Location and Surrounding
Selection
of a site for construction of a pharmaceutical factory is an important
decision. This decision should be taken after careful consideration of various
aspects. Ideally location of the factory site should be hygienic and its
surrounding should be such as to have minimum sources of pollution. It should
be away from open sewage, drain public lavatory or any factory which produces disagreeable
or obnoxious odor or fumes or large quantity of soot, dust or smoke, chemical
or biological emissions. Other factors that should be considered while
selecting a site for pharmaceutical factory include
-
Transportation facilities for transportation of men, equipment and materials
-
Availability of suitable water
-
Availability of electricity power
-
Availability of maintenance facility for repair and maintenance of plant
-
Availability of communication facility
-
Proximity of civic facilities like education, housing, recreation, local
transport, shopping, etc for factory personnel
-
Local statutory restrictions
-
Government incentives like cash subsidies, tax exemptions, etc
Building
First
step in construction of building is to make layout. There are many points which
should be kept in mind whiling designing a layout for factory premises. Silent
points are given below:-
- Total area of land available
- Percentage of area that can be converted under local laws
- Dosage forms to be manufactured (tablet, capsule, ointments, injection, etc)
- Scale of operation i.e. small scale, medium scale, large scale Different areas that are required, to be provided in pharmaceutical factory( storage area, weighing area, production area, quality control area, ancillary area)
- Requirement of building for hazardous materials
- Specific requirement for utilities (boiler for generation of steam, gases, water)
- Logical flow of material i.e. goods in store-production-quarantine and assembly- warehouse- goods out
- Provision for national or local factory law
- Future projects The layout and design must aim to minimizing the risk of contamination, permitting effective cleaning and maintenance in order to avoid cross contamination, build up of dust or dirt and any adverse effect on the quality products in general. Some general guidelines are given below which will be helpful in preparing layout, designing and construction of building.
- Since little modification can be carried out in water supply lines and drainage system after construction of the buildings, a thoughtful consideration should be given to these aspects.
- Toilets should be communicated directly either with production or with storage areas.
- There should be adequate facilities for changing and storing clothes
- Rest and refreshment room should be separate from other areas.
- As far as possible maintenance workshops should be separated from production areas
- If possible there should be separate building for animal house
- Floors should be smooth and impervious. This can be achieved in cement flooring or mosaic flooring. Where heavy equipment is to be moved from one place to another. Edge lines between floor and walls should be smooth and slightly curved so that these can be cleaned easily. Adequate slope should be provided towards drainage system. Floors of areas where acids or alkalis are handled may be constructed of acid proof tiles.
- Internal walls should be plastered with cement to smooth finish and should be finished with appropriate paint.
- Ceiling should be smooth and impervious. This can be achieved by plastering with cement to smooth finish and by painting.
- Overhead ducts, pipes, lighting fixtures should be avoided in production areas, because these are not cleanable surface. If unavoidable, these should be contained within suspended or false ceiling.
- Doors and windows should be hard, smooth and impervious. wooden doors should be avoided in production area, whenever required hydraulics door closer should be provided. Now a day a synthetic material Nuwud MDF is available. This material is fire retardant, moisture resistant, termite and fungus resistant.
- Drains in the building should be adequate size and should have trapped gullies. Where drains are connected directly to sewer, these must be provided with an air break or mechanical device to prevent back siphonage.
- Passage of adequate width should be provided to facilitate movement of personnel, machinery and materials.
Principle Areas of Pharmaceutical Manufacturing Facilities
The regulatory guidelines provide information on some common areas in the facility :
1. Ancillary area- These area covers:
- Rest and refreshment room, toilets and wash area
- Cloth storage area
- Change area of employees
- Engineering workshop
- Animal house and similar areas
2. Warehouse Area /Storage area- Various categories of the materials are required to store in a pharmaceutical manufacturing unit. Categories of the materials, which need special attention are:
- Starting material
- Packaging material
- Intermediates
- Bulk finished products
- Finished products
- Products in quarantine
- Release materials
- Rejected materials
-
Returned products
-
Recalled products
Sufficient space should be provided for different
categories of materials. These area should be maintained clean and dry. Where
special storage conditions (eg temperature and humidity) are required these
should be provided, checked and monitored.
