An introduction  Aseptic processing facility design,  Innovations in aseptic processing technology,  Sterile product manufacture using form fill seal technologies,  Aseptic processing transfer systems,  Qualification/validation of aseptic processing environments, systems and equipment.

2.  Aseptic Processing can be defined as
Handling sterile materials in a controlled
environment, in which the air supply, facility,
materials, equipment and personnel are
regulated to control microbial and particulate
contamination to acceptable levels.

3.  1) Suitably developed and validated sterilization
processes for the components, formulation, and
equipment product contact parts.
 2) Establishment/maintenance of a suitable
environment in which microbial contamination
is controlled appropriately to mitigate
contamination risk.
 3) Defined methods for the set-up and operation
of the sterilized equipment.
 4) Appropriately gowned and trained individuals
to conduct the process in the prescribed manner.
 5) A monitoring program for the assessment of
contamination control on an ongoing basis.

4.  “An advanced aseptic process is one in which
direct intervention with open product
containers or exposed product contact
surfaces by operators wearing conventional
clean room garments is not required and
never permitted.‖

5.  The origins of aseptic technique go back to
Joseph Lister who introduced them to the
medical profession in the 1860s to better
manage infection risk in patients undergoing
surgery. Lister‘s efforts revolutionized the
way surgery was conducted and similar
aseptic techniques spread to the then
nascent science of medical microbiology and
ultimately to the manufacture of sterile
products and medical devices.

6.  1] Non-classified Room
 Manual/semi-automated assembly by gowned personnel
in clean, but unclassified environments (the concept of
room classification had not yet fully emerged).
 2] Gloveboxes
 Manual assembly by personnel using a glove box (a non-
ventilated sealed unit accessed via gloves). The inherent
limitations in these processes are historical facts; a)There
were only limited available means for improvements in
safety during the entire period from Lister‘s first efforts
until the middle of the twentieth century, and b)These
improvements largely focused on manual aseptic
practices, a growing number of chemical disinfectants and
perhaps most critically preservatives.

7. The Benefit Of HEPA-Filtered Air Supply
a)The HEPA filter allowed entire rooms to reach levels
of particle and microbial cleanliness not previously
attainable and wholesale changes in facility designs
and operating practices resulted.
b)With large volumes of air effectively free of microbial
contamination, it was now possible to dilute and/or
remove from the environment human borne
contamination that is always the greatest source of
risk.
c)The advent of HEPA filtration made it possible to use
equipment inside a cleanroom to perform most, if not
all, of the aseptic process, with gowned personnel in
support.

8.  The first pharmaceutical isolators were used
for sterility testing where human-derived
contamination from the analyst was a
nagging concern.Their adoption for this
purpose has spread across the industry, to
where they are almost considered current
good manufacturing practices in North
America, Europe, and Japan for that purpose.

9.  RABS is believed to provide the sterility assurance
certainty of isolation technology with fewer technical
complications of the types delineated above.
 The RABS is a highly evolved barrier system that
builds upon the separative approaches used in
manned cleanrooms through the use of material
handling elements such as those used with isolators.
 RABS is derived from isolation technology, even
though in some applications it may have more in
common operationally with the manned cleanroom.

10.  In fact, RABSs are now further characterized as ―closed‖
RABS and ―open‖ RABS.
a) Closed‖ RABS
The closed designation means that similar to the isolator,
direct human intervention is not allowed in this particular
style of RABS operation.
In other words the ―closed‖ RABS approach is from the
separative perspective effectively identical to an isolator in
operation.
b) ―Open‖ RABS In contract ―open‖ RABS as originally
conceived contemplated operations in which the barriers
were closed most of the time, but open-door interventions
are allowed to correct certain manufacturing
contingencies.

11.  2] Blow-Fill-Seal and Form-Fill-Seal systems have been used for
sterile production for many years, but these too have witnessed
further improvement by the incorporation of RABS and/or
isolator-type environments for the background. One of the newer
designs in this area allows for the aseptic filling of small numbers
of bags at slower speeds, which can be ideal for clinical/bulk
subdivision/niche products of sterile fluids.
 3] Another approach for improved contamination control in
aseptic processing is the application of robots and automation.As
the principal criterion necessary for improved contamination
control is the elimination of personnel from the aseptic process, it
stands to reason that automation can play an important role in
this endeavor.

