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PHARMACEUTICAL ENGINEERING
THE OFFICIAL TECHNICAL MAGAZINE OF ISPE

JANUARY/FEBRUARY 2014, VOL 34, NO 1

facilities and equipment
©Copyright ISPE 2014
Multi-Purpose Plants
www.PharmaceuticalEngineering.org

Multi-Purpose Plants for API

Production
by Kazuo Tozaki, PE

This article summarizes the different types of multi-purpose plants and

clarifies the issues involved in their design.

H 
ow a facility is designed is a prime
factor in efforts to optimize cost effi-
ciencies since the facility is the center
of manufacturing activities and ac-
counts for the majority of the manu-
facturing cost to develop products.
This relationship will encourage the
designing of multi-purpose plants.
The concept of multi-purpose
plants has been raised and discussed on many occasions.
Recently, it has been the subject of discussion in Chapter
14 of the ISPE API Baseline® Guide,1 where the concepts of
“multi-use” as well as “multi-purpose” are introduced. In
this article, the concept of multi-purpose is studied from a
new viewpoint.
of products. The “multifunctionality” of a production facility
can be realized by adding to the number of trains employed,
by increasing the kinds of unit operations undertaken, or by
other means.
The construct of flexibility can be viewed as being il-
lustrated by the kind of situation in which the planning of a
manufacturing plant takes place in circumstances where the
nature and the composition of the product to be manufac-
tured has not yet been decided.
Usually, the products will be determined before the
design work for the manufacturing plant is started. How-
ever, if the products are not known at that stage, there will
be a requirement for the designer to create a plant that is
sufficiently flexible in its features and layout to be able to

Multi-Purpose Plant
Main Constructs
Multi-purpose plants for API manu-
facturing are already common in the
pharmaceutical industry, but their design
has been carried out on a “case-by-case”
basis. This can be viewed as a result of
the absence of a set of principles to guide
in this design process.
The underlying concept for multi-pur-
pose plants is viewed from the standpoint
of two constructs, namely multifunction-
ality and flexibility.
The construct of multifunctionality is
derived from the term “multiple” com-
bined with “function” to signify a system
which is capable of producing a number Figure 1. Multi-Purpose Plant.