Materials like narcotics, highly active materials and
materials having special risk of abuse, fire or explosion should be stored in a
safe and secure areas. These materials should be handled in accordance with the
provisions of legislation.
3.
Weighing area- Weighing operations are
generally carried out in storage areas and processing areas. Weighing
operations can produce dust and floating dust can contaminate other materials.
Therefore weighing area should be cubicalized. Where low bioburden is required
to be maintained, weighing area should be provided with laminar flow bench.
Sensitizing materials can be weighed in dedicated facilities meant for such
materials.
4.
Quality control area- like production
areas, quality control areas also have some features that should be taken into
consideration while designing and constructing. These include:-
i)
Quality control laboratories
should be located in distinctly separate area
ii)
Quality control laboratory
should designed to suit the intended operations
iii)
Different types of testing i.e.
chemical, instrumental, microbiological and biological should be physically separated
from each other.
iv)
If quality control laboratory
is busy in analyzing special products like radio isotopes, preparation of
either containing live pathogenic microorganism, dedicated facility should be
provided and appropriate precaution should be taken.
v)
Sufficient space should be
provided in quality control laboratory for installing of the equipment,
instruments and movement of men and materials. Sufficient space should be
provided for storage of
-
Storage of chemical and
reagents
-
Samples received for testing
-
Reference sample
-
Reference standard
-
Records
i)
Certain samples require
controlled conditions for storage for example, reference standard, microbial
cultures. For storage of such material appropriate storage facilities should be
provided ( e.g. refrigerator)
ii)
Certain work benches where
corrosive materials like acids are used should have acid proof tops
iii)
Appropriate exhaust systems are
required for removing laboratory fumes. Operations with excess fumes, fuming
cupboards should be constructed with powerful exhausts.
5.
Production Area-
i)
General category products
(other than antibiotics, cytotoxic and hormones) should be manufactured in
separate manufacturing facility
ii)
Highly potent, sensitive or
live micro-organism, etc should be produced in separate areas to avoid cross
contamination
iii)
Premises should be designed to
have a logical flow of materials, well organized layout of plant and machinery
and ease of cleaning both equipment and
facility
iv)
Depending on volume of material
to be handled, adequate space should be
provided to avoid mix-ups
v)
Production areas should be
properly ventilated with suitably designed HVAC (Heating, Ventilation and Air
Conditioning) system, appropriate to product being handled
vi)
Premises for packaging of
pharmaceuticals should be specifically designed and laid out so as to avoid
mix-ups and cross contamination.
Sanitation
CFR 211.56 gives guidelines of
sanitation. It states-
1.
Any building used for
manufacture, processing, packing or holding of a drug product shall be
maintained in a clean and sanitary condition, any such building should be free
from rodents, birds, insects, and other vermin.
2.
There should be written
procedures assigning responsibility for sanitation and describing in sufficient
detail the cleaning schedules, methods, equipment and materials to be used in
the cleaning the building and facilities, such written procedure should be
followed.
3.
There shall be written
procedure for use of suitable rodenticides, insecticides, fungicides,
fumigating agents and cleaning and sanitizing agents. Such written procedure
shall be designed to prevent the contamination of equipment, component drug
product container and closures, packaging and labeling materials or drug
products and shall be followed.
4.
Sanitation procedure shall
apply to work performed by contractors or temporary employees as well as work
performed by full time employee during the ordinary course of operation.
5.
Certain points to be noted in
this regards:-
i)
Disinfectant must be rotated
during the sanitation programme to avoid resistance development by microbes
ii)
Microbial profiles of the
critical areas in the manufacturing facility should be studied and monitored.
iii)
SOPs on sanitation should
clearly provide the frequency of sanitation, concentration of specific
detergents and disinfectant used.
iv)
Procedure for preparation,
filtration and storage of disinfectant. Diluted disinfectant must be used on
the same day and should not be stored for use in future
v)
Sanitary supervisor is an
important person in the system of sanitation and should be trained enough in
the requirement of sanitation in pharmaceutical
manufacturing facilities
vi)
SOPs should be available even
for cleaning and sanitation of external are of facilities like roads, lawn,
etc. cutting and disposal of lawns (grass) is an important aspect of
sanitation, since the cut grass has potential of presence of small crawling or
other insects and they can pose a danger to the operating facilities.
