ASEPTIC PROCESSING AND PRODUCTION CONTROL FOR PARENTERALS

•Part- II
• Compiled By
• Vaibhav Tripathi Dr. Anil K. Sahu
Dr. Deepak K. Dash

• PRODUCTION FACILITIES
• ASEPTIC PROCESSING/ PRODUCTION
CONTROL
• SELECTION OF CONTAINERS & CLOSURES
• FILLING & SEALING

• Production Facilities
• The production area can be divided into five
sections:
1. Clean-up area
2. Preparation area
3. Aseptic area
4. Quarantine area
5. Finishing & packaging area

• 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.

• 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.

• Aseptic area:
• The parenteral preparations are filtered,
filled into final container & 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.

• Aseptic area:
• The air in the aseptic area should be
free from fibers, dust and
microorganism.
• The High efficiency particulate air filters
(HEPA) is used with laminar flow
system.
• UV lamps are fitted in order to maintain
sterility.

• 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.

• Finishing & Packaging Area:
• Proper 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

• Aseptic Processing/Production Control
• Aseptic environment must be
maintained throughout the production
operation of parenterals
• The objective of aseptic processing is
to regulate air, temperature, humidity &
pressure as well as layout of the
premises
• To ensure pyrogen, micro-organism &
dust particles free production

• Documentation :
• Effective implementation of GMP & FDA
guidelines is mandatory to carry out
aseptic processing, which helps to
control the production operation.

• Premises Layout Control :
• The goal of the designer, when creating the
details for the architectural finishes and
joining methods,
• is to eliminate all edges or surfaces within
the room where dirt may accumulate.
• Proper ceiling, flooring must be done to avoid
any sort of contamination due to wear and
tear.

• Premises Layout Control :
• Walls and floors should be free from cracks
or crevices and have rounded corners. If the
walls or floors are to be painted, epoxy paint
is used.
• Room with high pressure must be located in
opposite direction to low pressure room
• Air lock door must be mounted to restrict
unwanted movement of personals.

• Premises Layout Control:
• zones as per gazette of India
• White zone:- final step
• (filling of parenteral)
• Grey zone:-
• weighing, dissolution & filtration.
• Black zone:- storage,
• worst area from
• contamination view point.

• Environmental Control (as per GMP)

• Environmental Control:
• To restrict air born contamination following
instruments are employed
1. HVAC : Heating, ventilation, and air
conditioning. it provides specific set of
condition for internal environment which is
required for production.

2. Laminar flow of air- Airflow moves in a single
direction and in parallel layers at constant
velocity.
3. ULPA filter : Ultra-low penetration air filter
with minimum 0.3 μm particle retaining
efficiency of 99.999 percent.
4. HEPA filter: High Efficiency Particulate Air

• Permissible limit for particulate matters is as
followed
• Particles are measured by automatic counters or
by manual microscopic method
Particle size Particle count (per cubic foot)
≥o.5 µ < 100,000 lakh
≥ 5.0 µ < 700

• The air flow should move with uniform
velocity along parallel lines. The velocity of
the air flow is 90-20 ft/m3.
• Maintaining higher air pressure (+ve
pressure) within the critical area to minimize
infiltration of airborne contaminants from
outside.
• Adjacent rooms of different grades should
have a pressure differential of 10 - 15
Pascals.

• Temperature is kept around 19- 23 ℃
• With relative humidity RH 45-55 %
• RH 15-30 % for freeze dried drugs

• Personnel Control:
• No. of workers should kept to a minimum.
• All employees should be in good health
• Subjected to Physical examination on regular
basis
• They should understood their responsibilities to
report own illness like cold, a sore throat, or
other infection.
• Uniform is made up of Dacron and Span
polyethylene.

• Hats & masks are sometimes made of special
parchment paper. Foot wears plastic and
rubber material.
• The movement of personnel should be
planned during the design of individual plant
areas.
• Each individual production area must be
designed for smooth and efficient personnel
flow pattern.

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

• Personnel flow path from zone to zone must be
such that access to higher level of cleanliness is
only through change rooms, gowning rooms,
locker rooms, or other areas as may be required.
• Entrance to a change area is normally through
vestibules whose doors are electrically
interlocked so that both cannot be opened
simultaneously, thus maintaining the necessary
air pressure differential to prevent the entry of
airborne contamination.

• Sterile Dry Fill Powders/ Freeze Dried
• Objectives:
• Dry fill/ freeze dried powders are generally
prepared for two reasons
1. The drugs degrade at high temperature during
processing.
2. The drugs are not stable in aqueous solution
for a long period (during shelf life)
Eg. Biological products like serum, toxins,
hormones etc.

