wall designs should be used where
serviceable mechanical components are located outside process
spaces (see Figure 2). Such items include HVAC air-control valves
and instrumentation, process filters, and operator workstations.
Remote grease fittings should be installed on fan bearings to min-
imize air handler entry. Adequate clearance should be allowed at
heat exchangers to permit coil removal and inspection. Redun-
dancy should always be considered for mission-critical systems,
including sanitary pumps, steam traps (see Figure 3), filter assem-
blies and regulators, and recorders on sterilizers. Ergonomics also
should be considered.
Reliable and controlled. Control systems such as programmable
logic controllers (PLCs) should be used to control equipment. Au-
tomation allows processes to be replicated without variability, a
fundamental principle on which GMPs are based. Mechanical-
type (cam) controllers should be avoided because regulations re-
quire that current and modern technology be used. Manual con-
trol also should be avoided where possible because replication is
inherently difficult. Any system that may alter batch-to-batch uni-
formity, and ultimately the product therapeutic response, must be
very carefully considered.
Correct for application. The correct design criteria must be spec-
ified. For example, clean compressed air must have a dewpoint
temperature of approximately –40
F to prevent condensation. Re-
frigerated air driers cannot meet this requirement. Oil-free com-
pressors should be used to exclude oil contamination unless sev-
eral levels of filtration are used (4). Industry standards allow no
more than 1 ppm (1 mg/m3) of oil/hydrocarbon in compressed air.
Besides developing some original standards for process equip-
ment design and construction, the pharmaceutical industry has
borrowed standards from industries that produce similar con-
sumer products, most notably the dairy industry. The 3-A Sani-
tary Standards are voluntary guidelines followed by dairy equip-
ment vendors and dairy operators. The standards provide material
specifications, design criteria, and other necessary information for
the construction of dairy equipment to satisfy public health con-
cerns. The ultimate objective is to safeguard public health from
contaminated dairy products.
To meet this objective, 3-A Sanitary Standards and 3-A
Accepted Practices ensure that dairy, food, and other microbial-
sensitive products are protected from contamination; that all prod-
uct contact surfaces can be cleaned in place or easily dismantled
for manual cleaning; and that all product contact surfaces can be
easily inspected to confirm cleaning effectiveness (5). The purpose
Figure 3: Duplex steam-trap assembly at a critical air-handling unit.
of these standards and their application to pharmaceutical man-
ufacturing are readily apparent. The 3A Sanitary Standards should
be consulted when equipment such as holding tanks, clean-in-
place systems, valves, and pumps are undergoing GMP compli-
ance review. Design errors are uncommon, however, because most
equipment vendors already fully understand and comply with these
standards.
For high-value projects and facilities intended to manufacture
sterile products, it is often required and worthwhile to contact the
local FDA district office. This alerts the agency that inspections
must be scheduled, often to coincide with critical construction
milestones and events. FDA Office of Regulatory Affairs Field Man-
agement Directive (FMD) 135 also encourages manufacturers to
contact FDA when facility and equipment designs are being pre-
pared (6). The following is a summary of FMD 135, which can be
found on FDA’s Web site:
Providing [FDA] review and comment is desirable because it
may reveal [design] defects early and prevent costly construc-
tion errors which could lead to defective operations and prod-
ucts. It also affords FDA the opportunity to become aware of
future work load obligations and, in some cases, new technolo-
gies. Early field involvement with new or modified facilities will
increase efficiency and result in the timely processing of appli-
cations (6).
Companies should understand and recognize that partnering
with FDA to review proposed designs is beneficial to both parties.
Costs and delays associated with rework can be avoided if prob-
lems are detected early. Definitive dates for facility inspections can
be established, which serve as endpoints that motivate project com-
pletion. Current agency inspectional focus also may be apparent,
foretold by the types of questions that are asked. Overall, early di-
alogue and FDA involvement may expedite facility completion, re-
duce engineering and construction costs, and lead to a smooth
transition from start-up to operation. These results are desirable
for all manufacturers, regardless of company size or complexity.
Scope definition,organization,and planning
Successfully implemented validation projects all begin with a well-
defined scope (i.e., the set of activities and deliverables that must
occur to complete the project). Scope definition is critical if con-
tracted validation resources are used because it becomes the basis
for cost estimates and assessing job completion.
Validation project scope definition usually begins by reviewing
the following drawings and documents (7):
• air-flow diagrams (see Figure 4);
3
 Table I: Estimated labor hours for commissioning and qualification.
