What are perenterals ?

Are sterile, pyrogen free preparations injected through skin or mucous

membrane into internal body compartments.

Sterile Product . . . . . . . . .
Are dosage forms of therapeutic agents that are free of viable

microorganisms.

Parenterals

Opthalmics

Irrigating preparations.

Why Peranterals ?
Para enterals : Besides the intestine

Circumvents:

Gastero Intestinal instability

Low absorption

Variable absorption

69
History Of Parenteral Therapy
1657: First recorded injection in animals

Sir Christopher Wren

1855: First subcutaneous injections of drugs using hypodermic needles

Dr. Alexander Wood

1920s: Proof of microbial growth resulting in infections

Dr. Florence Seibert

1926: inclusion in the National Formulary

1933: Application of freeze drying to clinical materials

1944: Discovery of ethelyne oxide

1946: Organization of Parenteral drug Association

1961: Development of laminar air flow concept

1965: Development of Total Parenteralnutrition(TPN)

Contemporary Development Of Parenterals

1970’s to date: Emergence of novel drug delivery systems/ patches

/implants, iontophoresis, targeted delivery

1980’s: Emergence of Home Health Care and Patient Controlled Analgesia

concepts

1982: Insulin and biotechnology products

Infusion pumps

Iontophorosis

Pharmacy on a chip?

70
 Feedback regulated delivery?

Virtual drug delivery? Other?

Routes Of Parenteral Administration

Intradermal (I.D.): Injections into the superficial layer of skin. Only small

volumes (0.1 ml) can be used. Absorption is slow by this route.

Subcutaneous (S.C., S.Q., Sub-Q, Hypo): Injections into the loose tissue

beneath the skin. Absorption is faster than intradermal

Intramuscular (I.M.): Injections into a muscle mass up to 5 ml can be given

Intravenous (I.V.): Injection into a vein. There is little limitation on volume

and absorption in instantaneous.

Intra Muscular (I.M.):- Injection into a muscle mass up to 5ml can be

given

Intradermal (T.D.):- Injection into the loose tissue beneath the skin. Only

small volumes (0.1 ml) can be used

Intra-arterial

Intracardiac: -Injections into heart chamber.

Intrathecal (spinal fluid): Injection into spinal fluid.

Drugs given by the intraspinal route must be in solution. Drugs given by the

intravenous route must be in solution or emulsions. Drug given by

subcutaneous, intramuscular or intradermal may be solutions, suspensions or

emultions.

Intrasynovial:- (joint fluid area): Injection into a joint fluid area.

Inttraspinal: Injection into a spinal column

71
Intra-articular:- Injections into a joint. This method is used for arthiritis

and joint injuries.

72
Disadvantages Of Parenteral Administration
Administered by trained personnel only using aseptic procedures

Pain on injection

Difficult to reverse an administered drug’s effects

Manufacturing and Packaging requirements

Cost

Needle sticks

Advantages Of Parenteral Administration

Fastest method of drug delivery (e.g. cardiac arrest, asthama, shock)

Viable alternative to unsuccessful oral therapy

Uncooperative, nauseous, or unconscious patients

Less patient control (I.e. return visits)

Local effect (e.g. dentistry, anesthesiology)

Prolonged action (e.g. intra- articular steroids, IM penicillins)

Correcting serious fluids and electrolyte imbalance

Total Parenteral Nutrition (TPN)

Types Of Sterile Products

Terminally sterilised : prepared, filled and sterilised

Sterilised by filtration

Aseptic preparation

73
cGMP Requirements For Sterile Products
Additional rather than replacement

Specific points relating to minimizing risks of contamination

microbiological

particulate matter

pyrogen

General Requirements
Production in clean areas

Airlocks for entry

personnel

material

Separate areas for operations

component preparation

product preparation

filling etc

Level of cleanliness

Filtered air

Air classification: Grade A, B, C and D

Laminar air flow:

air speed (horizontal versus vertical flow)

number of air changes

air samples

74
 Conformity to standards

Work station and environment

Barrier technology and automated systems

Manufacture Of Sterile Preparations

Classifications - I : Terminally Sterilized Products
Terminally sterilised

preparation:

