Parenteral Production process sterilisation and filling

OVERVIEW OF PARENTERAL DRUG MANUFACTURING
Basically the parenteral drug manufacturing process can be
divided into three types
1 . Manufacturing process for Terminally sterilized product
2. Aseptic processing
3. Direct filling of dry powder

TERMINAL STERILZATION
 The terminal sterilization process usually involves filling and sealing
product containers under high quality environmental conditions
designed to minimize microbial and particulate contamination of the
product.
 The product, container, and closure have low bioburden, but are not
sterile at the time of filling.
 The product is then subjected to a sterilization process in its final
container.
MANUFACTURING PROCESS FOR TERMINALLY
STERILIZED PRODUCT

APPLICABILITY OF TERMINAL STERILISATION
 Terminal sterilization is applicable to thermostable drugs
i.e Drugs which can with stand high temperatures

I TERMINALLY STERILISED PARETERAL MANUFACTURING
PROCESS
1.Washing of Containers
2.Washing of closures and seals
3.Cleaning of Equipment
4.Compounding,
5.Mixing,
6.Filtration,
7.Sterilizing the containers and equipment,
8.Filling product into containers,
9. Stoppering (either completely or partially for products to be freeze-
dried),
10. Terminal sterilization,

11.Closing and Sealing,
12.Sorting and inspection,
13.Labeling, and final packaging for distribution.

PROCESS FLOW CHART FOR TERMINALLY STERILSED PRODUCT

CONTAINERS AND CLOSURES
• Injectable formulations are packaged into
containers made of glass or plastic.
• Container systems include ampoules, vials,
syringes, cartridges, bottles, and bags

• Glass are original parenteral packaging material, has superior clarity,
facilitating inspection for particulate matter.
• Compared to plastics, glass less frequently interacts with the preparation it
contains.
• Plastic polymers used for parenteral packages include polyvinylchloride
(PVC) and polyolefin.
• Both types of plastic offer several advantages over glass, including
durability, easier storage and disposal, reduced weight, and improved
safety.
• Ampoules are all glass, whereas bags are all plastic.

• The other containers can be composed of glass or plastic and
must include rubber materials, such as rubber stoppers for vials
and bottles and rubber plungers and rubber seals for syringes
and cartridges.

CONTAINER MATERIAL TYPES
Glass
 Glass is employed as the container material of choice for most
SVIs.
 It is composed, principally, of silicon dioxide, with varying amounts
of other oxides, such as sodium, potassium, calcium , magnesium,
aluminum, boron, and iron.
 Migratory oxides other than boric oxide , may be leached into a
solution in contact with the glass, particularly during the increased
reactivity of thermal sterilization.
 The oxides dissolved may hydrolyze to raise the pH of the solution
and catalyze or enter into reactions.

 Additionally, some glass compounds will be attacked by solutions
and, in time, dislodge glass flakes into the solution.
 Such occurrences can be minimized by the proper selection of the
glass composition.
Types
The USP provides a classification of glass:
Type I(Borosilicate glass / Neutral glass)
• This is a type of glass container that contains 80% silica, 10% boric
oxide, small amount of sodium oxide and aluminium oxide.
• It is chemically inert and possess high hydrolytic resistant due to the
presence of boric oxide.

• It has the lowest coefficient of expansion and so has high thermal
shock properties.
• Type I glass is suitable as packaging material for parenteral
Type II, a soda-lime treated glass; (soda-lime-silica glass/
treated soda-lime glass/ De alkalized soda lime glass)
• This is a modified type of Type III glass container with a high
hydrolytic resistance resulting from suitable treatment of the
inner surface of a type III glass with sulfur.

• This is done to remove leachable oxides .
• Type II glass has lower melting point when compared to Type I
glass and so easier to mould.
Uses of Type II glass containers
•They are suitable for most acidic and neutral aqueous parenteral
preparations.
Type III, a soda-lime glass; (Regular soda lime glass)
• This is an untreated soda lime glass with average chemical
resistance. It contains 75% silica, 15% sodium oxide, 10% calcium
oxide, small amounts of aluminium oxide, magnesium oxide, and
potassium oxide.
• Aluminium oxide impacts chemical durability while magnesium
oxide reduces the temperature required during moulding.

