conceptual design of syringe fill finish pharmaceutical plant

2010

Conceptual design of Syringe Fill Finish Pharmaceutical

PlantFacility Design and Operation Assignment

SUBMITTED TO

DUBLIN INSTITUTE OF TECHNOLOGY

G r o u p 3

Facility Design and Operation Assignment Group 3


1 Contents

2 Layout..................................................................................................................5

2.1 Introduction........................................................................................................5

2.2 Definition............................................................................................................5

2.3 Aim.....................................................................................................................7

2.4 Summary...........................................................................................................9

3 Sanitation...........................................................................................................10

3.1 Introduction......................................................................................................10

3.2 Definition..........................................................................................................11

4 Cleanrooms........................................................................................................13

4.1 Clean Room Standards....................................................................................15

4.2 Isolators...........................................................................................................16

5 Sampling............................................................................................................18

6 Cleaning.............................................................................................................18

6.1 CLEANING OF EQUIPMENT..........................................................................19

7 Flow of Materials and Personnel........................................................................20

7.1 Material Flow...................................................................................................22

7.2 Personnel Flow................................................................................................23

8 Transport of materials........................................................................................24

9 Novel / Alternative Technology..........................................................................25

10 Bibliography part 2.........................................................................................29

11 PLANT LOCATION AND SITE SELECTON...................................................30

12 PLANT LAYOUT............................................................................................36

12.1 Plant Layout Strategies.................................................................................37


13 THE NEED FOR GOOD MANUFACTURING PRACTICE.............................40

13.1 WHY IS GMP AND QUALITY IMPORTANT?.................................................41

13.2 GMP REQUIREMENTS...................................................................................42

13.3 GMP AND THE INDIVIDUAL..........................................................................48

14 QUALITY........................................................................................................50

15 Organisational Structure.................................................................................70

15.1 Overall Company Structure..............................................................................70

15.2 Primary Processing Unit..................................................................................71

15.3 Secondary Process Unit Human resources.....................................................79

15.4 Research & Development................................................................................83

15.5 Site Leadership Team......................................................................................84

15.6 Project Organisation........................................................................................85

15.7 Start-up Team..................................................................................................86

15.8 Shutdown Team...............................................................................................87

16 10 Company Philosophy.................................................................................88

16.1 Introduction......................................................................................................88

16.2 Mission & Vision..............................................................................................88

16.3 Staff.................................................................................................................89

16.4 Environment.....................................................................................................91

16.5 Budget.............................................................................................................92

17 Safety.............................................................................................................93

17.1 Safety Philosophy............................................................................................93

17.2 Safety Statement.............................................................................................93

17.3 Maintaining a Safe Work Environment.............................................................94

17.4 Safety Training.................................................................................................95


17.5 Hazardous Process Safety..............................................................................96

17.6 Efforts to Eliminate Workplace Hazards..........................................................98

17.7 Safety Systems..............................................................................................102

18 References Part 3........................................................................................104

19 OBJECTIVES...............................................................................................106

20 INTRODUCTION..........................................................................................106

21 PROJECT BACKGROUND..........................................................................107

22 SCHEDULE..................................................................................................108

22.1 Resource and organisation............................................................................112

22.2 Commissioning and Qualification Considerations..........................................114

22.3 Production capacity.......................................................................................119

23 TECHNOLOGY TRANSFER AND START-UP.............................................120

23.1 Technology Transfer......................................................................................120

23.2 Start-Up.........................................................................................................123

24 MAINTENANCE, CONTINGENCY AND SHUTDOWN................................124

24.1 Maintenance..................................................................................................124

24.2 Contingency...................................................................................................125

24.3 Organization..................................................................................................126

25 Shutdown.....................................................................................................127

26 CONCLUSIONS...........................................................................................129

27 REFERENCES part 5...................................................................................129

2 Layout

Appendix A


2.1 Introduction

The efficiency of production depends on how well the various machines; production

facilities and employee’s amenities are located in a plant. Proper layout can ensure the

smooth and rapid movement of material, from the raw material stage to the end product

stage. Plant layout encompasses new layout as well as improvement in the existing

layout. It may be defined as a technique of locating machines, processes and plant

services within the factory so as to achieve the right quantity and quality of output at the

lowest possible cost of manufacturing. It involves a judicious arrangement of production

facilities so that workflow is direct.

2.2 Definition

Plant layout refers to the arrangement of physical facilities, within the factory building in

such a manner to have quickest flow of material at the lowest cost and with the least

amount of handling in processing the product from the receipt of material to the

shipment of the finished product. It is to design a physical arrangement that most

economically meets the required output – quantity and quality.

Within the scope the project planning, only the basic layout for the main apparatus and

instrumentation will be carried out. The detail layout and instrumentation planning is

very complex and can only occur after the submission of the P&I drawings, the plant

layout and the apparatus drawings within the framework of the detail engineering. For

the project planning phase, usually layouts in the form of simple to views and side views

are sufficient. In order to provide the customer with a better impression of the designed

plant, graphically processed three-dimensional views of the layouts can be generated


with suitable CAD system. For the preparation of the layout, process engineers involved

in layout design have to carry out the positioning of the main aggregates in the first

place. This requires a lot of experience, since sometimes the arising demands are

contradictory and a suitable compromise has to be found. For the first attempt it has

proven its worth to make a stencil of layout of the main aggregates on a suitable scale

and to shift it about until the optimum position is found. For the horizontal layout, the

components are usually arranged toward the main flow direction to avoid unnecessary

pipework. For the vertical arrangement, geodetic aspect such as evacuation possibilities

and the minimization of the pump number required have to be taken into account.

Based on the layout the space required for the plant can be determined, which for the

cost reason it to be minimized. In general, the layout of the main components is already

available in the form of the layout of the project planning phase. Unless there are no

procedural changes, this layout can be used as the basis for the ensuing detailed layout

design. First of all a basic grid has to be defined. 1

2.3 Aim

1 Process plant design, F.P.Helmus,2008.


An ideal layout can be influential in achieving the following objectives:

Proper utilization of available floor space

No delays - from one point to another point

Provide production capacity

Reduce material handling costs

Reduce hazards

Utilise labour efficiently

Reduce accidents, provide employee safety and health

Provide volume and product flexibility

Provide supervision and control

Easy to maintenance

Allow high machine or equipment utilization

Improve productivity


Figure 1 Conceptual Floor Plan


2.4 Summary

The machines and equipments are arranged in one line depending upon the sequence

of operations required for the product. The materials move from one workstation to

another sequentially without any backtracking or deviation. Under this, machines are

grouped in one sequence. Therefore materials are fed into the first machine and

finished goods travel automatically from machine to machine, the output of one machine

becoming input of the next. The raw material moves very fast from one workstation to

other stations with a minimum work in progress storage and material handling. The

grouping of machines should be done keeping in mind the following general principles.

All the machine tools or other items of equipments must be placed at the point

demanded by the sequence of operations

There should no points where one line crossed another line.

Materials may be fed where they are required for assembly but not necessarily at

one point.

All the operations including assembly, testing packing must be included in the

line

Advantages

Product layout provides the following benefits:

Continuous flow of work

Lesser investment in inventory and work in progress

Optimum use of floor space

Simple and effective inspection of work and simplified production control

Lower cost of manufacturing per unit

Shorter processing time or quicker output

Less congestion of work in the process

Low cost of material handling, due to straight and short route and absence of

backtracking

Smooth and uninterrupted operations


Disadvantages

Product layout suffers from following drawbacks:

High initial capital investment

Heavy overhead charges

Breakdown of one machine will hamper the whole production process

Lesser flexibility as specially laid out for particular product

Suitability

Product layout is useful under following conditions:

o Mass production of standardized products

o Simple and repetitive manufacturing process

o Operation time for different process is more or less equal

o Reasonably stable demand for the product

o Continuous supply of materials

3 Sanitation

3.1 Introduction

Facilities used for the production of vaccines should be designed to protect the purity of

the product during the production process and to protect the health of the personnel.

They must be constructed in the way that:


They can be easy cleaned

They provide adequate separation of preparation rooms

They have good ventilation

They have facilities for personnel (dressing room tec.) that are accessible

without passing through biological product preparation areas

3.2 Definition

Sanitization, in comparison to sterilization, is the “process of substantially reducing or

destroying a number of microbial organisms to a relatively safe level.” Sanitization

“generally requires a 99.9% or greater reduction of a test organism.” The “test organism

should be agreed upon with the inspecting agency” prior to completion of the design

and validation of the process.2

Sanitation is particularly important for the clean areas. They should be cleaned

frequently and thoroughly in accordance with an approved written SOP. Monitoring

should be regularly undertaken in order to detect the emergence of resistant strains of

microorganisms. In view of its limited effectiveness, ultraviolet light should not be used

as a substitute for chemical disinfection. Disinfectants and detergents should be

monitored for microbiological contamination; dilutions should be kept in previously

cleaned containers and should only be stored for defined periods unless sterilized.

Disinfectants and detergents used in grade A and B areas should be sterilized before

use. In order to control the microbiological cleanliness of the various grades in

operation, the clean areas should be monitored. Where aseptic operations are

performed, monitoring should be frequent methods such as settle plates, and volumetric

air and surface sampling (e.g. swabs and contact plates) should be used. The zones

should not be contaminated through the sampling methods used in the operations. The

results of monitoring should be considered when batch documentation for release of the

finished product is reviewed. Both surfaces and personnel should be monitored after

critical operations. Levels of detection of microbiological contamination should be

2 Good design Practices for GMP


established for alert and action purposes, and for monitoring the trends in air quality in

the facility.

Sterility and the elimination of contamination are dependent on the components and

processes used, personnel conformance to procedures, and environmental conditions

under which operations are performed. Requirements for environmental conditions

depend on the exposure the preparation during processing, is affected by the length,

the size of the critical area exposed and the nature of the critical site. Exposure of the

critical site should be minimized in the process (i.e. we should minimize time of

exposure during filling an unstoppered vial). Other critical factor – size of critical site is

also a factor for contamination (i.e. exposed open-vial). High priority is given to

prevention and elimination of airborne particles. To control particles typically are used:

cleanrooms and barrier isolators. In our case, sterility is achieved by dissolving the non-

sterile active pharmaceutical ingredient in a solvent, followed by filtration through a

sterilising filter with the pore size ≤ 0,22 mm. The preparation of that solution is done in

grade C environment. The sterile filtrate is further processed in sterilised equipment, the

substance is isolated and washed in a sterile centrifuge or on a sterile filter, before it is

packed in its final sterilised container - vial. During aseptic processing, operations

should be carried out where possible in closed equipment in classified environments.

Solutions may be sterilised by passage through filters with a nominal pore size of less

than or equal to 0.22mm. The sterilisation of the API by filtration is a critical step and

must be validated accordingly. Filters must be shown to microbiologically retentive

under worst case process conditions using actual product solutions where ever

possible. It must also be demonstrated that filters used neither significantly absorb any

component from, nor release any significant contaminant into the solution being filtered.

The integrity of assembled sterilising filters must be confirmed before and after each

use using an integrity test that is correlated with microbial retention. The time required

filter a known volume of solution and the maximum pressure differential across the filter

should be established during validation and deviations from these parameters during

routine use must be recorded and investigated. The length of use of the same filter and


maximum waiting times, should be established during process development and

confirmed by validation.3

4 Cleanrooms

A Clean Room - Clean Space is defined as a room or suite of rooms or an area of

controlled environment in which the concentration of airborne particulate matter is

strictly controlled and where other factors may be controlled within limits necessary to

cater for particular needs. 4

Clean areas for the manufacture of sterile products are classified according to the

required characteristics of the environment. Each manufacturing operation requires an

appropriate environmental cleanliness level in the operational state in order to minimize

the risks of particulate or microbiological contamination of the product or materials being

handled.

The classification of each room or module within an aseptic processing area must be

appropriate for its intended use. The highest level of control will be directed to those

areas, typically known as critical zones, in which aseptic manipulation of uncovered

containers, closures, or components occurs. These areas are designed to comply with

Class 5 of ISO 14644 (ISO Class 5 is functionally equivalent to traditional US Federal

Standard (FS) 209 E Class 100, and to EU Grade A)(12, 21, 22). These areas are

equipped with total-coverage HEPA filtration, and unidirectional airflow is maintained to

the extent it is technically possible to do so. European and United States aseptic

processing area zoning differs: In the United States, the area immediately adjacent to

the critical zone is typically Class 7 (FS 209 Class 10,000). In Europe, this area is

Grade B, for which there is no precise analog in either the ISO or now withdrawn 3 Pharmaceutical Process Validation, Drugs and the pharmaceutical sciences,3rd edition Volume 1294 International Journal of Pharmaceutical Compounding Vol. 8 No. 2 March/April 2004


(replaced by ISO 14644) FS 209E classification schemes. It may be beneficial to

include a HACCP analysis to support a firm’s cleanroom design strategy for an aseptic

operation. Other parameters typically considered in the design of an aseptic processing

area are direction of airflow, air balance, air changes per hour, and air velocity. The

adequacy of an air velocity and the closely related specification of air changes per hour

depends upon several factors, including total room volume and location of the HEPA

filter or air entry point relative to the work zone. Therefore, quite different velocities may

provide similar levels of performance depending upon the design and usage of the

facility. One must also recognize that when air velocity was included as a cleanroom

design specification, measurement of air velocity was taken approximately one foot from

the face of the HEPA filter.