Grade C: then immediate filtration and sterilisation

Grade D: Closed vessels

Grade A: Filling (Grade C environment) of parenterals

Grade C: Filling of ointments, suspensions etc

Classifications – II : Sterile Filtered Products

Sterilisation by filtration

Handling of starting materials

Grade C

Grade D: Closed vessels

Sterile filtration into containers: Class A (in Class B

environment) or Class B (in Class C environment)

Classifications – III : Products Produced From Sterile

75
 Materials
Aseptic preparation

Handling of materials

All processing

76
 Grade A in Grade B environment or

Grade B in Grade C environment

Premises
Design

avoid unnecessary entry

Clean areas

smooth, impervious, unbroken surfaces

permit cleaning

no uncleanable recesses, ledges, cupboards, equipment

no sliding doors

ceilings

pipes and ducts

sinks and drains

Changing rooms

designed as airlocks

flushed with filtered air

separate for entry and exit desirable

hand washing facilities

interlocking system

visual and/or audible warning system

77
Sanitation
Clean areas

frequency

SOP

Disinfectants

periodic alterations

monitor microbial contamination

dilutions, storage and topping-up

Fumigation

Monitoring

Viable and non viable particulate matter

Personnel
Outdoor clothing

Appropriate to air grade

Grade D

hair, beard and shoes

Grade C

hair and beard

suit covering wrists, neck

no fibres

Grade B

masks, gloves

78
Laundry and changes

79
 Minimum number in clean areas

aseptic processing

inspection and control

Regular training

manufacture

hygiene

microbiology

outside staff

Animal tissue and cultures of micro-organisms

Hygiene and cleanliness

contaminants

health checks

SOPs : Changing and washing

Jewellery and cosmetics

Equipment
Air supply:(HVAC)

Generation and supply of filtered air under positive pressure

Airflow patterns

Failure of air supply

Pressure differentials monitored and recorded

Conveyer belts

Effective sterilisation of equipment

80
 Maintenance and repairs

Planned maintenance, validation and monitoring

Water treatment plants

Environmental Monitoring
I Microbiological
Air

Surfaces

Personnel

II Physical
Particulates

Differential pressures

Air changes

Filter integrity

Temperature/humidity

Processing
Minimise contamination

No unsuitable materials e.g. live microbiological organisms

Minimise activities

staff movement

Temperature and humidity

Water sources and systems

81
monitoring

records

action taken

82
Bio-burden determination

raw materials

in-process materials

LVP : filtered immediately before sterilisation

sealed vessels: pressure-released outlets

Components, materials and containers

fibre generation

no re-contamination after cleaning

stage identified

sterilised when used in aseptic areas

Gas through a sterilising filter

Validation

new processes

re-validation: Periodic and after change

Aseptic process: Sterile media fill (“broth fills”)

simulate actual operation

appropriate medium/media

sufficient number of units

acceptable limit

investigations

revalidation: periodic and after change

Time intervals: Components, containers, equipment

washing, drying and sterilisation

83
ssterilization and use

time limit and validated storage conditions

84
 Time intervals: Product preparation

preparation and sterilisation

short as possible

maximum time for each product

Finishing Of Products
Validated closing process

Checks for integrity

Maintenance of vacuum (where applicable) checked

Parenteral products: Individual inspection

illumination and background

eyesight checks

breaks

validation

Usp Types Of Injection

[DRUG] Injection (Insulin Injection, USP): Ready for injection

Sterile [DRUG] (Sterile Ampicillin Sodium, USP): No additives, need addition

of solvents

[DRUG] for injection (Methicillin Sodium for injection, USP): Have additives,

need addition of solvents

Sterile [DRUG] suspension / Emulsion (Sterile Dexamethasone Acetate

Suspension, USP): Ready for administration, not I.v. or intraspinal

85
 Sterile [DRUG] for Suspension / Emulsion (Sterile Ampicillin for suspention,

USP): Addition of Vehicles requirement, not I.v. or intraspinal

Vehicles For Injection

AQEOUS VEHICLE

Frequently, isotonic (to blood) to which drug may be added at the time of

use.

