The purpose of this document is to present a potential design to the client for manufacture of a DNA vaccine facility in the United Kingdom. Facility will have capacity to produce 1 kg/annum of two plasmid products. Pivotal factors considered in design and layout of DNA vaccine facility were compliance to good manufacturing practices (cGMP), effective production, regulatory guidelines, contamination minimisation and effective cleanliness. Handling of raw materials and final product both on and off site has been studied to outline features and add-ups that can be implemented to minimise environmental impact: such measures include process safety and instrumentation. Impact of airborne particles, temperature, pressure and relative humidity on purity, efficacy and safety have been reduced through design of class 100 cleanrooms equipped with controlled-air environment accessible via airlock, HVAC and high efficiency particulate air filters (HEPA). Additionally, principles of process control and instrumentation have been applied throughout design stage of project with aim of creating a process that is ultimately safe, and one that complies with safety regulations, efficient and economically stable. Compliance to current good manufacturing practices (cGMP) and regulations are achieved through incorporation of key cGMP components such as validation master plan (VMP), quality control (QC), cleaning-in-place (CIP), sterilisation-in-place (SIP), trained personnel and waste treatment process. Economic evaluation of project indicates viability, net profit of £557,000,000 is a very lucrative figure for a 10-year investment. Project payback time of 5 months and entire project timeline of 1 year and 10 months demonstrates that this project is highly feasible and has potential to attract numerous investors.

1. Bio – pharmaceutical plant design
By
Sinthujan Pushpakaran
School of Chemical Engineering
College of Engineering and Physical Science
University of Birmingham
March 2017

2. Executive Summary
Purpose of this document is to present a potential design to the client for manufacture of a DNA
vaccine facility in the United Kingdom. Facility will have capacity to produce 1 kg/annum of two
plasmid products.
Pivotal factors considered in design and layout of DNA vaccine facility were compliance to good
manufacturing practices (cGMP), effective production, regulatory guidelines, contamination
minimisation and effective cleanliness.
Handling of raw materials and final product both on and off site has been studied to outline features
and add-ups that can be implemented to minimise environmental impact: such measures include
process safety and instrumentation. Impact of airborne particles, temperature, pressure and relative
humidity on purity, efficacy and safety have been reduced through design of class 100 cleanrooms
equipped with controlled-air environment accessible via airlock, HVAC and high efficiency particulate
air filters (HEPA).
Additionally, principles of process control and instrumentation have been applied throughout design
stage of project with aim of creating a process that is ultimately safe, and one that complies with
safety regulations, efficient and economically stable. Compliance to current good manufacturing
practices (cGMP) and regulations are achieved through incorporation of key cGMP components such
as validation master plan (VMP), quality control (QC), cleaning-in-place (CIP), sterilisation-in-place
(SIP), trained personnel and waste treatment process.
Economic evaluation of project indicates viability, net profit of £557,000,000 is a very lucrative figure
for a 10-year investment. Project payback time of 5 months and entire project timeline of 1 year and
10 months demonstrates that this project is highly feasible and has potential to attract numerous
investors.

3. Contents
1. Introduction …….……………......…………………………………................ 1
2. Details of the process …………………………………………………………
2.1 Process Description ………………………………………………….......... 2
2.2 Raw materials ……………..……………………………………................. 3
2.3 Equipment ………………………………………………………………….. 3
2.4 Personnel ……………………………………………………………………. 3
3. Design of manufacturing facility .............................................................
3.1 Plant location ………………………………………………………………… 4
3.2 Plant layout ……………………..……………………....……………………
3.2.1 Layout of plant site …………………..………………………….. 5
3.2.2 Layout of production house ……..……………………………… 6
3.3 Manufacturing flows ……...………………………………………………… 7
4. Plant Services, Systems and Utilities ……………...……….…………….. .
4.1 Heating, Ventilation and Air-Conditioning (HVAC) system ….………… 8
4.2 Water ………………………………….…………………………………….. 8
4.3 Clean Steam ………………………...……………………………………… 9
4.4 Heat and Power …………………………………………………………… 10
4.5 Cleaning-in-Place (CIP) ………………………………………….............. 10
4.6 Sterilising-in-Place (SIP) …………………………………………………… 11
4.7 Process Control and Instrumentation …………………………………….
4.7.1 Process Control …………………………………………………. 11
4.7.2 Instrumentation ………………………………………………..... 12
4.8 Cleanrooms ………………………………………………………………… 13
5. Process validation, cGMP …………………………………………………… 14
5.1 Validation Plan ………………………..……………………………………. 15

4. 5.1.1 Design Qualification (DQ)………………………………………. 15
5.1.2 Installation Qualification (IQ) …………………………………… 15
5.1.3 Performance Qualification (PQ) ……………………………….. 15
5.1.4 Operational Qualification (OQ) …………………………........... 16
5.1.5 Quality Assurance and Quality Control (QA/QC) ………………. 16
5.1.6 Product testing …………………………………..…………………. 16
6. Gantt Chart ………………………………………………………………………… 18
7. Costing …………………………………………………………………………….
7.1 Total Purchase Cost …………………………………………………………. 19
7.2 Physical Plant Cost (PPC) ………………………………………………….. 21
7.3 Working Capital ……………………………………………………………….. 21
7.4 Operating Costs ……………………………………………………………….. 21
7.4.1 Fixed Operating Costs …………………………………………….
7.4.1.1 Maintenance ……………………………………………… 22
7.4.1.2 Operating Labour ……………………..…………………. 22
7.4.1.3 Supervision ………………...…………………………….. 22
7.4.1.4 Training ………………..………………………………….. 22
7.4.1.5 Recruitment ………………………………………………. 22
7.4.1.6 Plant overheads …………………..……………………… 23
7.4.1.7 Insurance …………………...…………………………….. 23
7.4.1.8 Research and Development ……………………….……. 23
7.4.1.9 Licensing and Royalties ……..…………………………… 23
7.4.2 Variable Operating Costs …………...……………………………….
7.4.2.1 Raw materials ……………………..………………………. 23
7.4.2.2 Utilities ……………………………………………………… 24
7.5 Fixed Capital Investment …………………..…………………………………… 24

