1. M. Pharm Sem-II Presentations
ADVANCED STERILE PRODUCT MANUFACTURING TECHNOLOGY
SAVITRIBAI PHULE, PUNE UNIVERSITY , PUNE
PARTIAL FULFILMENT OF REQUIREMENTS FOR THE AWARD OF
MASTER OF PHARMACY
Pharmaceutical Manufacturing Techniques
Quality Assurance Technique
IN THE FACULTY OF SCIENCE AND TECHNOLOGY
Bhujbal Knowledge City,
MET’s Institute of Pharmacy,
Adgaon, Nashik, 422003.
Academic Year-2021-2022 1
(Roll no. 12)
Dr. S.P. Ahirrao
• Area planning and environmental control
• Wall and floor treatment
• Change room
• Personnel flow
• Utilities and utilities equipment location
• Engineering and maintenance
Advanced manufacturing is the use of innovative technology to
improve products or processes,with the relevant technology
being described as “advanced”,“innovative”, or “cutting edge”.
Advanced manufacturing industries “increasingly integrate
new innovative technologies in both product and processes.”
The rate of technology adoption and the ability to use that
technology to remain competitive and add value to define the
advanced manufacturing sector.
4. Manufacturing Area Planning
During facility designed, process requirement specific for each
product requirement must be consider also number of product
to be manufacture will impact facility design or area planning.
Chemical bulk drug substance[API]
Derived from chemical reaction. So facilities producing sterile
API will be required to provide protection to product during
synthesis, isolation, bulk filing.
An adjuvant produced by precipitation is an example of sterile
5. Potent compounds:
classified as those chemical drug that and considered toxic to humans
when exposure limits are exceeded, may cause allergic reaction, birth
defects, or other condition.
• For this reason it is acceptable to permit production of potent compound
in multiproduct facilities, provided the suite is segregated from other
Produced to treat bacterial or fungal infection.it must be separated from
other product as potential for cross contamination. In addition to b-lactam
[penicillin] and non penicillin based (cephalosporin)antibiotic are not
permitted to produced in same facility as there is evidence of intolerance
for one antibiotic not another.
6. Biological product
This include therapeutic proteins generated by fermentation or cell culture
and inactivated vaccines. The facility is to be designed in same way as API
production , except that terminal sterilization is often not feasible, due to
fragility of the product.
7. FACILITY TYPE
Single product, dedicated
This facility is designed to produce a single product at one time, through
the year without concern for cross contamination with a second. The
facility can be operated to produce multi products in a series of campaigns,
converting between product.
This facility is designed to produced multiple products simultaneously in
multiple products simultaneously in multiple sterile suites. sterile
operation in each suites are to be segrageted from one another to ensure
that cross contamination is prevented.
• Conventional aseptic technology (open)
In this the product is exposed to the room environment during operation .
for this reason aseptic operation are required to performed under ISO 5
condition by sufficiently gowned operators trained in aseptic techniques.
Sterility assurance levels for aseptic operation, including filing of vials or
syringe, can be maximized through the use of barriers such as restricted
access barrier system isolators.
• Restricted access barrier(open and closed)
A restricted access barrier system RABS can be utilized in many application
in a fill finish area. RABS provides an enclosed environment to reduced
contamination to product, container, closure, compared to the risk
associated with conventional clean room operation.
9. Terminally sterilized product:
Whenever possible, it is required to terminally sterilized filled unit of
product. Terminal sterilization is known as an overkill sterilization.
Sterilization can be steam, by heat, gas, or radiation.
Classification of spaces:
Classification designation for classified GMP spaces include ISO 5(A), ISO
7(B), ISO 8(C), and ISO 9(D),which are assigned to spaces on the basis of
specific operational characteristic, product type, and or technology used
10. • Grade A:- The local zone for high-risk operational
Example :- filling and making aseptic connections.(unidirectional airflow
• Grade B:-In aseptic preparation filling(background of A)
• Grade C &D:-Clean area for carrying out less critical stages in the
manufacture of sterile product (i.e. aseptic connection with aseptic
connectors and operations in closed system)
11. Classification of clean areas
Air cleanliness Maximum number of airborne
Count under non-operating conditions Count under operating condition
>=0.5 µm >=0.5µm >=0.5µm >=0.5µm
Grade A (ISO 5) 3,520 20 3,520 20
Grade B(ISO 7) 3,520 29 352,000 29,00
Grade C(ISO 8) 352,000 29,00 3,520,000 29,000
Grade D 3,520,000 29,000 Dependent on process Dependent on process
12. Floor system are critical and primary support areas of aseptic manufacturing
Facilities can be divided into two categories :sheet systems (PVC , Rubber)and
resin –based multilayer system.
The appropriate selection of either system is dependent on the following
1. Substrate conditions (New or existing concrete slabs)
2. Expected frequency of traffic (material loads)
3. Expected loading traffic (heavy rolling loads such as tanks, carts, etc )
In controlled ,non classified CGMP areas floor system such as pigmented
concrete sealer, sheet vinyl and thinner resin based systems may considered
for cost and functional reasons.
13. • It is composed of site fabricated assemblies (concrete block or metal stud
/gypsum board wall with applied coating) pre manufactured assembles
(modular clean room partition system ) or a hybrid of the two.