Table 1 Airborne particulate classification for manufacture of sterile preparation

These areas should be designed to reach certain specified air-cleanliness levels in the

“at rest” occupancy state. For the manufacture of sterile pharmaceutical preparations,

four grades are as follow:

Grade A: The local zone for high-risk operations, e.g. filling and making aseptic

connections. Normally such conditions are provided by a laminar-airflow

workstation. Laminar-airflow systems should provide a homogeneous air speed

of approximately 0.45m/s ± 20% at the working position.

Grade B: In aseptic preparation and filling, the background environment for the

grade A zone.


Grades C and D: Clean areas for carrying out less critical stages in the

manufacture of sterile products.5

An important part of cleanroom technology is the pressurization of the controlled area to

prevent migration of particulates.

4.1 Clean Room Standards

The standard international clean room standards are:

· US Federal Std 209E 1992

· EEC cGMP 1989

· France AFNOR 1989

· German VDI 2083 1990

· British BS 5295 1989

· Japan JIS B 9920 1989

· ISO EN 14611-1 1999

5 World Health Organization WHO Technical Report Series, No. 902, 2002


Table 2 Air Classification for International Cleanroom Standards 6

4.2 Isolators

Barrier isolators minimize the extent of personnel contact. Fine designed barrier

isolators offer an acceptable alternative to a cleanroom.

6 Farquharson G., “Cleanrooms and Associated Controlled Environments – The New CEN and ISO Containment Control Standards” Pharmaceutical Engineering Vol. 19, No 5.


Figure 2 Positive pressure isolator

Figure 3 Negative pressure isolator


5 Sampling

Samples taken for sterility testing should be representative of the whole of the batch,

but should, in particular, include samples taken from parts of the batch considered to be

most at risk of contamination, as well for products that have been filled aseptically,

samples should include containers filled at the beginning and end of the batch and after

any significant interruption of work. The sterility test procedure according to the

Pharmacopoeia methods, should be validated for a given product. For injectable

products, the WI, intermediate and finished products should be monitored for

endotoxins. The distribution of microorganisms in a given pharmaceutical production

batch is not homogenous thus microorganisms are lumped together. That is way

examination of only one sample is not gone to give us a good result of microbial

contamination. According to the USP, EP, and JP, the sample volume for a microbial

limit test must be a composite sample of a production lot by sampling a number of

containers and compositing the sample. The nature and the frequency of the testing will

depend on the nature of the product, manufacturing process, facility size, and

environmental conditions. It might be necessary to monitor different stages during the

manufacturing process to minimize the chance of microbial contamination. Sterility test

is performed after the product is manufactured as a final quality control tests, the

number of samples selected for sterility testing depends from the size of the lot. 7

6 Cleaning

7 Microbial Contamination Control in the Pharmaceutical Industry, Drugs and the pharmaceutical sciences, Volume 142


Cleaning is of prime importance because it affects the whole production system.

Improper cleaning may facilitate contamination of product, which may cause toxicity as

well as decrease therapeutic activity of drug. Especially in the production of injectors

change of pH or isotonicity may cause the rejection of whole batch.

6.1 CLEANING OF EQUIPMENT

The cleaning of equipment may be clean in place (CIP) and steam in place (SIP) In

clean in place system various sprayers with tank are attached to cover different

component of machinery. Cleaning agent selected on the basis of rapid solubilisation in

soiled area and quick removal from machinery. Final cleaning should be 180 ºF pyrogen

free water for injection. The end point of cleaning is determined by analysis of rinsing

water (conductivity).

A final rinse and drying step complete the cleaning process. Cleaned equipment is then

reassembled (if required) and may be placed into a container or bag for protection and

sterilization. As the equipment moves through the cleaning process, the surrounding

environment increases in cleanliness to correspond with the state of the equipment

being cleaned. The number of cycles, spray force, spray pattern, the spray nozzle and

their position is important which varies as per type of product to be cleaned. In steam in

place system steam pressure is applied for both drying of residual moisture and

simultaneously sterilization. Difficulty in establishing SIP as the portions should

withstand the pressure applied. Variables in this case are steam temperature, steam

penetration and length of exposure. Fixed equipment is disassembled with some

components removed from the room for cleaning out of place (COP) in a purpose-built

room. This also includes the removal of portable equipment for cleaning, typically at the

same location as fixed equipment. Remaining components are cleaned in place (CIP)

by flushing the system with a series of solutions and rinses while the system is closed.

Control of these fluids is managed by both the process equipment and a CIP system

(typically a skid) control units. COP typically consists of further disassembly of


equipment, where it is cleaned with an ultrasonic-type or detergent flushing cleaning

cycle (semi-automatic or automatic). 8

In the filled syringe plant on line will be carried out cleaning, siliconisation and

sterilisation of syringes in situ. This requires the use of Water for Injection (WFI) at

different rinse stages on the syringe manufacturing line and clean steam for steaming-

in-place. WFI and clean steam are supplied from water a purification plant. The facility

also will provide management of hot process waste. According to the FDA regulations

Water for Injection and clean steam have to be produced from Purified Water (PW) and

all three of these substances have to comply with the United States Pharmacopoeia

(USP).

7 Flow of Materials and Personnel

In sterile manufacturing facilities, the flows of materials and personnel are very

influential on product integrity, and agencies and quality personnel will often scrutinize

these flows. This is particularly true in rooms involving product contact and critical

operations. In these cases, unidirectional flow of personnel and materials is very

important to minimize risk of product contamination. This principle is applied from room

to room as well as within the room whenever possible. Proper material and personnel

flows are essential in pharmaceutical operations. Good flows efficiently manage and

control the movement of people and materials through processing operations,

minimizing risk of contamination whenever possible.9

The ISPE Oral Solid Dosage Guide highlights the following key architectural concepts in

terms of product flow design guidelines:

8 Good Design Practices for GMP Pharmaceutical Facilities Andrew A. Signore, Terry Jacobs, 2005,

Volume 146

9 Good Design Practices for GMP Pharmaceutical Facilities Andrew A. Signore, Terry Jacobs, 2005, Volume 146


o Provide logical, direct, and sequential flow, minimizing the potential for

confusion

o Minimize the moving distance; that is, the distance material has to move

o Provide adequate protection against contamination

o Provide adequate staging and access

o Provide the proper level of protection

Figure 4 General facility flow 9


Figure 5 One –way system9

7.1 Material Flow

It should be designed to prevent cross- contamination and material mix-ups (important

for multi product facilities), as well as most important for easy movement of materials.

We will introduce one-way flows.


Figure 6 Conceptual Material Flow

7.2 Personnel Flow

Personnel access for routine and non-routine maintenance should be allowed.

Personnel flows should be designed to:

prevent contamination to products and materials


ensure personnel safety

in aseptic facilities, controls to prevent simultaneous personnel flows

Figure 7 Conceptual Personnel Floor

8 Transport of materials

Materials that need to be transferred include empty syringes, final bulk product in liquid

form, stoppers and plungers, environmental monitoring samples, and filled syringes. In


a typical final-filling facility, stoppers and plungers arrive loose and nonsterile in bags.

They’re unloaded into a special washing machine that carries out

washing, siliconization, and sterilization. Other materials are moved into the filling

machine using rapid transfer ports. Formulated bulk fluid arrives by a stainless steel

vessel that has to be steam-connected to the line. Both transfer line and vessel must be

cleaned and sterilized in place (CIP, SIP). The most common means for transferring

materials is by pumps and pipes. Conveyors, chutes, gates, hoists, fans, and blowers

are examples of other kinds of equipment used extensively to handle and transfer

various materials. Many forms of special equipment are used for the treatment of

materials, as, for example, filters, blenders, mixers, kneaders, centrifugal separators,

crystallizers, crushers, grinders, dust collectors, kettles, reactors, and screens.10

9 Novel / Alternative Technology

We will introduce several single-use technologies. Decision criteria ware based on

following aspects:

10 Plant design and economics for chemical engineers, 4th edition, Max S. PetersKlaus D. Timmerhaus, 1991


no cleaning (no cleaning validation)

no risk of cross-contamination in a multiproduct environment

no steam sterilization validation for piping

no autoclave-loading validation

use of presterilized, preassembled components (no manipulations after

sterilization)

Suggestions for material transfer, with application:

IDC Biosafe rapid-transfer ports for both solids and aseptic fluids transfer onto

the line, allowing disposable bags to be docked to the isolators

3D brand bags for storing the bulk flu vaccine

Kleenpak brand connectors for rapid aseptic fluid flow connections.

Figure 8 Fluid transfer process11

Introduction of fully automated bag and tub opener will reduce need for manual

interference minimizes risk of contamination. This technology is processing of up

to 9,500 syringes per hour. This technology can work under class A cleanroom

conditions. 12

11 BioProcess International 4(6):S48-S51 (June 2006)12 www.boschpackaging.com


Introduction a new Syringe Filler. Featuring individual, automatic shut-off

sensors, Tridak Model 1100 allows filling of materials through tip of syringe

allowing syringes to be filled with plunger intact. Adjustable-level, dual photo-

sensors automatically detect when syringe plungers reach their full position, and

automatically shuts off filling cycle. Product utilizes disposable fluid path

technology ensuring contaminate-free packaging of pharmaceuticals products.

Figure 9 Tridak Model 110013

Introduction read-to fill vial which is supplied clean and sterile to the

pharmaceutical manufacturer. To obtain a clean and sterile vial, both vial body,

made of cycloolefin copolymer (COC), and thermoplastic elastomer (TPE)

stopper are molded in clean room Class 100 / Grade A / ISO 5 clean room and

directly assembled by robot. To ensure sterility, the container is gamma-

13 http://www.tridak.com


irradiated prior to delivery to the pharmaceutical manufacturer. The filling process

of this ready-to-fill container consists of a needle piercing the stopper and

dispensing the liquid. After needle withdrawal, to restore closure integrity, the

piercing trace is laser re-sealed. A cap, with the stopper surface protected until

use by the doctor, is placed by snap fit. All these operations are performed inside

a Closed Vial Filling System (CVFS) which ensure a permanent Class 100 /

Grade A / ISO 5 environment around filling operations. All classical vial and

stopper preparation steps (washing, siliconization and sterilization) have been

eliminated.

Figure 10 Read-to fill vial14

Introduction APS Combi machine. Machine designed and manufactured to

assemble syringes with plungers, to label the label the plungered syringes and to

assemble them with the safety device. Automated syringe packing in thermo

formed containers can be introduced followed by transfer system Robocombi.15

14 Pharmaceuticall Processing March 2009 15 www.ondrugdelivery.com


Figure 11 Corima APS Robocombi System


10 Bibliography part 2

1. Process plant design, F.P.Helmus,2008.

2. Good design Practices for GMP

3. Pharmaceutical Process Validation, DRUGS AND THE PHARMACEUTICAL

SCIENCES,3rd edition Volume 129

4. International Journal of Pharmaceutical Compounding Vol. 8 No. 2 March/April

2004

5. World Health Organization WHO Technical Report Series, No. 902, 2002

6. Farquharson G., “Cleanrooms and Associated Controlled Environments – The

New CEN and ISO Containment Control Standards” Pharmaceutical Engineering

Vol. 19, No 5.

7. Good Design Practices for GMP Pharmaceutical Facilities Andrew A. Signore,

Terry Jacobs, 2005, Volume 146

8. PLANT DESIGN AND ECONOMICS FOR CHEMICAL ENGINEERS, 4th edition,

Max S. PetersKlaus D. Timmerhaus, 1991

9. BioProcess International 4(6):S48-S51 (June 2006)

10.www.boschpackaging.com

11.http://www.tridak.com

12.Pharmaceuticall Processing March 2009

13.www.ondrugdelivery.com

http://www.tridak.com/

http://www.boschpackaging.com/


11 PLANT LOCATION AND SITE SELECTON

What is plant location?

Plant location refers to the choice of region and the selection of a particular site for

setting up a business or factory.

But the choice is made only after considering cost and benefits of different alternative

sites. It is a strategic decision that cannot be changed once taken. If at all changed only

at considerable loss, the location should be selected as per its own requirements and

circumstances. Each individual plant is a case in itself.

What is an ideal location?

An ideal location is one where the cost of the product is kept to minimum, with a large

market share, the least risk and the maximum social gain. It is the place of maximum

net advantage or which gives lowest unit cost of production and distribution. For

achieving this objective, small-scale entrepreneur can make use of locational analysis

for this purpose.

The geographical location of the final plant can have strong influence on the success of

the industrial venture. Considerable care must be exercised in selecting the plant site,

and many different factors must be considered. Primarily the plant must be located

where the minimum cost of production and distribution can be obtained but other factors

such as room for expansion and safe living conditions for plant operation as well as the

surrounding community are also important. The location of the plant can also have a

crucial effect on the profitability of a project.

The choice of the final site should first be based on a complete survey of the

advantages and disadvantages of various geographical areas and ultimately, on the

advantages and disadvantages of the available real estate. The various principal factors


that must be considered while selecting a suitable plant site are briefly discussed in this

section. The factors to be considered are:

1. Raw material availability

2. Location (with respect to the marketing area)

3. Availability of suitable land

4. Transport facilities

5. Availability of labour

6. Availability of utilities (Water, Electricity)

7. Environmental impact and effluent disposal

8. Local community considerations

9. Climate

10. Political strategic considerations

11. Taxations and legal restrictions

12. Price of land

13. Space for expansion

14. Distance from local communities

15. Banking and financial institutions are located nearby etc

Raw Materials Availability:

The source of raw materials is one of the most important factors influencing the

selection of a plant site. Attention should be given to the purchased price of the raw

materials, distance from the source of supply, freight and transportation expenses,

availability and reliability of supply, purity of raw materials and storage requirements.