Protocol Standard operating
Commissioning Protocol preparation execution Final procedures
System Doc. rev. Procedure Implement Doc. rev. IQ OQ IQ OQ Reports Oper. Clean. Mainten.
Utilities
Cold glycol 2 16 20
Hot glycol 2 16 20
Steam (50 lb.) 2 16 20
Instrument air 2 16 20
Process water 2 16 24 20 16 16 16 16
Nitrogen (50 PSIG) 2 16 24 20 16 16 16 16
Chilled water 2 16 20
Tempered glycol 2 16 20
Breathing air 2 16 20
Scrubber 2 16 20
Tempered water 2 16 20
HVAC 2 24 40 32 40 20 16 16
Vacuum pump LP2 2 16 20
Vacuum pump LP4 2 8 20
Subtotal 22 168 220 6 56 88 72 72 52 48 0 48
Process equipment
T-4000 mix tank 2 16 16 24 24 16 16 16 12
Mixing vessel (T-501) 2 16 16 20 16 16 16 16 12
Mixing vessel (T-502) 2 8 8 20 16 16
T-500 reactor 2 24 24 24 24 16 16 16 16
T-504 receiver 2 16 16 20 16 16 16 16 16
T-1003 mix tank 2 8 8 20 16 16
Transfer panel system 2 16 16 24 20 12 16 16 16
Walk-in hood 2 16 20 24 24 16 16 16 16
Subtotal 16 120 124 176 156 124 96 96 88
Total 22 168 220 22 176 212 248 228 176 144 96 136
Grand total 1848
Abbreviations: Doc. rev. is document collection and review; IQ is installation qualification; OQ is operational qualification; Oper. is operation;
Clean. is cleaning; and Mainten. is maintenance.

• piping and instrumentation diagrams;
• utility-flow diagrams;
• equipment lists.
These four types of documents are common and essential to
all validation projects, although the level of detail and content
may vary. Design-document quality is usually closely associated
with cost; the greater the upfront engineering costs, the more
detail that can be found in drawings and lists. Because facility
construction and protocol preparation require drawings that are
detailed, accurate, and thoroughly checked, increased funding
for engineering services is usually money well spent. In general,
one can expect that the cost of facility-design services will be ap-
proximately 10–12% of the facility’s total installed cost.
It is useful to identify project activities on a spreadsheet when
establishing project scope. Systems and equipment requiring
qualification and validation are first determined by reviewing the
project documents described previously. Then, the spreadsheet
is created and the first column is reserved for each identified sys-
tem and piece of equipment. Adjacent columns become a ma-
trix of activities necessary to complete system and equipment
4
qualification. Column headings and subheadings usually consist
of the following:
• document collection and review (to develop protocols and SOPs);
• calibration and metrology;
• protocol preparation (installation qualification [IQ], operational
qualification [OQ], performance qualification [PQ], and clean-
ing);
• protocol execution (IQ, OQ, PQ, and cleaning);
• final reports;
• turnover packages (contain construction test reports, as-built
drawings);
• SOPs (operation, maintenance, cleaning).
A checkmark is placed in each cell for which a specific activity
is required. This checkmark may be replaced eventually with the
name of the individual responsible for the activity. Assigning labor
hours to each checkmark is even more useful because this provides
an estimate of the labor required for each activity and for the en-
tire project (see Table I).
Figure 4: Typical air-flow diagram for an API facility.
Project labor requirements and budgeting
By revising the spreadsheet to include labor hours, and then total-
ing each row and column, a project labor estimate per activity and
system can be derived (7). Dividing total project hours by 2080
h/year provides an estimate of personnel required to complete all
activities. Total project headcount will vary depending on project
duration, however. Anticipating the number of labor hours is im-
portant because the labor involved may exceed available resources,
thus requiring that outside validation services be contracted. As-
signing a dollar amount (e.g., $75) to each hour of labor provides
an estimate of validation project costs, which often is used to jus-
tify requests for financial resources and to support the annual budg-
eting process.
Industry experience has shown that validation costs (excluding
commissioning and process validation) typically range from 2.5–5%
of the total installed cost of the facility. Aseptic-filling and biotech-
5
DATA AND REVIEW
nology facilities frequently have the highest validation cost, whereas
API facilities tend to be the least expensive. Care must be taken not
to apply these guidelines too tightly because the percentage vali-
dation cost will vary with project size. As an example, the purchase
and installation of a small steam sterilizer might have a total in-
stalled cost of $150,000; however, the validation costs may exceed
$50,000 (33%), when protocol preparation and implementation,
SOP development, and laboratory supplies are considered.