12.  The aseptic processing facility design is regulated to minimize
particulate, pyrogen, and microbiological contamination to sterile
products.
 Historically, the greatest potential for contamination comes from
human intervention within the aseptic processing rooms.
 Recent advanced processing improvements including restricted
area barrier systems (RABS) and isolation technology provide
enhanced segregation of the operators from the product.
 These technologies reduce the risk of contamination versus the
traditional aseptic facility design and are expected to effectively
replace the traditional manned design over the coming years.
One of the greatest difficulties in designing aseptic processing
facilities is the current lack of harmonization of the regulatory
requirements for operating area classifications.

13. 1) Area Classifications,
2)Transition Points,
3) The Aseptic Processing Suite
4) RABSTechnology- Based Aseptic Suite Design
5) IsolationTechnology- Based Aseptic Suite
Design
6) Architectural Finishes and Detail Design
Considerations,
7) Engineering Considerations,
8) Constructability Considerations,
9)The Design Process,
10)TheTrend.

14.  To control microbiological particulate
contamination, clean air classifications have
been developed to define the conditions for
all aseptic facility functions.
A] Class 100
B] Class 10,000
C] Class 100,000

15.  Fortunately in the most restrictive condition, the Class 100-ISO 5-
Grade A classification, for spaces that the product and/or
components are exposed to in the environment, the regulations
are in harmony because EU requires Grade A for both at-rest and
in-operation conditions.
 Traditionally, Class 100-ISO 5-Grade A conditions exist over the
filling operations and areas of local protection in the formulation
and parts wrapping rooms.
 With isolator technology, the Class 100-ISO 5-Grade A filling
operation is contained completely within the isolator.
 With RABS technology, current guidance includes an area of Class
100 airflow outside the RABS unit for a minimum width of the fully
opened doors should those doors be opened during operation .
This requirement creates significant design complexities that are
addressed later.

16.  The second area classification is Class 10,000-
ISO 7-Grade B that applies to spaces that are
immediately adjacent to the aseptic filling line.
 This classification has traditionally caused the
most confusion and is no longer an issue in
isolation technology facility design.
 It still creates significant issues for RABS facility
design.
 The EU requirements for Class 10,000 conditions
at rest can lead to more conservative air change
designs then would be typical for meeting FDA
requirements alone.

17.  The third area classification is Class 100,000-ISO
8-Grade C.This classification applies to aseptic
manufacturing support areas and becomes the
background environment for the filling room,
and the predominant classification for all other
spaces in isolation technology suites.
 The EU requirement for Class 100,000
conditions at rest can lead to the addition of
terminal HEPA filters depending on design
solutions.
 These spaces are designed to provide controlled
access to the actual production areas.

18.  TheTransition Points PerformTwo Functions;
a) First they provide the necessary pressure
differential between classifications, and
 b) Second, they provide a space for
personnel to don additional protective
coverings and for material to be prepared for
transfer.

19. Personnel typically transit from unclassified to CunC spaces through gender-specific
locker rooms.
 Access is controlled by an identity device.
 The locker rooms have unidirectional personnel flow with operators changing out
of street clothing into a dedicated plant uniform and proceeding to a shoe change
room to don dedicated plant shoes.
 Hair nets and Beard covers are added at this point.

The transition from CunC to ISO 8 typically involves
 If the CunC corridor supports a single aseptic suite; involves donning additional
shoe covers, hair nets, and beard covers
 If the CunC corridor provides access to multiple aseptic suites and/or inspection
and secondary packaging suites, an additional one or two piece over gown that is
gathered at the wrist and ankles is added.
To access ISO 7 or ISO 5 spaces,
 A gowning area for donning complete non-particulate shredding sterilized
uniforms with sterilized shoe covers, full head gear including face shields and
gloves shall be provided;
 This gowning process is time consuming, expensive, and a prime risk of
contamination is there due to poor operator technique.