PHARMACEUTICAL ENGINEERING JANUARY/FEBRUARY 2014 1

 facilities and equipment
Multi-Purpose Plants
accommodate easily and quickly the plant needs once the
products are known. The same requirement will be present
when the possibility of a change of the product or method at
some time in the future is contemplated.
To realize the above two constructs, that is multifunc-
tionality and flexibility, different design approaches will be
needed. This article will summarize the most common types
of multi-purpose plants and clarify the issues involved in
their design.
While the design issues involved in the application of the
two will frequently overlap, the constructs themselves are
mutually exclusive in nature - Figure 4 [link to PDF]. Hence,
the two will be discussed separately in the following sections.
Multifunctional Plants and Flexible Plants
In this article, the plant whose essential feature is multifunc-
tionality is referred to as the multifunctional plant, and
the flexible plant as one whose essential feature is flexibil-
ity. Multifunctional plants are discussed by classifying them
into two plant types. One type realizes the multifunctionality
by increasing the number of plant trains in a building (mul-
tiple plant trains in one building), and the other type will re-
alize it by producing several products with the use of a single
plant train (single plant train producing several products).
The flexible plant is studied according to those aspects
which will contribute to the flexibility of the manufacturing
plant, that is, the necessary process flow length, the level
and the range of process automation, the kinds and ranges
of necessary utilities, the selection of construction materials
and the kind of process water necessary - Figure 1.
Multifunctional Plants
When multiple plant trains are used, two cases should be
considered. One case is where multiple plant trains with
the same function exist in a single building and produce
only one product; that is, trains with the same function are
installed in parallel.
The other case is where multiple trains exist in a single
building, but have different functions from each other for
the purpose of producing different products. The latter case
has three variations according to its specific features. These
are:
a. Plant type variations involving issues of handling inter-
mediates and API
b. Plant type variations involving issues of providing differ-
ent types of unit-operations
c. Plant type variations involving issues related to the estab-
lishment of the piping line-up patterns
Meeting the GMP requirement of preventing cross-con-
tamination and mix-up is a common design issue raised in
relation to the above three cases.
2 JANUARY/FEBRUARY 2014 PHARMACEUTICAL ENGINEERING
Figure 2. Multifunctional plant.
Multiple Plant Trains in One Building
Multiple Trains with the same Function (Parallel
Installation)
Although this kind of arrangement may not be seen as an ex-
ample of multifunctional design, it is mentioned here as one
case because it has its own design issues as described below.
When the plant is expanded in response to the need for
increases in the production capacity, how to realize the effi-
cient and lean enhancement and/or expansion based on the
forecasted production capacity will be an important design
issue.
Enhancing and/or expanding the units which form a
bottleneck in the operation of the plant will be a first step.
That will be followed by an increase in the number of trains
and a consequent increase in the production capacity of the
plant as a whole.
Multiple Trains with Different Functions
The following types are discussed:
a. Plant Type Variations Involving Issues of Handling
Intermediates and API
The GMP significances of manufacturing processes will dif-
fer according to the nature of the materials handled. There-
fore, production plants will differ according to the phase of
the API for which the plant is responsible (from Phase1 to
commercial production) and of the stage of production.
These plants may be scaled up facilities, for which careful
study on the equivalency between them will be necessary.
Several trains with different capacities may be combined for
improving the utilization of the plant.
b. Preparation of Different Types of Unit-Operations
The following are examples of points to be raised for such
different types of unit-operations:
• Blade type options for the agitators which are used in the