Uses of Type III glass containers
•They are used as packaging material for parenteral products
or powders for parenteral use ONLY WHERE there is suitable stability
test data indicating that Type III glass is satisfactory.
•They are used in packaging non-aqueous preparations and powders
for parenteral use with the exception of freeze-dried preparations
•It is also used in packaging non-parenteral preparation
Type IV ,NP- a general purpose soda-lime glass not suitable for
containers for parenterals.
• This type of glass container has low hydrolytic resistance.

• This type of glass containers are not used for products that
need to be autoclaved
Uses of type IV glass containers
•It is used to store topical products and oral dosage forms

Siliconisation
 Schott developed a technology, called Plasma Impulse Chemical
Vapor Deposition (PECVD), that coats the inner surface of
Type I glass vials with an ultrathin film of silicon dioxide.
Uses of Siliconisation
 This film forms a highly efficient diffusion barrier that practically
eliminates glass leachables.
 Such treated glass is especially useful for drug products having high
pH values, formulations with complexing agents, or products
showing high sensitivity to pH shifts

 Glass containers must be strong enough to withstand
the physical shocks of handling and shipping and the
pressure differentials that develop, particularly
during the autoclave sterilization cycle.
 They must be able to withstand the thermal shock
resulting from large temperature changes during
processing, for example, when the hot bottle and
contents are exposed to room air at the end of the
sterilization cycle.
 Preparations that are light-sensitive must be
protected, by placing them in amber glass containers
Glass containers

 The size of single-dose containers is limited to 1000 mL by
the USP, and multiple-dose containers to 30 ml.
 A multiple-dose container is designed so that more than
one dose can be withdrawn at different times, the
container maintaining a seal between uses

o Ampules are sealed glass containers with an
elongated neck that must be broken off.
o Most ampules are weakened around the neck for easy
breaking; these will have a colored band around the
neck.
o The product should be filtered before administration
as there are chances of dislodging of glass particles
during ampoule opening
o The use of ampoules has been reduced due to their
unsuitability for multiple-dose use, the need to filter
solutions before use and other safety considerations.
AMPOULES

VIALS
• Drugs and other additives are packaged in vials either
as liquids or lyophilized powders.
• Vials are made of glass or plastic and are closed with a
rubber stopper. and sealed with an aluminium crimp.
• Certain drugs which are unstable in solution form are
packaged in vials in powder form and must be
reconstituted with sterile sodium chloride for injection
before use.
The advantages of vials over ampoules are
• vials can be designed to hold multiple doses (if it is
formulated with a bacteriostatic agent),

• Removal of the product is easier and the contamination of the
product with the glass particles during the process of opening gets
eliminated with the use of vials.
• However vials have certain drawback such as microbial
contamination may occur due to multiple withdrawals.
• A needle is used to add contents to or withdraw contents from the
vial.

PREFILLED SYRINGES
 Prefilled syringes are designed for quickest and
convenient administration.
 When packaged in these prefilled syringes, the drugs
can be administered in an emergency (e.g., atropine,
epinephrine) and may be available for immediate use.
 A cartridge type package, is a single syringe and
needle unit which is to be placed in a special holder
before use.
 Once the syringe and needle unit is used, they are
discarded but the holder is used again with a new
unit.

PLASTIC
 Plastics are synthetic polymers of high
molecular weight
 Plastic is the material of choice for primary
packaging of parenteral products.
 Plastic bags have been used for quite some
time for large volume parenteral.
 Thermoplastic polymers have been
established as packaging materials for
sterile preparations, such as large-volume
parenteral, ophthalmic solutions, and,
increasingly, small- volume parenteral.

