9/29/2011

Facility is a complete set of conditions carefully arranged and planned to

provide an un-naturally clean production environment.
 Core of the facility is the clean Production Area.

 The facility should be not only free and visibly clean from contaminants but
also free from microscopic, viable, non viable contaminants.
 Man movement, material movement and supplies all operate but still the
clean environment should be maintainable. (Concept of: As built, At rest and
In operation).
 Maintaining cleanliness is very complex: The system consists of barriers,
buffer areas, traffic control and environmental control. All are developed to
minimize unintentional access of contaminants to the plant itself.
 Total area is divided into zones as per the floor plan to enable specific
activities as required at appropriate level of cleanliness.
 Each zone maintains a buffer to the next more clean area.

 Progressively the plant becomes more clean by design and by control until
the cleanest area is achievable for safe production of Injectables (1. Exterior;
2.Warehouse; 3.Gen Production; 4.Clean area;5. Weighing, mixing, transfer;
6.Filling area; 7.Filling line)

9/29/2011 1 9/29/2011 2

Basic factors Pharmaceutically Important

 Site Selection factors
 Land availability
 Area Selection  Land cost  Basic plant requirements

 Space Planning  Construction cost  Energy availability: Pharma

 Tax
Industry is not a energy
 Designing intensive industry. Coal, fuel,
 Utility cost
 Construction features  Labor cost
Natural gas not used becoz of
pollution concerns
 Traffic flow of personnel  Labor availability  Water availability; For heating,
 Traffic flow of supplies All these factors do not affect the cooling, steam, formulation,
provision of a clean production cleaning, sterilization,
 Service features environment washing, distillation
 Air quality:

 Waste Disposal

 Non-technical factors

9/29/2011 3 9/29/2011 4

HVAC (Heating, ventilation and Air-Conditioning) systems are an essential

 Solid wastes of Parenterals include paper,
plastic film- These solids can be compacted,
buried in sanitary fills or incernated.
 Broken glass- These can be washed and then
disposed.
part of the plant premise as per the recent Schedule M and WHO-GMP
guidelines.
These consist of a number of AHUs (Air Handling Units)
The inlet air quality will determine the system requirements for the
purification of the ambient air
Cost and complexity of the system necessary to clean the ambient air will
vary.
Most difficult and expensive to control are:
 Very small airborne particles(< 1 µm)

 Lab animals- These can be buried  Excessive humidity

 Odours
 Liquid waste- This is fed to the effluent  Air borne salts : These specifically degrade the pretreatment systems

treatment plant before it is discharged into  Industrial gases e.g. nitrous oxides and hydrogen sulphide are difficult
to remove and create discomfort in a controlled area.
the drainage.  For site selection: Present air quality and future trends in local emission
both are to be considered.

9/29/2011 5 9/29/2011 6

1
 9/29/2011

Facility area planning is determined by the size and Various functions in a Pharmaceutical Plant include:
location of each operation to be carried out in the  Production

facility.  Warehouse

General Operational Assessment depends upon:  Administrative area

 Utilities
1. Type of Production line
 Quality Control
 Batch Operation
 Engineering and Maintenance
 Continuous Operation
 Employee services
 Integrated Operation
 Security
2. Diversity of Production line
3. Container Size
4. Product Characteristics

9/29/2011 7 9/29/2011 8

Planning of production facility requires

 Determination of functions necessary for the
particular plant Sterilization
Wash Area Depyrogenation
 Size and location of each function
Unpack Filling
 Proposed plant operation
 Type of environment necessary
 Functions that need to be integrated
 Functions that need to be segregated
From all the above factors we will be able to Packaging Inspect