Location:

The location of markets or intermediate distribution centers affects the cost of product

distribution and time required for shipping. Proximity to the major markets is an

important consideration in the selection of the plant site, because the buyer usually finds

advantageous to purchase from near-by sources.


Availability of Suitable Land:

The characteristics of the land at the proposed plant site should be examined carefully.

The topography of the tract of land structure must be considered, since either or both

may have a pronounced effect on the construction costs. The cost of the land is

important, as well as local building costs and living conditions. Future changes may

make it desirable or necessary to expand the plant facilities. The land should be ideally

flat, well drained and have load-bearing characteristics. A full site evaluation should be

made to determine the need for piling or other special foundations

Transport:

The transport of materials and products to and from plant will be an overriding

consideration in site selection. If practicable, a site should be selected so that it is close

to at least two major forms of transport: road, rail, waterway or a seaport. Road

transport is being increasingly used, and is suitable for local distribution from a central

warehouse. Rail transport will be cheaper for the long-distance transport. If possible the

plant site should have access to all three types of transportation. There is usually need

for convenient rail and air transportation facilities between the plant and the main

company head quarters, and the effective transportation facilities for the plant personnel

are necessary.

Availability of Labour:

Labour will be needed for construction of the plant and its operation. Skilled construction

workers will usually be brought in from outside the site, but there should be an adequate

pool of unskilled labors available locally; and labors suitable for training to operate the

plant. Skilled tradesmen will be needed for plant maintenance. Local trade union


customs and restrictive practices will have to be considered when assessing the

availability and suitability of the labors for recruitment and training.

Availability of Utilities:

The word “utilities” is generally used for the ancillary services needed in the operation of

any production process. These services will normally be supplied from a central facility

and includes Water, Fuel and Electricity which are briefly described as follows:

Water: - The water is required for large industrial as well as general purposes, starting

with water for cooling, washing and steam generation. The plant therefore must be

located where a dependable water supply is available namely lakes, rivers, wells, seas.

If the water supply shows seasonal fluctuations, it’s desirable to construct a reservoir or

to drill several standby wells. The temperature, mineral content, slit and sand content,

bacteriological content, and cost for supply and purification treatment must also be

considered when choosing a water supply. De-mineralized water, from which all the

minerals have been removed, is used where pure water is needed for the process use,

in boiler feed. Natural and forced draft cooling towers are generally used to provide the

cooling water required on site.

Electricity: - Power and steam requirements are high in most industrial plants and fuel

is ordinarily required to supply these utilities. Power, fuel and steam are required for

running the various equipments like generators, motors, turbines, plant lightings and

general use and thus be considered, as one major factor is choice of plant site.

Environmental Impact and Effluent Disposal:

Facilities must be provided for the effective disposal of the effluent without any public

nuisance. In choosing a plant site, the permissible tolerance levels for various effluents

should be considered and attention should be given to potential requirements for

additional waste treatment facilities. As all industrial processes produce waste products,

full consideration must be given to the difficulties and coat of their disposal. The


disposal of toxic and harmful effluents will be covered by local regulations, and the

appropriate authorities must be consulted during the initial site survey to determine the

standards that must be met.

Local Community Considerations:

The proposed plant must fit in with and be acceptable to the local community. Full

consideration must be given to the safe location of the plant so that it does not impose a

significant additional risk to the community.

Climate:

Adverse climatic conditions at site will increase costs. Extremes of low temperatures will

require the provision of additional insulation and special heating for equipment and

piping. Similarly, excessive humidity and hot temperatures pose serious problems and

must be considered for selecting a site for the plant. Stronger structures will be needed

at locations subject to high wind loads or earthquakes.

Political and Strategic Considerations:

Capital grants, tax concessions, and other inducements are often given by governments

to direct new investment to preferred locations; such as areas of high unemployment.

The availability of such grants can be the overriding consideration in site selection.

Taxation and Legal Restrictions:

State and local tax rates on property income, unemployment insurance and similar

items vary from one location to another. Similarly, local regulations on zoning, building

codes, nuisance aspects and others facilities can have a major influence on the final

choice of the plant site.

Prioritizing the Factors

The three major site location factors are usually the location of raw materials, location of

markets, and transportation. Once these aspects have been determined, other mportant


(but secondary) considerations can be identified and evaluated. When selecting a site

or a business it is important to

a. Purchase the property when possible

b. Lease the property to avoid the problem of mortgage payments

c. Rent or buy the property, whichever must be done in order to obtain

the specific site

d. Make comparisons between the rentals of neighboring stores and

property for sale

Looking at the three major site location factors listed above and other secondary

factors, it is proposed that the site should be located in KENTSTOWN IN COUNTY

MEATH.

WHY KENTSTOWN?

Transport: Kentstown is about 47km from the Dublin seaport and 41km fron the Dublin

airport with easy road access to both the airport and the sea port through the N2,M2,

and M50

Proximity to both the raw materials supply and the market for the product

chemical: The source of raw materials for the proposed plant and the market for the

product are basically worldwide therefore Kentstown has the advantage of being close

to both the airport and the sea port.

Availability of Suitable Land and Price of land: Kentstown has a large expanse of

land that is already zoned for industrial development and the land is relatively cheap.

Appendix B

Labour: There is availability of unskilled labour for the construction of the site and also

cost of living is cheap

Utilities: This is readily available


12 PLANT LAYOUT

A plant layout can be defined as follows: Plant layout refers to the arrangement of

physical facilities such as machinery, equipment, furniture etc. within the factory building

in such a manner so as to have quickest flow of material at the lowest cost and with the

least amount of handling in processing the product from the receipt of material to the

shipment of the finished product. The overall objective of plant layout is to design a

physical arrangement that most economically meets the required output – quantity and

quality. Plant layout ideally involves allocation of space and arrangement of equipment

in such a manner that overall operating costs are minimized.

Plant layout is an important decision as it represents long-term commitment. An ideal

plant layout should provide the optimum relationship among output, floor area and

manufacturing process. It facilitates the production process, minimizes material

handling, time and cost, and allows flexibility of operations, easy production flow, makes

economic use of the building, promotes effective utilization of manpower, and provides

for employee’s convenience, safety, comfort at work, maximum exposure to natural light

and ventilation. It is also important because it affects the flow of material and processes,

labour efficiency, supervision and control, use of space and expansion possibilities etc.

An efficient plant layout is one that can be instrumental in achieving the following

objectives:

a) Proper and efficient utilization of available floor space

b) To ensure that work proceeds from one point to another point without any delay

c) Provide enough production capacity.

d) Reduce material handling costs m

e) Reduce hazards to personnel

f) Utilise labour efficiently

g) Increase employee morale

h) Reduce accidents

i) Provide for volume and product flexibility

j) Provide ease of supervision and control


k) Provide for employee safety and health

l) Allow ease of maintenance

m) Allow high machine or equipment utilization

n) Improve productivity

After the flow process diagrams are completed and before detailed piping, structural

and electrical design can begin, the layout of process units in a plant and the equipment

within these process unit must be planned. This layout can play an important part in

determining construction and manufacturing costs, and thus must be planned carefully

with attention being given to future problems that may arise.

12.1 Plant Layout Strategies

There are two schemes that can be adopted for determination of the plant layout. First,

the 'flow-through' layout (or 'flow-line pattern) where plant items are arranged

(sequentially) in the order in which they appear on the process flowsheet. This type of

arrangement usually minimises process pipe runs and pressure drops, and is often

adopted for small plants. Second, the equipment is located on site in groupings of

similar plant items, e.g. distillation columns, separation stages, reactors and heat

exchangers, etc. The grouped pattern is often used for larger plants and has the

advantages of easier operation and maintenance, lower labour costs, minimising utility

transfer lines and hence reducing the energy required to transfer materials. These two

schemes represent the extreme situations and in practice some compromise

arrangement is usually employed. The plant layout adopted depends upon whether a

new ('grass roots') plant is being designed or an extension/modification to an existing

plant. Space restrictions are the most common restraints on plants to be developed on

existing sites, however, space limitations are usually imposed even with new sites.

Thus the economic construction and efficient operation of a process unit will depend on

how well the plant and equipment specified on the process flow sheet is laid out. The

principal factors that are considered are listed below:

1. Economic considerations: construction and operating costs


2. Process requirements

3. Convenience of operation

4. Convenience of maintenance

5. Health and Safety considerations

6. Future plant expansion

7. Modular construction

8. Waste disposal requirements

Costs:

Adopting a layout that gives the shortest run of connecting pipe between equipment,

and least amount of structural steel work can minimize the coat of construction.

However, this will not necessarily be the best arrangement for operation and

maintenance.

Process Requirements:

An example of the need to take into account process consideration is the need to

elevate the base of columns to provide the necessary net positive suction head to a

pump.

Convenience of Operation:

Equipment that needs to have frequent attention should be located convenient to the

control room. Valves, sample points, and instruments should be located at convenient

positions and heights. Sufficient working space and headroom must be provided to

allow easy access to equipment.

Convenience of Maintenance:

Heat exchangers need to be sited so that the tube bundles can be easily withdrawn for

cleaning and tube replacement. Vessels that require frequent replacement of catalyst or

packing should be located on the out side of buildings. Equipment that requires

dismantling for maintenance, such as compressors and large pumps, should be places

under cover.


Health and Safety Considerations:

Blast walls may be needed to isolate potentially hazardous equipment, and confine the

effects of an explosion. At least two escape routes for operators must be provided from

each level in process buildings.

Future Plant Expansion:

Equipment should be located so that it can be conveniently tied in with any future

expansion of the process. Space should be left on pipe alleys for future needs, and

service pipes over-sized to allow for future requirements.

Modular Construction:

In recent years there has been a move to assemble sections of plant at the plant

manufacturer’s site. These modules will include the equipment, structural steel, piping

and instrumentation. The modules are then transported to the plant site, by road or sea.

The advantages of modular construction are:

1. Improved quality control

2. Reduced construction cost

3. Less need for skilled labors on site

The disadvantages of modular construction are:

1. Higher design costs & more structural steel work

2. More flanged constructions & possible problems with assembly, on site

THE PLANT LAYOUT KEYWORDS

1. Raw material Storage

2. Maintenance Workshop

3. Process Site

4. Stores for maintenance and operating supplies

5. Product Storage

6. Canteen & Change house

7. Fire Stations and Fire Brigade


7. Central Control Room

8. Security office

9. Administrative Building

10. Site for Expansion project

11. Effluent treatment plant

12. Power house

13. Emergency water storage

14. Plant utilities

15. Vehicle parking space

16. Library and Laboratories

17. Training Centre

18. Researches and Development Centre

19. Green Belt Area

A detailed plant layout is drawn.

Quality is never an accident, it is always the result of high intention, sincere

effort, intelligent direction and skilful execution; it represents the wise choice of

many alternatives’

William A Foster

13 THE NEED FOR GOOD MANUFACTURING PRACTICE

People prescribing or being prescribed a medicine have little chance of detecting if it is

faulty or not. People who take a medicine trust the doctor who wrote the prescription

and the pharmacist who dispensed it. The doctor and pharmacist in turn put their trust in

the manufacturer who has a fundamental role in ensuring that the medicine is fit for its

purpose and is safe to use.

Product testing of medicines on its own cannot ensure quality. This is because a lot of

testing is destructive; meaning only samples from a batch can be tested. GMP tries to


ensure that quality is built into the organisation and the processes involved in

manufacturing. The activities involved in achieving quality cover much more that the

manufacturing operations themselves. There must be clear written specifications for the

materials, the packaging and the products themselves. There must be clear written

instructions and procedures covering processing and testing, handling, storage, receipt

and dispatch. Suitable premises, equipment and trained staff must be specified and

made available

13.1 WHY IS GMP AND QUALITY IMPORTANT?

Good manufacturing practice (GMP) and Quality are important aspect of the

manufacture of pharmaceuticals because of the following reasons

1. Patients taking medicines have very little chance of detecting anything wrong

2. If it is wrong, there is significant potential for a disastrous effect

3. They are complex products and as such, the manufacture of pharmaceuticals

requires a special approach

We need both a Quality Assurance (QA) and a Good Manufacturing Practice (GMP)

approach because:

a) Considerable limitations to drug product testing

b) Considerable risks from a low number of defectives

c) Low probability of detection (until too late) by the patient

GMP has been defined as:


The part of quality assurance which ensures that products are consistently produced

and controlled in accordance with the quality standards appropriate to their intended

use and as required by the Marketing Authorisation or product specification

13.2 GMP REQUIREMENTS

The “Rules and Guidance for Pharmaceutical Manufacturers and Distributors” has nine

chapters, which have the following titles:

1. Quality Management

2. Personnel

3. Premises and Equipment

4. Documentation

5. Production

6. Quality Control

7. Contract Manufacture and Analysis

8. Complaints and Product Recall

9. Self Inspection

The key points from each of the chapters, which are particularly relevant to the

pharmaceutical industry, are listed below.

Quality Management

· The manufacturer must produce products that are fit for their intended use and do not

place patients at risk.


Senior management is responsible for product quality and safety but the

participation and commitment of staff is vital, as is the support of suppliers.

There must be a comprehensive and effectively implemented Quality Assurance

system, incorporating Good Manufacturing Practice and Quality Control.

The system should be fully documented and its effectiveness monitored.

All parts of the Quality Assurance system should be adequately resourced with

competent personnel and proper premises, equipment and facilities.