5. 7.6 Total Investment …………………………………………………………………. 24
7.7 Revenue ……………………….…………………………………………………. 24
7.8 Gross Profit ……………………………………………………………………….. 25
7.9 Project Financing ………………………..........………………………………….
7.9.1 Financing Investments ………………………..…………….............. 25
7.9.2 Net Profit ………………………………………………………………. 26
7.9.3 Cumulative Cash Position ……………………………………………. 27
8. Conclusion …………………………………………………………………………… 28
Bibliography ………………………………….………………………………………………. 29
Appendix ……...................……………………………………………………….
Appendix 1 – Room 16 Data Sheet …………………………………………….. 31
Appendix 2 – Room 7 Data Sheet ………………….………………………....... 33

6. 1
1. Introduction
DNA vaccines are used in gene therapy, vaccination and treatment for diseases, such as HIV, malaria
and cancer. Reasons for their utilisation is largely due to triggering of safe and stable, cellular and
humoral immune responses (Prather et al., 2003). Because of its vast uses, there is a need to design
manufacturing facilities of DNA vaccines to meet growing demand.
However, to effectuate a successful design for biopharmaceutical production, design, operations and
layout of manufacturing facility must adhere to standards, specifications and guidelines specified by
various regulatory authorities, which include Medicines and Healthcare Products Regulatory Agency
(MHRA), World Health Organisation (WHO), European Medicines Evaluation Agency (EMEA) and
respective regulatory organisation of country where the facility will be constructed. In addition to
complying with the standards set, DNA vaccines production process, design and manufacturing
premises must also conform with good design practices (GDP) and current good manufacturing
practices (cGMP) (Przybylowski et al., 2007).
To ensure that manufacturing processes are achieved per design specifications and operational
procedures for delivery of quality, safe, efficient and pure product, commercial scale production of
DNA vaccines is validated through health, economics, compliance to legal standards, production
under Good Manufacturing Practices and safety and environment (Shamlou, 2003). Moreover,
International Society of Pharmaceutical Engineers (ISPE) has listed several fundamental steps to
effectuate GMP, which include layout design, current good manufacturing practices (cGMP), standard
operational procedures (SOPs), sterilization in place (SIP), adequate process control, validation of
process performance, cleaning in place (CIP), quality management, compliance to regulations and
maintenance of product identity.
Layout of manufacturing facility is to be designed to ease raw material, waste and personnel flow to
reduce risk, avoid cross contamination and ensure that production runs smoothly through an orderly
procedure. Within facility, a clean environment and rooms is required to proceed pharmaceutical
manufacturing process, whereby parameters such as pressure, temperature and relative humidity are
to specified conditions as imposed by regulators, for example MHRA.

7. 2
2. Details of the process
2.1 Process Description
DNA vaccines production initiates at a bench scale through pilot scale and eventually large scale
production (Ferreira et al., 2000). Large scale design of a facility for manufacturing of DNA vaccines
must take into consideration selection of suitable plasmid DNA constructs/vectors that is capable of
reproducing at high copy number such as pUC vectors and production microorganism cell bank,
typically Escherichia Coli.
Biotechnology process is based upon cultivation of micro-organisms that allow growth of final product.
This is then subsequently contained within a cell or excreted into surrounding liquor. To achieve
growth, micro-organisms need a carbon substrate and nutrient medium, as well as a water
environment for conduction of the microbial process (Bennett and Cole, 2010). Process for the
biotechnology processing of plasmid DNA comprises of three fundamental steps, namely
fermentation, recovery and purification (Bennett and Cole, 2010). Fig. [1] highlights process steps
involved in production of DNA vaccines.
Prior to consumption in production process, quality assurance of raw materials intake will take place.
Culture strains are to be maintained in master bank cells and working bank cells within facility, where
utilised bacteria is revitalized via use of a working bank cell vial and further cultured in a propagation
area.
As outlined by Fig. [1], process initiates through transport of bacterial cells from a 20-litre fermenter
for inoculation of a 200-litre fermenter located in the same suite. Fermenter will be operated in batch
mode to allow preparation of cells for inoculation of a 1000 litre fermenter located in a separate suite.
Upon establishment of bacterial cell growth, mixing of culture within fermenter is effectuated through
mechanical action of agitator to achieve even distribution of nutrients and dissolved oxygen and
improve heat and mass transfer rates (Saltzman et al., 2006). Cell growth subsequently reaches
plateau, where it is removed and transferred to a centrifugal tank to allow removal of accumulated