Water-miscible Vehicle

Portion of the vehicle in the formulation

Used primarily to effect solubility of drugs and / or reduce

hydrolysis

Ethyl alcohol; polyethylene glycol(liquid) and propylene glycol

Non Aqueous vehicles:

Fixed oils (Vegetable origin ,liquid , and rancid resistance ,

unsaturation, free fatty acid content) used in hormone preparations

Examples of Water-Miscible Vehicles

Aqueous Co solvent vehicles:

ethyl alcohol (Alcohol USP)

propylene glycol

Glycerin USP

Polyethylene glycol 300 NF

Examples of Non aqueous vehicles

Oleoginous Vehicles

Peanut Oil

86
 Corn Oil

Cotton seed Oil (Depo –Testosterone R- Upjohn)

Sesame oil

Soyabean oil (source of fat in intralipid R)

Ethyl oleate

Isopropyl myristate

Types Of Water For Injection

Highly purified Water used as a vehicle for injectable preparations

which will be subsequently sterilized.

Can be stored for less than 24 hr at RT or for longer times (5 or 80

° C).

Need to meet USP sterility test since used in products which will be

sterilized.

Need to meet USP Pyrogen test.

Maximum 1 mg/100 ml Total solids.

May not contain an added substance.

Sterile Water for Injection USP (SWFI)

Appropriate type of water used for making parenteral solutions

prepared under aseptic conditions and not terminally sterilized.

Needs to meet USP Sterility Test.

Can contain an added Bacteriostatic agent when in containers of 30 ml

or less.

Single dose containers no exceeding 1000ml.

87
Higher solids specification to allow leaching from glass packaging

during sterilization (22 – 40 ppm)

88
 Bacteriostatic Water for Injection USP

Is SWFI containing one or more suitable Bacteriostatic Agents.

Multiple dose containers not exceeding 30 ml

Not the vehicle of choice (SWFI is) when need later than 5ml due to

toxicity of Bacteriostatic agent.

Sterile water for irrigation

Wash wounds, surgical incisions, or body tissues

Sterile water for inhalation

Parenteral Added Substances

Antibacterial agents

Prevent the multiplications of microorganisms

Antioxidants

Prevent oxidization of drugs

Buffers

Prevent degradation

Adjusted to physiological pH when administered

Tonicity contributors

often buffer salts, provide patient comfort

Other:

Solubilizers, waiting agents, emulsifiers, local anesthetics, etc.

Antibacterial agents

Required to prevent microorganism growth

89
 Limited concentration of agents

Phenylmercuric Nitrate and Thimersol 0.01%.

Benzethonium chloride and benzalkonium chloride 0.01%

Phenol or cresol 0.5%

Chlorobutanol 0.5%

Effectiveness varies with formulation

e.g. Binding of parahydroxybenzoic acid with macromolecules

Refrigeration slows the growth, does not prevent Antibacterial agents

testing.

To determine the effectiveness of antimicrobial system for a parenteral:

Inoculum containing a known number of organisms (Candidida albecans,

Aspergillus niger, E-coli, Pseudomonas aeruginosa, and staphylococcus

aureus) is added.

Incubate at 32°C.

Adequate if no significant increase in microorganisms.

Antioxidants
Prevent the oxidation by being oxidized faster than the drug or by blocking

oxidization

Water soluble: acid, sodium bisulfate, sodium metabisulfite, sodium sulfite

Oil soluble: Butylated hydroxytoluene (BHT), Butylated hydroxyanisole

(BHA)

Displacing the air.

