FOCUS ON...
FACILITIES
Designing Efficient
Manufacturing Facilities
by Jim Levin
D
esigning efficient
facilities for the
manufacture of
biotechnology
products is an exercise
in reality-based creativity. It’s a
process of the imagination that’s
constrained by the many realities
faced by a growing company. We
all want to design facilities that
meet the many needs of differences
in scale, product development,
phase of clinical development, and
corporate growth. But we’re
limited by both budget realities
and the need to design for today’s
certainties. How can we get the
most for our money to meet the
challenges of today and tomorrow?
WHAT IS AN EFFICIENT
MANUFACTURING PLANT?
An efficient facility can meet our
needs for today, often at pilot or
clinical scale, and grow with our
company as we approach the rigors
of commercial production. We
can’t afford to build a plant that is
flexible enough to meet all those
needs, but we can certainly build in
efficiencies to meet many needs of
our growing company if we are
willing to figure out “Where am I
today, where will I be tomorrow,
and how will I operate the plant to
get there?”
What kinds of flexibility are
desirable? An efficient
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manufacturing plant accommodates
growth (increase in scale), different
products (multiuse or even
multiple technologies), and
different phases of development. It
can make large quantities of
product quickly and will be
inexpensive to build and operate.
These ideals tend to conflict with
one another, and with rare
exceptions, few of us ever have the
budget to accommodate that
tension. Although the ideal plant
may never be built, designers and
developers can follow the process
described here to include cost
effective efficiencies that improve
the utility of their manufacturing
facilities.
BALANCING COMPETING PRIORITIES
The process of designing an
efficient manufacturing facility is
much the same as designing a
house. We want to build it well, as
quickly as we can, and for the
fewest possible dollars (good, fast,
and cheap). We start by building a
solid foundation and build up the
house from there. In this case, our
foundation is the cGMP
regulations. They define a
minimum standard of construction
and operation for our
manufacturing facility. Sitting on
our foundation are the design
features we wish to include for the
fastest operations, which are
balanced by the design features we
can afford.
Figure 1: In a perfect world, both construction and operations would be both fast and cheap.
But in the real world, these desires must be balanced atop the quality systems used to
maintain compliance with cGMPs.
The reality is a little more
complicated. Our foundation is
really our quality systems, our
interpretation of the cGMP
regulations and how we intend to
implement them. We must also
balance “quick” and “cheap” against
construction and operations
constraints (Figure 1). A decision to
commission and qualify a system,
instead of fully validating it, may
speed up construction time and
decrease initial expenses. But it may
in fact cost more ultimately when
validation needs to be completed
after production has begun.
Similarly, a decision to install
transfer piping may cost more in the
construction phase but pay
handsome dividends once
operations begin.
Although it may seem as if we’re
balancing a spinning top on an
uneven table, the good news is that
this is still a paper exercise. The goal
is to accept our realities and, using
our quality systems, find a way to
achieve balance between these
conflicting corners. Here are a few
points to accept:
• No facility is perfect. Balancing
design and operations can
strengthen your facility.
• You can’t anticipate everything.
No one can know what tomorrow’s
“hot button” quality items will be.
• It’s cheaper to make changes
on paper than with bricks and
mortar. Spend time working out the
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design and then document your
assumptions. It is better to work out
the problems on paper than to be
required to move walls later.
• During design, remember
Newton’s third law of motion: “For
every action, there is an equal and
opposite reaction.” Speed costs
money, and succumbing to the
pressure to get the facility built on
time and on budget may hamper
both the cost and time of operations
later.
BUILDING AN EFFICIENT PROCESS
How do you design an efficient
manufacturing facility? Typically,
you start with wishful thinking, go
on to conceptual design, and then
advance with preliminary and
detailed architecture and
engineering.
Wishful thinking is the email from
your boss that asks for your ideas for
a new facility or the drawing on the
back of an envelope or napkin that
lands on your desk one day. It is
unconstrained thinking with little or
no basis in reality. There are no
constraints of budget, time,
constructability, or operations.