Plastic Containers For Pharmaceutical Products Are Primarily
Made From The Following Polymers
Polyethylene Polypropylene Poly Vinyl Chloride Polystyrene
Polymethyl Methacrylate Amino Formaldehyde Poly Carbonates
Types of Plastic Containers
• Plastic Ampoule
• Plastic Vials
• Plastic Syringe
• PVC Collapsible Bags

Plastics as packaging have proved useful for a number of
reason
i.e. Ease with which it can be formed
Durability and Flexibility
The freedom to design.
Plastic containers are extremely resistant to breakage and offer
safety consumers

 One of the principle advantages of using plastic
packaging materials is that they are not breakable, as
is glass; also, there is a substantial weight reduction.
 The flexible bags of polyvinyl chloride or select
polyolefins, currently in use for large-volume
intravenous fluids, have the added advantage that no
air interchange is required; the flexible wall simply
collapses as the solution flows out of the bag.
 Most plastic materials have the disadvantage of not
being as clear as glass, and, therefore, inspection of
the contents is impeded

Three principal problem areas exist in using these materials:
1. Permeation of vapors and other molecules in either direction
through the wall of the plastic container;
2. Leaching of constituents from the plastic into the product;
And
3. Sorption (absorption and/or adsorption) of drug molecules
or ions on the plastic material.
4.Chemical reactivity: Certain ingredients in plastic formulations may
react chemically with one or more components of the drug product.
Even in micro quantities if incompatibility occurs may alter the
appearance of the plastic or the drug produc

Sterilization
Sterilization of Plastic Containers Method of sterilization
Sterilization condition-
• Moist heat 121 degree Celsius for 15 min.
• Dry heat 160-180 degree Celsius for 1 to 3 hrs
• Gaseous sterilization Ethylene oxide with negative pressure or
inert gas

RUBBER CLOSURES
• To permit introduction of a needle from
a hypodermic syringe into a multiple-
dose vial and provide for resealing as
soon as the needle is withdrawn, each
vial is sealed with a rubber

EXAMPLES OF INGREDIENTS FOUND IN RUBBER CLOSURES
Ingredient Examples
Elastomer Natural rubber (latex)
Butyl rubber
Neoprene
Vulcanizing (curing agent) Sulfur Peroxides
Accelerator Zinc dibutyldithiocarbamate
Activator Zinc oxide
Stearic acid
Antioxidant Dilauryl thiodipropionate
Plasticizer/lubricant Paraffin oil
Silicone oil
Fillers Carbon black
Clay, Barium sulfate
Pigments Inorganic oxides
Carbon black

ALUMINUM FLIP OFF/TEAR OFF SEALS

1&2.WASHING OF CONTAINERS AND
CLOSURES
 Containers and equipment coming in contact with parenteral
preparations must be cleaned meticulously.
 Containers and closures are contaminated with such debris as dust,
fibers, chemical films, and other materials arising from such sources
as the atmosphere, cartons, the manufacturing process, and human
hands.

 A variety of machines are available for cleaning new containers
for parenteral products.
 These vary in complexity from a small, hand loaded, rotary
rinsers to large, automatic washers capable of processing
several thousand containers per hour.
 The selection of the particular type is determined largely by the
physical type of containers, the type of contamination, and the
number to be processed in a given period of time.
EQUIPMENT FOR WASHING OF CONTAINERS AND
CLOSURES

HIGH SPEED AUTOMATIC ROTARY VIAL WASHING MACHINE

HIGH SPEED AUTOMATIC ROTARY AMPOULE WASHING MACHINE

WASHING PROCEDURE
 The vials are kept on the feed table and pushed into the built in
rotary table.
 From the rotary table the vials move into the in feed worm
automatically by means of an inverting plate.
 The vials are transferred, mouth down, further into the vial
carrier.
 The washing is done by subjecting the vials to a predetermined
wash sequences

WASHING OF RUBBER CLOSURES/BUNGS
BUNG WASHING MACHINE

AUTOMATIC PROGRAMMABLE BUNG WASHING MACHINE

PROCESS FOR BUNG WASHING PROGRAMS :
• The Process of bung processing are loading, washing with
detergent, D.M. water&W.F.I.water rinsing ,siliconization ,
sterilization and drying.
WASHING
• The loaded bungs are washed with detergent solution via a fully
automatic detergent dozing system with online conductivity
sensor to add the required amount of Detergent in the sterilizer
during the cycle.
RINSING
• The washed bungs are rinsed with deionized water and WFI
water and the quality of WFI water at outlet will be checked
automatically to ensure the proper washing of the bungs.