90
Buffers
Added to maintain the pH

Result in stability

Not overwhelmed by Physiological buffer

Effective range, concentration, chemical effect

Examples:

Sodium Citrate and citric acid

Sodium Acitate and Acitic acid

Sodium Benzoate and Benzoic acid

Sodium tartrate and tartaric acid

Sodium Phosphate (Monobasic Sodium hydrogen phosphate (NaH2PO4

and Dibasic Sodium Hydrogen Phosphate)

Sodium Bicarbonate

Tonicity Agents
Reduce pain of Injection

Can include buffers

Sodium chloride

Potassium chloride

Dextrose

Mannitol

Sorbitol

lactose

91
Other Parenteral Adjuncts
Suspending or Viscosity Increasing Agents

Sodium carboxymethyl cellulose

Gelatin

Polyvinylpyrrolididone

Methylcellulose

Surfectants (Emulsifying , solubilizing, Wetting Agents)

egg yolk phospholipids

Polysorbate 20,60,80

Lecithin

pluronic F-68R

Polyethyleneglycol-400 castor oil

Chelating Agents
Inert gases

Ethylenediamine tetraacetic acid

N2 (OFN-OXIGEN FREE NITROGEN)

CO2 (CORBONDIOXIDE) for (sodiumbicarbonate injection)

Enhanced Drug Targeting Effect

vasoconstrictor in local anesthetic

Administration of Aids

Local Anesthetic; benzyl alcohol

xylocaine HCL, Procaince HCL

92
 Anti inflammatory

Agents: Hydrocrtisone

Anti –clotting agents: Heparin

Vasoconstrictors (prolong action); epinephrine

increase tissue

permeability: Hyaluronidase (enzyme)

93
Physical And Chemical Stability
Enhance the physical and chemical stability

e.g. (Antioxidants, inert gases, chelating agents, buffers)

Oxidative and hydrolytic chemical changes

Because of auto-oxidative nature, only small amount of oxygen needed

Combination of chelating agents with antioxidants

Remove metals which can catalyze the oxidation

Maintain the pH range

Unique Characteristics Of Parenterals

Sterile

Particle Free

USP microscopic methods for large –volume parenterals

not more than 50 particles/ml that are equal to or larger than 10

micrometers and not more than 5 particles/container that are equal

to or larger than 25 micrometers

USP electronic liquid-borne particle counting system for small volume

parenteral (<100ml)

Not more than 10,000 particles/container that are equal to or larger than 10

micrometers and not more than 1000 particles/container that are equal to

larger that 25 micrometers.

Pyrogen free (if parenteral)

94
 Pyrogen Test

Traditional tests uses rabbits, solution injected ear vein (n= 3) or

washing from a sterile device

Measure body temperature

LAL TEST: Simpler, rapid and greater sensitivity test than the pyrongen

test Limulus amoebocyte lysate of (limulus polyphemus) from the hoarse

shoe crab.

Contain a protein that clots with the presence of Bacterial

endotoxins.

Methods Of Sterilization In Parenterals

Sterilization
Methods of sterilization

heat sterilization: Method of choice

Validation

all processes

non-pharmacopoeia

non-aqueous or oily solutions

Suitability and efficacy

part of load

type of load

repeated: annually and after change

Biological indicators

95
96
 Differentiation between sterilized and not-sterilized products

labelling

autoclave tape

Sterilization By Heat
Recording of each cycle, e.g. time and temperature

validated coolest part

second independent probe

indicators

Heating phase

each load determined

Cooling phase

no contamination

leaking containers

Moist Heat Sterilization

Water wettable materials

Temperature, time and pressure monitored

Recorder and controller independent

Independent indicator

Drain and leak test

Removal of air

Penetration of steam, quality of steam

97
 All parts of the load: Contact, time, temperature

Dry Heat Sterilization

Air circulation and positive pressure in chamber

Filtered air

Temperature and time must be recorded

Removes pyrogens

validation (challenge tests with endotoxins)

Sterilization By Radiation
Suitable for heat sensitive materials and products

confirm suitability of method for material

ultraviolet irradiation not acceptable

Contracting service

Measurement of dose

Dosimeters

quantitative measurement

number, location and calibration

Biological indicators

Colour discs

Batch record

Validation

density of packages

98
 Mix-ups: Irradiated and non-irradiated materials

Dose: Predetermined time span

99
Sterilization By Ethylene Oxide Gas
Only when no other method is practicable

Effect of gas on the product

Degassing (specified limits)