crystallization reactor
• Options for solid-liquid separators
• Options for dryer types
• Preparation of several kinds of pulverization process ac-
cording to the required particle size specifications
• Adoption of a multiple function dryer in order to shorten
the process steps
The above points also will apply to the plant flexibility.
c. Establishing the Piping Line-up Patterns
In order to combine the plant trains and improve the uti-
lization of the plant, it may be profitable to adopt a piping
system that will allow the trains to be combined.
There exist several means for accomplishing pipe connec-
tions including those described below.
• Pipe connections are centralized in a dedicated room, and
pipe line-up is conducted in this room. This will be effec-
tive for simplifying the piping around the reactor, which
will contribute to a decrease in the risk of contamination
by foreign materials.
• Installation of pipe switching stations instead of the
dedicated room
• Installation of common pipe headers
The number of connecting headers, pipes and hoses will
need to be increased markedly to bring about improved
connecting flexibility. For this reason, practical study on
the means of achieving flexibility will be required. There are
several ideas that are put in use as described below.
• The range of piping which requires flexibility study will
be decreased by identifying the dedicated piping such
as around the reactors when a reactor and a receiver are
paired for a dedicated use and around the tanks which
are dedicated for their intended use, such as hydrochloric
acid tanks or reaction additive tanks, etc.
• The minimum required operational flexibility will be
ensured by preparing connecting pipes for the represen-
tative line-up patterns for specific flows.
One concept that has been put to practical use is to make the
tanks mobile and move them to appropriate positions for the
pipe connections.
The above mentioned means are also one of the steps to
realize the concept of flexibility.
d. Preventing Cross-Contamination and Mix-Up
Between Plant Trains
Operations involving different products should not be car-
ried out simultaneously or consecutively in the same room
facilities and equipment
Multi-Purpose Plants
unless it can be ensured that there is no risk of mix-up or
cross-contamination.
In order to prevent cross-contamination, the techniques
of containment are well known and are effective ways to
protect the API.
In practice, two methods are followed in the application of
containment technology.
One is to make use of mainly protection control and
cross-contamination control. That is, production equipment
should form a properly closed system, and production area
zoning, moving route analysis and a HVAC system should be
properly established.
The other way, which will be applied for handling potent
drugs, poisonous drugs and highly sensitizing drugs, is to
mainly make use of isolators in addition to the proper design
of zoning, the HVAC system and moving route analysis.
The range of process steps that must be protected by
containment technology will depend on the knowledge of the
process steps where the chemical compound is activated as a
drug, and this is clarified through the analysis of the critical
process steps.
In order to prevent mix-up, hardware and software as-
pects of countermeasures that will help to prevent opera-
tional errors will be necessary. In these respects, the design
study to ensure the sufficient working area, proper area
zoning and proper moving routes for operators and materi-
als are important.
The above mentioned means also apply to the plant flex-
ibility.
Single Plant Train Producing Several
Products
The design issues involved in the manufacture of several
products in the same plant are studied for the case of
campaign-type production which will be conducted accord-
ing to the operation time schedule.
When operation is conducted in parallel by using equip-
ment items of the same plant, the design issues described for
preventing cross-contamination and mix-up between plant
trains will be the same as those referred to the last section.
The following design issues will be raised:
1. Removing bottlenecks in the operation time schedule:
the issue of shortening the time required for cleaning the
internals of the facility will be raised as an example, and
Clean In Place (CIP) will be one of the effective solutions.
2. Preventing cross-contamination at product switch-
ing: the planning and the implementation of cleaning
validation will be important. At the planning stage, the
knowledge of the places where CIP is possible, and where
manual cleaning or cleaning with disassembly is neces-
sary, has to be confirmed and this knowledge must be
incorporated into the design study.
PHARMACEUTICAL ENGINEERING JANUARY/FEBRUARY 2014 3
 facilities and equipment
Multi-Purpose Plants
The detailed design of piping should be carried out so as
to enable CIP operation. The knowledge of critical process
steps should be taken into consideration to see where CIP
operations are critical.
3. Preventing human error at product switching: adopting
automation will be an effective way to prevent human er-
ror. However, the level and the extent of automation will
need careful study, because flexibility may be decreased
with the increase of automation.
Flexible Plant
Five elements which constitute flexibility will be considered
as listed in Figure 3.
The Level and Extent of Process Automation
This will be closely linked with the issue of how to decide the
extent of manual operation. The operation that require care-
ful attention in this respect includes steady state operation
(routine operation), and non-steady state operation (start-
up, shut-down, abnormal incident like electrical failure, trip,
etc.)
The three viewpoints described below will be important
when considering the issues with regard to automation.
a. Whether the process control between the unit operations
is conducted automatically or manually. This control will
be conducted in accordance with the SOP or based on the
results of In-Process Control (IPC).
b. Whether process control of the unit operation only is
enough. The feed-back and the feed-forward control of
the temperature, the pressure and the concentration etc.,
around the unit operations will be generally practiced as
parts of automatic control.
c. The extent of automation of the CIP.
It is normal practice for the spray nozzles installed in the
reactors to be operated automatically. The scope of CIP will
be decided based on the operational patterns.
Figure 3. Flexible plant.
4 JANUARY/FEBRUARY 2014 PHARMACEUTICAL ENGINEERING
Necessary Process Flow Length
a. The split of work in the production steps: the split of work
in the production steps will be determined according to
the company policy as to the phase of the API for which
the company is responsible and of the stage of produc-
tion. This also will be an issue involved in the outsourcing
policy of the company.
b. Flexibility in the formation of manufacturing processes:
the following cases will be considered:
• Combination of equipment: when the plant has
several trains with different capacities, the combina-
tion of these trains will create new plant trains which
may combine the large and the small capacity reactors
effectively and improving the utilization of equipment.
Careful studies to prevent cross-contamination be-
tween the different items of equipment as well as the
cleaning inside the reactors/piping will be important.
It will be worthwhile to study the versatility of the
manufacturing process in order to increase the utiliza-
tion and the agility of the facility by the use of common
pipe headers and the standardization of equipment.
The common pipe headers will establish the vari-
ous line-up patterns for multi-product manufactur-
ing. The standardization of equipment will be seen in
such aspects as the volume of the reactors, the nozzle
orientation, the pressure tightness and the thermal
resistance, and others.
The special types of equipment such as that with
high pressure tightness or with small capacity will be
identified as being for exclusive use.
The use of disposable, cheap, and versatile equip-
ment is a choice that can be made.
• Combination of sub-processes: API manufactur-
ing processes will be grouped into such sub-processes
as the synthesis process, the purification process, the
crystallization process and the crystal/powder process.
Expanding the facility by the combination of these
groups may be possible.
The combination of unit processes which is com-
posed of a minimum number of equipment items, may
form various kinds of process systems. The use of dis-
posable, cheap, and versatile equipment, as mentioned
above, will be a choice that can be made for this case
also.
The types of equipment used for the crystal/powder
process will decide the product range (flexibility).
• Combination of plants: the combination of produc-
tion plants may be possible. If the process units can
be standardized with a minimum number of reactors,
these units may be combined to form a new plant.