Conceptual design is the beginning
of reality-based definition, and it
leads to process diagrams, floor
plans, building layouts, and
estimates of construction time and
cost. Often this information is
captured in a document called the
basis of design. Many times, the basis
of design with its embedded
estimates is the vehicle used for
project approval by management.
Preliminary engineering turns the
information contained in the basis
of design into two-dimensional
drawings of the engineering systems
needed to run the facility. Those
drawings can also be used to obtain
cost quotes to build the plant and,
along with architectural drawings,
form the basis of building permit
applications. Finally, engineering
drawings are established showing all
the details of the equipment,
systems, and cleanroom design
needed for final construction and
cGMP documentation.
Clearly, this process requires
input from many people. In some
ways, the facility being designed is
like a diamond. It’s bright and shiny
to each of the beholders, and it
looks different depending on which
facet you’re looking at. Facility
design is a team exercise, and the
team will grow as the project
expands. A successful design
requires a diverse team because
many legitimate points of view need
to be balanced throughout the
process (see the Design Team box).
Facility design is an iterative
process. Many desired features will
need to be incorporated.
Unfortunately, some desires will
conflict with others (the good-fastcheap conflict, for example). The
team will need to resolve those
conflicts to meet as many needs as
possible. Management typically
controls the costs, and it will try to
cap spending with a budget.
Members of the team from quality
assurance and control will defend
minimum standards that preserve
the quality of the operations.
However, it’s the operating staff
that ultimately has to live with
decisions made by the group. It’s
important to record assumptions
and subsequent decisions along the
way so you have a record of how
and why the design changed over
time. It’s also important from a
morale standpoint to reach an
acceptable consensus. The
efficiencies gained in design can
easily be lost in practice if the staff
THE DESIGN TEAM
Architect(s)
Corporate management
Facilities engineers
Facilities operations specialists
Mechanical engineers
Process scientists
Process engineers
Quality specialists
Regulatory specialists
Validation specialists
feels that solutions were dictated to
them by others. The team should
voice many opinions and allow as
many ideas as possible to be part of
the ultimate solution rather then
being a part of some future
problem.
Design–Bid–Build or Design–Build?
One important decision the team
will need to make is whether to
perform a traditional design–bid–
build job or to go the design–build
route. Design–bid–build is a linear
process in which facility design is
completely separated from the
construction phase by the bidding
process for the facility construction.
It has a higher certainty of design
and associated construction costs,
but it takes significantly longer to
complete the project. It typically
costs more to complete because
construction companies charge for
their “preconstruction service,” and
cost will typically increase the longer
they have employees associated with
the project.
Modern construction has now
embraced the idea of design–build,
which accepts that uncertainties can
be managed (as they often are in
biotechnology). So foundation and
building shell construction can
begin while the internal design of
clean rooms and associated spaces is
being finalized. The parallel
processing of design and
construction is inherently more
efficient. Details are still finalized in
sequence but in less time. In many
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ways, it’s “just-in-time” engineering
and design.
THE BASIS OF DESIGN
Perhaps the most important
document in the design process is
the basis of design. In simple terms,
it is a written plan that lists the
specifications for the facility design.
It contains process diagrams, floor
plans, building layouts, and
estimates of construction time and
cost. It becomes critical for good
project quality and cost and
schedule control. Many design
concepts and efficiencies will be
incorporated into it, and if it is
followed, it will drive incorporation
of the proposed efficiencies into the
newly constructed facility.
When completed, the basis of
design will contain complete
descriptions of the process
objectives, process data and
definitions, and process flow sheets;
preliminary functional descriptions
of the facilities; and manufacturing
site data and requirements.
Preparing this document thoroughly
and early in the planning life cycle
of a manufacturing facility will go a
long way toward meeting the goals
of the project, including production
requirements.
A well-written basis of design can
serve as the road map for an entire
project. It should also force much of
the design to a level of detail
adequate for building permit and
construction drawings. The Basis of
Design box provides a checklist of
the items that should be clearly
covered in a basis of design.