Personnel

A satisfactory system of Quality Assurance depends on people.

There must be sufficient qualified personnel to carry out the necessary tasks.

The responsibilities of individuals should be clearly understood and recorded.

All personnel should be aware of the principles of GMP.

All personnel should receive initial and continuing training, relevant to their

needs.

Premises and Equipment

Premises and equipment must be built and maintained to suit the operations

being carried out.

The layout and design must aim to minimise the risk of errors and permit

effective cleaning and maintenance.

Premises and manufacturing equipment should be cleaned according to

detailed written procedures.

The entry of unauthorised people should be prevented and production and

storage areas should not be used as a ‘right of way’.


Measuring, weighing, recording and control equipment should be calibrated

regularly.

Defective equipment should be removed if possible or labelled as defective if

not removed.

Documentation

Clearly written documentation prevents errors from spoken communication.

Specifications, instructions, procedures and records must be free from errors and

available in writing.

Documents should be unambiguous, have clear and concise contents, a title and

purpose.

Documents should be regularly reviewed and kept up to date.

Documents should not be hand-written (except for the entry of data).

Records should be completed in ink.

Any alteration to a record should be signed and dated with the original entry still

visible.

Production

Production activities must follow clearly defined procedures and should be

performed only by trained and competent people.

All materials and products should be stored under the appropriate conditions

and in an orderly fashion to permit batch segregation and stock rotation.

At each stage of processing, products and materials should be protected from

microbial and other contamination.


Any deviation from instructions or procedures should be avoided. However,

changes may be approved in writing by a competent person, with the

involvement of the Quality Department if possible.

Significant amendments to the manufacturing process, including any change in

equipment or materials which may affect product quality and/or reproducibility of

the process should be validated.

Validation studies should be conducted to demonstrate that the process,

equipment and/or activity actually leads to the expected results.

Quality Control

Quality Control is not confined to laboratory operations, but must be involved in

all decisions that may concern the quality of the product.

The independence of Quality Control from Production is considered

fundamental to the satisfactory operation of Quality Control.

Sampling of product should take place in accordance with written procedures.

Analytical methods should be validated.

Complaints and Product Recall

All complaints and other information concerning potentially defective products

must be reviewed carefully according to written procedures.

The person responsible for Quality Control should normally be involved in the

study of product defects.

There should be written recall procedures that are regularly checked and

updated where necessary.

Recall operations should be capable of being initiated promptly and at any time.

Self Inspection (Internal Audit)


Internal Audits should be conducted in order to monitor the implementation and

compliance with GMP.

Internal Audits should be conducted in an independent and detailed way by

designated competent persons.

PRACTICAL CONSIDERATIONS

In addition to the key aspects of the requirements that GMP imposes on us (listed

above), there are some practical aspects of GMP, which affect all staff working in

relevant areas.

Documentation

Most people dislike paperwork. Computers are taking over some of the work but we still

have lots of paper in use, which although a ‘nuisance’, helps to keep our products safe.

Documentation is needed to allow us to:

Define in advance what we are going to do.

Check that we have done what we should have done.

Keep records of information, results and actions taken.

Investigate problems.

There are a number of different types of document in use. Manufacturing and other

instructions are contained within Standard Operating Procedures (SOPs), which

describe specific tasks in a stepwise fashion, instructing staff what to do and if

necessary how to do it, although the how is mainly part of training and job skills.

Although often called ‘operating’ procedures, there are other SOPs which deal with

more general aspects of procedure such as validation, corrective action, quality

incidents, training and so on which are mostly used by managers and supervisors.

Specifications for products and how they are to be tested are contained in documents

such as the ‘Guidelines for the Blood Transfusion Service’ (i.e. the “Red Book”). We use


these specifications when we are developing our manufacturing methods and

particularly when drawing up our quality standards and test methods.

Labeling

We use labels for internal identification purposes and also to inform users about our

products and about the contents of the container to which the label is attached.

Labels are of vital importance. An incorrect label could lead to a disaster. There are

some rules regarding the use of labels:

They should always be held securely and not left lying around.

Always notify somebody if labels are seen to be coming detached or appear to

be incorrect or are in the wrong place.

Report any labels that are damaged or dirty.

Never remove a label which has been incorrectly applied and never stick a new

label over an old one of the same type.

Cleanliness

One of the requirements of GMP is to prevent contamination of products. Dust, particles

and dirt can contaminate products as can chemicals and micro-organisms. Dirt harbors

micro-organisms and that is why our workplaces must be really clean, not just looking

clean.

The air is one source of contamination as are insects such as flies. People are also a

source, which is why there are hygiene rules that must be followed. Key aspects of

these rules are to maintain a high standard of personal hygiene, wear protective

clothing as directed, never eat drink or smoke in work areas, keep your work areas

clean and tidy and be on the alert for possible sources of contamination.


Training

GMP ultimately depends on people. The individual skills and understanding of people

about their work can be developed by training. It is also important for product safety that

staff do not carry out tasks for which they have not been trained and which either they

or their supervisors think they are not competent to carry out. Training should be given

on both the theory and practice of the work being undertaken in a particular area, as

well as relevant ‘on -the-job’ (i.e. task-based) training. Records of this training must be

available.

13.3 GMP AND THE INDIVIDUAL

GMP concerns all people who work in areas where it applies, whether they are

managers, supervisors or staff. It also affects those ‘indirectly’ involved, in activities

such as maintenance, cleaning, record keeping and in ‘support’ areas such as the

quality and personnel departments, etc. Although people working in GMP areas can be

carrying out quite different tasks using different skills there are some basic rules which

can be generally applied.

Under GMP:

(a) all manufacturing processes are clearly defined, systematically reviewed

in the light of experience, and shown to be capable of consistently

manufacturing pharmaceutical products of the required quality that comply

with their specifications

(b) qualification and validation are performed

(c) all necessary resources are provided, including:

(i) appropriately qualified and trained personnel

(ii) adequate premises and space

(iii) suitable equipment and services


(iv)appropriate materials, containers and labels

(v) approved procedures and instructions

(vi)suitable storage and transport

(vii) adequate personnel, laboratories and equipment for in-

process controls

(d) instructions and procedures are written in clear and unambiguous

language, specifically applicable to the facilities provided

(e) operators are trained to carry out procedures correctly

(f) records are made (manually and/or by recording instruments) during

manufacture to show that all the steps required by the defined procedures

and instructions have in fact been taken and that the quantity and quality

of the product are as expected; any significant deviations are fully

recorded and investigated

(g) records covering manufacture and distribution, which enable the complete

history of a batch to be traced, are retained in a comprehensible and

accessible form

(h) the proper storage and distribution of the products minimizes any risk to

their quality

(i) a system is available to recall any batch of product from sale or supply

(j) complaints about marketed products are examined, the causes of quality

defects investigated, and appropriate measures taken in respect of the

defective products to prevent recurrence.


Basic Rules of GMP

Here is a list of the basic rules, required by GMP:

1. Make sure you have the correct written instructions before starting a task.

2. Do not carry out a task for which you have not been trained or in which you do

not feel competent.

3. Always follow instructions precisely. Do not cut corners. If in doubt, ask.

4. Check that the equipment and the materials that you are using are the correct

ones, as stated in the procedure.

5. Check that the equipment you are using is clean.

6. Always be on your guard for labelling errors.

7. Keep everything clean and tidy (including yourself!).

8. Always be on the look out for mistakes, defects and unusual events. Report them

immediately.

9. Make clear accurate records of what was done and the checks carried out.

Ultimately quality depends on people. Although processes get more automated there

are still many activities which require the constant care and attention of staff.

14 QUALITY

INTRODUCTION

Quality is not created spontaneously. It is designed and manufactured: It has its own

sources. A somewhat elusive concept, quality is difficult to define and easy to perceive.


This combination of traits obscures the study of factors that help to discover, produce,

and distribute quality products and services. Quality is not just the result of will. It

requires systems and processes to make it consistently viable.

QUALITY DIMENSIONS FOR A PHARMACEUTICAL PRODUCT

Quality is a complex concept, made up of diverse elements. In this section we break

down the concept while applying it to pharmaceutical product, creating eight

dimensions, classified in three different categories, as shown

A. QUALITY FROM THE PRODUCT VIEWPOINT

1. Performance

2. Secondary features

3. Durability

B. QUALITY FROM THE PATIENT VIEWPOINT

4. Aesthetics

5. Perceived quality

6. Service

C. QUALITY FROM THE PROCESS VIEWPOINT

7. Conformance

8. Reliability

Performance

Performance deals with the basic characteristics of a product or service. For a

medicine, its selective therapeutic action is a fundamental characteristic of performance;


other performance characteristics are the degree of counter-productive effects the

product presents and the adverse interactions in which the drug participates. These

characteristics or performance components can be objectively measured.

Secondary features

By secondary features we mean aspects that complement basic functions of a product

or service. Easiness to provide the required drug amount to the patient, the degree of

risk of alterations in the drug, and the possibility that the drug has to substitute other

more expensive alternatives can all be considered secondary features or features.

Secondary features are a dynamic concept that evolves with time. For instance, in

diabetes treatment, ambulatory treatment was for many years a secondary feature,

while today it is a performance characteristic.

Durability

The durability dimension relates to the period that can elapse between the moment a

product is manufactured and the moment it is consumed. This period is in practice

limited by the expiration date printed on the package. Since products such as food,

drinks and medicines end their useful life a short time after consumption, the analysis of

durability does not present technical or economic complexity, as is the case with

products that deteriorate partially or gradually, or those that can be fixed when broken.

Aesthetics

Aesthetics is by etymology a word related to perception by human senses. Thus taste

and odour of a medicine and the visual attractiveness of a package are aesthetics

components of a pharmaceutical product. To a large extent, these components are

subjective, although there is usually a great deal of opinion agreement about them ix.

Hygienic aspect is another component of the aesthetics dimension.

Perceived quality

Perceived quality is an indirect comparative dimension. Given the complexities of

judging the quality of a pharmaceutical product, the public and, to some extent, the


medical profession, base their impressions on indirect signals. Drug originality and

immediate effect of a medicine are aspects of perceived quality, among others.

Service

A product cannot claim great quality if it is not available at drugstores and other points

of sale, or if interested parties cannot obtain clear, easy to read information on the

product and its effects. Thus, product availability at pharmacies and ample distribution

of information on the part of laboratories constitute a dimension we label “service.”

Conformance

Conformance is the degree of adherence of the design and manufacture of a product to

accepted industrial standards. In the case of pharmaceutical tablets, for example,

conformance measures the presence of cracks and the correspondence between the

quantities of tablets declared in the package and its real content. Unlike aesthetics or

perceived quality, conformance is a dimension that can be objectively measured.

Reliability

Reliability is the dimension that creates in the client the mental state of security about

the properties and effects of a medicine. The absence of adverse effects of components

and the correspondence between dose declared in the package and its real contents fall

under this dimension.

THE SOURCES OF QUALITY

Generally speaking, the sources of quality of a pharmaceutical product are found as

much in the policies and attitudes towards quality exhibited by management and

personnel as in the characteristics of the laboratory’s R&D processes, product design,

supplier selection and management, operations management and human resource

management.

More specifically, the GMP (Good Manufacturing Practices) standards and the GLP

(Good


Laboratory Practices) standards are quality sources in the pharmaceutical industry.

Finally, in an even more specific sense, it is possible to detect “specific sources”

corresponding to different quality dimensions of a pharmaceutical product. Let us look at

some of these specific sources.

Sources of performance

Effective therapeutical action of a drug is, in a fundamental sense, a function of the R&D

laboratory activity. The laboratory invents the product, defines production technology,

identifies adverse reactions that could cause quality problems or performance reduction,

collects data to design the manufacturing plant, and establishes control parameters

based on theoretical considerations on where, when, and how to perform the control

process. Likewise, minimal contraindications are searched through the R&D work.

Sources of secondary features

Just like performance, secondary features derive from the R&D laboratory, but in more

advanced stages of the R&D work; at these stages, pharmaceutical presentations that

are more convenient for the patient are sought.

Quality & GMP - Where does it come from?

Sources of durability

Medicine durability is associated with aspects such as packaging (which protect the

product against contamination and excessive heat, light or humidity) and

pharmaceutical formulae. Durability of a medicine is born at the development stage of

the pharmaceutical form, when drug characteristics as a function of time and its effect

on the human organism are studied. In addition, durability depends on the degree of

observance of manufacturing conditions, the type of equipment used in each

manufacturing country, logistics, and other factors.

Sources of aesthetics quality

To some extent, quality in its aesthetics dimension is obtained by rigorously applying

the GMP standards, by providing good training and work habit formation, by achieving


hygiene in all processes, by having permanent control of supplies and even by insuring

good personal appearance in the laboratory sales force.

Sources of perceived quality

As we mentioned above, indirect signals such as the quality of publicity, which over time

creates brand image is a source of perceived quality. The country of origin effect also

contributes to the perception of a product qualityx. Drug originality, especially when it is

promoted through the mass media and immediate effect (without adverse symptoms) of

a medicine are further aspects of perceived quality. Likewise, the laboratory history and

the quality of information delivered to doctors, pharmacists, and other stages of the

health care chain integrate the perceived quality dimension.

For these reasons, institutional marketing is a major source of the perceived quality

dimension. Communication components in marketing play a central role in shaping the

laboratory image and its brand image. However, in the long run a good marketing

approach is not enough if the company products are not valuable. For this reason, drug

suppliers are a key source of quality; in particular, the origin certificates of the supplies

enhance perceived quality among the pharmaceutical profession.

