GMP requirements and standards govern the production of sterile pharmaceutical products to ensure quality, consistency, safety and sterility. Sterile areas where these products are manufactured must tightly control particles and other environmental factors. They are classified into grades A through D depending on their risk of contamination during production activities such as component preparation, product filling, and terminal sterilization. Personnel, facilities, equipment and processes must all be carefully designed, operated and maintained to minimize any risk of microbial contamination and to uphold stringent sterility standards.

2. GMP Requirement For Sterile
Area

3. What is GMP
• GMP, which stands for Good Manufacturing Practices, is a set of rules and
standards that govern how pharmaceutical products are made. It includes
specifications for ensuring quality, consistency, and safety in the
development, manufacturing, and distribution of medicines. GMP was
designed to ensure that safe and effective drugs are produced for patients. It
also helps ensure that patients get the right drug at the right dose, with the
right side effects, and using the right manufacturing process.

4. what is sterile area
• Sterile area is the clean room in which the concentration of airborne particle is controlled,
and is constructed and used in a manner to minimize the introduction, generation and
retention of particles inside the clean room and in which the other relevant parameters e.g.,
Temperature, Humidity and Pressure are controlled as necessary.
• Clean rooms are fitted with HEPA filters and dehumidifier systems to allow preparation of
pharmaceutical products in a moisture free and contamination free environment.
• sterile means having an entire absence of viable microorganisms or organisms that have the
potential to reproduce. No life at all like (bacteria, fungi, and viruses)
• Sterile is basically, the surface and product contact part that is free from microbial
contamination. The products that are free from all pathogens and microorganisms are called
sterile products, small volume parenteral, and large volume parenteral and ophthalmic
products.
• The technique used for the removal of all harmful microorganisms or pathogens is called the
sterile technique.

5. General considerations
• The production of sterile preparations should be carried out in clean areas,
entry to which should be through airlocks for personnel and/or for equipment
and materials. Clean areas should be maintained to an appropriate standard
of cleanliness and supplied with air that has passed through filters of the
required efficiency.
• The various operations of component preparation (such as those involving
containers and closures), product preparation, filling and sterilization should
be carried out in separate areas within the clean area.

6. Grades of Clean Rooms
• For the manufacture of sterile pharmaceutical preparations, four grades of clean areas are
distinguished as follows:
• •Grade A: The local zone for high-risk operations, e.g. filling and making aseptic
connections. Normally such conditions are achieved by using a unidirectional airflow
workstation. Unidirectional airflow systems should provide a homogeneous air speed of
0.36–0.54 m/s (guidance value) at a defined test position 15–30 cm below the terminal filter
or air distributor system. The velocity at working level should not be less than 0.36 m/s. The
uniformity and effectiveness of the unidirectional airflow should be demonstrated by
undertaking airflow visualization tests.
• •Grade B: In aseptic preparation and filling, this is 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 or carrying out activities during which the product is not directly exposed (i.e.
aseptic connection with aseptic connectors and operations in a closed system).

7. Maximum permitted airborne particle concentrate
Maximum permitted number of particles per m3 greater than
or equal to the tabulated size
At rest
a
In operation
b
Grade 0.5 μm 5.0 μm 0.5 μm 5.0 μm
A 3 520 20 3 520 20
B 3 520 29 352 000 2 900
C 352 000 2 900 3 520 000 29 000
D 3 520 000 29 000 Not defined Not defined

8. Manufacture of sterile preparations
• Clean areas for the manufacture of sterile products are classified according to the required
characteristics of the environment. Each manufacturing operation requires an appropriate
level of environmental. Cleanliness in the operational state to minimize the risks of
particulate or microbial contamination of the product or materials being handled.
• Gowning System:
• In the manufacture of sterile drugs Gowning System is most important.
• 1)The gown must be sterilized and made of material which will not shed particles.
• 2)Everyone entering a clean or a sterile area must change gear garments and wear special
garments which includes head, musk and footwear.
• 3)The number of people must be as low as possible and restricted to authorized people.
• Environment Monitoring:
• Environmental monitoring is one of the most important tasks in the sterile department. It is a
regular check of view to take timely corrective measures for maintaining a favorable
manufacturing environment, minimizing the risk of product contamination. It is also a part of
validation exercise.
• The environmental monitoring approach is also adopted to ensure that there is no significant
risk of air borne cross-contamination.