On validation projects, personnel are often subdivided into
teams, with one team preparing SOPs, another team preparing
protocols, and so forth. Alternately, one person may be assigned
to a specific system, taking full responsibility for protocol and SOP
preparation, implementation, and final-report development. The
spreadsheet described previously helps with this decision. Either
method is satisfactory, but the one chosen must account for per-
sonnel availability and future operational needs. Often, contrac-
tors are employed to prepare protocols and SOPs only, while im-
plementation is reserved for company personnel. This approach
has several benefits. First, the contractor travel expenses are min-
imized because all document development can occur in the con-
tractor’s home office. Second, protocol implementation is per-
formed by those who will ultimately operate and maintain the
validated equipment and systems. This process may reduce the
transition time from start-up to manufacturing, and if properly
documented, can satisfy GMP training requirements.
Validation master plan development
The validation master plan complements the project scope. Al-
though master plans are not officially required by some regulatory
agencies, these documents may be submitted to FDA as part of the
preoperational review program (FMD 135) discussed previously.
Master plans typically describe the project scope in detail and in-
clude preliminary validation acceptance criteria. They also con-
tain a description of all programs that collectively make the facil-
ity GMP compliant. A well-conceived and well-written master plan
reduces the likelihood that a critical activity or program will be
omitted and provides regulators with a sense that the company is
quality-minded and operating in a state of control.
Once the project scope is determined and reduced to spread-
sheet format, the spreadsheet may be imported into the draft val-
idation master plan. Master plans usually are focused on project
deliverables, not costs. Therefore, estimated costs and labor hours
do not need to be presented. There is no standard format for val-
idation master plans, although the concept has evolved so that
many features are standard from company to company. Each mas-
ter plan is an analysis and evaluation of a manufacturing facility’s
validation and compliance requirements. Typical master plan con-
tents include the following:
• approval page (quality-assurance approval is required);
• introduction and facility description;
• project organizational chart (optional);
• descriptions of component and material storage areas, produc-
tion areas, quality assurance areas, critical utility systems (HVAC,
purified water, water-for-injection, building management sys-
tem);
• spreadsheet (described previously);
• system and equipment descriptions (in sufficient detail for im-
6
portation into corresponding protocols);
• preliminary acceptance criteria (for each system and piece of
equipment);
• SOP listing;
• other GMP-required activities (document control, training, en-
vironmental monitoring, and so forth);
• drawings, particularly facility layouts, piping and instrumenta-
tion diagrams, and air-flow diagrams.
If possible, special or unique features should be emphasized
in the master plan, especially those that ensure product unifor-
mity or the elimination of contamination and cross-contami-
nation. These features might include a description of extract
booths, personnel showers, and isolators used during toxic ma-
terials processing. Room air-change rates, personnel gowning
practices, and decontamination with formaldehyde or vapor-
ized hydrogen peroxide also are worth mentioning. It is impor-
tant to convey quality and attention to detail in the master plan
because this document is approved by the Quality Assurance
department and often is reviewed by FDA.
Other programs to describe in the validation master plan are
the facility revalidation program, turnover package develop-
ment, and system or equipment commissioning. With the pub-
lication of the International Society for Pharmaceutical Engi-
neering’s Baseline Pharmaceutical Engineering Guide:
Commissioning and Qualification in March 2001, greater em-
phasis has been placed on system and equipment commission-
ing (8). Until recently, commissioning was an activity often per-
formed without any involvement of quality assurance or
validation personnel. The construction team or an agent hired
by the project manager usually performed system commission-
ing. Commissioning documents were often prepared and exe-
cuted without any review or oversight by the Quality Assurance
department. In many instances, validation often repeated com-
mon commissioning tests and verifications, thereby increasing
costs and creating inefficiencies. In addition, systems often were
commissioned and validated where commissioning would have
satisfied operational requirements. It is worthwhile to identify
and describe the interaction between commissioning and val-
idation in the master plan. The plan may include a description
of required commissioning documents and how they support
the validation effort. In general, systems that have no product
contact are good candidates for commissioning only, although
there are occasional exceptions to this rule.