Maintenance
CFR 211.58 states that “Any building used
in the manufacture, processing, packing or holding of a drug product shall be
in a good state of repair.”
Facility maintenance includes the
following things
-
Spoilage of plaster
-
Peeling of a paint
-
Leakage from the ceiling or
other surfaces
-
Leakage from pipe lines of
waters, steam, gases, etc
-
Plumbing problems
-
Loose or broken tiles
-
Improper closing of doors,
windows
-
Improper electrical wiring
-
Improper electrical fitting/
fixtures
-
Missing tube lights , etc
A
detailed checklist may be prepared for the points to be looked into, during
routine inspection of the facilities and the identified deficiencies should be
rectified immediately and the facility must always be maintained in a state of
good repair.
Environment Control in
Sterile Area
Sterile
products are very critical and sensitive in nature hence it requires very high
degree of precaution and prevention is required in its preparation and there
shall be strict compliance with standard prescribed by regulatory
authorities.
Air
classification system for manufacture of sterile products
| Grades | Maximum permitted numberof particles/m3 |
Maximum no of viable microorgani sm permitted per m3 |
|||
|---|---|---|---|---|---|
| At rest | In operation | ||||
| 0.5 to 5 μm |
> 5 μm | 0.5 to 5 μm |
> 5 μm | ||
| A | 3500 | 0 | 3500 | 0 | Less than 1 |
| B | 3500 | 0 | 350,000 | 2000 | 5 |
| C | 350,000 | 2000 | 3500,000 | 20,000 | 100 |
| D | 3500, 000 |
20, 000 |
Not defined |
Not defined |
500 |
Types of operations to be carried
out in the various grades for aseptic preparation
|
Grade |
Types
of operations for aseptic preparation |
|
A |
Aseptic preparation and
filling |
|
B |
Background room
condition for activities requiring Grade A |
|
C |
Preparation of the
solution to be filtered |
|
D |
Handling of components
after washing |
Recommended limits for microbiological monitoring of clean area “In
operation”
| Grade | Air sample CFU/ m3 | Settle plates (dia. 90 mm CFU/2hrs) | Contact plates (dia. 55 mm CFU/plate) | Glove points (Five fingers CFU/glove) |
|---|---|---|---|---|
| A | <1 | <1 | <1 | <1 |
| B | 10 | 5 | 5 | 5 |
| C | 100 | 50 | 25 | - |
| D | 500 | 100 | 50 | - |
US
FDA guidelines for air classification
| Clean area classification | 0.5 μm particles/ ft3 | 0.5 μm particles/ m3 | Microbiological limit | |
|---|---|---|---|---|
| CFU/ft3 | CFU/m3 | |||
| 100 | 100 | 3500 | <1 | <3 |
| 1000 | 1000 | 35000 | <2 | <7 |
| 10000 | 10000 | 350000 | <3 | <18 |
| 100000 | 100000 | 3500000 | <25 | <88 |
Utilities and
Maintenance in Sterile Areas
In addition to general requirements of the building
and facilities, certain additional requirements must be met for manufacture of
sterile product
1.
Walls ceiling and floor
surfaces should be hard, smooth, impervious, non shedding, non-flaking, non
cracking, all corners covered, and with unbroken surfaces. T thin layer of
(2mm) epoxy coating may give desired finish.
2.
Avoid ledges and other
horizontal surfaces which could collect particulate matter or disturb uniform
air flows.
3.
Install pipes, ducts and other
utilities in a manner to avoid recesses and other difficult to clean and sanitize.
For this reason utility services may be dropped down close to the point of use
through a round, mirror polished SS 304 or 316 grade pipes.
4.
Adequate space for gowning
areas, garment storage, soiled garments disposal and hand washing should be
provided. Hot air dryers should be provided for drying hands and feet wherever
required.
5.
Gowning area should be
separated from other areas of material movement. Change rooms for gowning may
be provided with number of air locked rooms. Generally entry to aseptic area
and exit from aseptic area should be from different routes. Cleaner side
airlocks should be at relatively higher air pressure than that of less cleaner
side. Adjacent rooms should have minimum 15 pascal (1.5 mm of water gauge)
pressure differential to achieve desired effect.
