Upload
jkkumar
View
6.922
Download
8
Embed Size (px)
Citation preview
What are perenterals ?What are perenterals ? Are sterile, pyrogen free preparations injected through skin or mucous
membrane into internal body compartments.
Sterile Product . . . . . . . . .Sterile Product . . . . . . . . . Are dosage forms of therapeutic agents that are free of viable
microorganisms.
Parenterals
Opthalmics
Irrigating preparations.
Why Peranterals ?Why Peranterals ?Para enterals : Besides the intestine
Circumvents:
Gastero Intestinal instability
Low absorption
Variable absorption
69
History Of Parenteral TherapyHistory Of Parenteral Therapy1657: 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 ParenteralsContemporary Development Of Parenterals1970’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?
Feedback regulated delivery?
70
Virtual drug delivery? Other?
Routes Of Parenteral AdministrationRoutes Of Parenteral AdministrationIntradermal (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
Intra-articular:- Injections into a joint. This method is used for arthiritis
and joint injuries.
71
72
Disadvantages Of Parenteral AdministrationDisadvantages 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 AdministrationAdvantages 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 Types Of Sterile Products Terminally sterilised : prepared, filled and sterilised
Sterilised by filtration
Aseptic preparation
73
cGMP Requirements For Sterile ProductscGMP Requirements For Sterile Products Additional rather than replacement
Specific points relating to minimizing risks of contamination
microbiological
particulate matter
pyrogen
General RequirementsGeneral 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 PreparationsManufacture 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
PremisesPremisesDesign
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
SanitationSanitationClean areas
frequency
SOP
Disinfectants
periodic alterations
monitor microbial contamination
dilutions, storage and topping-up
Fumigation
Monitoring
Viable and non viable particulate matter
PersonnelPersonnelOutdoor 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
EquipmentEquipmentAir 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 MonitoringEnvironmental Monitoring
I Microbiological
Air
Surfaces
Personnel
II Physical
Particulates
Differential pressures
Air changes
Filter integrity
Temperature/humidity
ProcessingProcessing Minimise contamination
No unsuitable materials e.g. live microbiological organisms
Minimise activities
staff movement
Temperature and humidity
Water sources and systems
monitoring
81
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 ProductsFinishing Of ProductsValidated 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 InjectionUsp 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 InjectionVehicles 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 InjectionTypes 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.
Higher solids specification to allow leaching from glass packaging
during sterilization (22 – 40 ppm)
87
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 SubstancesParenteral Added SubstancesAntibacterial 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
88
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.
89
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
90
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
91
Anti inflammatory
Agents: Hydrocrtisone
Anti –clotting agents: Heparin
Vasoconstrictors (prolong action); epinephrine
increase tissue
permeability: Hyaluronidase (enzyme)
92
Physical And Chemical StabilityPhysical And Chemical StabilityEnhance 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 ParenteralsUnique 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)
93
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 ParenteralsMethods 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
94
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
All parts of the load: Contact, time, temperature
95
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
Mix-ups: Irradiated and non-irradiated materials
Dose: Predetermined time span
96
97
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
98
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 TestingSterility TestingSamples 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
99
What Are The PYROGENS?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
100
Lyophilization (Freeze Drying)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 OfPackaging, Labeling And Storage Of
InjectionsInjections 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.
101
Available InjectionsAvailable 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 IncompatibilityParenteral IncompatibilityPhysical
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
effect
102
e.g. Cortisone antagonizing heparin.
103
Vial Washing and Tunnel sterilizerTechnical 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”.
104
CleanToday, 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
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.
105
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
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.
106
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.
107
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.
108
Tunnel SterilizerTunnel 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.
109
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.
110
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.
Sterilizing Chamber
111
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).
112
Filling and Stoppering MachineFilling 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.
113
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.
114
Sealing MachineSealing 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.
115
116