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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5428_Библиотеки_им_академика_М_И_Перельмана
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warm area and together with moisture and a little air, these become ideal places for
bacterial growth at a rapid rate.
The hands can be the source of many microorganisms. Every personnel must wash
his/her hands with soap and water located at each hand washing station. Hands must
be washed at least in the following situations:
Before starting the work,
After break time,
Before and after lunch,
After using the washroom (the number of bacteria on one’s fingertips becomes
double after using the washroom),
After blowing the nose,
After handling garbage, after touching a pallet, skid, floor mat or picking up
product from the floor, or whenever somebody’s hands have become
contaminated.
Always dry the hands using the disposable paper towels provided. Never dry or wipe
the hands-on clothing as it may be contaminated with microorganisms.
The protective clothing provided must be changed daily and when necessary,
throughout the day.
All soiled laundry must be placed in the laundry holder provided. No soiled or dirty
laundry (dress) is to be left in the production area.
One cannot carry personal items such as pens, knives, cellphones, or other small
articles in uniform pockets.
Hands must be washed properly before putting on new pair of gloves.
Gloves must be changed at every break, when torn, after touching garbage, and after
touching your face or blowing nose. Gloves must be changed as often as required to
ensure safety of the products. Extra gloves are not to be carried in pockets of working
clothes since there is the probability of gloves falling unnoticed into equipment or
finished products.
All used gloves must be disposed in the garbage cans provided.
These are precautions one must take to prevent the contamination of the product he/she is
working with. These precautions are listed below:
Any activity that can cause contamination of the product must be prohibited. This includes:
Eating, drinking and chewing in production area,
Chewing gum,
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Spitting,
Smoking,
Coughing or sneezing, Coughing or sneezing must be directed away from product and
must be blocked by shoulder or upper arm.
Wash the hands frequently with hand soap using warm, running water for 30 seconds.
Refrain from touching the nose or face. If it is done – the hands must be washed
immediately.
If someone wears gloves, the same rules apply.
The hands must be washed after removing gloves and before applying new gloves.
Hand-washing signs and proper techniques are posted in all employee facilities.
The clean utensils or equipment or floor should not be touched unless proper cleaning
and sanitizing procedures have been performed.
The product and /or packaging material should not be touched.
If product makes contact with the floor, it must be deemed inedible and placed in the
garbage bins.
The cardboard boxes or bags should not be placed on the floor. These should be kept
on skids, stands or packaging tables.
The cardboard boxes should not be placed on product contact surfaces. They must
have been handled many times and have sat in unsanitary environments making them
a potential source of bacteria and physical contamination.
If someone is ill or injured, he/she must report immediately to the Production Manager
or Supervisor, or QA designate. The Production Manager or Supervisor or QA
designate will assess each situation. Under this situation one must comply with the
following rules:
All cuts, sores, scratches, or other wounds must be covered with a waterproof covering
such as band-aid which could firmly cover the wound. The microorganisms from an
infected area can be easily transferred to the products if handled. Glove must be worn
on the top of band-aid or bandage.
There must be no coughing or sneezing in the production area. Microorganisms can be
readily transferred by the spray droplets and mucous from coughs and sneezes.
Sneezes and coughs must be blocked by using the shoulder or upper arm.
If someone blocks a sneeze or a cough with his/her hands, the gloves must be
immediately disposed of and then, the hands are to be washed and sanitized.
If someone is suffering from or is a carrier of an infectious illness such as vomiting or
diarrhea, it must be brought to the notice of the Supervisor immediately. The infected
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person may not work in a production area but may be assigned to “modified work” in
a non-critical area.
Cross-Contamination
Protective Clothing and Hairnets
Protective clothing is not to be worn in the lunchroom, washrooms or outside the
building.
When leaving the production area the coats are not to be left there in the production
area, should be hung on hooks provided. This is to prevent cross contamination of
foreign and potential harmful bacteria to the production area that could cause spoilage
of drug and/or its product 8 .
Limited Access I Traffic and Air Flow
All doors must be kept closed.
Housekeeping
Garbage must be emptied on a regular basis to prevent overflowing.
The floor must be kept free of trash, broken pellets, spilled products, etc.
A dry sweep is to be done if required during production.