8. 3
cellular materials at bottom of the tank. These cellular materials are also known as pellets which
contain plasmid DNA and other cell organelles.
2.2 Raw materials
Manufacturing facilities of DNA vaccines require various raw materials, reagents and utilities such as
plasmid DNA vectors, glucose, sterile air, water for injection, nutrients, liquid N2, salt, buffer capacity
for stabilisation of pH fermentation and antibiotic, alkaline master cell bank and working cell banks.
Plasmid DNA is critical raw material; thus, it should be fully characterized and undergone an
extensive clinical evaluation prior to its arrival from a manufacturing batch. Plasmid DNA vaccine
characterization is achieved through development of manufacturing process for production of
pharmaceutical-grade plasmid DNA that encompasses a well-controlled, reproducible, and validated
process. Moreover, development of analytical methods at each process step for assessment of
product yield and contamination removal is also to be incorporated.
2.3 Equipment
Manufacturing facility is at its preliminary design stage thus only major operating units would be
considered. Auxiliary equipment such as pumps, valves and pipes require client’s approval, hence will
not be included. Upon requirements of client, major operating units are listed in Table [1], which
include five fermenters and three waste containers specific to stages of process, namely liquid, solid
and filtrate wastes. In addition, two waste containers for two 200 litre culture vessels are also
required, which will be located with separated isolated suites. Additional operating units will be
included upon client’s request.
2.4 Personnel
Manufacture of medicinal products depends on compliance of current good manufacturing practices
(cGMP) and regulatory guidelines on people and good management structure, thus an adequate
number of personnel who possess necessary qualifications and practical experience is needed.

9. 4
Working personnel will have sufficient knowledge of cGMP regulations and will undergo suitable
training for regular maintenance and repairs around facility. Training will include internal and external
training courses that are designed to deliver required level of knowledge and understanding of facility
to floor workers and affiliated personnel, whilst considering day-to-day working environment
(Medicines and Healthcare Products Regulatory Agency., 2014).
3. Design of manufacturing facility
3.1 Plant location
Facility is to be in Cambridge, a renowned global UK city, with innovation in science and medicine
through its world-class university and state-of -the -art science park. Science park is home to a large
concentration of biopharmaceutical, biotechnology and medical research companies thus it will be
beneficial if facility is situated around its competitors.
City offers access to world-leading scientific expertise and provides opportunities for collaboration
with renowned pre-eminent hospitals, cutting-edge biotech companies and academic research
institutions. Rapid growth of pharma sector has created demand for talent in city, although it is in a
prime position to recruit local talent, rate of growth highlights need for external recruitment. There is
an increasing need for experienced pharmaceutical professionals, thus opportunities of acquiring
specialist workforce for specified facility would be highly beneficial.
Talent and resources are available through several companies located together in same city, thus it is
undoubtedly regarded as number one city for pharma in the UK and a prime location for industry in
Europe.

10. 5
3.2 Plant layout
3.2.1 Layout of plant site
Visitor/Executive/Disabled
Parking for 20 vehicles
Offices
Analytical Labs GMP Suites
Suit 3 Suit 2
Suit 1
Process
Development
Suites
Plant
Central Facilities
Staff parking for 50 vehicles
Substation
Substation
External
StorageArea
River
Figure [4]: Plant site layout

11. 6
3.2.2 Layout of production house
Store
after
Decon.
Decon.
Autoclave
Wash Up
& Prep.
Clean
Equipment
Store
Calib.W/
Shop Clean Utilities Cell Bank
Cell Culture -1
Cell
Propagation Cell Culture – 2
Upstream,
Store &
Staging
Media
Prep.
Initial Purification - 1
Final Purification - 1
Blend &
Bulk Fill
Final Purification - 2 Initial Purification - 2 Buffer
Prep.
Final
Product
Store
Staging
Weigh &
Dispense
Circulation
Package
& Label
Receipt &
Despatch
Dock
GasBottleStore
NitrogenOthers
Sample
AmbientQuarantine
AmbientRelease
Ambient
Development
Raw Materials Store
Cold
Quarantine
Cold
Release
Cold
Developm
ent
Development Laboratory
ChangeCirculation
Female
Change
Male
Change
Female
W.C.
Male W.C.
Circulation
Staff
Area
Reception
Offices
Q.C. Laboratory
In-Process&Relocated
SampleStorage
Airlock Supply
Airlock
Buffer Hold
Supply
Airlock Change
Airlock Change
Change
Airlock
Change Airlock
Buffer Hold
Change Airlock
Change Airlock
Airlock Change Change Airlock Change Airlock
Airlock
Return
Change
Lab
Coats
InactivationSystem
EquipmentStore
Airlock/
Change
Rejects
Airlock
InProcessStore+4°C
Materials Entrance
Figure [3]: Production house layout

12. 7
3.3 Manufacturing flows
Store
after
Decon.
Decon.
Autoclave
Wash Up
& Prep.
Clean
Equipment
Store
Calib.W/
Shop Clean Utilities Cell Bank
Cell Culture -1
Cell
Propagation Cell Culture – 2
Upstream,
Store &
Staging
Media
Prep.
Initial Purification - 1
Final Purification - 1
Blend &
Bulk Fill
Final Purification - 2 Initial Purification - 2 Buffer
Prep.
Final
Product
Store
Staging
Weigh &
Dispense
Circulation
Package
& Label
Receipt &
Despatch
Dock
GasBottleStore
NitrogenOthers
Sample
AmbientQuarantine
AmbientRelease
Ambient
Development
Raw Materials Store
Cold
Quarantine
Cold
Release
Cold
Developm
ent
Development Laboratory
ChangeCirculation
Female
Change
Male
Change
Female
W.C.
Male W.C.
Circulation
Staff
Area
Reception
Offices
Q.C. Laboratory
In-Process&Relocated
SampleStorage
Airlock Supply
Airlock
Buffer Hold
Supply
Airlock Change
Airlock Change
Change
Airlock
Change Airlock
Buffer Hold
Change Airlock
Change Airlock
Airlock Change Change Airlock Change Airlock
Airlock
Return
Change
Lab
Coats
InactivationSystem
EquipmentStore
Airlock/
Change
Rejects
Airlock
InProcessStore+4°C
Materials Entrance
Material
Personnel
Waste
Material
Figure [4]: Manufacturing flows