SILICONIZATION
• After cleaning closures are siliconized using a silicone emulsion or
oil.
• Siliconization of closures is necessary to prevent the release of
plasticizers and other compound added during the compounding
of elastomeric closures, to prevent any reaction between the
closure and the medication stored or to ensure smooth operation
of the machines used for bunging.
STERILIZATION
• In Sterilization the closures are sterilized with steam.
• A pre-vaccum process is employed to ensure effective removal of
air and penetration of steam.

DRYING
 After sterilization the closures are dried using a vaccum drying
process.
 The drying efficiency is further improved by the continuous
rotation of the closures.
 Process ensures bone dry closures on unloading.

2.CLEANING OF EQUIPMENT USED IN
MANUFACTURING AND FILLING
 Residues from previous use must be
removed from used equipment,
before it is suitable for reuse.
 Equipment should be reserved exclusively
for use only with parenteral preparations
and, where conditions dictate, only for one
product to reduce the risk of
contamination.
 All equipment should be disassembled as
much as possible to provide access to
internal structures.

 Surfaces should be scrubbed thoroughly with a stiff brush,
using an effective detergent and paying particular attention to
joints, crevices, screw threads, and other structures where
debris is apt to collect.
 Exposure to a stream of clean steam aids in dislodging residues
from the walls of stationary tanks, spigots, pipes, and similar
 For many operations, particularly with biologic and
biotechnology products, equipment is dedicated for only one
product.

3 &4 . PREPARATION OF SOLUTION(COMPOUNDING AND
MIXING)
 Dissolve the API in water for injection with constant stirring. After
completely dissolving the drug, other excipients are added one by
one and stirred until dissolved.
 The pH is adjusted to the required range by using pH adjusting agent
and buffering agents.
 Make up the volume and mix with water for injection.
 The pH is again adjusted if necessary.
 If isotonicity is to be maintained add 0.9% Nacl

5. FILTRATION OF SOLUTION-MEMBRANE FILTRATION

MEMBRANE FILTRATION
• Membrane Filtration: The process of membrane filtration
uses pressure to force a carrier fluid, such as water, through a semi-
permeable (porous) membrane in order to separate suspended
particulate matter from the fluid and soluble components.
• In membrane filtration today, polymers like poly(ether)sulfones,
polysiloxanes, and polyamides are the most common materials used to
create the barrier and achieve the separation.
• Membranes with different pore sizes are available for different
particles.
REMOVABLE PARTICLES PORE SIZE
MF
Pollen, Asbestos,
Bacteria, Cells
0.1 - 1 µm

6. STERILISATION
 Sterilization is a term referring to any process that eliminates (removes)
or kills all forms of microbial life, including transmissible agents (such
as fungi, bacteria, viruses, spore forms, etc.) present on a surface,
contained in a fluid, in medication, or in a compound such as biological
culture media.
 Microorganisms exhibit varying resistance to strerilisation procedures.
The degree of resistance varies with the type of organism and in
addition spores are more resistant than vegetative forms.
 So the conditions required for a sterilization process must be planned to
be lethal to the most resistant spores of microorganisms normally
encountered

 Sterilization can be achieved by applying the proper combinations of
heat, chemicals, irradiation, high pressure, and filtration.
Alu.Flip off seals and rubber stoppers
DIFFERENT STERILISATION TECHNIQUES

Terminal sterilization:
 A process whereby a product is sterilized in its final container or
packaging, which permits the measurement and evaluation of
quantifiable microbial lethality
 Terminal Sterilization can be achieved by the use of moist or dry heat,
radiation with ionizing radiation, gases
 All medical, ophthalmic and parenteral equipment are sterilized in
batches, and usually sterilized using heat.
CLASSIFICATION OF STERILIZATION
 Sterilization process can be basically separated as Terminal and Non
Terminal process based on stage at which the preparation is subjected
to the process of sterilization.