The facility revalidation program also should be described in
the master plan because the validation life cycle continues long
after the facility is mechanically complete and handed over for op-
eration. Revalidation usually takes two forms: time or event based
(9). Time-based revalidation is the practice in which a system or
process is recertified at a specified interval. Time-based assessments
also can include a review of historical system performance data.
Event-based revalidation is implemented whenever physical or op-
erational changes are made to the system outside the scope of the
original validation. All such modifications are the subject of the
facility’s change control program, which also should be described
in detail in the master plan.
Turnover package (TOP) development also can be described
in the master plan. Turnover package is a system for organiz-
ing all documents related to facility and system design, con-
struction, and start-up relevant to the eventual commissioning
and qualification of systems and equipment (10). Turnover
packages are usually prepared by the construction manager and
turned over to the owner at project completion. TOP docu-
ments construction activities and contributes to system IQ, OQ,
and PQ and usually is a prospective or concurrent activity (i.e.,
design, construction and start-up documents are compiled as
system construction proceeds). Turnover packages will be dis-
cussed in detail in Part 2 of this article.
Summary
This article provides a basic introduction to four components that
are fundamental to all successful validation projects. Part 2 will de-
scribe three additional programs that should be considered and
implemented. Before undertaking any validation project, careful
planning to arrive at a logical, uncomplicated approach is required.
All projects are labor and capital intensive, and incorrect or inef-
ficient use of either resource ultimately escalates cost and extends
the schedule.
All validation projects must begin with a comprehensive design
review and include FDA assistance if necessary. Once a compliant
design is finalized, validation project scope must be established
and properly communicated to all project stakeholders. Concur-
rent with project-scope definition is the development of a labor
estimate, and by extension, a cost estimate. Knowing labor require-
ments and costs early helps identify potential shortfalls in person-
nel and permits appropriation of sufficient funding to complete
the project. Accurately defining project scope also avoids misun-
derstandings, errors, and omissions when work is assigned to con-
tractors and company personnel. A comprehensive validation mas-
ter plan follows design review and scope definition in the project
timeline. The master plan identifies critical project activities, com-
© Reprinted from PHARMACEUTICAL TECHNOLOGY, December 2005
municates expectations, and conveys a quality mindset and state
of control to regulators. Each of these project components, in con-
junction with the guidelines and programs described in Part 2 that
follows, helps assure that the project is completed on time and
within budget. More importantly, quality is built into the project
from the start, regulatory compliance is realized, and the transi-
tion from start-up to operation is optimized. In the current envi-
ronment of cost control, expedited product introductions, and in-
creased regulatory oversight, the benefits of efficient validation
project management should be evident.
References
1. US Food and Drug Administration, Code of Federal Regulations, Title 21
(FDA, Washington, DC, April 1, 2005), pp. 120–141.
2. W. Garvey,“Integrated Validation Programs for Solid Dosage Facilities—
Part 1,” Am. Pharm. Rev. 2 (2), 33–39 (1999).
3. The Construction Specifications Institute (Alexandria, VA).
4. Department of Health, Education and Welfare, “Human Drugs—Cur-
rent Good Manufacturing Practice in Manufacture, Processing, Packing
or Holding of Large Volume Parenterals, and Request for Comments Re-
garding Small Volume Parenterals,” Fed. Regist. 41 (106), 22022–22115
(June 1, 1976).
5. 3-A Sanitary Standards Inc., McClean, VA.
6. FDA, “ORA Field Management Directive 135, Pre-Operational Reviews
of Manufacturing Facilities” (FDA, Washington, DC, Dec. 4, 1995).
7. W. Garvey,“Effective Validation Project Management,” oral presentation
given at Interphex Conference 2005, New York, NY, April 26–28, 2005.
8. ISPE Baseline Pharmaceutical Engineering Guide, Pharmaceutical Engi-
neering Guides for New and Renovated Facilities, Vol. 5, Commissioning
and Qualification, (International Society for Pharmaceutical Engineer-
ing [ISPE], March 2001), pp. 11–15.
9. ISPE Baseline Pharmaceutical Engineering Guide, Pharmaceutical Engi-
neering Guides for New and Renovated Facilities, Vol. 5, Commissioning
and Qualification, (ISPE, March 2001), p. 111.
10. M. Chin,“TOP: A Rational Approach For Ensuring Proper Biopharma-
ceutical Plant Construction,” in proceedings from PharmTech Confer-
ence ’87 (Aster Publishing Corporation, Eugene, OR, 1987), p. 73. PT
Printed in U.S.A.