Direct contact with microbial cells

Nature and quantity of packaging materials

Humidity and temperature equilibrium

Monitoring of each cycle

time, pressure

temperature, humidity

gas concentration

Post-sterilization storage

ventilation

defined limit of residual gas

validated process

Safety and toxicity issues

Sterilization by Filtration
Previously sterilized containers

Nominal pore size 0.22 µm or less

remove bacteria and moulds

not viruses or mycoplasmas

Double filter layer or second filtration

100
 No fibre shedding or asbestos filters

Filter integrity testing

Time taken and pressure difference validated

Length of use

one working day

or validated

Filter interaction with product

removal of ingredients

releasing substances

Sterility Testing
Samples representative of the batch

aseptic fill

beginning, and end of batch, or interruption

heat sterilization

coolest part of the load

Last of series of control measures

Adequate testing facility (e.g. Class A in B environment)

Test failure: Second test subject to investigation:

type of organism

batch records, environmental monitoring records

101
What Are The PYROGENS?
Products of metabolism of microorganisms

Endotoxins the most prevalent lipopolisaccharaides from the gram –ve

bacteria cell wall

Can cause fever, malaise, muscle ache, and in seriously illpatients shock-like

symptoms.

Heating at high temperatures prevents pyrogens (e.g. 250 ° for 45 minutes

etc.)

Sources of pyrogens: water, containers, equipments, solutes, etc.

Pyrogen Testing
Rabbit method

LAL test (endotoxin monitoring)

Injectable products

water, intermediate, finished product

validated pharmacopoeia method for each type of product

always for water and intermediates

Test failures

cause investigated

remedial action

102
Lyophilization (Freeze Drying)
Process of drying in which water is sublimed from the product after it is

frozen, following steps are involved:

freezing an aqueous product

evacuate the chamber

(usually below 0.1 torr= 100 micrometers Hg)

Introducing heat to the products to allow for subliming of ice into a

cold condensing surface

Packaging, Labeling And Storage Of Injections

Multiple – dose container

Single dose container (ampules and vials)

Types of Glass

Type I, Boroslicate glass

Type II, soda-lime treated glass

Type III, a soda-lime glass

NP, Soda-lime not suitable for parenterals

Rubber closures

Labels : Name, Percentage, Route of administration, Storage

condition, Manufacturer, Lot number.

103
Available Injections
Small Volume Parentrals (25-50ml)

Requires little or no manipulation

Extended stability

Little wastage

Do not offer flexibility in quantity/concentration

Large volume Parentrals

Flexible but requires manipulation

Used for maintenance or replacement therapy

Parenteral Incompatibility
Physical

Changes in the appearance of the mitures, eg.

Precipitation, Color, gas formation

Precipitation of the Sodium salt of weak acids in I.V Fluids

having an acidic pH.

Chemical

Decomposition of drugs in parenteral fluids

Hydrolysis

oxidation

reduction etc.

Therapeutic:

Combination results in antagonistic or synergistic therapeutic

104
effect

e.g. Cortisone antagonizing heparin.

105
 Vial Washing and Tunnel sterilizer
Technical Specifications
MAKE : HAMISH ENGINEERING INDUSTRIES
PVT. LTD.
MODEL : CMW 15 X 3
SERIAL No. : 0204010
OVER ALL DIMENSIONS : 1000mm(L) X 1000mm(W) X 1200mm(H)
VIAL SIZE : 2 – 100 ml
OPERATION : AUTO / MANUAL
THROUGHPUTS : 7000 VPH, 5-10 ml
P.L.C : Mitsubishi (FXAR-4HD-PT 1Z9418)
M.M.I : Beigers E 300 Compatible with Mitsubishi
MATERIAL OF CONSTRUCTION : SS 304

Vial Washing, Sterilizing And Depyrogenation

Directive 21CFR part 211.92 states that containers used for parenteral

drugs, shall be "clean", "sterile" and "pyrogene free". This can be accomplished by

washing machines and sterilization/depyrogenation equipment.

Washing contributes an critical role in pharmaceutical world. Hence to

understand ‘washing’, first lets understand the term “Clean”.