6.
Everywhere personnel entry and
material entry should be separate
7.
Clean room should not have
drains and sinks (in grade A and B areas) in C grade area, if drain or sink is
needed they should have sufficient hygienic control over there.
8.
When two different grade areas
n(say b and C) are separated by windows, these windows should have double
glass. The relatively non critical area should have openable window glass,
which can help in cleaning and sanitizing the enclosed space in the two glass
windows
9.
Furniture like tables ,chairs, etc
in the critical clean room area should be made from SS304
10. Employee welfare rooms (like canteen, restrooms, etc), animal house
are potential source of contamination and hence they should be well segregated from
clean area operations.
11. The facility should be designed in a fashion that A and B grade
activities could be seen through the double glass window. This help senior supervisor
staff to supervise the activities without entering that area.
12.
HVAC System- i) Temperature-
this has to be product specific but normally in critical area (A, B and C) it
may be 23 °C± 2 °C.
ii) Relative Humidity- this is also product specific but generally a
relative humidity of 45% ±5% is recommended
iii) Air velocity- In case of HEPA filters the air velocity normally
required is between 80-120 feet per minute.
iv) Differential pressure and
room to room air balancing- normally a differential pressure between the
adjacent rooms is recommended to be 15 Pascal. (10pascal= 1 mmg water gauge)
v) HEPA filter and their integrity- it must be tested regularly by
DOP or DOS testing methods
vi) Laminar Air Flow Units (LAF) - All class A installation should
have LAF units working. They can be either vertical or horizontal.
i)
Air System Failure Alarm (ASFA)
- all aseptic area (grade A nod B) must be fitted with ASFA. This can be only
audio or audio visual.
Control
of Contamination
Following
information should be given to the person working in this area
-
There are two main types of
contamination- Living and Non-living
-
While making sterile products
our concern should be particularly with preventing, removing or destroying
micro-organisms (bacteria. Moulds, yeasts, viruses).
-
Some microbes are very
dangerous to us. Others can be quite harmless and even useful in some
circumstances. ALL OF THEM MUST BE KEPT AWAY OR REMOVED FROM STERILE PRODUCT.
-
Non-living contamination,
whether it is undesired chemical substance or just inactive dust, powder or fibers
must be kept out of sterile products
-
Microorganisms can produce
dangerous PYROGENS. These must not be allowed to develop in or on sterile
products.
1.
Controlling contamination-Clean Rooms
i)
A number of stages in sterile
product manufacture are carried out in clean rooms
ii)
The term ‘Clean Room’ has
special meaning in sterile product manufacture.
The clean room is the room
where the air is supplied, under pressure (positive), through special filters
(HEPA) designed to keep any micro organisms and other particles in the air down
to defined low level.
iii) In sterile area all the surface
of floors, walls, ceiling, etc should be hard and free from cracks to avoid
dust and micro organism accumulation and should permit easy cleaning.
1.
Control of contamination- People
All people who are going to work in the aseptic area
should be emphasized on the following points to control the contamination
i)
Keep, body, hair, face, hands
and fingernails clean.
ii)
Report any illness, cuts or
respiratory, gut or skin problem
iii)
Follow the written changing and
wash-up procedure exactly.
iv)
Do not wear cosmetics, jewelry
or wrist watches
v)
Leave all personal items
(wallets, coins, keys, comb, etc) in the changing room.
vi)
Do not take papers, documents
into a clean room
vii)
Always move gentle and steadily
(Brisk movement shed large particles from body movement)
viii)
Keep talking to an absolute
minimum (No talk should be the objective)
2.
Control of contamination by cleaning and disinfections
i)
The written procedures
regarding cleaning and disinfection should be followed EXACTLY and STRICTLY.
ii)
Before disinfection, it is
necessary to clean the area completely.
iii)
All the cleaning and
disinfecting agents and materials themselves should be clean
iv)
Avoid cleaning by mops ,use
equipment
v)
Use vacuum cleaner for sucking
dust
vi)
Always start cleaning walls and ceiling from
top to avoid recontamination.
vii)
Special care should be taken
for selecting right cleaning and disinfecting agents in right dilution.
viii)
All the equipments and
accessories must be cleaned after used and stored in clean and dry place.
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