20.  Sufficient space should be provided to wipe the
material down or remove protective coverings.
 Personnel will leave material in and pick
material up from air locks, and should never pass
completely through a material air lock.
 Doors shall be interlocked to maintain pressure
differentials between area classifications.
Equipment is accommodated in a similar fashion
through the same air locks.

21.  Definition
Aseptic processing is reserved for products that
are not capable of maintaining efficacy under
the more stressful conditions of terminal
sterilization. In the aseptic process, the drug
product, fully closed product containers, and
product contact parts are subject to separate
pre-sterilization methods and the drug product
and container are brought together in a highly
controlled environment.

22.  The aseptic processing suite is composed of
three primary functions and their associated
rooms:
A. Product preparation,
B. Component and product contact part
preparation, and
C. Filling /sealing or assembly.

23. A) Product Preparation
Product preparation is performed in the formulation room
that typically includes areas for weighing the ingredients,
making ingredient additions into tanks, and formulating
the product.
B) Component and Contact Parts Preparations
Component and contact parts preparations are carried out in
a series of rooms that typically progress in a unidirectional
flow from the least clean to progressively cleaner spaces.
C) Filling /sealing or assembly
The final space in the aseptic suite is the filling/sealing room
where the product and components are integrated.

24. Aseptic processing suite design requirements
are the same for traditional clean room and
RABS technologies.
a)The formulation room is typicallyClass
10,000-ISO 7-Grade B.
b)The component preparation suite is typically
Class 100,000-ISO 8-Grade C.
c)The filling room is class 100-ISO 5-GradeA
over critical operations with a Class
10,000ISO 7-Grade B background.

25. The use of isolation technology greatly simplifies
the design of aseptic facilities.The entire suite
can be classified as Class 100,000-ISO 8-Grade C.
 There are now only single gowning, de-gowning,
and material air locks per suite.
 In fact, depending on the products, single sets
of transition points can serve several suites.
 All three aseptic functions, (i) product
preparation, (ii) parts washing, and (iii) filling
operations, can now be accessed by personnel
without re-gowning.

26. A] Central Corridor Design:
In early isolator facilities design, personnel and material proceeded through the transition points
into a central corridor that connected to the product preparation area, the component/change
parts area, and the filling room.
This layout is still preferred for potent product design for containing potential contamination to
the smallest area possible.
B]The Ballroom Layout:
Another design possibility connects the transition points directly to the central filling room that is
adjacent to and connects directly to all of the other necessary rooms in the aseptic suite.
This design, which has been referred to as ―the ballroom layout,‖ can reduce the area of the suite
by around 10% compare with the central corridor option.
C]The Parallel Suite Design:
A third possible configuration for facilities that have multiple filling lines, shares the
component/parts preparation area with multiple formulation/filling suites.
The optimum proportion is usually one parts-preparation suite for three formulation/filling suites,
depending on throughput and number of products.
This configuration is referred to as the parallel suite design and is a variation of the central clean
corridor design.
The aseptic isolator-based Class 100,000-ISO 8-Grade C facility parallel suite option can also
provide an efficient design opportunity for leveraging support facilities for filling multiple
product delivery systems.

27. All surfaces in aseptic processing rooms shall be designed to facilitate cleaning.
The following design standards are accepted current good manufacturing practices
1) All surfaces in aseptic processing rooms shall have smooth, durable monolithic finishes. They
should resist aggressive cleaning/sanitizing agents.
2) All inside corners shall have approximately three inch radius corners.
3) All door frames and windows shall be flush with surrounding walls.
4) Minimize the use of caulking. Caulking materials deteriorate over time or can be damaged easily
by contact creating potential cavities that could promote growth. Use caulking only when no
other material is viable to provide a seamless connection between two dissimilar materials.
5) Avoid the use of drywall, especially when using isolators. The drywall installation generates
particulates during construction, which creates issues when integrating simultaneous installation
with the filling lines. Drywall construction also maximizes the need for caulking at connections.
6) Recess all fixtures, panels, and equipment to be flush with the wall surface. Avoid all potential
horizontal surfaces. Provide flush closure panels around all equipment and cabinets that do not
meet walls, floors, or ceilings.
7) Provide radius floor sweeps at all low-wall returns. Avoid louvers as they are difficult to clean and
they conceal the dust that accumulates at the bottom of the duct returns.