METHODS OF TERMINAL STERILIZATION
Thermal methods
 Lethal effect of microorganisms depends on degree of heat, the
exposure period, and the moisture content.
• For example, sterilization may be accomplished in 1 hour with dry
heat at a temp of 170°C, but may require as much as 3 hrs at a temp of
140°C.
 The mechanism by which microorganisms are killed by heat is
coagulation of protein of the living cell.
 Thermal methods are divided into two, dry heat and moist heat

Dry heat
 Substances that resist degradation at temp above 140°C. may be
rendered sterile by means of dry heat. 2 hrs of exposure to a temp of
180°C or 45 mts at 260° C can be exposed to kill spores as well as
vegetative forms of all microorganisms.
Moist heat
 Moist heat is more effective than dry heat for thermal sterisation.
Moist heat causes the coagulation of protein at much lower
temperature than dry heat.
 The thermal capacity of steam is much greater than that of hot air. At
the point of condensation (dew point) steam liberates thermal
energy equal its heat of vaporization. This amounts to approximately
524 calories per gram at 121°C.

 Whereas heat energy liberated by hot air is equivalent to 1 calorie per
gram air each degree of centigrade of cooling.
 So when saturated steam strikes a cool object and is condensed, it
liberates approximately 500 times the amount of energy liberated by
an equal weight of hot air.
Terminally sterilized Infusions
 According to the FDA Large volume parenterals means a terminally
sterilized drug product packaged in a single dose container with a
capacity of 100 ml or more and intended to be administered
intravenously.

Sterilization cycle
• The total sterilizing cycle
time normally includes a lag
time for the substance to
reach the sterilizing temp of
the oven chamber, an
appropriate hold period to
achieve sterilization, and a
cooling period for the
material to return to room
tem
• The cycle time is most
commonly prescribed in
terms of hold time, for ex. 2
hrs at 180°C.

• The hold time is shown by sensors detecting the temp of the
chamber at the coolest spot.
• The coolest spot is found through validation during which
thermocouples are placed at different points inside the chamber
Operation
STEP 1:
• Decontaminate, clean and dry all instruments and other items to be
sterilized.
STEP 2:
• If desired, wrap instruments in aluminum foil or place in a metal
container with a tight-fitting, closed lid. Wrapping helps prevent
recontamination prior to use. Hypodermic or suture needles should be
placed in glass tubes with cotton stoppers.

STEP 3:
• Place loose (unwrapped) instruments in metal containers or on
trays in the oven and heat to desired temperature.
STEP 4:
• After the desired temperature is reached, begin timing.
The following temperature/time ratios are recommended

STEP 5:
After cooling ,unload packs and /or metal containers into sterile areas
Loose items should be removed with sterile forceps/pickups and used
immediately or placed in sterile containerswith a tight –fitting lid

MOIST HEAT STERILISATION
Moist heat sterilization technology is the most widely used
given its versatility and effectiveness for heat resistant
products
 Steam sterilization is basically used to sterilize different types of
solid materials: clothing, stainless steel equipment, filters,
component parts of other equipment, etc., and also for liquids in
sealed or ventilated containers, etc

Different types of Autoclaves;
A simple autoclave has vertical or horizontal cylindrical body with a
heating element, a perforated tray to keep the material/article, a lid
that can be fastened by screw clamps, a pressure gauge, a safety
valve and discharge tap.

• In the Autoclave Chamber, terminal sterilization is based on
highly efficient heat transfer from the saturated steam to
autoclave load.
• Heat transfer occurs by the release of the latent heat from
saturated steam under pressure as it condenses.
• Heat transfer from saturated steam to the chamber environment
is much more effective and timely for the coagulation and
denaturation of nucleic acid and proteins than from dry heat or
superheated heat

PROCESS
 STEP 1: Decontaminate, clean and dry all instruments and other items
to be sterilized.
 STEP 2: All jointed instruments should be in the opened or unlocked
position, while instruments composed of more than one part or sliding
parts should be disassembled.
 STEP 3: Instruments should not be held tightly together by rubber
bands or any other means that will prevent steam contact with all
surfaces.
 STEP 4: Arrange packs in the chamber to allow free circulation and
penetration of steam to all surfaces
 STEP 5: When using a steam sterilizer, it is best to wrap clean
instruments or other clean items in a double thickness of muslin cloth