13. 8
4. Plant Services, Systems and Utilities
4.1 Heating, Ventilation and Air-conditioning (HVAC) system
Heating, ventilation, and Air Conditioning (HVAC) system plays a pivotal role in manufacture of
pharmaceutical products. Function of an HVAC system is to convey fresh air into facility, allow it to
mix with recirculated air and subsequently condition mixture through filtration or heating.
Prior to selection and sizing of HVAC system, particular conditions are defined which include
hygroscopic or temperature sensitive characteristics of product during manufacturing, effect of
product on operating or process environment conditions and protective equipment for operators, such
as Tyvek suits, full-face respirators or full-body suits which require lower space temperatures than
those defined by ASHRAE (American Society of Heating, Refrigerating and Air-Conditioning
Engineers) are needed to provide operator comfort (Jacobs and Signore, 2016).
HVAC systems provide environment for required manufacture of DNA vaccines whilst maintaining
product quality, efficacy, safety and purity. This is achieved through monitoring of various parameters
such as room temperature, air borne particles, pressure, relative humidity and cross contamination
(Gupton, 2002) in accordance to standards and classifications as specified by BSS5295, ISO 14644-
1, EEC, etc. (Van Zyl, 2005). Modern technology allows effective management of these parameters
under an automated program known as Building Management Systems (BMS) which is to be
incorporated.
BMS is a computer software program that control, monitor and manage all equipment in facility, such
as heating, ventilation, lighting, security and cooling through use of sensors (Seeley, 2003). Moreover,
automated system allows for identification of faults locations, hence proving to be highly
advantageous in resolving problems promptly prior to occurrence of a more fatal incident. Other
advantages include reduced risk of human error and increased reliability, reduction in clerical staff
and management costs, and easy adaptation to alterations to building (Seeley, 2003).
An array of HVAC systems exists for pharmaceutical facilities and selection on most suitable system
is based upon required environmental conditions and level of product containment. As degree of
these factors increases, complexity and thus cost of HVAC system also increases proportionately
(Bennett and Cole, 2010).
4.2 Water
A water treatment plant will utilise river located nearby and wastewater exiting facility as a cost-
effective water source for manufacturing facility.

14. 9
Water is a major element of bio-pharmaceutical processes and it will be used within facility as a raw
material for process or as cleaning medium for sterilisation of facility’s equipment, thus quality of
water for these diverse operations is imperative.
Various grades of water exist in pharmaceutical industry and types which will be utilised in facility are
described below:
Although various grades of water are utilised, issues regarding respective generation and
containment arise, thus these parameters should be considered. In scenario of WFI, water
specifications in Europe and America has left manufacturers with a dilemma in marketing their
products. In regards to containment, upon treatment of purified water or WFI, water is to be collected
in a cylindrical dished end vessel that allows to withstand vacuum imposed by steam sterilization, thus
on this basis, when issuing a new water system, it is important to affirm the desired final product
specification (Bennett and Cole, 2010).
4.3 Clean Steam
Clean steam is to be produced in a dedicated steam generator that allows removal of entrained liquid
droplets which may contain bacteria or endotoxins through a device fitted within unit, normally in form
a demister pad or baffle arrangement (Bennett and Cole, 2010). Generator is to be manufactured in
stainless steel 316 L due to corrosive nature of water, however it is to be noted that adequate non-
condensable gas is to be let through into steam distribution system as it will exhibit formation of a
coating in the vessel that prevent efficient heat transfer (Bennett and Cole, 2010).

15. 10
Steam distribution systems need to consider removal of condensate, as it poses risk of micro-
organism growth and reduction in effectiveness of sterilization. To avoid these issues, steam traps at
all low points and 30m intervals of pipework are to be implemented (Bennett and Cole, 2010).
4.4 Heat and Power
Facility will obtain its source and supply of power from onsite CHP station which is to operate on
biomass and waste from local farm lands or natural gas upon client’s discretion. A CHP system is
utilised over conventional coal/natural gas station because of higher overall efficiency of
approximately 80%.
Both set of sources can provide effective heat and power, where excess heat is to be utilised towards
steam generation and other applications within facility which require heating using Pinch technology.
In addition, because of high overall efficiency, excess generated power in terms of electricity can be
vended to the National grid upon client’s discretion.
4.5 Cleaning-in-Place (CIP)
In order to successfully implement Clean In Place methods, an appropriate design of equipment is
needed as either semi-automatic or fully automatic systems can be problematic. For example,
sanitary type pipework without ball valves are to be used due to challenging nature of cleaning non-
sanitary ball valves (Bennett and Cole, 2010). In addition, operators performing cleaning procedure
are to be aware of potential problems and specially trained.
Clean in place is achieved through heating of a tank filled with correct concentration of cleaning
medium to required cleaning temperature through recirculation, which is subsequently introduced into
pipework or vessels and eventually drained (Bennett and Cole, 2010).
Following drainage, treated equipment is subject to hot/cold rinse for removal of any product residues.
Further rinsing with caustic detergent is to be executed to eliminate remaining product and cleaning
agent residues. To neutralise effects of caustic agent, hot/cold acid is to be utilised for treatment of
equipment followed by rinsing via water.
Complete purity of treated equipment is to be measured via Near infrared (NIR) absorption or
scattered light sensors installed at CIP return points. Principle of operation is achieved through
detection in quality of rinsed water leaving treated equipment that in turn indicates achieved level of