determine the Area requirement for a particular

function and
Location of each functional area

9/29/2011 9 9/29/2011 10

Batch operation
 Features: A fixed volume of product, its related assemblies and
packaging components are moved step by step through
Production process, maintaining accountability at each step.
This type of operation is setup with:
 Minimum financial investment
 Small Production volume
 Product quality, consistency and homogenity can be easily
controlled
 Step by step operation is carried out
 All steps and their working details are documented
As a result
Limited equipment and space is required
Scope of operation is limited
A series of small sections /rooms are required
Environmental control of each area as per requirement is easier to
obtain
Shortfalls of this type of Operation are:
 Transfer of material from one area to the other is manual and so
chances of contamination are high
 High labor costs are involved
 Manual transfer limit the speed of operation
 Care needs to be taken when aseptic environment is required
while transfer
 More the manpower– more will be the chances of introduction of
contaminants and particulate matter.
 These operations are useful when the volume of production are
not very high and the cost of continuous operation are not
justifiable
 These are labor demanding operations and the cost of
maintenance of this large labor is generally high
Not a preferred process for very high scale of operation and not
expected to give a very high output, though the quality can be
maintained from batch to batch.

9/29/2011 11 9/29/2011 12

2
 9/29/2011

This type of operation is suitable for a very high volume of Production.

Features:
Labor requirement is low (when compared to production volume)
Production time required is low
Environmental exposure is low
Wash Area Depyrogenation Filling Sterilization Inspect Packaging
Shortfalls of this type of Operation are
Unpack Quality assurance is challenging
It is impossible to document each and every step in a continuous operation
and the process is easily done in case of batch operation
Documentation of this type of process emphasizes on the process control
parameters
e.g. Sterilization in batch operation and in a continuous operation: in batch
operation a particular unit under deviation is traceable
but in case of a continuous operation the unit under deviation cannot be
identified and segregated.
However, with much advancement in the machineries being used for the
manufacturing process, there are little chances of deviation in the
process.

9/29/2011 13 9/29/2011 14

Advantages of a continuous operation process include

 Negligible risk during handling
 Low labor cost and maintenance Filling
Wash Area
Shortfalls in these types of operation
Requirement of a highly specialized and complex Unpack
Sterilization
machinery for the production purpose Depyrogenation

Requirement of a large amount of space for carrying

out the process
Challenging to maintain the production environment Packaging Inspect
as requirement in the particular area as per the
process e.g. filling area requirement, manufacturing
area requirements, etc.
These type of operation are suitable for a very high
scale of manufacturing.

9/29/2011 15 9/29/2011 16

Advantages of Batch mixing and a continuous process both are included in

this type of operation
 Manufacturing operation is divided into discrete steps as in case of  There is a considerable reduction in
batch operation the size of the filling area, which
 Small steps are integrated to make more efficient steps leads to a lot of cost reduction in
installation and maintenance of the
 E.g. in the Fig. unpacking, washing and depyrogenation are being
area and its requirements
carried out in a continuous step but unpacking is environmentally  Operators and the product are
segregated from the rest of the operation. separated and so there is a
 Next area-Filling area considerable reduction in the
Filling Area exposure to the product and thereby
 Then, a Unique area-Sterilization
the contamination is minimal,
 Next-Inspection and packaging enhancing the Quality of the product
Shortcomings of this type of operation are: and facilitating an easier
maintenance of the area.
 There is a significant interaction between the Production personnel and
 Isolation suits including gloves, head
the product. enclosures and breathing gases are
To overcome this shortcoming “BARRIER TECHNOLOGY” has been provided in the isolator suits for any
developed. operator desirous of working into the
In Barrier Technology Filling area through the Isolators
The whole filling line is covered by a barrier system.
Barrier enclosing creates a “micro environment” within the manufacturing
facility by separation of people and the product

9/29/2011 17 9/29/2011 18

3
 9/29/2011

 Product line- limited  There are different requirements at plant level for SVPs and
1. If product line is limited, layout can be adjusted for LVPs
best efficiency.  Production equipment: large containers require large
equipment and more space
 Product line- diverse  Filling lines: Small ampoules may be moved to feeding
1. If product line is diverse, more space is required to position of a manufacturing line in a single load (For a
accommodate a more flexible operation complete shift), large 1L bottles may require continuous
2. More complex machines(M/C) are required. replenishment
 Packing lines and Packing areas: For LVPs manufacturing, an
3. More containers, storage and more change parts are additional unpack or load transfer area may be needed to
req. prevent an unnecessary particulate load near washing
4. M/C may be required to be moved.  At the end of filling lines, large LVPs will require mechanized
5. Cross contamination may be there material-handling equipment and storage areas.
6. Strict control is required to be kept on labels,  Door sizes must be large to accommodate large carts in case
booklets, documents, products and mis-marking of LVPs while for SVPs manual handling and transfer may be
possible.
and mis-labelling