 (Unwrapped instruments must be used immediately after removal
from the sterilizer, unless kept in a covered, sterile container.)
 STEP 6: Sterilize at 121°Cfor 30 minutes for wrapped items, 20
minutes for unwrapped items; time with a clock.
 STEP 7: Wait 20 to 30 minutes (or until the pressure gauge reads
zero) to permit the sterilizer to cool sufficiently.
 Then open the lid or door to allow steam to escape.
 Allow instrument packs to dry completely before removal, which
may take up to 30 minutes. (Wet packs act like a wick drawing in
bacteria, viruses and fungi from the environment.)

CHEMICAL AND BIOLOGICAL AUTOCLAVE INDICATORS

DEPYROGENATION ,STERILISATION OF CONTAINERS AND
EQUIPMENT
 Pyrogens can be destroyed by heating at high temperatures.
 A typical procedure for depyrogenation of glass containers
and equipment is maintaining a dry heat temperature of
250°C for 45 min.
 Exposure of 650°C for 1 min or 180°C for 4 hours, like wise,
will destroy pyrogens.
 The usual autoclaving cycle will not do so .

DEPYROGENATION ,STERILISATION OF RUBBER CLOSURES
 Rubber closures are cleaned and depyrogenated by rinsing with
Water for Injection and, if necessary, a cleaning agent like sodium
hydroxide, Liquid Safe-Kleen (LSK-9), or tri-sodium phosphate
(TSP).
 Many rubber formulations contain polymer surfaces that do not
require siliconization and process without difficulty.
 However, if siliconization is required, like with glass, it is done
prior to sterilization, but after the depyrogenation procedure, and
usually in the stopper washer.
 A pre-determined amount of silicone is added to the stopper
washer during a specified period of the washing cycle.

 Sterilization of rubber closures occurs by steam sterilization in an
autoclave using a validated cycle.
 Rubber plungers used in pre-sterilized, ready-to-fill syringes are
sterilized by gamma radiation.
 Alternatively, stoppers may be purchased directly from the
stopper manufacturer already washed, siliconized, de
pyrogenated, and/or sterilized.

7 .FILLING & SEALING OF VIALS AND AMPOULES
LIQUIDS
 There are three main methods for filling liquids into containers
with high accuracy: volumetric filling, time/pressure dosing,
and net weight filling.
 Volumetric filling machines, employing pistons or peristaltic
pumps, are most commonly used.

AUTOMATIC AMPOULE FILLING AND SEALING MACHINE

AUTOMATIC VIAL FILLING MACHINE

AUTOMATIC VIAL FILLING AND RUBBER STOPPERING MACHINE

AUTOMATIC VIAL FILLING,STOPPERING AND & SEALING OF
PARENTERALS

 Filling machines should be designed so that the parts through which
the liquid flows can be easily demounted for cleaning & sterilisation.
 These parts should be constructed of non-reactive materials such as
borosilicate glass/SS.
 Syringes are usually made of SS when the pressure required for
delivery of viscous liquid or large volumes would be unsafe for glass
syringes.
 The pressure pump filler often is operated semi automatically & differs
from gravity filler principally in that the liquid is under pressure.
 It is usually equipped with an overflow tube connected to a receiver to
prevent excess filling of the container.

 Vacuum filling is commonly used in large volume of liquids
because it is more adaptable to automation.
 A vacuum is produced in a bottle when a nozzle gasket makes a
seal against the lip of the bottle to be filled.
 The vacuum draws the liquid from a reservoir through the
delivery tube into the bottle, when the liquid level reaches the
level of adjustable overflow tube, the seal is mechanically
loosened & vacuum is released.

PROCESS OPERATION
 The incoming dry vials (sterilized and
siliconised) are fed through the in-feed turn
table and suitably guided on the moving delrin
slat conveyor belt at the required speed of the
correct placement below filling unit.
 The filling unit consists of filling head, syringe
& nozzle uses for filling.
 Syringe is made of Stainless Steel 316L
construction. A Star Wheel is provided which
holds the vial during filling operation. A sensor
is provided for ''No Vial-No Filling'' operation.