16. 11
cleaning (Optek, 2010). In regards to grade of water utilised during rinsing, purified water is to be for
whole cleaning cycle except for final stage where WFI is to utilised. A schematic of this process is
highlighted in Fig. [5].
4.6 Sterilising-in-Place (SIP)
Biotechnological processes make use of sterilising in place for cleaning of vessel between batches
and periodic cleaning of Water for Injection storage and distribution systems. Prior to SIP, vessel is to
be cleaned by CIP as steam will only sterilize surface along with a cleanliness check of vessel
internals. Degree of sterilisation is attained through use of temperature sensors such as
thermocouples which are to be inserted into the equipment prior to sterilisation procedure (Bennett
and Cole, 2010).
Vessel sterilisation is to be achieved via injection of pure steam at highest point with relative
conditions of 1.2 Barg and 121 oC respectively, which represents the temperature at which Bacillus
Stereothermophilis spores are destroyed (Shukla and Gottschalk, 2013).
To ensure that this process is feasible, vessel must be able to withstand vacuum produced by
condensation of steam to minimize crevices in vessel and connecting pipework. Furthermore, care is
to be taken in regards to condensate produced as it can undergo drainage as warm condensate will
not be able to be sterilised, thus swabbing or utilisation of strips infused with a substance with ability
to change colour at exposure of a given time or temperature combination is to be incorporated
(Bennett and Cole, 2010).
4.7 Process Control and Instrumentation
4.7.1 Process Control
Manufacturing process encompasses a variety of process elements and factors that influence overall
process operation, thus to control these factors, Process and Instrumentation control system, also
known as P&I control system is implemented.
Facility will utilise four main control strategies, which are respectively Feedforward control (FFC),
Cascade control, Feedback control (FBC) and Adaptive control and are to be used at various

17. 12
locations for a given control element. The process control room found within facility are to oversee
these strategies and through onscreen viewing, personnel will have opportunity to observe and
manipulate any variables.
Ultimately, cascade control is to be implemented for comparison of a measured variable to a set point
for one control loop, leading to a set point for a separate control loop that exhibits a ‘master
controller’, whose function is to manage set point for ‘slave controller’. Control loop response times
are to increase via use of cascade control due to rapid detection of disturbances during coupled
operation of master controller and slave controller.
4.7.2 Instrumentation
Instrumentation is designed to allow easy access to relevant process operating conditions within site.
Hazard studies, such as a complete Hazard and Operability Study (HAZOP) of process design and
control systems will be implemented to match design criteria and required safety standards. Table [2]
highlights various variables and related measuring instrumentation.

18. 13
Probes and other measuring devices are to be used for in-line measurement to process parameters
such as temperature, pressure, etc. from product stream. Meanwhile, on-line measurement is to be
located within vicinity of process with a fully automated system for monitoring of critical variables of
process. External devices such as valves and pumps are also to be controlled through on-line system
as part of analysis sequence (MEP Instruments, 2009).
4.8 Cleanrooms
Cleanliness and aseptic operations for contamination prevention by microorganisms during plant
operations and changes in room conditions are one of principles under which GMP operates
(McFadden, 2010). Henceforth, production of biological drugs, such as DNA vaccines are to be
manufactured in clean rooms under specification at which temperature, relative humidity, air quality
and pressure are controlled for prevention of contamination through microorganisms, impurities and
dust found in atmosphere.
Various governing bodies worldwide, categorise clean rooms into different grades. Table [3] highlights
clean room classification in Europe set by the European Union Guidelines to Good Manufacturing
Practice.
Manufacturing facility is to have clean rooms of grade B to D and situated at various locations across
facility. Monitoring and controlling of pressure fluctuation, humidity, air flow rates and temperature is
to take place through total environment control measures.
Ventilated air is to be filtered through High Efficiency Particulate Air filter (HEPA), where airborne
particulates with a size of 0.3 µm and 99.97% minimum particle collective efficiency can be filtered
(McFadden, 2010).
Fig. [6] highlights the ventilation system utilised. Air is to be introduced via laminar air flow mechanism
to grade C rooms. Once introduced, air is to be filtered by HEPA filters mounted on ceiling, followed
by subsequent exiting through filters located on walls near room floor. Described flow pattern proves
to be highly effective due to constant sweeping of particulates from working space (Gad, 2008).