Sources of service quality

To a great extent, service quality is a consequence of customer-oriented logistics. A

good sales forecasting system, for example, can contribute to improve availability at

pharmacies of the laboratory products, thus enhancing service quality. In principle, the

marketing strategy of the firm, and the larger or shorter time horizon it defines in its

relationship with clients will shape service logistics.

Sources of conformance

The manufacturing process, in particular, respect for manufacturing standards, is at the

roots of conformance. Manufacturing for conformance requires respect for tolerance of

mix proportions and observance of master specifications of components and final

products.


Sources of reliability

GMP and GLP standards, if correctly applied, are the basis of reliability; when GMP and

GLP are implemented, robust quality assurance systems operate to increase reliability.

These systems must be well designed, implemented and controlled, and adequate

personnel and equipment are required in order to get quality objectives.

In respect to pharmaceuticals, quality can be describes as ‘fitness for purpose’

It is the correct product

It is the correct strength or purity

It is free from contamination

It has not adversely deteriorated

It is correctly labelled and in the correct container

It is correctly stored

QUALITY MANAGEMENT IN THE DRUG INDUSTRY

In the drug industry at large, quality management is usually defined as the aspect of

management function that determines and implements the “quality policy”, i.e. the

overall intention and direction of an organization regarding quality, as formally

expressed and authorized by top management. The basic elements of quality

management are:

An appropriate infrastructure or “quality system”, encompassing the

organizational structure, procedures, processes and resources;


Systematic actions necessary to ensure adequate confidence that a product

(or service) will satisfy given requirements for quality. The totality of these

actions is termed “quality assurance”.

Within an organization, quality assurance serves as a management tool. In contractual

situations, quality assurance also serves to generate confidence in the supplier. The

concepts of quality assurance, GMP and quality control are interrelated aspects of

quality management. They are described here in order to emphasize their relationship

and their fundamental importance to the production and control of pharmaceutical

products.

Quality assurance

“Quality assurance” is a wide-ranging concept covering all matters that individually or

collectively influence the quality of a product. It is the totality of the arrangements made

with the object of ensuring that pharmaceutical products are of the quality required for

their intended use. Quality assurance therefore incorporates GMP and other factors,

including those outside the scope of this guide such as product design and

development.

The system of quality assurance appropriate to the manufacture of pharmaceutical

products should ensure that:

a) pharmaceutical products are designed and developed in a way that takes

account of the requirements of GMP and other associated codes such as

those of good laboratory practice (GLP) and good clinical practice (GCP)

b) production and control operations are clearly specified in a written form and

GMP requirements are adopted

c) managerial responsibilities are clearly specified in job descriptions

d) arrangements are made for the manufacture, supply and use of the correct

starting and packaging materials


e) all necessary controls on starting materials, intermediate products, and bulk

products and other in-process controls, calibrations, and validations are

carried out

f) the finished product is correctly processed and checked, according to the

defined procedures

g) pharmaceutical products are not sold or supplied before the authorized

persons have certified that each production batch has been produced and

controlled in accordance with the requirements of the marketing authorization

and any other regulations relevant to the production, control and release of

pharmaceutical products

h) satisfactory arrangements exist to ensure, as far as possible, that the

pharmaceutical products are stored by the manufacturer, distributed, and

subsequently handled so that quality is maintained throughout their shelf-life

i) there is a procedure for self-inspection and/or quality audit that regularly

appraises the effectiveness and applicability of the quality assurance system

j) deviations are reported, investigated and recorded

k) there is a system for approving changes that may have an impact on product

quality

l) regular evaluations of the quality of pharmaceutical products should be

conducted with the objective of verifying the consistency of the process and

ensuring its continuous improvement.

The manufacturer must assume responsibility for the quality of the pharmaceutical

products to ensure that they are fit for their intended use, comply with the requirements

of the marketing authorization and do not place patients at risk due to inadequate

safety, quality or efficacy. The attainment of this quality objective is the responsibility of

senior management and requires the participation and commitment of staff in many

different departments and at all levels within the company, the company’s suppliers, and


the distributors. To achieve the quality objective reliably there must be a

comprehensively designed and correctly implemented system of quality assurance

incorporating GMP and quality control. It should be fully documented and its

effectiveness monitored. All parts of the quality assurance system should be adequately

staffed with competent personnel, and should have suitable and sufficient premises,

equipment, and facilities.

Complaints

The person responsible for handling complaints and deciding on the measures to be

taken to deal with them should have appropriate training and/or experience in the

specific features of the quality control of pharmaceutical products. There are basically

two types of complaint, product quality complaints and adverse reactions/events.

The first type of complaint may be caused by problems such as faulty manufacture,

product defects or deterioration as well as, particular to herbal medicines, adulteration

of the herbal material. These complaints should be recorded in detail and the causes

thoroughly investigated (e.g. by comparison with the reference samples kept from the

same batch). There should also be written procedures to describe the action to be

taken.

To address the second type of complaint, reports of any adverse reaction/ event should

be entered in a separate register in accordance with national and international

requirements. An investigation should be conducted to find out whether the adverse

reaction/event is due to a quality problem and whether such reactions/events have

already been reported in the literature or whether it is a new observation. In either case,

complaint records should be reviewed regularly to detect any specific or recurring

problems requiring special attention and possible recall of marketed products.

The licensing authority should be kept informed of any complaints leading to a recall or

restriction on supply and the records should be available for inspection.


1) All complaints and other information concerning potentially defective

products should be carefully reviewed according to written procedures

and the corrective action should be taken.

2) A person responsible for handling the complaints and deciding the

measures to be taken should be designated, together with sufficient

supporting staff to assist him or her. If this person is different from the

authorized person, the latter should be made aware of any complaint,

investigation or recall.

3) There should be written procedures describing the action to be taken,

including the need to consider a recall, in the case of a complaint

concerning a possible product defect.

4) Special attention should be given to establishing whether a complaint

was caused because of counterfeiting.

5) Any complaint concerning a product defect should be recorded with all

the original details and thoroughly investigated. The person

responsible for quality control should normally be involved in the

review of such investigations.

6) If a product defect is discovered or suspected in a batch,

consideration should be given to whether other batches should be

checked in order to determine whether they are also affected. In

particular, other batches that may contain reprocessed product from

the defective batch should be investigated.

7) Where necessary, appropriate follow-up action, possibly including

product recall, should be taken after investigation and evaluation of

the complaint.

8) All decisions made and measures taken as a result of a complaint

should be recorded and referenced to the corresponding batch

records.


9) Complaints records should be regularly reviewed for any indication of

specific or recurring problems that require attention and might justify

the recall of marketed products.

10)The competent authorities should be informed if a manufacturer is

considering action following possibly faulty manufacture, product

deterioration, counterfeiting or any other serious quality problems with

a product.

Product recalls and returned goods

Product recall is a process for withdrawing or removing a pharmaceutical product from

the pharmaceutical distribution chain because of defects in the product or complaints of

serious adverse reactions to the product. The recall might be initiated by the

manufacturer/importer/distributor or a responsible agency.

1) There should be a system to recall from the market, promptly and

effectively, products known or suspected to be defective.

2) The authorized person should be responsible for the execution and

coordination of recalls. He/she should have sufficient staff to handle all

aspects of the recalls with the appropriate degree of urgency.

3) There should be established written procedures, which are regularly

reviewed and updated, for the organization of any recall activity.

Recall operations should be capable of being initiated promptly down

to the required level in the distribution chain.

4) An instruction should be included in the written procedures to store

recalled products in a secure segregated area while their fate is

decided.

5) All competent authorities of all countries to which a given product has

been distributed should be promptly informed of any intention to recall

the product because it is, or is suspected of being, defective.


6) The distribution records should be readily available to the authorized

person, and they should contain sufficient information on wholesalers

and directly supplied customers (including, for exported products,

those who have received samples for clinical tests and medical

samples) to permit an effective recall.

7) The progress of the recall process should be monitored and recorded.

Records should include the disposition of the product. A final report

should be issued, including a reconciliation between the delivered and

recovered quantities of the products.

8) The effectiveness of the arrangements for recalls should be tested

and evaluated from time to time.

9) Recalled products should be identified and stored separately in a

secure area until a decision is taken on their fate. The decision should

be made as soon as possible.

10)Products returned from the market should be destroyed unless it is

certain that their quality is satisfactory; in such cases they may be

considered for resale or relabelling, or alternative action taken only

after they have been critically assessed by the quality control function

in accordance with a written procedure. The nature of the product, any

special storage conditions it requires, its condition and history, and the

time elapsed since it was issued should all be taken into account in

this assessment. Where any doubt arises over the quality of the

product, it should not be considered suitable for reissue or reuse. Any

action taken should be appropriately recorded.


QUALITY CONTROL

Quality control is an essential operation of the pharmaceutical industry. Drugs must be

marketed as safe and therapeutically active formulations whose performance is

consistent and predictable. New and better medicinal agents are being produced at an

accelerated rate. At the same time more exacting and sophisticated analytical methods

are being developed for their evaluation.

Quality control is the part of GMP concerned with sampling, specifications and testing,

and with the organization, documentation and release procedures which ensure that the

necessary and relevant tests are actually carried out and that materials are not released

for use, nor products released for sale or supply, until their quality has been judged to

be satisfactory. Quality control is not confined to laboratory operations but must be

involved in all decisions concerning the quality of the product.

The independence of quality control from production is considered fundamental.

Each manufacturer (the holder of a manufacturing authorization) should have a quality

control function. The quality control function should be independent of other

departments and under the authority of a person with appropriate qualifications and

experience, who has one or several control laboratories at his or her disposal. Adequate

resources must be available to ensure that all the quality control arrangements are

effectively and reliably carried out. The basic requirements for quality control are as

follows:

(a) adequate facilities, trained personnel and approved procedures must be

available for sampling, inspecting, and testing starting materials,

packaging materials, and intermediate, bulk, finished products, and where

appropriate for monitoring environmental conditions for GMP purposes

(b) samples of starting materials, packaging materials, intermediate products,

bulk products and finished products must be taken by methods and

personnel approved of by the quality control department

(c) qualification and validation must be performed


(d) records must be made (manually and/or by recording instruments)

demonstrating that all the required sampling, inspecting and testing

procedures have actually been carried out and that any deviations have

been fully recorded and investigated

(e) the finished products must contain ingredients complying with the

qualitative and quantitative composition of the product described in the

marketing authorization; the ingredients must be of the required purity, in

their proper container and correctly labeled

(f) records must be made of the results of inspecting and testing the

materials and intermediate, bulk and finished products against

specifications product assessment must include a review and evaluation

of the relevant production documentation and an assessment of deviations

from specified procedures

(g) no batch of product is to be released for sale or supply prior to certification

by the authorized person(s) that it is in accordance with the requirements

of the marketing authorization. In certain countries, by law, the batch

release is a task of the authorized person from production together with

the authorized person from quality control

(h) sufficient samples of starting materials and products must be retained to

permit future examination of the product if necessary; the retained product

must be kept in its final pack unless the pack is exceptionally large.

Quality control as a whole will also have other duties, such as to establish, validate and

implement all quality control procedures, to evaluate, maintain, and store the reference

standards for substances, to ensure the correct labeling of containers of materials and

products, to ensure that the stability of the active pharmaceutical ingredients and

products is monitored, to participate in the investigation of complaints related to the

quality of the product, and to participate in environmental monitoring. All these

operations should be carried out in accordance with written procedures and, where

necessary, recorded.


Assessment of finished products should embrace all relevant factors, including the

production conditions, the results of in-process testing, the manufacturing (including

packaging) documentation, compliance with the specification for the finished product,

and an examination of the finished pack.

Quality control personnel must have access to production areas for sampling and

investigation as appropriate.

Control of starting materials and intermediate, bulk and finished products

1. All tests should follow the instructions given in the relevant written test procedure

for each material or product. The result should be checked by the supervisor

before the material or product is released or rejected.

2. Samples should be representative of the batches of material from which they are

taken in accordance with the approved written procedure.

3. Sampling should be carried out so as to avoid contamination or other adverse

effects on quality. The containers that have been sampled should be marked

accordingly and carefully resealed after sampling.

4. Care should be taken during sampling to guard against contamination or mix-up

of, or by, the material being sampled. All sampling equipment that comes into

contact with the material should be clean. Some particularly hazardous or potent

materials may require special precautions.

5. Sampling equipment should be cleaned and, if necessary, sterilized before and

after each use and stored separately from other laboratory equipment.

6. Out-of-specification results obtained during testing of materials or products

should be investigated in accordance with an approved procedure. Records

should be maintained.

7. Each sample container should bear a label indicating:


i the name of the sampled material

ii the batch or lot number

iii the number of the container from which the sample has been taken

iv the number of the sample

v the signature of the person who has taken the sample

vi the date of sampling.

Test requirements for Starting and packaging materials

Before releasing a starting or packaging material for use, the quality control manager

should ensure that the materials have been tested for conformity with specifications for

identity, strength, purity and other quality parameters.

An identity test should be conducted on a sample from each container of starting

material. It is permissible to sample only a proportion of the containers where a

validated procedure has been established to ensure that no single container of starting

material has been incorrectly labeled.

This validation should take account of at least the following aspects:

— the nature and status of the manufacturer and of the supplier and their

understanding of the GMP requirements

— the quality assurance system of the manufacturer of the starting material

— the manufacturing conditions under which the starting material is produced and

controlled and

— the nature of the starting material and the medicinal products in which it will be

used.