106
Clean
Today, most glass vials are of high quality and require little if any cleaning.
However after the manufacturing process, vials are subject to uncontrolled
environments and are likely to become contaminated with particulates and micro-
organisms. For this purpose, vial washers are used throughout the Pharmaceutical and
Biotech Industry.
The performance of a vial washer can be validated through two studies:

Particulate Removal
To determine the effectiveness of the vial washer, it is recommended to spike
vials with a styrene polymer bead suspension prior to washing. The vial washer should
be able to remove all particulates.

Chemical Contaminants Removal

To test the ability to remove chemical contaminants, vials are spiked with a
Sodium Chloride (NaCl) solution. After washing, no traces of NaCl should be detected.

Principle
The most effective way to remove contaminants from vials is through "scrubbing"
action with utilities. Most commonly used utilities for washing of vials are Purified Water
and Water For Injection (WFI), which is not only without particulates, but also without
microorganisms and pyrogenes. The "scrubbing" action is accomplished by high
pressure water jets.

The effectiveness of this "scrubbing" is a function of the following factors:

1) The energy level of the WFI
2) The amount of WFI used per vial.

Energy Level Of WFI

The higher the WFI temperature, the higher the energy level. High temperature

107
WFI (80-90° C) is more effective in particulate removal than WFI at ambient
temperature. High pressure water jets are more effective than low pressure water jets.

Amount Of WFI
The amount of WFI is subject to the size of the vial. Obviously, larger vials
require more WFI than smaller vials.
In a vial washing machine, the amount of WFI is determined by:
1) The cycle time (or speed setting) of the machine,
2) The number of spraying stations
3) The orifice of the spraying opening.

As WFI is part of the ongoing operational cost, it does not make sense to use
more WFI per vial than necessary. Ideally, the amount of WFI per vial should be
empirically determined.

Sterilizing And Depyrogenation

Cleaning plays an important role but still our aim is to obtain a "clean", "sterile"
and "pyrogen free" parenteral drug. Thus sterilization and depyrogenation process even
contributes equally to achieve the goal. Lets understand sterilization and
depyrogenation in detail.

Sterile
Vials can be sterilized in dry-heat ovens and sterilization tunnels. Dry-heat ovens
are designed to sterilize at a temperature of 170°C. Sterilizing tunnels are designed to
sterilize at twice that temperature.

Heat destroys microorganisms. The destruction process of micro-organisms is a

function of time and temperature. The rate of destruction is more or less logarithmic,
meaning that in a given time interval and at a given temperature, the same percentage

108
of the bacterial population will be destroyed. For example, if the time required to destroy
1-log cycle (90%) is known, and the desired thermal reduction has been decided (e.g. 4-
log), then the time required can be calculated.
Example: If the bacterial population is 1 million CFU (Colony Forming Units), and it

takes 5 minutes to destroy 1-log cycle at a certain temperature, then the

remaining population after 5 minutes is 100,000 CFU, after 10 minutes 10,000 CFU,

after 15 minutes 1,000 CFU and after 20 minutes 100 CFU (4-log cycles).

Pyrogene Free
During the destruction of the cell-wall of bacteria (also called death-phase),
endotoxins are released. Endotoxins are pyrogenic (Gr: pur, gen. puros=fire,
gennaeo=to generate). When pyrogenes (inadvertently) enter the blood stream, white
blood cells are activated by encapsulating the pyrogenes. This process causes elevated
temperatures (fever) in humans and animals.

Pyrogenes are too small to be eliminated by filtration. However, heat will

disintegrate pyrogenes (high-molecular lipo-polysaccharides) to harmless molecules.

At 250°C, the time required to disintegrate pyrogenes 1-log cycle, is 5 minutes

(D-value). Empirically has been determined that for every 46.4°C. increase in
temperature, the D-value will be reduced by 1-log cycle.

In other words, at a temperature of 296.4°C, a 1-log pyrogene reduction is

accomplished after 30 seconds. At a temperature of 342.8°C., a 1-log pyrogene
reduction is accomplished after 3 seconds.

109
Refer the table given below:

1-log cycle 2-log cycle 3-log cycle 4-log cycle

Z250 D5min. D10min. D15min. D20min.
Z296.4 D30sec. D60sec. D90sec. D120sec.
Z342.8 D3sec. D6sec. D9sec. D12sec.