9/29/2011 19 9/29/2011 20

 Containers and closures  Containers are washed Liquid product Powder

are sterilized and
depyrogenated by hot air
ovens/tunnels.
 Filling requires Class 100
environment with
attendant support rooms
 Maintain aseptic
environment until the
product is totally sealed
in primary packaging
 Sealed containers are
inspected and packaged
and rinsed with WFI and
dried
 Filling is followed by
sealing and then
sterilization
 Sealed containers are
kept in segregated area
and then transferred to
area for sterilization
 After sterilization the
containers are labelled
and packed.
 Easy to handle
 Large batch sizes are complicated to
transfer while small ones can be
transported manually.
Emulsions
 These require compounding areas
close to filling lines to facilitate
transfer.
 Pumping may be very critical
 Overhead gravity feed is desirable
Suspensions
 Maintaining homogenity of
suspension during filling a must.
 Maintaining minimum residence in
piping, reservoir, pump, etc a must.
 Powders are difficult to handle
 Batch type processing necessary
to prevent loss and cross-
contamination in material
handling
 Dust control systems necessary
 Frequent cleaning a must
 Low RH a must to prevent
moisture absorption by powder
(for flow enhancement & for
preventing degradation of
moisture sensitive powders)
 Very low RH in turn may enhance
electrostatic problem in powders

Product characteristics
Aseptic Process Non aseptic Filling Product characteristics
A Class 100 cleanroom is designed to never allow more than 100 particles (0.5
microns or larger) per cubic foot of air. 9/29/2011 21 9/29/2011 22

Man movement should be planned at the design step itself.

Man movement must be viewed for individual production area and
for the plant as a whole where more than one production area
are involved.
Crowded man movement can
 Decrease the efficiency
 Make the maintenance of the area problematic
 Security concerns may arise
Man movement problems including crowding occur in a two
dimensional plants( single storey)
These can be overcome by making the Production area in several
levels. This would
 Lessen the chances of crowding e.g. Mfg. and filling would be
designed to be on different floors
 Flow of liquid will be by gravitation
 There will be separation between the Product and the people
 Personnel should have a direct and well-defined path from
the entrance to the area of their work
 Movement from one zone to other is such that access to
higher levels of cleanliness is only through, change rooms,
gowning area, lockers and other required preparation
 Minimum access should be allowed to the controlled areas
 Though man-movement and material-movement thru a
common corridor is usual, but this should be minimized
 Dedicated material flow paths reduce the contamination of
the product including packing material contamination
Visitor Arrangement
Arrangements for visitors must be made right from the
planning of Plant
Glassed balcony/ liberally placed windows provides the best
view of the plant without disturbing the Plant operations

9/29/2011 23 9/29/2011 24

4
 9/29/2011

Of maximum importance are  Enough space for equipment

 Enough space for personnel movement
 Filling areas  Should have a small component storage
 Wall and floor  Should have a minimum excess space
 Area should be maintained under laminar airflow hood (LAF)
 Miscellaneous Controlled area details
 Area should be Class 100 or better
Filling Area:  Gas or other pipelines should come through sanitary connections in the
wall of the area
 This is the most Critical area  No Cylinders, etc should be allowed into the area
 Has the maximum potential of contamination of the  No storage of the Production component should be allowed into the

product
 Area planning of Filling area is critical and some key
concern for this area is to prevent the entry of viable
microorganisms
 Area should have working space and reasonable
access area to allow man and equipment movement
area. These product components should be stored in other sterile areas.
Provisions should be made for
 Careful segregation of the production by batch, providing for hold areas
 Incoming flow of containers and product
 Outgoing flow of filled product
 Flow of personnel
 Gowning or change rooms for entry into the controlled area
 Each line is dedicated and fully supported operation