Under such a system it is possible that a validated procedure for exemption from the

requirement for identity testing of each incoming container of starting material could be

accepted for the following:

— starting materials coming from a single product manufacturer or plant or

— starting materials coming directly from a manufacturer, or in the manufacturer’s

sealed container where there is a history of reliability, and regular audits of the

manufacturer’s quality assurance system are conducted by the purchaser (the

manufacturer of the medicinal product) or by an officially accredited body.

It is improbable that such a procedure could be satisfactorily validated for either:

— starting materials supplied by intermediaries, such as brokers, where the source

of manufacture is unknown or not audited or

— starting materials for use in parenteral products.

Each batch (lot) of printed packaging materials must be examined following receipt. In

lieu of testing by the manufacturer, a certificate of analysis may be accepted from the

supplier, provided that the manufacturer establishes the reliability of the supplier’s

analysis through appropriate periodic validation of the supplier’s test results and through

on-site audits of the supplier’s capabilities. Certificates must be originals (not

photocopies) or otherwise have their authenticity assured. Certificates must contain at

least the following information:

(a) identification (name and address) of the issuing supplier

(b) signature of the competent official, and statement of his or her

qualifications

(c) the name of the material tested

(d) the batch number of the material tested

(e) the specifications and methods used


(f) the test results obtained

(g) the date of testing.

In-process control

In-process control records should be maintained and form a part of thebatch records.

Finished products

For each batch of drug product, there should be an appropriate laboratory determination

of satisfactory conformity to its finished product specification prior to release. Products

failing to meet the established specifications or any other relevant quality criteria should

be rejected.

Batch record review

Production and quality control records should be reviewed as part of the approval

process of batch release. Any divergence or failure of a batch to meet its specifications

should be thoroughly investigated. The investigation should, if necessary, extend to

other batches of the same product and other products that may have been associated

with the specific failure or discrepancy. A written record of the investigation should be

made and should include the conclusion and follow-up action. Retention samples from

each batch of finished product should be kept for at least one year after the expiry date.

Finished products should usually be kept in their final packaging and stored under the

recommended conditions. If exceptionally large packages are produced, smaller

samples might be stored in appropriate containers. Samples of active starting materials

should be retained for at least one year beyond the expiry date of the corresponding

finished product. Other starting materials (other than solvents, gases, and water) should

be retained for a minimum of two years if their stability allows. Retention samples of

materials and products should be of a size sufficient to permit at least two full re-

examinations.


Stability studies

Quality control should evaluate the quality and stability of finished pharmaceutical

products and, when necessary, of starting materials and intermediate products. Quality

control should establish expiry dates and shelf-life specifications on the basis of stability

tests related to storage conditions. A written programme for ongoing stability

determination should be developed and implemented to include elements such as:

(a) a complete description of the drug involved in the study

(b) the complete set of testing parameters and methods, describing all

tests for potency, purity, and physical characteristics and

documented evidence that these tests indicate stability

(c) provision for the inclusion of a sufficient number of batches

(d) the testing schedule for each drug

(e) provision for special storage conditions

(f) provision for adequate sample retention

(g) a summary of all the data generated, including the evaluation and

the conclusions of the study.

Stability should be determined prior to marketing and following any significant changes

in processes, equipment, packaging materials, etc.


15 Organisational Structure

15.1 Overall Company Structure

Figure 12 Overall company structure


15.2 Primary Processing Unit

Figure 13 Primary Processing Unit


Manufacturing Operations Manufacturing Support

Figure 14 Manufacturing Operations & Support


Services / utilities

Engineering

Figure 15 Engineering


Technical Services

Figure 16 Technical Services


Quality

Figure 17 Quality


Facilities

Figure 18 Facilities


Environmental, Health & Safety

Figure 19 Environmental, Health & Safety


Training Supply Chain

Figure 20 Training & Development Supply Chain


15.3 Secondary Process Unit Human resources

Figure 21 Human Resources


Regulatory Affairs

Figure 22 Regulatory Affairs


Sales & Marketing Information Systems

Figure 23 Sales & Marketing Figure 24 Information Systems


Finance

Figure 25 Finance


15.4 Research & Development

Figure 26 Research & Development


15.5 Site Leadership Team


Figure27 Site Leadership Team

15.6 Project Organisation

Figure 28 Project organisation


15.7 Start-up Team

Figure 29 Start-up Team


15.8 Shutdown Team

Figure 30 Shutdown Team


16 10 Company Philosophy

16.1 Introduction

As one of the current market leaders in the pharmaceutical and healthcare

industry we recognize that the needs of our society are changing at an ever

increasing pace. We strive to adapt to these evolving needs and to contribute

to the overall health of our world.

At Green Field we continually review and make every effort to reduce our

impact on the environment. We recognize the need for a workplace of

diversity and inclusion, a workplace that values teamwork but also rewards

outstanding individual efforts.

We make every possible effort to conduct responsible business practices,

and carry out the company's business in a legal, ethical and socially

responsible manner.

16.2 Mission & Vision

Green Fields Mission

Our mission is to achieve better health for humanity as a whole, by producing

products that improve lives in a safe, ethical and environmentally friendly way.

Green Fields Vision

We aim to become a major contributor to human health throughout the world by

developing superior pharmaceutical products


16.3 Staff

Management Approach

At Green Fields our management staff empower those around them, by rewarding

outstanding team and individual efforts. Working together to achieve common

goals is the foundation of our success. Our management team leads by example,

taking pride in their work, and by doing so are able to achieve difficult goals by

inspiring and motivating others. It is only by maximising the capability of our work

force that we ensure our future as one of the world’s strongest pharmaceutical

manufacturers.

We value our diversity and our policy of inclusion enables us to create a workplace

where each of our employees is free to reach their maximum potential. We have

put all of the necessary steps in place to ensure that all employees are fairly

evaluated and rewarded for the results they achieve.

In addition, the company has put management systems in place to address any

issues relating to:

Staff health and safety

Contractors

Suppliers

Employee development

Environmental protection

Reporting Structure


We operate a multi level tiered reporting structure that emphasises communication

and re-enforces the company’s objectives. A two-way reporting structure has been

set out in order to allow feedback to be passed back up the line. This is an integral

cornerstone of our structure, and is one which encourages communication,

development and inclusion.

Our ultimate aim of the reporting structure is to oversee and guide employees

without constraining them or dampening their initiative.

Contractors & Suppliers

At Green Fields when we work with contractors and suppliers we always ensure

that we do business with people of the highest levels of quality, expertise, and

experience. We expect our contractors and suppliers to comply with all legal and

regulatory requirements for the workplace, including health and safety and

diversity.

We sub-contract some utilities such as catering, cleaning, security and facilities

(HVAC). In additional to this we also have a number of manufacturing staff that

work under contract. These contracts are based on changes in production quantity,

new product implementation, and facility expansion.

Employee Development

We recognise that our most important resource is our staff, and we are committed

to further developing the skills and talents of all of our employees. We provide an

infrastructure in which they can grow and where they are encouraged to display

their abilities to the fullest extent. We have created a culture of continuous learning

that places a high value on innovation, teamwork and effective leadership.


We have many resources available to all staff members to help facilitate them in

their career development. These learning and development programs range from

traditional classroom training that is administered on-site to online self-paced

courses and external professional development programs. We also encourage staff

to go back to education part-time and reimburse a portion of their college or

university fees after successful completion of their chosen course.

Benefits

At Green Fields we recognise the importance of flexibility in our work environment.

We offer a wide variety of competitive benefits, services and programs in order to

provide our employees with the resources that they might need to achieve their

goals, both in the workplace and in their personal lives.

As well as the employee development program outlined previously, we have a

structure in place that enables our employees to enhance their financial well-being.

This includes benefits such as retirement / pension plans, financial planning

services, bonuses, healthcare, life insurance, and a credit union facility.

We also offer our employees benefits such as flexible work arrangements, crèche

facilities, holidays, and leaves of absence.

16.4 Environment

Green Fields is committed to protecting the environment and the health and safety

of our employees, contractors, customers, and the public by conducting our

business in a safe and environmentally sustainable manner. We recognise the

importance of energy reduction, waste minimization and water conservation. Our

aim is not just to comply with environmental regulations but to surpass and

continually better them.


We work closely with the environmental protection agency (EPA) on issues such

as, air emissions, waste-water, noise and other important areas of environmental

impact. We are committed to complying with all applicable requirements and

regulations and conduct regular evaluations to monitor our environmental health

and safety performance.

We integrate fundamental principles of resource conservation into our business

processes, facilities, operations, and products. In addition, at Green Fields we work

closely with our business partners to support responsible environmental health and

safety practices among our suppliers, contractors, and customers. We have a

dedicated EHS team and all staff undergoes educational programs and training

which develops their understanding of best practices relating to environmental

issues.

16.5 Budget

To ensure the competitiveness and economic health of our company, we strive to

continually identify optimal resource levels for each of our operations. At times we

have the need to expand our resources, in order to develop our business needs. In

other economic times we need to decrease our resources in order to keep

competitive in a contracting marketplace.

At Green Fields, we regularly assess the effectiveness of our organisational

functions and amend out budgets accordingly. This process includes evaluation of

resources such as, wealth and assets, staffing, and product licensing.


We have a responsibility to our customers, to keep our product as affordable as

possible, and the responsibility to our shareholders, to maintain our dominance in

the marketplace, and overall economic health.

17 Safety

17.1 Safety Philosophy

At Green Fields, employee health and safety are among our highest priorities. Our

long-term vision is to eliminate work-related injuries and illnesses as much as

possible.

Section 20 of the Safety, Health and Welfare at Work Act 2005 requires that an

organisation produce a written programme to safeguard:

the safety and health of employees while they work

the safety and health of other people who might be at the workplace,

including customers, visitors and members of the public

In accordance with this, we have put in place measures to ensure to the upmost

degree, the health and safety of every person that may come into contact with any

of our workplace facilities. Furthermore, we have chosen a safety statement that

represents our commitment to health and safety.

17.2 Safety Statement

Our objective is to ensure to the utmost degree, the health and safety of all of our

employees, by providing them with a safe and healthy work environment. We also

make it our responsibility to provide our customers, contractors and members of

the public with the same duty of care that we give to our staff.


Our policy is to maintain our property as a safe and healthy work environment for

all our employees and others who may be affected by our operations. We

guarantee the selection of competent people, equipment and materials. Our work

operations are carried out with the highest regard for health and safety, and the

greatest care has been given to the goods and services that we provide to our

customers.

We ensure that the contents of this safety statement are brought to the attention of

all employees, contractors and visitors at each of our facilities.

17.3 Maintaining a Safe Work Environment

Section 8 of the Safety, Health and Welfare at Work Act (2005) imposes a general

duty on employers to ensure, in so far as is reasonably practicable, the safety at

work of all their employees to include the provision of:

A safe place of work.

Safe means of access and egress.

Safe plant and machinery.

Safe systems of work.

Appropriate information, instruction, training and supervision.

Suitable protective clothing and equipment, where hazards cannot be

controlled or eliminated.

A competent person to advise and assist in securing safety of employees

where necessary.

The facility for pregnant and nursing mothers to rest.

Other duties include:


The preparation and revision of emergency plans

The prevention of risks to health from any article or substance, including

plant, machinery and equipment.

The provision and maintenance of facilities and arrangements for the

welfare of employees, where necessary.

*(1) PSI safety statement 2009

In accordance with this, Green Fields provide the necessary resources to ensure

each place of work is safe and healthy. We ensure safety factors are taken into

account in the operation and maintenance of the buildings, plant and equipment

and our health and safety specialists carry out hazard audits on each of these

areas. Where necessary, we provide appropriate protective clothing and equipment

to our employees.

17.4 Safety Training

In accordance with the Safety, Health and Welfare at Work Act, all instruction,

training and supervision is provided in a manner, form and language that is

reasonably likely to be understood. Training is continuously adapted to take

account of new or changed risks in the workplace.

Training is provided to all staff:

On recruitment

When an employee is transferred or tasks change

On the introduction of new or changed work equipment or work systems

On the introduction of new technology


All contractors etc, carrying out work in the employer‘s premises will receive all

relevant safety instructions.

17.5 Hazardous Process Safety

Examples of Hazardous Processes Are:

Vessels (Pressurized)

Plant steam (60psi, 150C)

Clean steam (20-30psi)

WFI (Water for Injection)

Compressed air (95-105psi)

CIP systems (~100psi, ~80C, CORROSIVE)

Solution transfer lines

Oxygen and nitrogen gas (& cylinders)

Possible Hazards:

Impact from a blast or release of compressed liquid or gas

Traumatic injury from flying parts

Burns from the release of hot liquid or gasses

Contact with released liquid or gas (chemical burns)

Fire resulting from the escape of flammable liquid or gas (e.g. ethyl alcohol

or oxygen leaks)

Projectile hazards:

Unsecured gauges, valves, and probes can become “bullets” shot from tank

penetrations

Double check tightness before adding pressure

Relieve pressure before disassembling by Venting


- Hoses Drain Systems

- Process Components

- Sampling Points

Flailing Hoses:

Pressurised Hose connection that fails will flail.

Double Check tri-clamp connection before adding pressure to hose.

Routinely check the condition of hoses for any signs of bulging or failure.

A whipping line can break bones and damage equipment,

If the line gets free leave the area immediately and shut off flow to the line.

Never attempt to grab a whipping Line or Hose.