Be Detailed: Many issues need to
be considered to get to the level of
detail adequate for this document.
For example, once the project
objectives are defined, the
manufacturing process should be
described with process data and
definitions. It should include the
process specifications, process flow
diagrams, equipment list, utility
requirements, and process
separation requirements in some
detail. Once the process is
understood and agreed upon, the
details of the facility can begin to be
fleshed out. Process, people, and
material flows can’t be mapped out
until the process itself is laid down.
HVAC classifications, zoning,
and containment are functions of
governmental regulation, the
manufacturing process, risk
tolerance, and corporate philosophy.
The same is true for process
containment and separation, the
capital equipment list, and the
utility list. Although the minimum
standards are driven by regulation
and industry practice, the extent of
the need in each of these areas will
be driven by corporate
considerations.
Remember the Standards: It’s
important that all of the engineering
standards to be used in the project
are written down in careful detail.
These standards become important
influences on project cost and
timelines.
Finally, the basis of design should
have time and cost estimates for the
project and some explanation of
construction issues and timing for
management to consider. Although
design is an iterative function, many
assumptions must be made
throughout the process. The basis of
design becomes a useful document
BASIS
OF
DESIGN CHECKLIST
Assessment and auditing
questions
Contamination control criteria
International standards and
regulations
HVAC and architectural issues
Functionality flows
Isolation technology
Environmental monitoring
Process equipment
Process support services
Process support utilities
Commissioning
Validation
Turn over documents
Courtesy of Scott Mackler
to record those assumptions. It is
often the first real stake in the
ground for corporate project
approval, and the many assumptions
made play a big role in where that
stake gets located. Should the scope
of the project change, as it most
likely will, the basis of design
becomes an important record of one
point along the way.
THE BASIS OF OPERATIONS
One difficulty in designing a facility
is deciding how to perform many of
the operations. In design, form
typically follows function. The
function is mostly defined by the
process and the myriad regulations
that apply to cGMP manufacturing.
However, even within such a tightly
regulated environment, a single goal
can be achieved in different ways.
For example, you can choose
stainless steel tanks or polypropylene
bag systems to hold or transport
liquids. Or you could use a transfer
piping system to move liquids
throughout the plant. There are
many variables to consider and
many pros and cons to every choice.
To help simplify our design
decisions, we generated a
complementary document we called
the basis of operations. If form
follows function, then form
becomes easier to design and more
efficient in operation when the
function is well defined. We defined
the basis of operations to be our
detailed description of the
manufacturing procedures and
quality systems — based on our
experiences, corporate culture, and
organizational philosophies — that
we would use to manufacture our
products. If step one is to decide
what the plant will produce and step
two is to define the process to be
used for manufacturing, then we
found that step three was to sit
down and figure out just how we
intended to run our plant. Working
within the regulations and our
quality systems, we still had many
decisions to make before we could
consider our facility design.
Things to Consider: Our basis of
operations covered three main areas:
manufacturing process related items,
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process rooms and hallways, and
process support matters.
Manufacturing process items
included media and buffer prep
questions such as
• Batch size
• Frequency
• The physical movement of
solids and liquids and their
preparation and dispensing
• The use of disposable liquid
systems compared with reusable
systems compared with hard piping
• Control system and automation
philosophies
• Desires for performance of
open or closed operations
• The use of paper or electronic
data and document systems
The most
substantial
V A L U E of
the basis of
operations was
that it allowed our
basis of design to
clearly and easily
follow the
functions we
wanted to
perform.
• Choices for clothing and
gowning
• Utility provisions and access
• Room and equipment cleaning
and sanitization
• Containment philosophies
• Material distribution into,
through, and out of the facility.
Process room and hallway
decisions focused on
• Our process separation
philosophies
• Our choice of the desired scale
of the facility; room size, number,
location, and orientation within the
facility
• Room and equipment layout
• Utility access within the rooms
• Process storage needs.
Process support matters
considered such things as
• Washing of dirty process
equipment
• Autoclaving and
depyrogenating product-contact
items
• Storage space for clean or inuse items
• Waste disposal
• Decontamination support
• Raw material handling
• Product storage and shipment.
