Technology-III

Production of parenteral products, in general, involves the

following operations:

I. Planning and preparation

II. Compounding the product
III. Filtration of solution
IV. Filling
V. Sealing
VI. Sterilization
VII.Packaging and labeling
1. Preparation and storage of WFI:-
 Prepared by distillation or reverse osmosis
 Normally WFI should not be stored for more than 24 hours at room
temperature but can be held at 80C preferably for continuous usage.
2. Cleaning and sterilization of containers:-
 Containers and closures should be bought sterile or should be clean
and sterilized using standard procedures.
3. Cleaning and sterilization of equipments:-
 Steam, water, detergents, disinfectants etc. are used for cleaning
 Dry heat, moist heat, gas etc. are used for sterilization
4. Preparation of personnel :-
 Washing, taking shower, dressing with appropriate clothing and other
accessories (mask, hood, gloves)
5. Preparation of the aseptic area / clean room and setting up the desired
environment
1. Cleaning of containers, closures & equipments:
Thoroughly cleaned with detergents with tap water distilled
water finally rinsed with water for injection.
2. Collection of materials:
All raw material of preparation should be collect from warehouse after
accurate weighed. Water for injection should be Pyrogens free
3. Preparation of parenteral products:
The parenteral preparation must be prepared in aseptic
conditions. The ingredients are accurately weighed separately
and dissolved in vehicle as per method of preparation to be
followed
4. Filtration: The parenteral preparation must be filtered by bacteria
proof Filter
5. Filling the preparation in final container:
The filling operation is carried out under strict aseptic precautions.
6. Sealing the container:
Sealing should be done immediate after filling in aseptic environment.
7. Sterilization:
For thermostable substances the parenteral products are sterilized by
autoclaving method at different temp. & pressure.
• Heat sensitive or moisture sensitive material are sterilized by
exposure to ethylene oxide or propylene oxide gas .
8. Evaluation of the parenteral preparation:
The following tests are performed in order to maintain quality control:
1. Sterility test 2. Pyrogen test 3. Clarity test 4. Leakage test 5. Assay
9. Labeling &packaging
Process developed and followed according to the type of
dosage form –
 Solution,
 Concentrated solution for dilution,
 Powder for solution,
 Suspension,
 Powder for suspension,
 Emulsion

Aseptic area may not be requires or feasible in all cases.

High quality ingredients should be used. Errors must be
avoided in compounding.
Solution must be filtered but the objective may vary

Clarification – to give a polishing effect. Removal of

particulate matter down to at least 3.0 µm.

Sterilization – removal of viable micro-organisms and their

spores. Removal of particulate matter down to at least 0.22
µm. Polishing is automatically achieved.

Sterilization by filtration is employed for thermo-labile

products.
 Filling of liquids –
1. Relatively easy to divide and fill into individual containers in
comparison to solids.
2. Filling machines apply gravity, pressure or vacuum principle for
filling operations.
3. Stainless steel and, in some cases, borosilicate glass are
materials used for construction of parts directly coming in
contact with the product and can be sterilized when required.
4. Filling of small volume parenteral of potent drugs is more
delicate than filling of large volume of less potent drugs.
5. Modern machineries are associated with the facility of flushing
with nitrogen gas before and after filling.
6. Filling of ampoules require deep insertion and careful
withdrawal of the delivery tube to avoid wetting of the neck.
Filling of solids
The process of filling of solids is difficult in comparison
to filling of liquids.
Problems associated with solid filling:-
 Stratification of particles(Formation or deposition of
layers) due to varying particle size
 The development of electrostatic charge within the
mass of dry solid particles
 The formation of air pockets
 Uneven flow due to clumping of the particles
Filled containers are sampled at regular interval for in
process control.
Fig: Filling of solids
Filling and sealing are done in
sequence without any lapse of
time

(a) Ampule sealing -

► tip seal (bead seal)

► pull seal

Pull seal produces better

quality sealing than tip seal.
(b) Bottle, cartridge and vial sealing –
In recent times, automatic machines
have been designed and developed
which performs the filling and sealing
operation in a consecutive manner
with little involvement of manual
activities.
Developed in Europe - 1930s

Introduced in USA - 1960s

The basic concept of blow fill seal (BFS) is that a container is formed,
filled, and sealed in a continuous process without human
intervention, in a sterile enclosed area inside a machine. Thus this
technology can be used to Aseptically Manufacture sterile
pharmaceutical liquid dosage forms.