19. 14
5. Process validation, cGMP
Validation and qualification holds great importance in pharmaceutical industry as it is an integral part
in operation of manufacturing practices under cGMP guidelines. Documentary evidence produced
assures satisfactory and consistent production of DNA vaccines facility.
Main purposes of validation are (Bennett and Cole, 2010):

20. 15
5.1 Validation Plan
Objectives set out by validation are to be represented in form of a validation master plan (VMP). This
will be a guideline for sections that require validation along with methods on how validation is to be
conducted.
Agreement between individuals in validation work frame gives rise to VMP, where at its completion, it
is to be utilised as a demonstrating device to represent client’s regulation compliance with regulatory
officials. Description of procedures put in place for compliance of facility with cGMP’s are form part of
VMP document, such documentation includes (Chaloner – Larsson, 1997):
5.1.1 Design Qualification (DQ)
Design qualification is executed on various production pieces of equipment of manufacturing facility
such as bioreactor, anion-exchange chromatography, microfiltration system, centrifuge, size exclusion
chromatography, lyophilizer and HVAC systems for verification and documentation to prove that
equipment designs conforms with regulatory standards, such as ISO 9000, etc.
5.1.2 Installation Qualification (IQ)
Installation qualification confirms that supporting utilities (CIP, SIP, etc.), manufacturing facility layout,
process equipment and HVAC systems are implemented in compliance with designed specification
and manufacturer’s recommendations (Chaloner – Larsson, 1997). Each IQ documentation of
equipment/system comprises name of equipment/system, model and identification number, safety
feature, description, utility requirements, date, location, personnel and approver.
5.1.3 Performance Qualification (PQ)
Documented verification that highlights consistent performance to required specification for production
of DNA vaccines under designated operating ranges of manufacturing facility and supporting utilities.
The systems and equipment that undergo validation performance check are:

21. 16
5.1.4 Operational Qualification (OQ)
Documentation that highlights accordance of equipment operation to designed specifications and
operation conditions. Achieved through testing switches, control systems, alarms and providing
standard operations procedures (SOPs).
5.1.5 Quality Assurance and Quality Control (QA/QC)
Good quality assurance and quality control are pivotal factors in consistent production of DNA
vaccines for conformation of therapeutic specification of purity, potency, efficacy and safety. Quality
control is a key component in current good manufacturing practices (cGMP) and regulatory guideline
of ISO 9000, MHRA, WHO, etc. It is performed through testing procedures and checking for uniform
batch-to-batch production of DNA vaccines and ensure that raw materials utilised meet standard,
specification and quality.
Quality of raw materials and product purity is determined via an array of tests performed in quality
control testing laboratory, which consists:
5.1.6 Product testing

22. 17

23. 18
6. Gantt Chart
Figure [8]: Project schedule
Figure [8] represents scheduling. Project is to begin on the 3rd September 2017 and end on the 2nd January 2019. Completion of project is expected to take 1 year and 10 months.
03-Sep 23-Oct 12-Dec 31-Jan 22-Mar 11-May 30-Jun 19-Aug 08-Oct 27-Nov 16-Jan
Environmental Impact Assessment (EIA)
Preliminary Design
Detailed Design
Site Preparation
Procurement
Building and Construction
Landscaping
Commissioning and Validation of facility
Regulatory Agencies Approval

24. 19
7. Costing
7.1 Total Purchase Cost
Cost estimation of facility is to be effectuated through calculation of total purchase cost of equipment (PCE). Cost of
each unit operations are estimated through size, quantity and complexity of each unit and per a 2014 U.S Gulf Coast
Basis, thus conversion to 2016 UK Basis is required.
Fermenters were estimated based on size, whilst Cell lysis vessel and Packed Tower – gel filtration unit were
assumed to be a 200L agitated reactor and packed column respectively. Cost of various process units were calculated
using purchase cost for the year 2014 on a U.S Gulf Coast Basis alongside Consumer Price indices 2014 and 2016.
All 2014 U.S Gulf Coast Basis costs of equipment were obtained through (Match, 2014) and highlighted in Table [5].
Adding up individual equipment costs, total purchase cost of equipment (PCE) of US $ 603,200 on a 2014 U.S Gulf
Coast Basis was obtained.
Total purchase cost of equipment was then converted to a 2016 UK Basis via use of cost indices and location factors
(Towler at al., 2013). Although a cost index for 2017 was not available, cost index for 2016 will be taken as an
estimate instead. Cost indices were utilised in following equation:
Therefore, total purchase cost of equipment (PCE) on a 2016 U.S Gulf Coast Basis:
Given that manufacturing facility will be in the United Kingdom, location factors were applied and implemented using
following equation (Towler et al., 2013):

25. 20
Ultimately, currency must be converted from dollars (USD) to pounds (GBP). Exchange rate, as of 25th February 2017,
is 1.25 USD per 1 GBP, therefore total purchase cost of equipment on 2016 UK Basis:
Pharmaceutical processes have a Lang factor of 6.0 – 7.0 (Towler et al.,2013), thus for DNA vaccine production a
Lang factor of 7 will be utilised, therefore:
Fixed capital costs are spread over two years, therefore:

26. 21
7.2 Physical Plant Cost (PPC)
In addition to fixed capital costs, total physical plant cost (PPC) was also calculated using Lang’s factorial method.
Table [6] represents various Lang factors on basis that process is a fluids-solids type. Moreover, building factors,
storage costs and site development were not considered at this stage (Towler et al., 2013). Therefore:
7.3 Working Capital
Working capital was considered to cover initial solvent charges, such as plant start-up and operations, thus for this
project, 5% of the fixed capital cost was used to calculate working capital (Towler at al., 2013), therefore:

27. 22
7.4.1 Fixed Operating Costs
7.4.1.1 Maintenance
Includes cost of maintenance of labour and materials. Maintenance costs for chemical plants are typically 5 – 10% of
fixed capital costs (Towler at al., 2013), thus for this process, a 10% installation cost will be accounted, therefore:
7.4.1.2 Operating Labour
Manpower required for operation of plant. Cost is estimated through number of shifts and average current salary.
Estimation also accounts for holidays, shift allowances, National Insurance and pension contributions. Table [7] lists
total number of workers and shifts per day.
Based on assumption that average salary between workers is £24,000, a labour cost per annum can be calculated,
thus:
7.4.1.3 Supervision
Operating supervision and management of plant. Management team is to consist of four shift workers, area supervisor
and his assistant. Estimation for this cost is calculated by taking 20% of labour costs (Towler et al., 2013), therefore:
7.4.1.4 Training
Training of personnel is required for any production facility, thus an annual cost of £100,000 has been included.
7.4.1.5 Recruitment
Facility is not an extension to an existing manufacturing plant or associated with another company, thus recruitment
costs are to be paid to ensure qualified and specialist staff. Recruitment costs are estimated by taking 1% of labour
costs, thus:

28. 23
7.4.1.6 Plant overheads
It is associated with general costs of plant operation, such as canteen, general management, plant security and
safety. Plant overhead cost is estimated through total labour cost, and lie in a range between 50 – 100%. For this
facility, 50% of labour cost is taken, therefore:
7.4.1.7 Insurance
Annual insurance paid to insurers, and estimated as 1-2% of fixed capital cost. For this facility, 1% is to be estimated,
therefore:
7.4.1.8 Research and Development
Costs of research executed for development of process and/or products. Estimated by taking 5% of fixed capital cost,
therefore:
7.4.1.9 Licensing and Royalties
Cost of paying for intellectual property and estimated through 3% of fixed capital cost, therefore:
Based on various costs mentioned, fixed operating costs are estimated to be:
7.4.2 Variable Operating Costs
7.4.2.1 Raw materials
Therefore, cost of total raw materials per batch:

29. 24
On the basis that 2 batches of each product are manufactured based on 50 weeks/annum, 200 batches are produced,
therefore cost of total batches per annum:
7.4.2.2 Utilities
Utilities costs encompasses steam, power, process water, cooling, compressed air and effluent treatment. However,
due to unavailability of energy balances, a cost for facility cannot be estimated.
Although utilities cost cannot be evaluated at this stage, a costing figure from literature has been assumed (Adkin,
1998), being:
Henceforth, variable operating costs are estimated to be:
Therefore, estimation for total operating costs:
7.5 Fixed Capital Investment
Capital cost of entire project is sum of all costs, therefore:
7.6 Total Investment
Corresponds to sum of fixed capital investment and working capital, therefore:
7.7 Revenue
Proposed selling prices and number of doses per annum of products are highlighted in Table [9].

30. 25
7.8 Gross Profit
Gross profit margin given by:
Therefore:
Margin percentage indicates on how profitable process is going to be, correspondingly a percentage of 77.8% is very
economically feasible for a pharmaceutical plant.
7.9 Project Financing
7.9.1 Financing Investments
Financing of project is based upon financial structure, exploring debt and equity will give an indication in regards to
generation of cash flow for financing of project. Project has a life span of 10 years, thus evaluation of annual present
value of project is achieved through calculation of Net Present Value.
Source of finance under consideration is through private investment and following equation is utilised:
Discount factor represents earning power of money and it is equivalent to current interest rate of money could earn if
invested. NPV of project is to be calculated via a table of yearly net annual profit. Discount factor of 25% was used as
it represents a realistic value for a well-established technology. Table [10] represents private investment at a 25%
interest rate

31. 26
NPV on private investment indicates economic feasibility on a 25% interest rate basis. Total of £224,000,000 signifies
lucrativeness of project.
7.9.2 Net Profit
Net profit is obtained by deducting tax from gross profit. Adjusting of accurate taxable value is achieved through a
depreciation allowance equation:
An assumption of 10% of capital costs is made to calculate annual scrap value, thus a depreciation allowance of
£1,902,700 is obtained. Final net profit is determined via this figure with an assumed corporation tax value of 21%.

32. 27
7.9.3 Cumulative Cash Position
Alternative way to outline profit of plant is through demonstration of change in cash flow throughout years. However,
certain assumptions are made for application of cumulative cash position:

33. 28
Fig. [9] represents a graphical comparison of Cumulative Cash is plotted against time of total life span of project.
Through use of this graphical data payback time for project can be estimated, given by equation:
8. Conclusion
This project provides an NPV of £224 million at a discount factor of 25%, which is very healthy. It is shown that base
case is very robust through analysis of changes in plant cost, utility cost and sales monies. Large changes of these
parameters could produce a negative NPV. In addition, project may face issues if costs are found to be higher in line
with a drop-in sales money. Risk can be avoided through extensive market research, long term supplier
contacts/alternative sources of supply, and extensive concept design to secure figures.
Implementation of current good manufacturing practices (cGMP) from initial design and layout stage of DNA vaccine
facility, production processes and manufacturing premises specified in report ensure that regulatory specifications are
met.