110
Tunnel Sterilizer
Technical Specifications
MAKE : HAMISH ENGINEERING INDUSTRIES
PVT. LTD.
MODEL : V-450
SERIAL No. : 0202024
OVER ALL DIMENSIONS : 3000mm(L) X 1100mm(W) X 2350mm(H)
DRYING ZONE DIMENSIONS : 655mm(L) X 612mm(W) X 640mm(H)
HOT ZONE DIMENSIONS : 1195mm(L) X 900mm(W) X 1250mm(H)
COOLING ZONE DIMENSIONS : 1320mm(L) X 612mm(W) X 640mm(H)
VIAL SIZE : 2 – 100 ml
OPERATION : AUTO / MANUAL
THROUGHPUTS : 7000 VPH, 5-10 ml
P.L.C : Mitsubishi (FXAR-4HD-PT 1Z9418
M.M.I : Beigers E 300 Compatible with Mitsubishi
MATERIAL OF CONSTRUCTION : FRAME : SS 304
CONVEYOR BELT : SS 304

Types Of Tunnel Sterilizers

Two types of tunnels can be distinguished:
1) Radiant heat tunnels
2) Laminar Air Flow (LAF) tunnels.

Radiant heat tunnels use Infrared heating elements to heat vials by radiation.
Laminar Air Flow tunnels apply heated and filtered air to heat vials by convection. The
term "Laminar" is actually incorrect. There is little if any laminarity of air in a LAF tunnel.
It would be more appropriate to speak of "Hot Air" tunnels.

111
Sterilizing/Depyrogenation tunnels consist of three chambers:
1) The infeed chamber
2) The sterilizing chamber
3) The cooling chamber

Advantages Of Hot Air Tunnels Over Radiant Heat Tunnels

1) Heat transfer by convection is faster than by radiation. The sterilizing
chamber of a Hot Air tunnel can therefore be shorter that of a radiant heat
tunnel. This results in a smaller foot print.
2) Particulates generated by the vials and the tunnel itself (transport belt) are
continuously removed by HEPA filters. Hot Air tunnels are "cleaner" than
Radiant heat tunnels.
3) Better control of air over-pressure in the clean room by balancing the air
pressures in the three sections of the tunnel.
4) Better process control by automatically adjusting the air pressure and air
velocity per section.

Note 1:

Glass vials can be safely exposed to 350°C. Higher temperatures should be avoided

as the surface of the vials is subject to change. The result is increased friction

between vials which may adversely affect down stream vial handling. The optimum

working temperature of a sterilizing tunnel is therefore 350°C.

Note 2:

Typically, sterilization/depyrogenation tunnels are validated at no less than 4-log

pyrogene reduction. This includes a 1-log cycle safety margin.

112
Filters
Each of the three sections of the tunnel is equipped with High Efficiency
Particulate Air (HEPA) filters. HEPA filters are 99.99% effective regarding 3µ
particulates. In the sterilizing chamber, heat resistant HEPA filters are used with an
efficiency of 99.97%.

DOP Testing
HEPA filters are tested for efficiency by the "DOP" test procedure. DOP stands
for Di-Octyl Phlalate. Because of concerns that DOP may have carcinogenic properties,
it has been substituted by a compound called Emery 3004, although the acronym DOP
has been retained. Each section of the tunnel has provisions to conduct the DOP test.

Automatic Door Setting

The three sections of the tunnel are separated by doors. The height setting of
these doors depends on the height of a vial and is automatically set by the PLC.

Vial Loading
Tunnels can be equipped with an external conveyor with vial loading system, to
be integrated with the outfeed of the upstream washing machine.

The tunnel conveyor is moved by an AC motor with frequency control. The

conveyor travel distance per loading stroke is subject to the vial diameter and is
controlled by the PLC.

Infeed Area
The purpose of the infeed area is to create a thermal barrier between the vial
washing room and the sterilizing chamber, and to dry and preheat the vials by means of
air flowing back from the sterilizing chamber.

113
Sterilizing Chamber
Heat is generated by stainless steel, SCR-controlled heating elements.
Depending on the format, vials stay approximately 6-10 minutes in the
sterilizing/depyrogenation chamber. The recirculated hot air is blown at a speed of
approximately 0.7 m/s over the vials.