28.  The ideal material for aseptic room walls and ceilings is proven to be
chemically welded modular panels.
 Beware of panel systems that use ―batten‖ mechanical
connections with square corners that are imposable to clean.
 There are currently three-door options that provide completely
flush surfaces and can be easily cleaned: frameless glass, molded
frameless PVC, and stainless steel.
Material for Aseptic Room floor/base
 Unfortunately, there are currently no ideal floor/base materials.
 The monolithic options are seamless vinyl sheet goods or epoxy
flooring.
 The vinyl flooring cannot withstand wheel torque from heavy carts
or pallets and the epoxy floors wear out and become porous over
time.
 The epoxy floor is also more susceptible to poor workmanship.

29. A] Structural Systems
A steel frame structural design is preferred over a poured concrete design based on
flexibility for mechanical and piping penetrations through the slabs. Spray fire
proofing can be a disadvantage for steel frame installations due to material
particulating issues; the fireproofing can be eliminated in many cases by reducing
the area between fire separations. A 24 ft. by 36 ft. bay generally works well,
avoiding conflict with equipment layouts. Because steel columns for this
arrangement are typically 22-inch square, they can easily be integrated into
mechanical chase walls limiting the number of inside corners in the classified rooms.
B] Mechanical Systems
Mechanical system design requirements for filling rooms vary dramatically between
RABS- and isolator-based facilities.The major differences are the requirements for
large volumes of Class 100 air supply in RABS facilities and the integration of the
isolator air system with the room air system in isolator facilities.The first time cost
as well as the life cost is significantly less for an isolator facility.With the current
focus on green design, the RABS option is undesirable.


30. C] Plumbing Systems
The major current plumbing issue is providing an air break
between equipment and drains and providing back flow
prevention at floor drains.This is easier when the aseptic
suite is on an upper building floor versus on grade.
D] Electrical Systems
The major electrical concern in aseptic facility design is
maintaining continuous power supply (CPS) to critical
systems during the production process. With the high value
of the new aseptic products, use of redundant systems
including uninterrupted power supply, emergency
generators, or CPS systems become prudent business
options.

31. E] Process Systems
 Process system designs primarily addresses the
formulation process, process water systems and clean in
place/sterilize in place (CIP/SIP) systems design.
 The process technologies tend to be the most difficult to
manage during start up and continuous operation.This is
one case where the simpler the better.
 The major complications arise around the CIP/SIP process
for the product contact lines from fixed formulation tanks
to the filling needles.
 Using portable tanks with direct aseptic connections to
the filling machine with a completely disposable product
path (including needles) is becoming the preferred option
for many manufacturers to minimize the need for the
CIP/SIP systems.

32.  If possible, lyophilizers should be located along an exterior
wall with the condenser and compressor skids on the ground
floor and the chamber above. In this configuration, the
lyophilizer will determine the ground to second floor ceiling
height.
 The most difficult installation access is generally for the filling
line, the parts washer and the parts autoclave which by
definition are located in the aseptic core of the facility.
 Modular wall/ceiling panels provide a tremendous advantage
over stick built construction during the equipment installation
process because the ceiling and wall panel installation can be
easily removed and reinstalled along the rigging path in a
single day.

33. The following process includes techniques that optimize the project design effort
. 1)The initial design focus is to lock the business plan and objectives.
 Because the facility will be used for 15 to 20 years, most of the products that will be made there have not
yet been identified, so facility flexibility should be evaluated based on potential product profiles.
 The project variables of cost, schedule, and program scope should be prioritized to determine the best
project delivery system. Once the business parameters are fully understood, the design programming effort
can commence.