34. 29
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36. 31
APPENDIX
APPENDIX 1 – Room 16 Data Sheet
ROOM NO: 16
ROOM DATA SHEET
Project Title: Concept Bio-pharmaceutical Facility PDS No: XXX
Room Name: BIO REACTOR Proposed Purpose of Room:
Room Dimensions: Width: 3700 Length: 7940 Height: 2700 Area: 29.378 m2
Floor Finishes
VINYL SHEET LAID ON LATEX SMOOTHING COMPOUND
COVED TO WALL (MIN 100mm)
Wall Finishes
INTERNAL METAL PARTITION
VINYL SHEET ON PARTITION OR PROPRIETARY CLEAN ROOM PANEL SYSTEM
Ceiling Types
SEALED METAL (POWDER COATED) SUSPENDED PROPRIETARY SYSTEM
Door Details
GRP WITH METAL FRAME
VISION PANEL
Other (Including Fitted Furniture/Shelves/Display Equipment Etc.)
Benching, Shelves, Storage, PC
Electrical Services
Lighting (Type & Level): FLUORESCENT 500Lux @ 900mm ABOVE FINISHED FLOOR LEVEL
Powder Distribution: Double sockets x 4 on each wall: 1 extension cable
Special Requirements: Protected against water ingress
Cabled Services:
Datacom Requirements: 2 x Computer ports
Telecom Requirements: 2 x Telephone ports
Fire detection: Yes Sprinklers: No
Equipment/Plant Alarms: Bioreactor, Safety Cabinets, HVAC
Security Systems:
Environment:
Temperature – Limits: 19 +/- 2C Humidity – Limits: Operator Comfort
Air Change Rates: > 12 Pressure Regimes: 45Pa
Recirc.Air: TBD Filtration: Grade C
Operating Times: 24 Hours No. of occupants: Approx. 4
Equipment Loads: CIP/SIP of Bioreactors

37. 32
Special Requirements: Grade C
Local Exhaust Ventilation
Fume Cupboards: No. Size: Face Vel.:
Biosafety Cabinets: No. 2 Type: TBD Size: Face Vel:
Bioreactor Vent: No. 2 Type: 0.2 µm filter Size: Face Vel:
Water Services & Drainage
Sinks: No: 1 Size: 12mm Type: Hand wash Taps: H&C
Wash Basins: No: Size: Type: Taps:
Hose Points: No: Type: Mounting:
Floor Gullies: Yes: Size: Type
Steam:
Drainage: 3 Domestic: Sewerage: Effluent:
Gases
Compressed Air: 3 CO2: 3 Oxygen: 3
Nitrogen: High Vacuum: Low Vacuum:
Other:
Loose Furniture/Equipment (Project Supply)
Chairs
Equipment to be Installed (Non-Project Supply)
Bioreactors, Analyser, Microscope, Waterbath, Trolleys
Approval
Prepared by (Signature) Approved by (Signature))
Block Capitals Date Block Capitals Date
REVISIONS
REV DESCRIPTION DATE BY
O1 Preliminary Comments Incorporated 10/03/17 DT

38. 33
APPENDIX 2 – Room 7 Data Sheet
ROOM NO: 7
ROOM DATA SHEET
Project Title: Concept Bio-pharmaceutical Facility PDS No: XXX
Room Name: GENERAL PREP ROOM Proposed Purpose of Room:
Room
Dimensions: Width: 3500
Lengt
h: 6620
Heigh
t: 2700 Area:
23.17
m2
Floor Finishes
VINYL SHEET LAID ON LATEX SMOOTHING COMPOUND
COVED TO WALL (MIN 100mm)
Wall Finishes
INTERNAL METAL PARTITION
VINYL SHEET ON PARTITION OR PROPRIETARY CLEAN ROOM PANEL SYSTEM
Ceiling Types
SEALED METAL (POWDER COATED) SUSPENNDED PROPRIETARY SYSTEM
Door Details
GRP
VISION PANEL
Other (Including Fitted Furniture/Shelves/Display Equipment Etc.)
Benching, PC, Autoclave Monitoring System
Electrical
Services
Lighting (Type & Level): FLUORESCENT 500Lux @ 900mm ABOVE FINISHED FLOOR LEVEL
Powder Distribution: 4 X Double Sockets on each wall
Special Requirements: Protection against water ingress
Cabled Services:
Datacom Requirements: 2 X Dataports
Telecom Requirements: 2 X Telephone ports
Fire detection: Yes Sprinklers: No
Equipment/Plant Alarms: HVAC
Security Systems: TBD
Environment:
Temperature – Limits: 19 +/- 2oC
Humidity –
Limits: Operator Comfort
Air Change Rates: > 20/Hr
Pressure
Regimes: 100Pa
Recirc.Air: TBD Filtration: Grade C
Operating Times: 24 Hours
No. of
occupants: Approx. 5
Equipment Loads: Autoclave, Glasswasher
Special Requirements: Grade C

39. 34
Local Exhaust Ventilation
Fume
Cupboards: No. Size: Face Vel.: N/A
Ventilated
Cabinets: No. 1 Type:
Powder Containment
Booth Size: Small Face Vel: N/A
Other Vent’d
Spaces: No. Type: Size: Face Vel: N/A
Water Services & Drainage
Sinks: No: 1 Size: TBD Type: TBD Taps: TBD
Wash Basins: No: 0 Size: N/A Type: N/A Taps: N/A
Hose Points: No: 1 Type: TBD Mounting: TBD
Floor Gullies: Yes: 1 Size: TBD Type TBD
Steam: Clean Steam, Boiler Steam
Drainage: 3 Domestic: No Sewerage: No
Effluen
t: 3
Gases
Compressed Air: 3 CO2: 3 Oxygen:
Nitrogen: High Vacuum: Low Vacuum:
Other:
Continuous Environmental Monitoring Vacuum – non-
viable monitoring
Loose Furniture/Equipment (Project Supply)
Chairs, Trolleys (General), Autoclave trolleys
Equipment to be Installed (Non-Project Supply)
Autoclaves, Glasswashers, Column packing station, Buffer Preparation Station, Laminar Air Flow units x 2
Approval
Prepared by (Signature)
Approved by
(Signature))
Block Capitals Date Block Capitals Date
REVISIONS
REV DESCRIPTION DATE BY
O1 Preliminary Comments Incorporated 10/03/17 DT