 Syringe is mounted on eccentric block & driving
through bottom main gear box. Volume can be
increased & decreased by adjusting stroke length
of piston.
 Syringe is having non return valve for sucking &
delivering situation to avoid volume variation.
 Liquid reaches to filling nozzles through silicon
transparent pipe.
 Nozzle having up & down movement with help of
cam mechanism and it go down when starwheel
hold the vial and starts filling when it starts to
move up.

 After completion of filling operation, starwheel delivers vial on
stoppering unit for rubber stoppering operation.
 The sterilized & siliconised rubber stoppers stored in the vibrator bowl
moves vertically to the rubber stopper chute.
 Vials are hold firmly by starwheel, which rotate in continuous rotary
motion.
 Vials coming from filling unit move in rotary direction along with
starwheel, during movement it picks up the rubber stopper from the
exit end of the chute & rubber stopper get pressed by fix spring loaded
single pressing roller.
 Duly Stoppered Vials are delivered to sealing unit through same
starwheel.

II ASEPTIC MANUFACTURING
 Aseptic manufacturing is used in cases, where the drug substance is
instable against heat, hence sterilisation in the final container closure
system is not possible.
 In Aseptic manufacturing the drug substance and excipients were
sterilized appropriately and all materials, equipment and container
closure systems were used only after sterilisation.
 Aseptic processing presents a higher risk of microbial contamination of
the product than terminal sterilization.
 In an aseptic filling process, the drug product, containers and closures
are sterilized separately and then brought together under an extremely
high quality environmental condition designed to reduce the possibility
of a non-sterile unit

APPLICABILITY OF ASEPTIC MANUFACTURING
 Aseptic manufacturing is used in cases of thermolabile drugs ,
i.e drug substance which is Unstable against heat, hence sterilization
in the final container closure system is not possible.

ASEPTIC MANUFACTURING
Stoppering &
Under LAF
Class 100 area

PROCESSING
Bulk solution
 For bulk solution (parenteral preparation)sterility is best achieved
through sterile filtration of the bulk using a membrane filter (0.2 µm
or less) in sterile container closure systems and working in a clean
area.
 All working steps were performed in so called clean areas to avoid
contamination.

MEMBRANE FILTERS-FILTRATION STERILISATION
PLEATED MEMBRANE FILTERS
Sterilizing Grade PES Membrane Filters
Paper filters

 Membrane filtration traps contaminants larger than
the pore size on the surface of the membrane.
 Membrane filters are the basic tools for
microfiltration and ultra filtration.
 They are used in the preparation of sterile solutions
 Membrane filters or “membranes” are microporous
plastic films with specific pore size ratings.
 Also known as screen, sieve or microporous filters,
membranes retain particles or microorganisms
larger than their pore size primarily by surface
capture.

Selection of membrane filter
The selection depends on the function of the size of the particles to be
removed
Pore size (microns) Particle removed
0.2(0.22) All bacteria
0.45 All coliform bacteria
0.8 All airboirne particles
1.2 All nonliving particles considered
dangerous in I.V fluids
5.0 All significant cells from body fluids
.

Polytetrafluoroethylene (PTFE)
membrane filters
CARTRIDGE FILTERS

FILTER INTEGRITY TEST
 Membrane filters have been used successfully for many years to
remove yeast, bacteria and particulate from fluid streams.
 Filter integrity testing is an essential procedure to detect defective
filter cartridges and to avoid their use in the process.
 An appropriate testing procedure for filter integrity is required prior
to and after the filtration step to ensure that the filter is according to
the supplier’s specification and that the filter is not changed by
sterilisation or damaged by other unforeseeable events.
 The ultimate integrity test for a sterilizing grade membrane filter is
the bacterial challenge

 During production of sterile product, the filter should be subjected to
such an integrity test before and after filtration.
 This is done to ensure that the filter meets specification, is properly
installed and intact during filtration, and to confirm the rating of the
filter.