9/29/2011 25 9/29/2011 26

 Unidirectional man
movement
 Two filling areas utilizing
 Simplest type of filling area a single gowning &
degowning facility
 Non intersecting flow paths for:  Unidirectional gowning
equipment and container facility
preparation, product preparation,  Degowning segregated
product accumulation and
completely from gowning
personnel gowning
 Mimimum contamination
from the degowning
 Each line is dedicated and fully
supported operation
process
 Each line is dedicated
and fully supported
operation

9/29/2011 27 9/29/2011 28

 Unidirectional man  Multi use equipment room

is available, where several
movement pieces of equipment are
 Clustered filling areas, located in the same room,
although one equipment is
utilizing a common used at a time.
gowning facility  Partial segregation of
 Product preparation operations
and material  Cross-flow operations
 Cost effective
preparation rooms
 Increases environmental
dispersed for each control problems
filling area  Increases chance of cross
 Each line is dedicated contamination
and fully supported  Not a very ideal situation
for filling lines
operation

9/29/2011 29 9/29/2011 30

5
 9/29/2011

 Walls, floors, ceiling, fixtures and partitions

 Pumping is at times a  Higher construction should be smooth & cleanable
difficult function cost  Exposed columns, wall studs, bracing/clamp,
 Flow by gravity much  Lack of visual pipes, etc are unacceptable
easier and convenient communication  All ledges/projection or surfaces within the room
between areas should be eliminated.
 Leakage problems may  All joints and finishes should be such where no
occur thru floor or dirt accumulates
ceiling openings or  Surface finish should be such that it can
withstand cleaners and disinfectants, without any
access to services surface degradation.
 These should be resistant to frequent cleaning
and disinfection
Advantages Disadvantages

9/29/2011 31 9/29/2011 32

Type of wall Advantage Treatment reqd. Shortfall

Type of wall Advantages Treatment Shortfalls
Concrete block Sturdy and easily Coating with block 1. Not fit for
wall constructable fillers prior to cleaning
required
painting 2. Paint prone to Gypsum board or A properly •Joints of boards 1. Cannot withstand
peeling sheets fastened to constructed board need to be taped and abrasion /bumps
3. Walls crack wood/metal studs dry wall is very sealed to form a without damage .
resistant to cracking continuous surface. 2. Wall bumpers
along joints •Epoxy paint and corner
Use of ceramic employed to create a guards are
faced block for surface resistant to required
good finish cleaning
Plastic Wall Sturdy and Epoxy paint is 1. Vulnerability to Heavy covering Applied as sheets Need to be glued 1. Expensive
moderately used to increase nicks and chips applied as sheets over existing walls. 2. Installation
e.g. Vinyl sheeting Joints of vinyl sheet around pipes is
resistant to the durability and from
are heat sealed to difficult
cracking impermeability of equipment form a large
surface 2. Repair easy but monolithic sheet
finish is by
Spray-on /Brush-on Hard and more - 1. Easier to apply
paint only
coating durable surface than coverings

9/29/2011 33 9/29/2011 34

Type of wall Advantages Treatment Shortfalls Concrete floors

required  Concrete slab is ideal base, very durable but is not suitable alone
 Plain concrete is soft and generates dust
Metal clad walls Very durable - Any damage  Surface of plain concrete is porous and prone to become more and more porous
incurred may  To decrease porosity, a very smooth surface may be given to the floor but this will
cause skidding
leave permanent  Sealers may be applied on the concrete floor to reduce dusting
scar which is  Hardeners may be added to concrete to increase surface hardness
difficult to ◦ This will increase the resistance of the floor to scratching
repair ◦ Colored hardeners are available to increase aesthetic appearance
Problems with concrete floors
Painted metal Easily removable _ Available as  However, cracks is a serious problem in concrete floors due to poor concrete, poor
installation, shrinkage, soil movement
walls/ SS walls small panels  Once cracked, a concrete floor can be repaired only if the floor movement
Modular wall Arrive at _ Joints must be stabilizes
 Crack can be filled with resilient filler that will expand and move as the floor
system construction site caulked with moves
and faster to silicon caulk  A concrete floor is therefore not fit alone for use in parenteral area becoz of
erect which is potential of cracking
resistant to
microorganism.