• Sterile Dry Powders
• Formulation :
• Freeze Dried (lyophilized):
• In this method the formulation is
processed by freeze drying (lyophilization)
Ingredients Use
Mannitol Filler/ tonicity adjuster
NaOH/ HCl pH adjuster
Water for injection Solvent

• The powders are prepared from their
solution by removing solvents by
sublimation (lyophilization) with minimum
degradation.
• Magnitude of degradation is more in case
of evaporation than that of sublimation.
• There are three methods are used for
freeze drying:

1. Freezing in standard freezer at -18 to – 50
℃
2. Freezing in a lyophilization chamber at -
50 ℃ or below
3. Freezing in a liquid Nitrogen tunnel
• Method
• Preparation of solution
• Sterilization

• Filling
• Freeze drying
• Frozen preparation
• High Vacuum applied
• Frozen solvent sublime
• Residual solvent is removed by applying
small amount of heat

• Once drying is completed
• Vials are sealed & packed immediately
• Dry Fill
• Since freeze drying produces crystalline or
a mixture of crystalline and amorphous
powders.
• The stability of powder may be greatly
affected

• Dry Fill
• That’s why dry fill method is employed in such condition.
• Dry fill tech. is comparatively economical
• The processing is not time consuming
• Productivity is more
• In dry fill method only drug or a combination of drug and
additives are filled into the container under aseptic
environment.
• In case of combination the physical compatibility of
additives should b checked with the API

• Large Volume Parenterals (LVP)
• As per USP, “LVP” is an injection in single
dose container of 101 ml or more.
• It contains aqueous preparation of drug.
• It may be IV infusion, irrigating solution,
peritoneal dialysate or blood collecting unit
containing anti- coagulant.
• LVP is administered to supply water,
electrolytes and simple carbohydrates

• As a vehicle for infusion of drugs
• To maintain acid-base balance in body
• Dialyzing agent in improper kidney function
condition
• Provide nutrients, when oral administration is
not possible.

• Formulation :
1. Solubilizer: solubility is not a problem for
developing an LVP.
• But concentrated solution may crystallize
under normal storage condition.
• Eg mannitol 15% solution
• Mannitol is warmed before making solution.

• Formulation :
2. pH adjuster: suitable buffering agents are
used to prevent spoilage due to pH alteration.
• acetic acid, citric acid, K- phosphate buffer
3. Vehicle: water for injection is used
4. Anti- oxidant: added to certain LVPs.
• Na metabisulphate

• Formulation :
5. Tonicity: mannitol is widely used
• Na, K, Ca, Mg & Cl are most commonly used
in LVP.
• Theophylline, heparin, dopamine, lidocaine
are used as LVPs with dextrose/ NaCl

• Selection of Containers & Closures
• Selection of packaging articles is governed by
the composition of the parenteral product
• And the guidelines governing the choice of
containers & closures are set by the National
pharmacopoeias.
• Eg. US pharmacopoeial convention (USP),
• Japanese pharmacopoeia(JP)

• Characteristics:
• They must protect the preparation from
environmental conditions.
• They must not be reactive with the product.
• They must not impart to the product tastes or
odors.
• They must be nontoxic.
• They must be FDA approved.

• Characteristics:
• They must meet applicable tamper-resistance
requirements.
• They must be adaptable to commonly
employed high speed packaging equipment.
• Acceptability of the pack to the consumer or
user

• Packaging Materials:
1. Glass - ampule, vials, syringe, SVI, LVI,
vaccine storage, dropper (primary packaging)
• Type I ( Neutral or Borosilicate Glass)
• Type II ( Treated Soda lime glass)
• Type III ( Soda lime glass)
• Type IV ( General purpose soda lime glass)

2. Plastics - ampule, vials, syringe, SVI, LVI,
vaccine storage, dropper (primary packaging as
well as secondary packaging)
• Polypropylene, PVC, Polystyrene, Nitrile
polymers.
• Plastic is more preferred over glass as
packaging material for no of reasons.

• Ease to form
• High quality
• Freedom of design
3. Metals - vials (primary packaging)
• A silver and zinc-containing zeolite matrix
(AgION) coated stainless steel.

4. Rubbers – closures for vials, syringe’s
plunger, vaccine closer (primary packaging)
• Butyl Rubbers
• Natural Rubbers
• Neoprene Rubbers
• Poly-isoprene rubbers
• Silicone Rubbers

• Types of Packaging Materials:
1. Ampoules
• They are intended for single use only.