All products must be removed from an area if a wet wash is required during breaks.
Pellets and plastic crates must be neatly stacked and must not be left up against a wall.
Tools and equipments used for housekeeping activities can also be the source of
contamination. Hence, the actions are recommended to avoid such contamination.
Squeegees
Squeegee is to be used to remove water from the floor.
A squeegee must not be used to remove water from drug contact surfaces. This action
would cause cross-contamination of bacteria from the floor to the drug contact surface
via the squeegee.
Rags
Rags are not allowed. Rags can harbor bacteria in the cloth material and within a short
time the bacteria can multiply and cross contaminate the product.
Disposable paper or jay cloths are the only tools allowed to clean drug contact
surfaces. Excess water can be removed by tipping the table top surface initially and
then by the disposable paper towels provided.
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Facilities
Washrooms/Change Rooms
The washrooms should be equipped with clean, modern washroom facilities. Persons
using are expected to help keeping the facilities clean because they are part of the
work place. Before using the washroom facilities, one must remove his/her protective
clothing and hang it on the hooks provided at the designated location. This can
eliminate any contamination of the work clothes. One must not forget to wash his/her
hands just after using and before leaving the washroom’.
The change room/locker facility is provided for keeping the street clothing and
personal belongings.
No food, work clothing or equipment such as gloves, aprons, etc. must be stored there.
All foot wear is to be stored on shoe racks in change rooms.
Lunchroom
To maintain a drug or its product safe, proper environment for employees are provided to
enjoy lunch and breaks.
The lunchroom should be kept clean and tidy at all times.
Personal coffee mugs, containers and utensils must not be left dirty in the sink.
Access
Through designated staff entrance/gate all the personnel should enter into the building
within the time.
Personnel must proceed to change room and remove the street cloths, put on work
cloths and put on production foot wear and then proper uniform. They must put on
hair net.
Immediately the hands must be washed for about 30 seconds.
Exit is the exact reverse of the entrance procedure.
Visitors must register at reception desk before entering the building and he/she must
be accompanied by an authorized employee.
Chemicals
Only authorized personnel are allowed to use chemicals.
When not in use, the chemicals must be stored in chemical storage in the designated
area.
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Fig. 4.2 Factors influencing the location of a pharmaceutical industry
Layout of Buildings
The pharmaceutical industry is supposed to deliver the safe and therapeutically effective
products which shall retain its potency till it is consumed by a patient within the shelf life.
To meet this challenge, it is necessary to manufacture the products in a suitable environment
and following GMP. The suitable environment includes the manufacturing premise. Hence,
the drug should be processed in a building which is suitably planned, designed, constructed,
and validated. The manufacturing operations are complex in nature and that can meet the
world class pharmaceutical standards
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Location of a plant refers to an establishment of a pharmaceutical industry at a particular
place. The performance of an enterprise is considerably influenced by its location. The
selection of a site depends mainly on its size and nature. The size of an industry may be of
three types – small, medium, and large. Location of plant partly determines the cost of
operation and capital requirement. It determines the nature of investment costs to be incurred
and the levels of operating costs. Location sometimes determines the physical factors of the
overall plant designs for example, requirements for heating and ventilation, storage capacity
and availability of raw materials, transportation of raw material s and finished goods, power
requirement, cost of labors, taxes, cost of construction, fuel, etc. Keeping in view of the
national benefits, the government sometimes plays an important role.
The location of a plant is selected based on the following:
Availability of raw materials
Nearness to the potential market
Nearness to source of power operation
Supply of labor
Transport and communication facilities
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Suitability of land and climate
Mixing with other group of companies
Availability of housing, other amenities, and services
Local building and planning regulations
Safety requirements
Miscellaneous considerations
However, the site can be selected both in rural and urban area based on the facilities
availability as shown in Fig 4.2.
Once a decision is taken on the location of the plant, a suitable layout of the plant should be
made. In fact, efficiency and performance of good machineries depend greatly on the layout
of the plant. Plant layout refers to the method of allocating machines and equipment,
different processes of production, and other necessary services required in transformation of
processes necessary for manufacture of product in the available space of the premise, so that
various operations can be performed efficiently, and the output is of high quality at a
minimum cost. Planning of layout of a plant is a continuous process and involves continuous
development or improvement of the existing arrangement. The disposition of the various
parts of a plant plus all equipment is known as plant layout. Thus, the layout should be such
that all the personnel can handle or use the equipment comfortably, smoothly, and efficiently.