Many of these decisions turn out
to be “soft” decisions that were
made not by construction
considerations, but by corporate
preference. Nonetheless, such
decisions can ultimately have a
significant effect on the cost of the
program, its success, and the
efficiencies that can be achieved
during the design process. We
found that the best efficiencies were
gained when our functional
requirements were well defined and
we had the luxury of knowing how
we wanted the facility to operate.
For example, when we fully
defined our mammalian cell process,
we discovered that we could design
our operations to maximize the use
of variously sized disposable
bioprocess containers for many of
our buffers and intermediates. This
had a number of repercussions. It
lowered our capital budget by
eliminating the need for portable
stainless steel tanks. It reduced the
requirements for labor, space, and
cleaning capacity related to those
tanks. It also improved our
flexibility in regard to running
another mammalian cell culture
process within our facility. We’ll pay
a small cost for the disposable bags
over time, but we feel this is greatly
offset by the other savings and the
process operating flexibility we gain
by this decision.
The most substantial value of the
basis of operations was that it
allowed our basis of design to
clearly and easily follow the
functions we wanted to perform.
Continued on p. 74
Many times in our design process,
we were confronted with a conflict
between construction and operating
costs or timing. By going back to
our basis of operations, we could
first examine what our stated
minimal standards were, whether
our assumptions about operations
were sound, and whether we
perceived any flexibility in our
operating decisions. By creating this
interaction between form and
function, we could decide where to
invest money, time, or energy to
solve problems and eliminate
potential conflicts. Last, we had a
useful record about our decision
process to make sure we understood
all the ramifications of our choices
and a clear record when we
modified assumptions or desires as
we moved through the design
process.
DESIGN CREEP
One of the last issues in the design
process that affects designing
efficient facilities is the budget effect
of design creep. Design creep is the
process whereby the intent of a
project gets corrupted by including
well-intentioned suggestions that
cause its scope to expand and
exceed the budget. It happens on
every project. It occurs because the
project scope was inadequately
developed, the design process was
not well controlled, or the intent of
the project got lost in the
excitement of design. Once design
creep occurs, the remedy is usually
an exercise called value engineering.
That is where the basis of operations
and the basis of design begin to
demonstrate their value.
When design creep sets in,
address a few basic questions. First
and foremost, decide whether each
change is required or simply desired.
That helps prioritize what must be
added and helps clarify the
justification for each change. Next,
assign a cost to each element. Then
indicate what is to be gained. It
might be time, money, quality,
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certainty, or effort. Finally, from the
listed information, determine what
the return or value of each item is.
Value judgments can be difficult
to make because they are highly
subjective. However, we found that
our well-written basis documents
gave us the guidance we needed to
determine value. Once we viewed
each addition as a possible
investment with a quantified return,
it became relatively easy to decide
where money was well spent and
where we had poorly justified
investments. When we still couldn’t
quite meet our budget, and it was
clear that staying within budget was
a priority, we performed a similar
exercise on some of our base
assumptions and design features.
Again, the two basis documents
were invaluable in defining the value
proposition, and we uncovered
some modifications we could make
in our operations and facility design
to stay within budget without losing
flexibility or efficiency.
Designing efficient facilities is a
dynamic and iterative process. It is
highly creative and at the same time
highly challenging. Although often
limited by both budget realities and
the need to design for today’s
certainties, the goal is still to design
facilities that meet the many needs
of differences in scale, product
development, clinical development,
and corporate growth. Despite the
many unknowns, it remains a
manageable process to balance the
tensions among doing it “good,
fast, and cheap.” When done right,
it’s a rewarding exercise in realitybased creativity that delivers efficient
facilities to meet the challenges of
today and tomorrow. Jim Levin is vice president of
manufacturing and development at
Unither Pharmaceuticals, a division of
United Therapeutics, 15 Walnut Street,
Suite 300, Wellesley, MA 02482, 1781-416-1505, fax 1-781-235-7412,
jlevin@unither.com.