2)Too often engineers begin the design before they have locked the program scope, which is the greatest single
cause for redesign and project delays.
3)The first programming step is to define the product manufacturing process; remember the goal is to
manufacture an aseptic product in a robust compliant manner not to build a signature building.
4) For aseptic facility design, once the manufacturing process is defined, detailed gowning and material transfer
procedures can be established.
5) Next the process technology and equipment should be selected.
 In aseptic facilities, especially when using isolation technology, it is imperative that the equipment
manufacturers and models be selected prior to commencing detailed engineering design.
 It is also important to order the process equipment at this point to ensure timely deliveries. With both RABS
and isolator technologies, it is important to perform factory acceptance tests at the individual vendor sites
as well as an integrated test usually at the filling machine vendor site.

34. The advancements in aseptic facility design involve RABS and isolation
processing technologies.
 Advanced aseptic facility design using isolation technology are
proving to be simpler for personnel, material and equipment flows,
area classifications, and operating procedures.
 Isolator facilities have become cost competitive to construct and
are substantially less expensive to operate.
 Isolator-based facilities are much more energy efficient and a
greener design option.
 The issues with early isolator designs including cleaning and change
over times, and in-process interventions have been resolved with
the new generation isolator designs.
 The advantages of isolators over RABS are so overwhelming that by
comparison in the future, RABS may become known as a
―ridiculous attempt being sterile.

35.  Aseptic Processing can be defined as Handling sterile
materials in a controlled environment, in which the air
supply, facility, materials, equipment and personnel are
regulated to control microbial and particulate
contamination to acceptable levels.
1] Plastic Materials
2] Room and Enclosure Environmental Decontamination
3] Personnel
4] Disposables
5] Equipment
6] Automation
7] Next-GenerationTechnologies

36. Form fill and seal (FFS) is a process by which a
container is formed, filled with product, and
sealed in a continuous and uninterrupted manner.
FFS is a process used to package sterile products
including:
 Medical devices
 Injectable drugs
 Ophthalmic products
 Respiratory therapy products
 Biotechnology products, and
 Topical products.

37.  There are several types of FFS packaging
used for sterile products, including
1)Blister pack filling,
2) Pouch filling,
3) Bag filling,
4) Cup filling, and
5) Blow fill seal (BFS).

38. 1] Ophthalmic SOLUTIONS
2] Inhalation PRODUCTS
3] Oral Electrolytic Rehydration Solutions
4] Parenteral Preparations

39. Transfer systems which can be used in aseptic and/or containment
applications as follows:
A. SimpleTransfer Systems
1) Hinged Doors
2) HatchbackWindows
3) Airlocks
4) Utility Panels
5) Drum Doors and Bag Ports
B. Interface Systems
Process Equipment Interface
C. SophisticatedTransfer Systems
1) Split ButterflyValves
2) RapidTransfer Ports (RTP)
D. OtherTransfer Systems
1) DocumentTransfer Systems
2)TrayTransfer Systems
3) Sterile LiquidTransfer
4) Pack-off Heads

40. Validation is a defined program which in combination with routine production methods and quality
control techniques provides documented assurance that a system is performing as intended
and/or that a product conforms to its pre-determined specifications.
The life cycle approach to validation provides for cradle-to-grave consideration of a system‘s
compliance in a validated state.This model is appropriate for all types of systems, including both
physical systems such as heating, ventilation and air conditioning (HVAC), and isolators, and
computerized systems controlling process equipment.
The various stages of the model include
1. User requirements;
2. Conceptual design and planning;
3. Detailed design and construction/fabrication
a) Detailed design and construction for assembled systems
b) Detailed design and fabrication for purchased equipment
4. Installation and operational qualification;
a) System and equipment installation/commissioning
b) Equipment/system qualification 5. Automated and computerized systems
6. Sterilization cycle development (if required);
7. Performance qualification and Operational use of system
a) Isolation technology b) Use of advanced aseptic processing systems
8. Maintenance.

41. 1. Agalloco. J., Akers. J., 2010. Advanced Aseptic
ProcessingTechnology., Informa Health Care.
2. Guidance for Industry Sterile Drug Products
Produced by Aseptic Processing Current Good
Manufacturing Practice, U.S. Department of
Health and Human Services Food and Drug
Administration, September 2004
Pharmaceutical CGMPs
3. ParagV. Ingle, Design Considerations for
Parenteral Production Facility ,International
Journal of Pharma Research & Review, August
2014; 3(8):15-28 ISSN: 2278-6074