Necessary Utility Range and the Construction
Material Selection
The utility operating range available in the factory will limit
the product range. The heat sources, the pressure genera-
tors, and the vacuum generators available are examples.
Especially, the wide operating temperature range may
require several kinds of refrigerants that will result in a com-
plex refrigerant system. In order to avoid such complexity, a
single refrigerant system has been put to practical use.
The use of high grade materials will increase the flexibil-
ity as it will increase the resistance against corrosives. On
the other hand, it will bring about an increase in the cost of
the equipment.
Necessary Process Water
The types of process water available also will limit the
product range. There are many kinds of process water such
as potable water, purified water, sterile purified water, and
WFI, etc. These are selected according to the requirements
of the API.
The selection of the type of process water may be decided
according to the requirements of the following drug formula-
tion (preparation) process.
The discussions so far are expressed in the form of an
association chart in Figure 4 [link to PDF], in order to make
the whole view easier to read.
Summary
The concept of multi-purpose plants was reviewed from the
standpoint of two constructs, namely multifunctionality
and flexibility, and related GMP items were discussed and
important design issues were derived which are summarized
in Figure 4.
facilities and equipment
Multi-Purpose Plants
References
1. ISPE Baseline® Pharmaceutical Engineering Guide,
Volume 1 – Active Pharmaceutical Ingredients, Inter-
national Society for Pharmaceutical Engineering (ISPE),
Second Edition, June 2007, www.ispe.org.
2. Guidebook on GMP hardware of pharmaceutical API fac-
tory, GMP hard kenkyu-kai, JIHO
3. Tozaki, K., “A Risk Assessment Approach to Planning an
API Production Factory,” Pharmaceutical Engineering
Online Exclusive, May/June 2009, Vol. 29, No.4, www.
PharmaceuticalEngineering.org.
About the Author
Kazuo Tozaki, PE is a member of the
ISPE API COP Japan, API COP Process
Technology Committee and API COP Steer-
ing Committee. He has worked for 37 years
with JGC Group of Japan in the API area as
well as in chemical plant projects. He holds
an BS and a MS from Kyoto University in sanitary engineer-
ing and finished the Ph.D. course in 1976. He has executed
more than 10 EPC projects together with a number of basic
design jobs for API production plants in the past 25 years.
He is a registered consulting engineer (chemical), a regis-
tered management consultant and a registered provisional
auditor of ISO22000. He can be contacted by telephone:
+81-45-743-7469, or email: tozaki.kazuo@jgc.co.jp.
JGC Plant Innovations Co., Ltd, 13-1 Saido 1-chome,
Kounan-ku, Yokohama 233-8550, Japan.
PHARMACEUTICAL ENGINEERING JANUARY/FEBRUARY 2014 5