9/29/2011 35 9/29/2011 36

6
 9/29/2011

Epoxy or Urethane for  Bare concrete floors are etched with acid, all the cracks and
joints coated with an elastomer and terrazzo floors are installed.
 This is applied as a coating over a cured (acid  In order to prevent surface from cracking, a membrane is
cleaned)concrete surface installed over the concrete surface
 Acid cleaned surface is required before the  Application of this terrazo floor is labor intensive
application of coats of finish  Coved base can either be field applied or precast cove base can

 These are less resistant to scratching or cutting

 Cannot patch cracks, but once the crack has
stabilized, a fine crack can be covered
Advantages
 These can be applied on the existing concrete floors
 These floors are resistant to dusting and slippage
 They provide a continuous seal
 These are available in a number of colors
 Ideal for areas with there is primarily high foot traffic
be used
 Finally the floor is sealed with several coats of urethane
 The result is a very attractive floor that is extremely impact and
abrasion resistant
Vinyl sheets or polyvinylchloride sheets
 These can be applied on concrete base floor, even preexisting
one
 These are easy to install, and can cover cracks
 These are available in a number of colors and are available in
slip-resistant finish
 These are more susceptible to cutting by wheels and glass, but
are easily reweldable.
 These are more comfortable for workers becoz of resilience

9/29/2011 37 9/29/2011 38

The purpose of the steam generators is to recover the latent heat of

Steam is required in Pharmaceutical plant for the following purposes: vaporization, when the steam condenses.
 For space heating Steam system efficiency increases with an increase in temperature or
 For water heating pressure of the steam generation system. However, the cost of such
 To drive engines and turbines steam generation is high.
 For sterilization In Pharmaceutical Industry, temperatures required are between 100-
The usual ingredients added to steam to enhance operation and to prevent 1500C.
corrosion are unacceptable in the Pharmaceutical operation. The energy transfer process is efficient except for a few losses
Steam :Generation and distribution including:
Boilers are used for steam generation. These may be fed by gas or oil. 1. Piping heat losses: Well insulated piping minimizes radiant
 Additives (to prevent scaling and corrosion) may be added to the boilers loss/conduction loss.
(Strictly unacceptable in the Pharma Industry)
2. Friction losses: Piping causes loss because of friction of flowing
 These may be volatile at steam temperature, and will be carried as gas
fluid.
 Non volatile additives will be carried over as liquid
Velocity α Loss due to friction
 Steam condensed by heat loss is called condensate and is returned to boiler
High velocity High loss due to friction drop in
 Steam is distributed and returned in piping systems of “black iron” pipe of
suitable strength for bearing pressure pressure
 Condensate combines with carbon dioxide to form carbonic acid, which is So, for keeping P constant, velocity needs to be minimized
corrosive 3. Makeup water : Water/ steam lost thru leak, process use, flush,
 Unchecked corrosion may fail the return piping. This is controlled by the etc should be replaced with additional requirement from system
addition of a volatile additive in the boiler which will carry over with the
steam and inhibit condensate corrosion

9/29/2011 39 9/29/2011 40

Compressed can be used to

 Actuate air cylinders
Advantages of dedicated separate system are:
 Drive air motors
 Cleaning If need of compressed air supply is widely spread, then
 Drying dedicated systems may be better than the cost of distribution
 Vessel pressurization system
Quality of compressed air needs to be controlled as the compressed air will
come into contact with the product. Separate systems are more flexible and any breakdown in the
Compressed air facility may be Centralized / Dedicated. supply may not hamper the complete plant supply
Centralized facility needs a single Compressor to be installed and this The quality of supply to different areas may be different so,
feeds all the required “points of use”
Advantages of Centralized system are: dedicated systems may be more suitable
1. Single installation are easier to control
2. The total initial and operating costs are high
3. Better grade of filtration and drying equipment can be justifiable
4. Single distribution system easier to maintain
5. Greater total reliability from fewer total components
6. More efficient use of the system