Flexible hosing should be kept as short as possible

Temperature burns and scalds:

Hot WFI at 85 Degrees C

Clean Steam at 145 Degrees C

Both at Pressures between 6 Bar and 1.2 Bar.

High Risk of Scald injury from hot spray or leak.

High risk of Burns from surface of hot pipe work or adjacent hot equipment.

*(2) Facility Design & Operation

17.6 Efforts to Eliminate Workplace Hazards


Slips, Trips and Falls

Cables: All trailing cables should be eliminated where possible by using cable

managed furniture and locating work positions at suitable floor and wall outlets.

Where this cannot be arranged, cables must be kept to an absolute minimum and

taped to adjoining surfaces. Matting may be used to cover trailing cables on floors.

Doors: Automatic doors must be maintained to ensure that safety features function

correctly.

Revolving doors must be checked regularly to ensure ease of movement.

Automatic door closers should function in such a way as to close doors without

undue force.

Glass Doors and Windows: All glass doors and certain windows should be

clearly marked by brightly coloured stripes or dots to make them clearly visible.

Mats: Care must be exercised when using mats to ensure the edges do not curl.

Mats must be property positioned at all times. Where countersunk frames are

provided, the mat and frame must be flush with the floor surface. Mats which are

uneven and frayed must be disposed of.

Ramps, stairways, passageways and landings, including in particular fire

exits: Handrails must be fitted on all stairways exceeding 1.8 metres in width.

Steps must be maintained in good condition. Where possible, the edge of all steps

must be clearly marked. Handrails must be fitted on all ramps and the surfaces of

these ramps must be covered with non-slip materials. Under no circumstances are

objects to be stored in these areas.

Floor box outlets, service duct/manhole covers: Where floor box outlets exist,

desks should be placed over them where possible to prevent accidental tripping.


Manhole covers, service duct covers and floorboards must be maintained flush

with surrounding surfaces.

Floor surfaces and coverings: Floors must be cleaned and dried regularly or as

often as necessary. Floor surfaces will be changed to a non-slip finish over a

period of time, particularly in reception areas. Spillages on floors must be attended

to immediately. Frayed edges and torn or worn patched on carpets must be

repaired or renewed as soon as possible. Care must be taken when applying

polish to floors lest the surface be made too slippery.

General Workplace hazards

Lighting: Suitable and sufficient lighting, whether natural or artificial, should be

provided in every part of the office which is in use. Glazed windows and skylights

are to be kept clean and free from obstruction except to the extent necessary to

eliminate glare or heat. Steps should be taken to prevent discomfort or injury from

glare or from reflection of light into the eyes of workers.

Ventilation: Adequate mechanical ventilation or openable windows must be

provided for the purpose of ventilating the property. Harmful draughts must be

prevented. Under Section 47, Tobacco Smoking (Prohibition) Regulations

2003smoking is banned in all workplaces.

Electrical hazards: All frayed cables and exposed conductors must be corrected

immediately by a qualified electrician. All plugs must be wired in accordance with

manufacturer’s instructions. Electrical fittings must be inspected at regular

intervals.


All distribution boards must be locked to prevent unauthorised access. Keys must

be held by a responsible official. A safe means of access/egress must be provided

and maintained to the distribution boards and a clear work area provided at all

times.

Any apparatus that requires ventilation must not be placed in a cluttered area.

Objects must not be placed over or near the ventilation ducts as this could result in

overheating and cause failure or possibly fire.

Fire, Emergency, Evacuation: A separate fire safety manual covering all aspects

of fire and associated hazards has been issued to each place of work. Please refer

to this manual for instructions regarding fire, emergency and evacuation.

Machinery: All machinery must be operated as instructed by the

manufacturer/supplier. Machinery guards provided for safety reasons must always

be used. Any item of machinery not functioning properly must be taken out of use

and marked accordingly. Repairs must not be attempted by those unqualified to do

so.

Substances (Chemicals): Care must be taken in storing chemical substances.

Proprietary brands will generally give direction in this regard. If in doubt ask

supplier for a material safety data sheet. Never store, or allow others to store,

supplies greater than will meet your immediate needs. Substances should never be

stored where they could easily become mixed. Containers must always be clearly

labelled and kept away from flammable material.

Protective clothing & equipment: Protective clothing and equipment, where

provided, must be utilised. Contractors are required to provide their own protective

equipment.


First Aid: Each place of work will be provided with a first aid kit and kept supplied.

Construction: All floors, steps, lifts, passages and gangways should be of sound

construction and properly maintained. Substantial handrails should be provided on

every staircase: an open side should be guarded by a lower rail or other effective

means.

Fire Escapes: While any person is in an office no exit door may be locked or

fastened in such a manner that it cannot be easily opened from the inside. There

must be a clear passageway through workrooms. Employees must be made

familiar with fire escape arrangements.

Emergency Escape Routes: It is strictly prohibited to store/ leave any boxes,

tables or other such items in an escape pathway.

Manual Handling

All employees are advised to exercise due care in this activity.

Trolleys and mechanical aids if provided should be used to eliminate

unnecessary handling.

Employees are advised against overloading trolleys and should make

additional trips if necessary.

Particular care must be taken when moving trolleys in restricted areas or

over ramps or uneven floor surfaces.

Ensure trolleys are suitable for the load to be carried.

General guidance for manual handling is as follows:


Look out for splinters, nails and wire.

Size up the job, remove obstructions, and make sure there is a clear space

where the load is to be set down. Ensure you can see over the load when

carrying it.

Stand close to the load and, with feet up to 8 to 12 inches apart, one foot in

advance of the other, prepare to lift.

Bend your knees into a crouch position, back straight (not necessarily

vertical).

Pull you chin in, avoid dropping your head forwards.

A good grip is required, preferably one hand around the front of the load and

one hand underneath to prevent the load slipping forward or down.

Pull the object close to the chest, as it is easier to handle and there is less

chance of it slipping.

An even lift is required to complete the exercise.

Remember - a sudden lift or jerk could result in back injury as could failure

to observe the above guidelines.

*(3) PSI safety statement 2009

17.7 Safety Systems

Safety Signs

Safety signs must be used whenever a hazard or danger cannot be avoided

adequately or reduced in another way. Before installing safety signs an employer

should examine whether the hazard can be avoided or reduced by collective

precautions (precautions that protect everybody) or safer ways of doing the work.


Examples of Prohibition Signs

Examples of Mandatory Signs

Examples of Warning Signs

*(4) HSA - FAQ’s – Safety Signs

Personal Protection Equipment

PPE should only be used as a last resort

Employees must be primarily safeguarded by eliminating risks at source,

through technical or organisational means or by collective protection

Collective protective measures covering numbers of employees such as

reducing the noise from a machine must have priority over measures

applying to individual employees

PPE only protects the wearer

With PPE, theoretical levels of protection are seldom reached in practice

With PPE, actual levels of protection are difficult to assess


To cater for the physical differences in employees, more than one type or

size of PPE should be available

Use of PPE always restricts the wearer to some degree, e.g. in movement

PPE may be uncomfortable to wear and cause irritation

In some cases, the individual wearing PPE psychologically feels more

protected than he or she actually is

*(5) HSA - Safety Toolkit and Short Guide to General Application Regulations 2007

Personal Protective Equipment Section

18 References Part 3

1) PSI safety statement 2009

http://www.pharmaceuticalsociety.ie/Council/upload/File/

Corporate_Governance/PSI_Safety_Statement_2009_CK091109.pdf.

2) Facility Design & Operation

http://eleceng.dit.ie/gavin/DT275/cppt9010.php

3) PSI safety statement 2009

http://www.pharmaceuticalsociety.ie/Council/upload/File/

Corporate_Governance/PSI_Safety_Statement_2009_CK091109.pdf.

4) HSA - FAQ’s – Safety Signs

http://www.pharmaceuticalsociety.ie/Council/upload/File/Corporate_Governance/PSI_Safety_Statement_2009_CK091109.pdf





http://www.hsa.ie/eng/FAQs/Safety_Signs/

5) HSA - Safety Toolkit and Short Guide to General Application Regulations 2007

Personal Protective Equipment Section

http://www.hsa.ie/eng/Publications_and_Forms/Publications/Retail/

Gen_Apps_Toolkit_isplay_Screen_Equipment.pdf.

Bibliography:

‘Facility Design & Operation’ Notes, by Clement Farrar

www.Pfizer.com

www.Wyeth.com

www.bms.com

www.pharmaceuticalsociety.ie

www.HSA.ie

http://www.HSA.ie/

http://www.pharmaceuticalsociety.ie/

http://www.bms.com/

http://www.Wyeth.com/

http://www.Pfizer.com/

http://www.hsa.ie/eng/Publications_and_Forms/Publications/Retail/Gen_Apps_Toolkit_isplay_Screen_Equipment.pdf

http://www.hsa.ie/eng/Publications_and_Forms/Publications/Retail/Gen_Apps_Toolkit_isplay_Screen_Equipment.pdf


19 OBJECTIVES

- To design and construct a high quality, cost effective Syringe Fill Finish Facility

(SFF) on schedule, meeting the requirements established as part of the Project

Premises.

- To develop a proactive plan to effectively utilise available resources.

- To verify during the construction stage that all tests and protocols are carried out

on each element of the system in order to assure the success of the project,

inside the scope and limits of the project.

20 INTRODUCTION

The present document will give the conceptual engineering for the construction of a

new green Field Syringe Fill Finish Facility (FSS), including modular clean room

construction, a high level of process automation, pre-sterilised Hypak syringes, a

filling line and fully automatic syringe inspection.

This document contains information about Construction, Commissioning,

Qualification considerations, Tech transfer, Start-up, Maintenance, Contingency

and Shut-down.

The facility will be designed to meet worldwide cGMPS’s for the Irish Market.


21 PROJECT BACKGROUND

The new Green Field Syringe Fill Finish Facility (SSF) will be designed according

to the following guidelines [1]:

Key steps

- Equipment preparation

- Formulation

- Filling

- Inspection

Technology & Facilities

- Modular clean room construction

- High level process automation

- Pre-sterilised Hypak syringes

- Filling line

- Fully automatic syringe inspection

Recipe

1. The vaccine conjugates formulated with a saline buffer solution and then

sterile filtered together into a product vessel.

Aluminium phosphate suspension is bulk manufactured: terminally sterilised

by heating and transferred into 20 litre cans. The suspension is added

aseptically to a mobile product vessel to give a batch size of 150 litres

(≈260k syringes per batch).


2. The product vessel is connected to the filling machine. The empty sterile

syringes arrive in sealed Hypak tubs. Stoppers arrive in sealed bags. Each

Hypak contains 100 syringes in a nest. The sealed tubs are conveyed

through the E-Beam technology to sterilise the exterior surfaces of the

sealed tubs. The filing machine fills the syringes to a volume of 0.58 and

inserts the stoppers at approx 300 per minute.

3. A grade A environment is required for filling and stoppering the syringes.

Then can be carried out in a grade A room, or in an isolator in a grade C

room. The lid and liner of the Hypak tubs are automatically removed as part

of the filing line.

4. The filled syringe tubs are de-nested, and the syringes loaded in single file

on the conveyor to the automatic inspection machine. Each syringe is

inspected for foreign particles in the liquid and cosmetic defects such as

cracks. After inspection the syringes are put in the nest. The tubs are then

packed for shipping to the packing.

22 SCHEDULEThe project construction and validation is estimated to be completed in 300 days

and is expected to start its operations in February 2011. The Key Phases of the

Project and deliverables are show in table 3,

Table 1 Project Phases

Phase Description Deliverables

1 Process Design • Equipment specification: Equipment description,

utilities (EPA Licence), Process Flow diagram.

• Layout specification: Room Classification & Floor


Layout.

• Funding Approval

• Purchase Orders (Equipment procurement)

• Factory Acceptance Testing (FAT) document,

(Equipment Fabrication)

2 Construction &

Procurement

• Kick-off meeting Agreement (milestones &

communication plan)

• Site Acceptance Tests (SAT) document.

• As-built documentation.

3 Commissioning &

Start Up

• Integration testing documents:

- IQ (Installation Qualification), OQ (Operational

Qualification) of facility, utility systems and process

equipment.

- PQ (Performance Qualification) of the system in

an integrated run.

- Media Trials

4 Validation •IQ/OQ/PQ activities following commissioning

5 Maintenance • Preventive Maintenance

- Maintenance Management System (SAP)

Engineering Stores-Spare parts (SAP)


Phase 1, Process Design, will provide the specifications for Construction. This

stage might include partial contract to seek the advice and provide feasibility

studies. Then, once the design finishes, phase 2, Construction and Procurement

phase begin. Good planning and control in this phase is very important for the

erection of the project. During phase 3 several testing documents will be produced

according to GMP in order to assure the quality of the product by ensuring key

attributes, including correctness and legibility of manufacturing and control

documentation. After that the new will be facility is officially validated and finally

can starts operation.

There is also a Preventive maintenance (PM) program performed on all lines every

month on a rotational basis.

The master schedule of the new Green Field Syringe project is shown in figure 31,


Figure 31 Master Schedule

New Green Managing Director

Development

Regulatory Affairs

Supply Chain

Finance

Operations Management

Technical Services Human Recourses

Site Engineering, Maintenance Communications & Public Affairs

EHS & Site Services Business Systems & Processes

Quality & Compliance


22.1 Resource and organisation

The new Green Pharmaceutical Plant site leader team structure chart has around

forty team members and it is divided 12 functional departments, Operations,

Engineering, Quality, Validation, Training, Manufacturing Support and Technical

Services [3], each section report to a single line and the project manager

coordinates the activities of the team members, as shown in figure 32:

Figure 31 Organisational Chart for the Site Leadership Team at the Green Field

plant.