 It is given preference by FDA for aseptic processing.

 In ‘blow fill seal’ process, a container is formed, filled, and sealed

in a continuous process in a sterile enclosed area inside
The BFS process is carried out in five steps:
– Extrusion
– Blow
– Fill
– Seal
– Ejection/out
1. Extrusion: Firstly pharmaceutical-grade thermoplastic resin is vertically heat
extruded through a circular throat, to form a hanging tube called the Parison.
2. Blow: When the parison reaches the proper length, the mold is closed and the
parison is cut. The bottom of the parison is closed and the top is held in place. The
mold is then conveyed to a position under the blowing and filling nozzle.
3. Fill: The mould is transferred to the filling zone, or sterile filling space where filling
needles mandrels are lowered and used to inflate the plastic to form the container
within the mould. Following the formation of the container, the mandrel is used to
fill the container with liquid; following filling the mandrels are removed.
4. Seal: Seal the filled container at the top.
5. Out: The mold opens and formed container is conveyed out from the machine.
 Blow fill seal technology reduces
personnel intervention
 Making it a more robust method for
the aseptic preparation of sterile
pharmaceuticals.
 BFS is used for the filling of vials for
parenteral preparations and
infusions, ophthalmic products and
inhalation products
 It is SIP process.
• No chance of adulteration
• Savings on glass bottle washing & handling cost
• 40-50% packaging cost reduction than glass pack.
• Can fill any thin liquid
• No breakage
• Complete avoidance of reused bottle hence
complete hygiene
• Saves crown cap & its printing cost
• Huge savings on storage space
• Savings on freight for raw material & finished
product
• 15-18 times light weight makes product
handling very easy
• No opener is reqd. as bottle comes with pilfer
proof twist open bottle cap being single use
• Aesthetically much better product appearance
• Saving of administration Cost of stores
employees
• Easy distribution
• Ultra light carton reqd. for secondary
packaging & Handling system
The production area where the parenteral preparation
are manufactured can be divided into five sections:
 Clean-up area
 Preparation area
 Aseptic area
 Quarantine area
 Finishing & packaging area
1. Clean-up area:
 It is not aseptic area.
 All the parenteral products must be free from
foreign particles & microorganism.
 Clean-up area should be withstand moisture, dust
& detergent.
 This area should be kept clean so that
contaminants may not be carried out into aseptic
area.
2. Preparation area:
 In this area the ingredients of the parenteral preparation are
mixed & preparation is made for filling operation.
 It is not essentially aseptic area but strict precautions are
required to prevent any contamination from outside.
3. Aseptic area:
 The parenteral preparations are container
filtered, filled into final & sealed in aseptic
area.
 The entry of personnel into aseptic area
should be limited & through an air lock.
 Ceiling, wall & floor of that area should be
sealed &painted
 The air in the aseptic area should be free
from fibers, dust and microorganism.
 The High efficiency particulate air filters
(HEPA) is used for air.
 UV lamps are fitted in order to maintain
sterility.
4. Quarantine area:
 After filling, sealing & sterilization the parenteral product
are held up in quarantine area.
 Randomly samples were kept for evaluation.
 The batch or product pass the evaluation tests are transfer
in to finishing or packaging area.

5. Finishing & packaging area

 Parenteral products are properly labelled and packed.
 Properly packing is essential to provide
protection against physical damage.
 The labelled container should be packed in cardboard
or plastic container.
 Ampoules should be packed in partitioned boxes