9/29/2011 41 9/29/2011 42

7
 9/29/2011

1. General requirements 16. Quality Control systems

2. Warehousing Area 17. Specifications
3. Production Area 18. Master formula records
4. Ancillary area 19. Packaging Records
5. Quality Control Area 20. Batch Packaging Records
6. Personnel 21. Batch Processing Records
7. Health, clothing and sanitation of 22. Standard Operating procedures(SOPs)
workers and Records, regarding
8. Manufacturing Operations and 23. Reference Samples
Control 24. Reprocessing and Recoveries
9. Sanitation in Manufacturing premises 25. Distribution Records
10. Raw material 26. Validation and Porcess records
11. Equipment 27. Product recalls
12. Documentation and records 28. Complaints and Adverse Reactions
13. Labels and printed material 29.Misc
14. Quality Assurance General information, Personnel
15. Self Inspection and Quality Audits Premises, Equipment, sanitation,
Documentation, Production, etc,

9/29/2011 43 9/29/2011 44

Pharmaceutical Manufacturing facilities where pharmaceutical

These requirements are required to be met in addition to the products, utensils and manufacturing equipments are exposed to
General requirements outlined in Part I of the Schedule M the environment should be classified as “Cleanrooms”.
 A Cleanroom is an area or zone where the particulate and microbial
1. General contamination is limited to specified levels.
2. Building and Civil work  Normally the level of cleanliness should be defined by the number of
3. Air handling system contaminants per cubic metre of the room air. The smaller the
number of contaminants, the cleaner the room classification.
4. Environmental Monitoring
 Pharmaceutical manufacturing facilities should validate their
5. Garments systems to a defined cleanroom classification, on a risk based
6. Sanitation approach. Air supply filtration quality, as well as the air change rate,
should ensure that the defined cleanroom classification is attained.
7. Equipment
 In order to achieve a cleanroom environment the contaminants need
8. Water and Steam system to be removed.
9. Manufacturing Process  External contaminants should be removed by efficient filtration of supply air
 Internal contaminants should be removed by dilution and flushing of contaminants in
10. Form-full-seal technology or blow, fill-seal technology the room or by displacement airflow.
11. Product Containers and Closures
12. Documentation

9/29/2011 45 9/29/2011 46

Types of Operations to be carried out in the

Grade At Rest (b) In Operation (a) various Grades for Aseptic Preparation
Maximum number of permitted particles per cubic metre equal Grades Type of operation for aseptic Corresponds Corresp
to or above preparation to –Class of onds to
US system -ISO
0.5µm 5µm 0.5µm 5 µm
A Aseptic preparation and filling Class 100 Class 5
A 3520 29 3500 29
B Background room conditions Class 1,000 Class 6
B (a) 35,200 293 3,52,000 2,930 for activities requiring Grade
A
C (a) 3,52,000 2,930 35,20,000 29,300
C Preparation of solution to be Class 10,000 Class 7
D (a) 35,20,000 29,300 Not defined Not defined © filtered
©
D Handling of components after Class Class 8
washing 1,00,000

9/29/2011 47 9/29/2011 48

8
 9/29/2011

Grade Types of Operations to be carried out in the various Grades

for Terminally Sterilized Products Grade Air Sample Settle plates Contact plates Glove points
(cfu/ml) (Dia. 90 (Dia. 55 mm) (five fingers)
A Filling of products, which are usually at risk mm)cfu/ 2h cfu per plate Cfu per
glove
A <1 <1 <1 <1
C Placement of filling and sealing machines, preparation of
solution, when usually at risk. Filling of product when
unusually at risk B 10 5 5 5

D Moulding, blowing (pre-forming) of plastic containers,

Preparations of solutions and componenets for subsequent C 100 50 25 -
filling

D 500 100 50 -

9/29/2011 49 9/29/2011 50

Environmental factors in the design of

Parenteral Production Facilities: Site selection,
container size, environmental control needs
and product characteristics, personnel flow,
design concepts, steam, its generation and
use in sterilization, compressed air.

9/29/2011 51