The resource utilization is based at standard working times of 8 hour shift.

The organizational chart for the new green Field Syringe Fill Finish Facility (SFF)

Project is presented in figure 33. The project will operate with an owner-builder

type of contract.

Steering Committee

Fill/Finish Leader

Doc. Control

Admin

Scheduler

Cost Controller

Engineering

Tech. Transfer Validation

Materials & Logistics

Quality

Operations/Production Manager

Shift Managers


Figure 23 Fill Finish Facility Project Org. Chart Syringe

The new Fill Finish Facility (SFF) Project Leader is responsible for planning,

organizing engineering and construction and controlling the Project. During the

Construction phase, the Leader will ensure that execution of the field activities are

carried out in accordance with the strategies and plans developed in all preceding

phases. Construction management also include purchasing equipment,

instrumentation and contractual agreement for testing and documentation of the

factory acceptance testing (FAT) at the vendor’s facility.

The Operation/Production Manager will be involved from the beginning of the

planning phase in order to ensure that the new facility is according to operational

needs and to ensure that the project will involve preventive maintenance.

Moreover, master external services are arranged for validation.


22.2 Commissioning and Qualification Considerations

During these stages the SSF equipment and clean room is tested and validated

using detailed qualification protocols according to GMP (Good Manufacturing

Practice) and recommended Practices and Standards for aseptic operations such

as IEST-RP-CC003.3 [4]. Some parameters evaluated are:

• Coverall components

• Headwear styles

• Footwear styles

The good planning of the Commissioning phase will facilitate the validation process

and accelerate Start-Up.

Validation Protocol

Installation Qualification (IQ): The purpose is to verify that the product received is

as specified and sterile. This section of the validation includes an audit of the

supplier, verification of quantifiable data, list spare parts/part numbers, and

drawings and could also mention to add particular equipment to the Preventive

Maintenance (PM) Program.

Operational Qualification (OQ): The purpose is to verify that the system can be

work into the sterile environment and remain sterile. This section of the validation

includes personnel training, execution of standard operation procedures and

verification of quantifiable data.

Performance Qualification (PQ): The purpose is to prove that the equipment is

capable of performing its activity on a consistent basis during use. This section

should include an in-use trial and verification of accrued quantifiable data.

User Requirements

Functional Requirements

Design Specifications

PQ

OQ

IQ

BUILD

TEST


Media Trials: The purpose is to demonstrate that the process, equipment, people

and utilities in operation are able to produce a sterile product.

Figure 34 shows different pieces of equipment of the facility that constitute

qualification requirements [5]

Figure 34 Equipment Validation

Table 2 shows and example of the types of activities for major equipment.

Table 4 Major Equipment - Normal Qualifications Required

Equipment IQ OQ PQ

Glove box X X N/A

Mixer X X X

Transfer pumps X X X

Transfer vessels X X N/A

DESIGN


Coater/dryer/

laminator

X X X

Slot dies X X N/A

Slitter/re-laminator X X X

Packaging equipment X X X

Note: All equipment to be included in process validation.

All protocols should reflect the item on which validation is performed and

correlation with other documents. Figure 4 show correlation with other documents

and figure 35 shows sample protocol and process validation protocol cover page

needs associated with current good manufacturing practice (CGMP) [5].


Figure 33 Process Validation document references to other support documents

Figure 34 Recommended protocol cover page


Figure 35 Recommended summary cover page


22.3 Production capacity

The fully automatic filling and sealing manufacturing facility for pre-sterilised nested

syringes in sealed Hypak tubs is designed to give a batch size of 150 liters, which

correspond to approximately 260000 syringes per batch. The filling machine fills

the syringes to a volume of 0.58 ml, 100 per nest: 4300 syringes per hour [2], and

inserts the stoppers at approx 300 per minute.

Syringesbatch=150 liters0. 58ml

=258620≈260000

Equation 1 Number of syringes per batch

Therefore, assuming that the plan will operate 24 hours a day and is available for

operation 8000 hours per year, the production capacity (Number of syringes) per

year can be determined as;

Syringesyear=8000

hoursyear

60 .5hours

batch

=132batches

year≈34400000

syringesyear

Equation 2 Number of syringes per year


23 TECHNOLOGY TRANSFER AND START-UP

23.1 Technology Transfer

As seen in the Commissioning and Qualification considerations section, process

validation is part of the continuum activity of the Technology Transfer.

Figure 36 Tech Transfer process

Technology Transfer includes factors for the development of the new Green Field

Syringe Fill Finish Facility (SFF) manufacturing process according to Current Good

Manufacturing Practice Drivers for Finished Pharmaceuticals [7] that constitute an

important contribution for the validation process. The TT Plan for the Project

involves specification of adequate raw materials and dispatched products

characterizations and the use of accumulated process and method knowledge.

This plan is a crucial reference for integrating a new product, for change-control

program management and troubleshooting. The TT success is measure with Key

Performance Indicators – KPI such as: Size of batch against target and Number of

lots completed for validation vs. target.

The Technology Transfer is a collaborative effort among cross-functional

technology teams representing various site departments and specialities that

transfer all the required information, support the new project and evaluate the

transferred information.

Senior Management

TT Team

Steering Committee

TT Sub-team

Strategic Decision Making

Team Leader, Transferring Site development, Receiving Site Manufacturing, Development Operations, Quality, Engineering, Regulatory Affairs, Materials & Logistics.

Project and Technical Decision Making


It is made on internal and external basics through documentation and in-person

transfer meetings in order to tech transfer best practices, and learn from other

facilities related to aseptic processing. Figure 8 show the organizational chart for

TT Team and Table 5 shows key product and process/method aspects that tech

transfer could involve,

Figure 37 Empowered TT Teams

TT responsibilities:

Strategic Decision Making:

- Site Management: Approve plans & reports and assign site recourses.

- Steering Committee: Management for Originating and receiving sites

specific for the project, appoint TL, define SOW, ensure compliance with

Quality & Tech Transfer Agreements and approve plans & reports.


Project and Technical Decision Making

- TT Leader: Construction & maintenance of overall TT plan, primary liaison.

- TT Team: Organise and execute TT plan, compile TT report, ensure all

required documentation, appoint sub-teams.

Originating facility: Provision of analytical expertise to receiving site, provision of

process expertise to receiving site, provision of all required documentation,

provision of standards and other information required for TT.

Receiving Facility: Perform Gap Analysis, practical work involve in local Gap

closure and identify, procure & quality equipment to support the process.

Table 5 Technology Transfer Key Learning Areas

Pro

cess

TT

Business Considerations

Pro

cess

/Met

ho

d T

T Specific Test or Process Steps

Shipping Considerations Specifications

Material Availability Process/method development & validation

Regulatory Considerations Process related Facility Considerations

Strategic Facility

Considerations

The Technology Transfer for the new Green Field Syringe Fill Finish Project is

expected to be completed in December 2010 and regulatory approval is expected

in February 2011.

Steering Committee

Fill/Finish Leader

Engineering – Design Engineering – Construction

Admin

Eng. Commissioning & Start-UpQualification

Scheduler

Operations/Production Manager

Consultant

Shift Managers

Engineering

SchedulerAdmin


23.2 Start-Up

During the Start-up, the Installation Qualification (IQ) protocol used in the validation

phase is implemented to assure that the new Green Field Syringe Fill Finish

Facility (SFF) is installed properly and all necessary utility services, piping of the

refrigeration and heat transfer system, are in place. Moreover P&ID’s and the

control system are rewiring.

During Start-Up of the new Green Field Syringe Fill Finish Facility, both Facility and

Consultant (Engineering) Teams are required. The organizational chart for Start-Up

is shown in figure 38.

Figure 48 Start-Up project team

During the Start-Up activities such as Automation Services, Debugging,

Engineering Support, Initial Production, Maintenance Training, Operator Training

and Systems Checkout are required. In Start-Up check lists are use to check

utilities, pressure testing/purging and Equipment.

AREA MANAGERS QA

SYSTEM ADMIN

ENGINEEING/OPERATION STORES

MAINT. TECH OR CONTRACTOR

ENG STORES

WORK ACTIVITIES

REVIEW MAINTENANCE REQUIREMENTS

MMS Reports

SOP’s

Work Order

Equip. Logbook


24 MAINTENANCE, CONTINGENCY AND SHUTDOWN

24.1 Maintenance

All maintenance, preventive and corrective, work for the new Green Field Syringe

Fill Finish Facility (SFF) will be based on SAP Maintenance Manager. This

software application is already implemented in the facility as it allows maintenance

applications and also further administration tools such as Material Management,

Process Costing and Generation of Batch Records.

The maintenance plan for the new facility covers maintenance work during normal

and abnormal operation based on the results of the IQ program. During normal

operation (preventive maintenance), typical activities include recalibrating field

instrumentation and computer I/O cards in accordance with site calibration

procedures, running system diagnostics. Calibration of critical instruments and

system components are controlled by a calibration schedule according to

guidelines from the quality/maintenance engineer and the manufacturer

recommendations. Preventative maintenance for the SFF facility will be performed

every month.

The preventive maintenance overview is showed in figure 39 [3],

RESPONSABILITIES SYSTEMS

DOCUMENTATION

Figure 41 Preventive Maintenance Overview


During abnormal operation, corrective maintenance, an emergency repair will be

carried out either by site engineering or by the system supplier.

Detailed reports on corrective and preventive maintenance will be made by

equipment item,

by site and by service order such as,

Table 6 SAP Maintenance Reports

Report Description

Maintenance Cost

Reporting

Include actual labour rates, purchase cost for

maintenance, including internal orders.

Notification health

check

Information required for Notification Process.

Schedule Adherence Schedule accuracy with selected parameter.

Order Estimate vs.

Actual

Completed Orders, Estimated Cost, Planned Cost and

Actual Cost.

Work Order

Completions

All scheduled finished and whether the Work Order are

completed or not.

24.2 Contingency

The Contingency Plan for the SSF Facility gives information regarding recovery

plans and procedures to facilitate the decision-making process and its timely

response to any disruptive or extended interruption of the facility's normal

operations.

Contingency Plan Coordinator

Damage Assessment Team Procurement team System Contingency Coordinator Admi. Management Team

Operations Team

Communications TeamEngineering Team


The SSF Facility Contingency Plan provide recovery plans to ensure the safety of

employees and the resumption of time-sensitive operations and services in the

event of an emergency (fire, power or communications blackout, flood, earthquake,

civil disturbance, etc.)

24.3 Organization

In the event of a disaster or an emergency, the normal organization of the Facility

will shift into that of the contingency organization.

Figure 9 Contingency Planning Organizational Chart

The SFF Facility’s contingency organization will operate through phases of

response, resumption, recovery, and restoration. Each phase involves exercising

procedures of the Facility Contingency Plan and the teams executing those plans.

Each of the teams is comprised of individuals with specific responsibilities or tasks,

which must be completed to fully execute the plan. The Plan follows international

regulation agencies such as OSHA, An Example action Plan Checklist [6] is given

in Appendix C.


25 Shutdown

An Annual programmed shutdown in summer is programmed in the Plan

Maintenance in order to carry out Preventive Maintenance.

It is also possible a shutdown can occur at any time due to an emergency. In this

case, a shutdown of the facility would mean inability to supply major clients for

major orders.

The SSF facility normal organization will shift for shutdown procedures as,


Figure 10 Shutdown Organizational Chart

Shutdown Project Manager

Quality AutomationEng. OPS Upstream

Coordinator

Shutdown Execution

Eng. OPS Utilities

Shutdown Execution

Procurement Manufacturing Control System

Shutdown Scheduler

26 CONCLUSIONS

A carefully planned and coordinated program for the new Green Field Syringe Fill

Finish Facility (SFF) is essential in order to achieve each of these objectives of the

project.

All documentation and protocols during the different phases of the project are very

important and serve to establish that the facility is capable of performing its activity

on a consistent basis according to GMP. This information is essential for the

validation stage where the facility is officially validated to starts operation.

27 REFERENCES part 5

[1] C. Farrar, 2009: Manual Assignment Module CPPT 9010.

[2] BOSH-PHARMA USA, 2009: FXS 2020 Filling and sealing machines for pre-

sterilized, pre-filled syringes,

http://www.boschpackaging.com/Boschpharma-us/eng/64350_63978.asp

[3] C. Farrar, 2009: Module 9010: Facility Design and Operation lecture notes.

[4] IEST – Institute of environmental Sciences and Technology, 2009: Practices and

Standards, http://www.iest.org/i4a/pages/index.cfm?pageid=3280

[5] M. Dekker, 2003: Pharmaceutical Process Validation, Vol. 129.

[6] OSHA, 2009: Evacuation Plans and Procedures,

http://www.osha.gov/SLTC/etools/evacuation/

[7] GMP INSTITUTE, 2008: OGMPSHA, 2009: 21 CFR Parts 210 and 211 - Current Good Manufacturing

Practice In Manufacturing, Processing, Packing or Holding of Drugs; General and Current Good

Manufacturing Practice For Finished Pharmaceuticals, http://www.gmp1st.com/drreg.htm

http://www.gmp1st.com/drreg.htm

http://www.osha.gov/SLTC/etools/evacuation/

http://www.iest.org/i4a/pages/index.cfm?pageid=3280

http://www.boschpackaging.com/Boschpharma-us/eng/64350_63978.asp