Wall system also evaluation on the basis of
• Expected frequency of reconfiguration/ relocation
• Ease of modification (future installation/removal of panels, door,
• Design and construction schedule
• Regulations set by building code authorities and recommendation by
15. • ENVIRONMENTAL CONTROL ZONE :
Zone 1: Plant Exterior – The environment within which a plant is located is the
first environment control zone.
Zone 2: Warehousing – The second environmental control zone provides
minimal protection and product . this barrier may be only marginally effective
against insects , rodents and birds.
Zone 3: General production and administration area- the third zone of
environmental control is formed by the periphery of the general production
Zone 4: Clean Area –Production area immediately proceeding or following a
controlled environment area in the production flow are often controlled as an
area intermediate between general production area and a controlled
16. Zone 5: weighing, mixing , and transfer area- Those activities of “Weighing,
mixing, filling or transfer operation ” addressed by cGMP section
212.81which are not handled as zone 6 but which require a controlled
Zone 6 : Filling Area- District zone of the controlled environment area for an
aseptic filling process but may not be a district zone for non-aseptic filling
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 last
barrier to contamination.
17. CHANGE ROOM:-
Personnel access to all controlled areas should be through change rooms.
change room concept may vary from single closet size room to expensive
multi room complexes.
Entrance to change room area is normally through vestibules whose door
are electrically interlocked so that both cannot be opened simultaneously,
thus maintaining the necessary air pressure differential to prevent the
entry of airborne contamination
Upon entry to change room wash sinks provided for scrubbing hands and
forearms special filtered air driers are available to minimize creation of
18. IN some facilities , a foamed type of alcohol is dispensed on hands which
then evaporates. This is used to eliminate need for tap water and sinks in
the gowning rooms, since this can be potential source of contamination.
After hands are dry, garments are taken from dispensers and donned
while moving across a dressing bench. As a final gowning step ,aseptic
gloves are put on and sanitized.
Separated de gowning rooms are provided where the clean room
garments can be discarded prior to leaving the controlled zone.
21. The movement of personnel should be planned during the design of
individual plant areas.
Each individual 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 controlled.
Security concern about the personnel flow may include minimized access to
controlled substance and minimizing the personnel traffic in or near work
area where controlled substance are handled.
The flow of material and personnel through corridors are in efficient and
unsafe path for moving material, particularly if heavy forklifts are required.
22. Parenteral plants, like any other plant have visitors and the degree of access
to be granted must be determined.
A glassed mezzanine or balcony provides absolute solution yet may give an
excellent view of the process, but not adaptable for single floor layouts.
Discontinuous and crowded flow pattern can decrease production efficiency,
increase security problems, and increase the problem of maintaining a claean
23. UTILITIES AND UTILITY EQUIPMENT LOCATION
UTILITIES: Piping system in particular, must be initially often
periodically cleaned and serviced.
Exposed overhead piping is not acceptable from a cleanliness or
contamination standpoint since it collect dirt is difficult to clean amd may
leak. Buried or concealed pipe may require unacceptable demolition for
cleaning or repair.
Whenever possible, major utility distribution services should located
outside of clean area.
Distribution system be exposed and not buried with in walls or ceilings.
24. UTILITIES EQUIPEMENT LOCATION
Public utilities require space for metering in addition to meeting electrical
power system require for switchgear and transformer.
Water system usually require treatment to ensure consistent quality. Plant
generated utilities typically require steam boiler room air, compressors,
and distillation, the typical boiler room approach.
Although a central location minimized distribution problems and
minimizes service distribution distances.
Proper equipment maintenance is difficult in foul weather especially
winter, heavy equipment may damage the roof structure,particularly if
the equipment location may requires numerous penetration through the
roof which coupled with equipment vibration will invariably lead to
25. ENGINEERING AND MAINTENANCE
From an engineering stand point , even a location outside the plant can
serve well if access to the production area by engineers for field work is
not too difficult often particularly in small or less complex plants ,
maintenance or other pant services function such as utilities or combined
with engineering , making an I plant location desirable.
Maintenance responsibilities cover all area of the plant and can generally
be grouped into two categories
1. Plant maintenance
2. Production maintenance
26. Production maintenance is a direct production support function and
include all the routine and recurring operation maintenance work.
production maintenance facilities are usually minimal.
Plant maintenance operation , in contrast are more diverse .they vary
from heavy maintenance on production equipment to cosmetic work on
the building exterior and often include plant sevice function such as
sanitation ,ground sweeping , or waste disposal.
Facilities required are extensive and mostly include provides for
equipment cleaning .disassembly major rebuilding of equipment and
painting and these operation can present a contamination risk to
pharmaceutical operation and must be isolated.
Aseptic processing with discipline and taking advantage of the numerous
technical developments that have occurred over the year results in sterile
products that can be administered with complete confidence.
The wider adaptation of advanced aseptic processing will result in further
evolutionary improvements in aseptic processing.
The industry is at the beginning of the era in which human-scale aseptic
processing will be completed replaced by separative technologies and process
Additionally improved in-process controls are likely to be implemented making
validation easier and easing the compliance burden.
• REFERENCES :-
1.International conference for standardization (ICH) (2004), cleanroom and
associated controlled environment –part7:separative devices (clean air hoods,
gloveboxes, isolators and mini environments), ISO 14644-7.
2.Whyte, w, and Eaton T.(2004),Microbiological contamination models for use
in risk assessment during pharmaceutical production, Eur J parental pharm