 High standards have to be established concerning the
manufacturing room, the personnel, the equipment and the supply
systems (air system, water for injection, sterile gases used in the
working process; for example compressed air, nitrogen etc.).
The objective of aseptic processing is to maintain the sterility of a
product that is assembled from components, each of which has been
previously sterilized
The operating conditions should be such as to prevent microbial
contamination.

In order to maintain the sterility of the components and the product
during aseptic processing, careful attention needs to be given to:
— the environment;
— personnel;
— critical surfaces;
— container/closure sterilization and transfer procedures;
— the maximum holding period of the product before filling into the
final container; and
— the sterilizing filter
Owing to the potential additional risks of the filtration method
as compared with other sterilization processes, a double-filter
layer or second filtration through a further sterilized
microorganism-retaining filter immediately prior to filling is
advisable.

The final sterile filtration should be carried out as close as
possible to the filling point.
 There fore, this operation is carried out with a minimum
exposure time, even though maximum protection is provided by
filling under a
blanket of HEPA-filtered laminar-flow air within the aseptic area.
 Most frequently, the compounded product is in the form of
a liquid.
 However, products are also compounded as dispersed systems
(e.g., suspensions and emulsions) and as powders.

 Aluminium caps are kept in vibratory bowl automatically oriented
in right direction before entering the delivery chute.
 Vial during its rotation movement picks up aluminum seal from the
retaining finger of delivery chute & correctly position on the vial
before entering sealing turret
 Vials now moves on the spring loaded sealing platform, where free
spinning sealing rollers moves gradually inside to complete the
sealing operation during rotational movement of sealing platform
turret.
 Now sealed vials are transferred to exit starwheel pocket & further
moves out on to the flat conveyor belt for further labeling
operations.

OPERATION
• Sterilised ampoules are loaded in the tray.
• After that, this tray is directly loaded into slant hopper of unit.
• Now the machine starts to process, while synchronized start wheels
start to deliver one at a time moving in the rack in single, twos, fours
or sixes.
• The rack stops sequentially and during this period, its every single
procedural process is carried out like pre-gassing, filling, post-
gassing, pre-heating and finally sealing it out.
• All the sealed ones are then, collected on tray for collection without
manual touching.

Sealing operation of Ampoules
 It may be closed by melting a portion of
the glass of neck to form either bead
seals (tip-seals) or pull seals.
• Tip seals are made by melting sufficient
glass at the tip of ampoule neck to form a
bead of glass & close the opening.
 Pull-seals are made by heating the neck
of rotating ampoule below the tip, then
pulling the tip away to form a small,
twisted capillary just prior to being melt
closed.

HIGH SPEED AUTOMATIC AMPOULE FILLING & SEALING
MACHINE

Process Operation
• Empty washed & sterilized ampoules fed into wire mesh conveyor belt
from the left hand side of the machine.
• Eight ampoules fed through feeding cassette to receiving rack.
• The moving rack which moves horizontally collect eight ampoules from
the receiving rack and transfer the ampoule to the machine in left to
right in an inclined position through pre-gassing.
• Pre-gassing, Filling, Post Gassing, Pre-heating & sealing stations
completes filling & sealing operations.
• Filled & sealed ampoules are collected automatically in SS tray in
upright position without hand touch.

Filling equipment for solids – Sterile solids such as antibiotics are more
difficult to subdivide accurately & precisely into individual dose
containers than are liquids.
STERILE SOLIDS/DRY POEDERS FILLING
III. STERILE SOLIDS/DRY POEDERS FILLING

DRY POWDER INJECTION
Dry Heat
Of Powder in sterile containers

 The rate of flow of solid material tends to be slow & irregular,
particularly if finely powdered. Small, granular particles flow
must be evenly.
 In general, these involve the measurement and delivery of a
volume of the granular material that has been calibrated in
terms of the weight desired.
 In the machine shown below, an adjustable cavity in the rim of
a wheel is filled by vacuum and the contents held by vacuum,
until the cavity is inverted over the container.
 The solid material is then discharged into the container by a
puff of sterile air.

Parenteral Production process sterilisation and filling

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