There should be no congestion, waste, frustration and inefficiency
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There are three components involved in a manufacture of product – personnel,
manufacturing cost, and control and supervision of production.
The personnel or workers involved in production expect that
The number of operation and material handling should be as minimum as possible,
Production should be completed as quickly as possible; so that the length of haul and
motion between the operations should be reduced.
More output per man hour; that is, it should give more labor productivity.
There should be no chance of accident; that is, there should be more safety and
security to the workers.
It should provide better working conditions so that efficiency can be improved.
The management desires the following
It should require less cost of maintenance and replacement.
Manufacturing loss due to waste and spoilage should be least.
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The quality of product should high enough and there should be lesser movement of
material and man, time, and cost.
Cost of control should be as low as possible.
Premises must be located, designed, constructed, adapted, and maintained appropriately to
suit the operations to be carried out. At the time of designing following points are to be
considered:
The layout and design of the premises must be intended to reduce the risk of errors
and allow effective cleaning and maintenance to avoid cross-contamination, build-up
of dust or dirt, and any adverse effect on the quality of products.
Where dust is generated for example, during sampling, weighing, mixing, and
processing operations, packaging of powder, adequate measures should be taken to
avoid cross-contamination and facilitate cleaning.
Premises should be in an environment that can protect the manufacturing processes,
presents the smallest risk of contamination of materials or products.
Premises used for the manufacture of finished products should be suitably designed
and constructed to help good sanitation.
Premises should be carefully maintained, to ensure that repair and maintenance
operations cannot present any hazard to the quality of products.
Premises should be cleaned and disinfected, where applicable, according to the
detailed written procedures. Records should be maintained.
Electrical supply, lighting, temperature, humidity, and ventilation should be
appropriate. They should not adversely affect, directly or indirectly, either the
pharmaceutical products during their manufacture and storage, or the accurate
functioning of equipment.
Premises should be designed and equipped to give maximum protection against the
entry of insects, birds, or other animals. There should be a procedure for control of
rodent and pest.
Premises should be designed to ensure the logical flow of materials and personnel.
Ancillary areas
Rest and refreshment rooms should be separate from manufacturing and control areas.
Facilities for changing and storing clothes and for washing and toilet purposes should
be easily accessible and appropriate for the number of users. Toilets should not be
directly attached to production or storage areas.
Workshops for maintenance should be made separated from production areas.
Whenever parts and tools are stored in the production area, they should be kept in
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rooms or lockers reserved for the same purpose.
Animal houses should be well isolated from other areas, with separate entrance for
access to animals and air-handling facilities.
Storage areas
The capacity of storage areas should be sufficient to allow storage of the various
categories of materials and products in a orderly manner with proper separation and
segregation: starting and packaging materials, intermediates, bulk and finished
products, products in quarantine, and released, rejected, returned or recalled products.
Storage areas should be designed or adapted to provide good storage conditions.
Particularly, they should be clean, dry, sufficiently lit and maintained within
acceptable temperature limits. Where special storage conditions are necessary such as
temperature, and humidity. These should be provided, controlled, monitored, and
recorded appropriately.
Receiving and dispatch lines should be separated. They should protect the materials
and products from the weather. Receiving areas should be designed and equipped to
allow containers of incoming materials to be cleaned, if necessary, before storage.
Where quarantine area is provided by storing in separate areas, these areas must be
clearly marked, and their access must be restricted only to authorized personnel. Any
system replacing the physical quarantine should give equivalent security.
Storage of rejected, recalled, or returned materials or products is to be done in separate
areas. These should not be mixed with approved products.
Highly potent and radioactive materials, narcotics, other dangerous medicines, and
substances that can present special risks of abuse, fire or explosion should be stored in
safe and secure areas.
Printed packaging materials are considered to be critical to the conformity of the
pharmaceutical product. Special attention should be paid to its labeling, sampling, and
safe and secure storage of these materials.
