Miss Mohini Tawade presents an overview of advanced sterile product manufacturing technology, emphasizing the importance of innovative processes, contaminant control, and environmental conditions in aseptic production. Key areas of focus include the design of clean zones, area planning for personnel and material flow, and strict compliance with regulatory standards to ensure product safety. The document also outlines the requirements for utilities, maintenance, and personnel access in maintaining sterile environments.

1. ADVANCED STERILE PRODUCT
MANUFACTURING TECHNOLOGY
Presented By:
Miss. Mohini Tawade,
First Year M. Pharmacy,
Department of Quality Assurance,
Dr. D.Y. Patil College of Pharmacy, Akurdi, Pune.

2. INTRODUCTION:
▪ Advanced manufacturing is the use of innovative technology to improve products or
processes
▪ It can be defined as “The rate of technology adaptation and the ability to use that
technology to remain competitive and add value to the advanced manufacturing
sectors”
▪ In advanced aseptic processes, direct contact of the open product with an operator
wearing a conventional cleanroom garment is not allowed
▪ Isolators effectively provide a seal against the entry of external contaminants using air
over-pressure.
▪ Gloves or half-suits are used to separate the human operator and the aseptic environment

3. Examples:
1. Blow-fill-seal system, prevents direct human contact during the filling/sealing process.
2. Closed-vial filling system, avoids direct contact with the critical zone where the filling
needles and post-irradiated closures surface are exposed.
3. Filling of product directly into sealed sterile containers.
4. Restricted access barrier system (RASS): reduces or eliminates intervention into the
critical zone.

4. AREA PLANNING:
The main objective of area planning is to design manufacturing operations so that the flow of
products, people, and raw materials are maintained in a clean environment; likewise,
the flow of waste material and products must be separated from the flow of clean
personnel and product to prevent contamination.
Warehousing includes functions such as receiving, shipping, and in-process storing of raw
materials and finished products.
1. Receiving and storage of incoming material
2. Receiving areas include unpacking, sampling, and incoming quarantine material
3. Shipping area contains quarantine material before shipment
4. Storage of finished products and certain raw materials need special environmental
storage conditions, such as temperature and humidity control.

5. Administrative Area:
▪ Administrative area planning requires careful analysis of the direct and indirect
administrative requirements of a particular plant.
▪ Successively higher levels of supervision usually provide larger office areas.
▪ Some offices are individual, while some are grouped in an “open area concept”

6. ENVIRONMENTAL CONTROL:
Sterile products are very critical and sensitive in nature hence it requires a very
high degree of precautions and prevention in their preparation and there shall be strict
compliance with standards prescribed by regulatory authorities.
Zones as per the Gazette of India
White zone: final step (filling of parenteral)
Gray zone: weighing, dissolution, filtration
Black zone: storage
BLACK
GRAY
WHITE

7. Environmental control zone grouping:

8. Zone 7: Filling line
▪ The walls of the filling area are the last physical barrier to the ingress of contamination,
but within the filling area, a technique of contamination control known as laminar flow
may be considered as the barrier to contamination.
Zone 6: Filling area
▪ Zone 6 is a distinct zone of the controlled environment area for an aseptic filling process
but may not be a distinct zone for a non-aseptic filling process.
Zone 5:- weighing, mixing, and transferring area
▪ Zone 5 encompasses activities of “weighing, mixing, filling or transfer operations”
addressed by c GMP section 212.81 which are not handled as zone 6 but require a
controlled environment.

9. Zone 4: clean area
▪ Activities in this may include washing and preparations of equipment or accumulation
and sampling of filled products.
Zone 3: General production and administration area
▪ The third zone of environmental controls is formed by the periphery of the general
production area. Only essential materials handling, equipment, and personnel.

10. ▪ Sterile products are very critical and sensitive in nature hence requires a very high
degree of precaution and prevention is required in their preparation and there shall be
strict compliance with standards prescribed by regulatory authorities.
▪ Air handling units for sterile product manufacturing shall be different from those of
other areas.
▪ Critical areas such as aseptic filling areas, sterilized components unloading areas, and
changing rooms should conform to grades B, C, and D respectively, and shall have
separate "Air handling units". The filter configuration in the Air handling unit shall be
suitably designed to achieve the grade of air

11. ▪ For products that are filled aseptically, the filling room shall meet Grade B conditions at
rest.
▪ The Filling operation shall take place under Grade A conditions which shall be
demonstrated under working of simulated conditions which shall be achieved by
providing a Laminar air flow workstation with suitable HEPA Filters.
▪ For products that are terminally sterilized, the filling room shall meet Grade C
conditions.
▪ Manufacturing and component preparation areas shall meet Grade C conditions.
▪ After Completion of preparation, Washed components and vessels shall be protected
With a Grade C background.