9. • Terminally sterilized products
• Components and most products should be prepared in at least a Grade D environment to
ensure low microbial bioburden and particulate counts prior to filtration and sterilization.
Where the product is at unusual risk of microbial contamination (e.g. because it actively
supports microbial growth, must be held for a long period before sterilization, or is
necessarily processed mainly in open vessels), the preparation should generally be done in
a Grade C environment.
• The filling of products for terminal sterilization should generally be done in at least a Grade C
environment.
• Where the product is at unusual risk of contamination from the environment (e.g. because
the filling operation is slow, the containers are wide- necked or are necessarily exposed for
more than a few seconds before sealing), the filling should be done in a Grade A zone with at
least a Grade C background.
• The preparation and filling of ointments, creams, suspensions and emulsions should
generally be done in a Grade C environment before terminal sterilization.

10. • Aseptic processing
Aseptic processes is a process performed maintaining the sterility of a material that is
assembled from components ,each of which has been previously sterilized. This is acheived by
using adequate conditions and facilitates designed to prevent microbial contamination.
Aseptic processesrelies on several independent factors for thje prevention of recontamination of
previously sterilized components, it presents a higher riak of microbial contamination of the
product than terminal sterilization.

11. sterilization
• Whenever possible products intended to be sterile should be terminally sterilized by heat in
their final container. Where it is not possible to carry out terminal sterilization by heating due
to the instability of a formulation or incompatibility of a pack type (necessary to the
administration of the product, e.g. plastic eye-dropper bottles), a decision should be taken to
use an alternative method of terminal sterilization following filtration and/or aseptic
processing.
• Types of sterilization
• Sterilization can be achieved by the use of moist or dry heat, by irradiation with ionizing
radiation (noting that ultraviolet irradiation is not normally an acceptable method of
sterilization), by ethylene oxide (or other suitable gaseous sterilizing agents), or by filtration
with subsequent aseptic filling of sterile final containers. Each method has its advantages
and disadvantages. Where possible and practicable, heat sterilization is the method of
choice. In any case the sterilization process must be in accordance with the marketing and
manufacturing authorizations.

12. Types of sterilization

13. • Precautions

14. • PERSONNEL
Only the minimum number of personnel required should be present in clean areas; this is
particularly important during aseptic processes. As far as possible, inspections and controls
should be conducted from outside such areas.
All personnel (including those concerned with cleaning and maintenance) employed in such
areas should receive initial and regular training in disciplines relevant to the correct
manufacture of sterile products, including hygiene and the basic elements of microbiology. .
High standards of personal hygiene and cleanliness are essential and personnel involved in the
manufacture of sterile preparations should be instructed to report any conditions that may
cause the shedding of abnormal numbers or types of contaminants; periodic health checks for
such conditions are desirable. The action to be taken in respect of personnel who might be
introducing undue microbial hazards should be decided by a designated competent person.
Changing and washing should follow a written procedure designed to minimize the
contamination of clean-area clothing or the carry-through of contaminants to clean areas. The
clothing and its quality should be appropriate for the process and the grade of the working area.
It should be worn in such a way as to protect the product from contamination.

15. • Outdoor clothing should not be brought into changing rooms leading to Grade B and C
rooms. For every worker in a Grade A/B area, clean sterile (sterilized or adequately
sanitized) protective garments should be provided at each work session. Gloves should be
regularly disinfected during operations. Masks and gloves should be changed at least every
working session. Operators working in Grade A and B areas should wear sanitized goggles.
• Wrist-watches, cosmetics and jewellery should not be worn in clean areas.
• The clothing required for each grade is as follows:
• •Grade D. The hair and, where relevant, beard and moustache should be covered. Protective
clothing and appropriate shoes or overshoes should be worn. Appropriate measures should
be taken to avoid any contamination from outside the clean area.
• Clothing used in clean areas should be laundered or cleaned in such a way that it does not
gather additional particulate contaminants that can later be shed. Separate laundry facilities
for such clothing are desirable. If fibres are damaged by inappropriate cleaning or
sterilization, there may be an increased risk of shedding particles. Washing and sterilization
operations should follow standard operating procedures.