There should normally be a separate sampling area for starting materials. If sampling
is done in the storage area, it should be conducted in such a way that the
contamination or crosscontamination can be prevented.
Weighing areas
The weighing of starting materials and the determination of yield by weighing should
be carried out in separate weighing areas designed for the same purpose; for example,
provisions for dust control should be made. Such areas may be part of either storage or
production areas.
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Production areas
Production areas should be well lit, particularly where visual online controls are
carried out.
To reduce the risk of a serious medical hazard due to crosscontamination, dedicated
and self-contained facilities must be available for the production of particular
pharmaceutical products, such as highly sensitizing materials such as penicillins or
biological preparations such as live microorganisms. The production of certain other
highly active products, such as some antibiotics, hormones, cytotoxic substances and
certain nonpharmaceutical products should not be conducted in the same facilities. In
exceptional cases with specific precautions the same facilities can be used. However,
necessary validations including cleaning validation are made. The manufacture of
technical poisons, such as pesticides and herbicides, should not be allowed in premises
used for the manufacture of pharmaceutical products
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Premises should preferably be built up in such a way that allows the production to take
place in areas connected in a logical order corresponding to the sequence of the
operations and to the requisite cleanliness levels.
The adequacy of the working and in-process storage space should permit the orderly
and logical positioning of equipment and materials so that the risk of confusion
between different pharmaceutical products or their components are minimal and can
avoid cross-contamination, and reduces the risk of omission or wrong application of
any of the manufacturing or control steps.
Where starting and primary packaging materials and intermediate or bulk products are
exposed to the environment, interior surfaces such as walls, floors and ceilings should
be smooth and free from cracks and open joints, should not shed particulate matter,
and should allow easy and effective cleaning and, if necessary, disinfection.
Pipe work, light fittings, ventilation points and other services should be designed and
kept to avoid the creation of recesses that are difficult to clean. For maintenance, they
should be easily accessible from outside the manufacturing areas.
Drains should be of proper size and designed and equipped to prevent back-flow.
There should not be open channels, but if they are necessary they should be shallow to
facilitate cleaning and disinfection.
Production areas should be effectively ventilated, with air control facilities including
filtration of air to a sufficient level to prevent contamination and cross-contamination,
as well as control of temperature and, where necessary, humidity suitable for the
products to be handled, to the operations to be undertaken and to the external
environment. These areas should be regularly sanitized during both production and
non-production periods to ensure compliance with their design specifications.
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Premises for the packaging of pharmaceutical products should be specifically designed
and laid out so that there is no mix up, contamination, or cross-contamination.
Quality control areas
QC laboratories should be separated from production areas. The areas where
biological, microbiological or radioisotope test methods are performed should be
separate from each other.
QC laboratories should be designed as per the requirements of the operations to be
carried out in them. Sufficient space should be given to avoid mix ups and crosscontamination. There should be adequate, suitable storage space for samples,
reference standards (if necessary, with cooling), solvents, reagents and records.
The design of the laboratories should consider the suitability of construction materials,
prevention of fumes and ventilation. There should be separate air supply to
laboratories and production areas. Separate air-handling units and other provisions are
to be provided for biological, microbiological and radioisotope laboratories.
A separate and suitable room should be provided for instruments to protect them
against electrical interference, vibration, contact with excessive moisture and other
external factors, or where it is necessary to isolate the instruments.
Service Equipments and their Maintenance
Equipment must be placed, designed, constructed, adapted, and maintained appropriately to
suit the operations to be carried out. The layout and design of equipment must be intended to
minimize the risk of errors and allow effective cleaning and maintenance
crosscontamination, adherence and accumulation of dust or dirt, and any adverse effect on
the quality of the products. These should be sanitized and/or sterilized at appropriate
intervals to avoid malfunctions or contamination that would alter the safety, identity,
strength, quality, or purity of the drug product beyond the official or other established
requirements
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Equipment should be installed in such a way that any risk of error or of contamination
can be minimized.
Fixed pipe work should be clearly labeled to indicate the contents, where applicable,
and the direction of flow.
All service piping and devices should be properly marked and special attention to be
paid to the provision of non-interchangeable connections or adaptors for dangerous
gases and liquids.
Balances and other measuring equipment of required range and precision should be
available for production and control operations and these balances should be
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