• Limitation
• Unsuitability for multiple
dose use
• Sometimes, need to filter
solutions before use
• Other safety considerations

2. Vials:
• Glass or plastic containers are closed with a
rubber stopper and sealed with an aluminum
crimp.

2. Vials:
• Advantages over Ampoules.
• They can be designed to hold multiple doses
(if prepared with a bacteriostatic agent).
• It is easier to remove the product.
• They eliminate the risk of glass particle
contamination during opening.

2. Double Chambered Vials:
• Some drugs that are unstable in solution are
packaged in vials in powder form and must be
reconstituted with sterile sodium chloride for
injection before use.
• Some of this drugs come in vials that contain
a double chamber.

• Top chamber - sterile water for injection
• Bottom chamber- un reconstituted drug

• Both chambers are separated by a rubber
closure.
• To dislodge the inner closure and mix the
contents of the compartments,
• external pressure is applied to the outer
rubber closure.

3. Pre-filled Syringes:
• Designed for quickest administration and
maximum convenience.
• Drugs administered in an emergency (e.g.
atropine, epinephrine) may be available for
immediate injection when packaged in
prefilled syringes.

3. Pre-filled Syringes:

• USP requirements for packaging:
• Single dose container should not be more
than 1 liter.
• Intra-spinal and intra-cisternal administered
product must be in single dose container.
• In case of multiple dose container dose should
not be more than 30 ml.

• Filling & Sealing
• Filling & sealing process comprises of
• Benches for filling and sealing.
• Bacteriological filters.
• Filling and sealing unit under laminar flow
work station.

• Procedure:
• Connect the tubing of filling lines.
• Connect solution tank to the inlet of the filling
assembly.
• Connect the nitrogen over lay in tank for pre
and post flushing.
• Pump the solution in filling tubing up to the
filling nozzle (remove any air bubble)

• Procedure:
• After that wipe the filling nozzle with
70%alcohol.
• Subsequently, sealing is done with the help of
vial/ ampule sealing machine under aseptic
environment.

• BFS (Blow –Fill- Seal )Technology:
• It was developed in the early 1960s and was
initially used for filling many liquid product
categories, for example foods and cosmetics.
• The technology has been developed to an
extent that this system is used to aseptically
produce sterile pharmaceutical products such
as
• respiratory solutions, ophthalmic, Biological
and wound-care products as well.

• BFS (Blow –Fill- Seal )Technology:
• It refers to the technology and related equipment and
procedures in which the formation of the container,
• its filling with liquid pharmaceutical material, and
subsequent formation and application of a seal
• for container are achieved aseptically in an
uninterrupted sequence of operations without
exposure to non-sterile environments.

• Steps involved in BFS technology:
1. Extrusion and parison formation
2. Blowing
3. Filling
4. Sealing
• the formation of plastic containers by
blow/vacuum-molding.
• An endless sterile plastic tube is continuously
extruded from the melted granulate in the filling
cavity of the mould.

2. Blowing
• The nozzle assembly lowers into the parison
until the nozzles form a seal with the neck of the
mould.
• Container formation is completed by applying a
vacuum on the mould-side of the container
• and blowing sterile filtered air into the interior of
the container.
• Final container is produced by sterile air
pressure from Blow and Fill nozzle.

2. Blowing

3. Filling
• The patented electronic fill system delivers a
precise dosage of product into the container.
• The nozzles then retract into their original
position.
• After the container is formed inside the mould,
sterile liquid product is introduced into the
container.

3. Filling

4. Sealing
• Following completion of the filling process, the
top of the container remains semi-molten.
• Separate seal moulds close to form the top
and hermetically seal the container.
• The moulds open and the container is then
conveyed out of the machine.
• Final container is sealed in place by closing of
the seal mould form onto the container top.

4. Sealing

• Advantages of BFS technology:
• There is no need to purchase and stock a range
of pre-fabricated container and closures.
• Cleaning and sterilizing pre-fabricated container
and closures are not required.
• A clean sterile container is made with in the BFS
machine.
• The cost of material transport, storage and
inventory control is reduced.
• Validation requirement are reduced.
• There is a large choice of neck and opening
device shapes.

1. Pharmaceutical dosage forms (Parenteral
Preparation) by Kenneth E. Avis, Leon
Lachman, Vol-1.
2. Pharmaceutical dosage forms (Parenteral
Preparation) by Kenneth E. Avis, Leon
Lachman, Vol-2.
3. Pharmaceutical process Validation by Loftus
& Nash: 29-90.
4. Sterile Pharmaceutical Manufacturing by
Groves Gisan.
5.Pharmaceutical science by Remington, 20th
edition

ASEPTIC PROCESSING AND PRODUCTION CONTROL FOR PARENTERALS

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