16. • Premises
• All premises should as far as possible be designed to avoid the unnecessary entry of
supervisory or control personnel. Grade A and B areas should be designed so that all
operations can be observed from outside.
• In clean areas all exposed surfaces should be smooth, impervious and unbroken to minimize
the shedding or accumulation of particles or microorganisms and to permit the repeated
application of cleaning agents and disinfectants, where used.
• False ceilings should be sealed to prevent contamination from the void space above them.
• Pipes and ducts and other utilities should be installed so that they do not create recesses,
unsealed openings and surfaces that are difficult to clean. Sanitary pipes and fittings
should be used and threaded pipe connections should be avoided.
• Sinks and drains should be avoided wherever possible and should be excluded from
Grade A and B areas where aseptic operations are carried out. Where installed they should
be designed, located and maintained so as to minimize the risks of microbial contamination;
they should be fitted with effective, easily cleanable traps and with air breaks to prevent
backflow. Any floor channels should be open and easily cleanable and be connected to
drains outside the area in a manner that prevents the ingress of microbial contaminants

17. .
• Changing rooms should be designed as airlocks and used to provide physical separation of
the different stages of changing and so minimize microbial and particulate contamination of
protective clothing. They should be flushed effectively with filtered air. The final stage of the
changing room should, in the at-rest state, be the same grade as the area into which it leads.
The use of separate changing rooms for entering and leaving clean areas is sometimes
desirable. In general hand-washing facilities should be provided only in the first stage of the
changing rooms.
• There should not be a change of more than one grade between airlocks or passages and
changing rooms, i.e. a Grade D passage can lead to a Grade C airlock, which leads to a
Grade B changing room, which leads to a Grade B clean room. Changing rooms should be
of a sufficient size to allow for ease of changing. Changing rooms should be equipped with
mirrors so that personnel can confirm the correct fit of garments before leaving the changing
room.
• Airlock doors should not be opened simultaneously. An interlocking system and a visual
and/or audible warning system should be operated to prevent the opening of more than one
door at a time.

18. • A filtered air supply should be used to maintain a positive pressure and an airflow relative to
surrounding areas of a lower grade under all operational conditions; it should flush the area
effectively. Adjacent rooms of different grades should have a pressure differential of
approximately 10–15 Pascals (guidance value). Indicators of pressure differentials should be
fitted between areas where this difference is important, and the pressure differentials should
be regularly recorded and failure alarmed.
• Consideration should be given to restricting unnecessary access to critical filling areas, e.g.
Grade A filling zones, by means of a physical barrier.

19. • Equipment
• Whenever possible, equipment used for processing sterile products should be chosen so
that it can be effectively sterilized by steam or dry heat or other methods.
• As far as possible, equipment fittings and services should be designed and installed so that
operations, maintenance and repairs can be carried out outside the clean area. Equipment
that has to be taken apart for maintenance should be re-sterilized after complete reassembly,
wherever possible.
• When equipment maintenance is carried out within a clean area, clean instruments and
tools should be used and the area should be cleaned and disinfected again, where
appropriate, before processing recommences, if the required standards of cleanliness and/or
asepsis have not been maintained during the maintenance work.
• All equipment such as sterilizers, air-handling and filtration systems, air vent and gas filters,
water treatment, generation, storage and distribution systems should be subject to validation
and planned maintenance; their return to use should be approved.

20. • References
• WHO Good Manufacturing Practices for sterile pharmaceutical products
Annex 6
• https://www.pharmaguideline.com/2012/09/gmp-for-sterile-pharmaceutical.html