13. UTILITIES AND MAINTENANCE IN THE STERILE
AREA:
▪ Sterile areas/ aseptic processing areas should have
▪ 1. Smooth and easily cleanable Floors, Walls, and Ceilings.
▪ 2. Temperature and humidity controls.
▪ 3. Air supply with HEPA filters under positive pressure.
▪ 4. Environmental conditions monitoring system.
▪ 5. A system for Cleaning and disinfecting to produce aseptic/ sterile conditions.

14. ▪ Floors, walls, and ceilings of sterile areas should be subjected to intensive and
frequent cleaning and sanitation.
▪ Floors, walls, and ceilings of sterile areas should be composed of smooth and
hard surfaces with minimum joints and should be resistant to abrasion.
▪ Temperature and humidity in the sterile areas should be controlled and maintained
according to operations performed (68◦F temperature and 45% Relative Humidity
is suitable).
▪ The air in sterile areas should be provided by an air supply fitted with HEPA
filters (less than 100 particles of 0.5 Micron with Not more than 1Cfu/cm3); an
airflow rate of 90 feet/ minute is recommended.

15. CHANGE ROOM:
1. Personnel access to all controlled areas should be through change rooms. Change
room concepts and layouts vary from single closet size rooms to expensive multi-room
complexes.
2. Entrance to a changing area is normally through vestibules whose doors are
electrically interlocked so that both cannot be opened simultaneously, thus
maintaining the necessary air pressure difference to prevent the entry of airborne
contamination.
Upon entry into the change room wash sinks are provided for scrubbing hands and
forearms. Further control may be achieved by using filtered and heated compressed air for
drying to reduce further particular potential.

16. ▪ After hands are dry, garments are taken from dispensers and put on while moving across
a dressing bench.
▪ As a final growing step, aseptic gloves are put on and sanitized.
▪ Exit from the changing room to the controlled area

18. PERSONAL FLOW:
▪ The movement of personnel should be planned during the design of individual plant
areas.
▪ Each production area may have a smooth and efficient personnel flow pattern, a
discontinuous or crowded pattern may develop when several individual production
area plants are combined.
▪ The flow of material and personnel through corridors is inefficient and unsafe paths
for moving materials, particularly if heavy forklifts are required.

19. • Discontinuous and crowded flow patterns can decrease production efficiency,
increase security problems, and increase the problem of maintaining a clean
environment.

20. UTILITIES AND UTILITY EQUIPMENT
LOCATION:
▪ Utilities:
A piping system, in particular, must be initially and often periodically cleaned
and serviced. Exposed overhead piping is not acceptable from a cleanliness or
contamination standpoint since it collects dirt, is difficult to clean, and may leak. Buried
or concealed pipes may require unacceptable demolition for cleaning or repair.
▪ Utility equipment location:
Public utilities require space for metering. In addition to the meeting, an
electrical power system requires switchgear and a transformer.

21. • Water systems usually require treatment to ensure consistent quality.
• Plant-generated utilities typically require steam boilers, air compressors, and
distillation, the typical “boiler room” approach. Proper equipment maintenance
is difficult in foul weather, especially in winter.
• Heavy equipment may damage the roof structure, particularly if the equipment
location requires numerous penetrations through the roof which, coupled with
equipment vibration, will invariably lead to leakage.

22. ENGINEERING AND MAINTENANCE:
From an engineering standpoint, even a location outside the plant can serve well if access
to the production area by engineers for fieldwork is not too difficult often particularly in
small or less complex plants, maintenance, or other plant service functions such as utilities
or combined with engineering, making an in-plant location desirable.
Maintenance responsibilities cover all areas of the plant and can generally be grouped into
two categories: plant maintenance and production maintenance.
▪ Plant maintenance operations
They vary from heavy maintenance on production equipment to
cosmetic work on the building exterior and often include plant service functions such as
sanitation, ground sweeping, or waste disposal.

23. ▪ Production maintenance
It is a direct production support function and all the routine and
recurring operating maintenance work.

24. THANK YOU!