Cooling Chamber
Depending on the size of the tunnel. Regular tap water or chilled water can be
used to cool the surrounding environment. Depending on the size of the cooling zone
and the set speed of the conveyor, vials stay approximately 15-20 minutes in the cooling
chamber.

HMI (Humane Machine Interface)

The Humane Machine Interface provides the communication between the
operator and the equipment. The software package is used is designed according to
Title 21 Code of Federal Regulations (21CFR part 11).

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Filling and Stoppering Machine
Technical Specifications
MAKE : HAMISH ENGINEERING INDUSTRIES
PVT. LTD.
MODEL : KL-D-4.12
SERIAL No. : 0204012
OVER ALL DIMENSIONS : 1950mm(L) X 1060mm(W) X 1600mm(H)
VIAL SIZE : 2 – 100 ml
OPERATION : AUTO / MANUAL
THROUGHPUTS : 7000 VPH, 5-10 ml
MATERIAL OF CONSTRUCTION : FRAME : SS 306
TOP COVER : SS 316
SIDE PANELS : SS 304
PUMPS(SYRINGES) : SS 316L

Description
The Duobloc consists of the rotary Unscrambler, Delrin slat conveyor with

variable speed conveyor drive for vial transportation, automatic liquid filling

machine with 4 heads having pre and post gassing arrangement and 12 head

elastomeric closure (rubber stoppers) inserter for small vials and 12 head for large

size, and Drip collect trays below the conveyor.

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Operating Principle
Clean sterile vials loaded on outfeed dead plate of Tunnel are moved to the filling
machine on the delrin slat conveyor from the rotary Unscrambler. The vials are
transported on the conveyor to the filling stations in a row and are locked in by a infeed
starwheel. This infeed starwheel acts as an indexer, releasing four vials at a time. It also
controls alignment of the vials for the diving nozzles. After the vials are fillied, the
pumps(syringes) rotates to the suction mode, and the nozzles are in their original
[position, the starwheel gets unlock and allows four filled vials to move on before locking
again. The no vial machine stop arrange ment is made with the help of a proximity
device.

Note: The pump cylinders (syringes) are valve less type and self suctioned. They do

not require the reservoir manifold to be pressurized.

After filling, filled vials are transported to stoppering station through the conveyor.
Then the vials are precisely positioned to stoppering stations by a screw provided on
the conveyor. Stoppers are coming from an anticlockwise hopper, via a linear chute and
then transferred to a pickup transfer wheel. From transfer wheel the stoppers are picked
up by the Robotic Ferris wheel and the same robotic wheel will insert stoppers in the
vial neck. After stoppering , the vial will move under the stopper pressing wheel, where
the stoppers get fully pressed. The NO STOPPER- MACHINE STOP arrangement is
made with the help of a photocell device.

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Sealing Machine
Technical Specifications

MAKE : FABRICA STEEL CORPORATION

MODEL : MH-120
SERIAL No. :
OVER ALL DIMENSIONS : 1200mm(L) X 800mm(W) X 1600mm(H)
VIAL SIZE : 2 – 100 ml
OPERATION : AUTO / MANUAL
THROUGHPUTS : 7000-9000 VPH, 5-10 ml
MATERIAL OF CONSTRUCTION : FRAME : SS 306
TOP COVER : SS 316
SIDE PANELS : SS 304
PUMPS(SYRINGES) : SS 316L

Description
The machine consist of Conveyor,Synchronised Infeed Star wheel andBack

guide, Vibrotory feeder, Feeder chute, Sealing Platform, Synchronised Exitstar

wheel and Back guide and Control Panel.

Operating Principle
The containers are continuously fed through infeed conveyor to Synchronized
Infeed Star wheel in a chock-fed manner. During the rotation, the containers picks up
aluminium cap from the feeder-chute outlet and transfer it into the sealing platforms
pocket. The sealing head now comes down and completes the sealing operation during
the rotation of the platform. The synchronized exit star-wheel now picks up the sealed
containers and transfers it on to the exit conveyor.

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