Parenterals & CGMP. What are parenterals? ► Sterile, pyrogen free preparations injected through skin or mucous membrane into internal body compartments

Parenterals & CGMPParenterals & CGMP

What are parenterals?What are parenterals?

►Sterile, pyrogen free preparations Sterile, pyrogen free preparations injected through skin or mucous injected through skin or mucous membrane into internal body membrane into internal body compartments.compartments.

Sterile Product Sterile Product

►Are dosage forms of therapeutic Are dosage forms of therapeutic agents that are free of viable agents that are free of viable microorganismsmicroorganisms Parenterals Parenterals OpthalmicsOpthalmics Irrigating preparations.Irrigating preparations.

Why Parenterals?Why Parenterals?

►Parenterals : Besides the intestine

►Circumvents:Circumvents:►Gastero Intestinal instabilityGastero Intestinal instability►Low absorptionLow absorption►Variable absorptionVariable absorption

History of Parenteral History of Parenteral TherapyTherapy► 1657: First recorded injection in animals1657: First recorded injection in animals

Sir Christopher WrenSir Christopher Wren► 1855: First subcutaneous injections of drugs using 1855: First subcutaneous injections of drugs using

hypodermic needleshypodermic needles Dr. Alexander WoodDr. Alexander Wood

► 1920s: Proof of microbial growth resulting in 1920s: Proof of microbial growth resulting in infectionsinfections Dr. Florence SeibertDr. Florence Seibert

► 1926: inclusion in the National Formulary1926: inclusion in the National Formulary► 1933: Application of freeze drying to clinical 1933: Application of freeze drying to clinical

materialsmaterials► 1944: Discovery of ethelyne oxide1944: Discovery of ethelyne oxide► 1946: Organization of Parenteral drug Association1946: Organization of Parenteral drug Association► 1961: Development of laminar air flow concept 1961: Development of laminar air flow concept ► 1965: Development of Total Parenteralnutrition(TPN)1965: Development of Total Parenteralnutrition(TPN)

Contemporary Development Of Contemporary Development Of ParenteralsParenterals

► 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?► Feedback regulated delivery?► Virtual drug delivery? Other?

Routes Of Parenteral Routes Of Parenteral AdministrationAdministration

► 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

Routes Of Parenteral Routes Of Parenteral AdministrationAdministration

► 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.

Disadvantages Of Parenteral Disadvantages Of Parenteral AdministrationAdministration

►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 Advantages Of Parenteral AdministrationAdministration

► 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

cGMP Requirements For Sterile cGMP Requirements For Sterile ProductsProducts

►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

General RequirementsGeneral Requirements

►Laminar air flow: air speed (horizontal versus vertical

flow) number of air changes air samples

►Conformity to standards►Work station and environment►Barrier technology and automated

systems

Manufacture Of Sterile Manufacture Of Sterile PreparationsPreparations

►Classifications - I: Terminally Classifications - I: Terminally Sterilized ProductsSterilized 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 Classifications – II: Sterile Filtered ProductsProducts

►Sterilisation by filtration Handling of starting materials

►Grade C►Grade D: Closed vessels►Sterile filtration into containers: Class A (in Sterile filtration into containers: Class A (in

Class B Class B


►Classifications – III: Products Produced From Sterile Materials

►Aseptic preparation Handling of materials All processing Grade A in Grade B environment or Grade B in Grade C environment

PremisesPremises

►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

PremisesPremises

►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

SanitationSanitation

►Clean areas frequency SOP

►Disinfectants periodic alterations monitor microbial contamination dilutions, storage and topping-up

►Fumigation►Monitoring

Viable and non viable particulate matter

PersonnelPersonnel

► 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

► Laundry and changes► Minimum number in clean areas

aseptic processing inspection and control

PersonnelPersonnel

► 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

EquipmentEquipment

► 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►Maintenance and repairs► Planned maintenance, validation and

monitoring►Water treatment plants

Environmental Monitoring Environmental 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 records action taken


►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 ssterilization and use

►time limit and validated storage conditions

►Time intervals: Product preparation preparation and sterilisation short as possible maximum time for each product

Finishing Of ProductsFinishing 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 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

► 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 VehiclesExamples of Water-Miscible Vehicles

Vehicles For InjectionVehicles For Injection

► Aqueous Co solvent vehicles: ethyl alcohol (Alcohol USP) propylene glycol Glycerin USP Polyethylene glycol 300 NF

► Examples of Non aqueous vehicles Examples of Non aqueous vehicles ► Oleoginous Vehicles

Peanut Oil Corn Oil Cotton seed Oil (Depo –Testosterone R- Upjohn) Sesame oil Soyabean oil (source of fat in intralipid R) Ethyl oleate Isopropyl myristateIsopropyl myristate

Types Of Water For Types Of Water For InjectionInjection►Highly purified Water used as a Highly purified Water used as a

vehicle for injectable preparations vehicle for injectable preparations which will be subsequently sterilized.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.

Types Of Water For Types Of Water For InjectionInjection►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)

Types Of Water For Types Of Water For InjectionInjection►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 Parenteral Added SubstancesSubstances► 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.

Parenteral Added Parenteral Added SubstancesSubstances►Antibacterial agentsAntibacterial agents

Required to prevent microorganism growth 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

Parenteral Added Parenteral Added SubstancesSubstances►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 albicans, Aspergillus niger, E-coli, Pseudomonas aeruginosa, and staphylococcus aureus) is added.

Incubate at 32°C. Adequate if no significant increase in

microorganisms.

Parenteral Added Parenteral Added SubstancesSubstances►AntioxidantsAntioxidants

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

Parenteral Added Parenteral Added SubstancesSubstances► BuffersBuffers

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

Parenteral Added Parenteral Added SubstancesSubstances►Tonicity AgentsTonicity Agents

Reduce pain of Injection Can include buffers

►Sodium chloride ►Potassium chloride ►Dextrose►Mannitol►Sorbitol►Lactose

Parenteral Added Parenteral Added SubstancesSubstances►Other Parenteral AdjunctsOther 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

Parenteral Added Parenteral Added SubstancesSubstances► Chelating Agents 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

Anti inflammatory►Agents: Hydrocrtisone

Anti –clotting agents: Heparin Vasoconstrictors (prolong action); epinephrine increase tissue

►permeability: Hyaluronidase (enzyme)

Physical And Chemical Physical And Chemical StabilityStability►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 Unique Characteristics Of ParenteralsParenterals

► 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.

Unique Characteristics Of Unique Characteristics Of ParenteralsParenterals

►Pyrogen free (if parenteral)►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 Methods Of Sterilization In ParenteralsParenterals

► 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 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


►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


► 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 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 substancesreleasing substances

Sterility TestingSterility 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

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

Lyophilization (Freeze Lyophilization (Freeze Drying)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 Packaging, 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.

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 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 effect►e.g. Cortisone antagonizing heparin.

Vial Washing and Vial Washing and Tunnel sterilizerTunnel sterilizer

Technical SpecificationsTechnical Specifications

Vial Washing, Sterilizing And Vial Washing, Sterilizing And DepyrogenationDepyrogenation

►Directive 21CFR part 211.92 states Directive 21CFR part 211.92 states that containers used for parenteral that containers used for parenteral drugs, shall be "clean", "sterile" and drugs, shall be "clean", "sterile" and "pyrogene free". This can be "pyrogene free". This can be accomplished by washing machines accomplished by washing machines and sterilization/depyrogenation and sterilization/depyrogenation equipment. equipment.

►Washing contributes an critical role in Washing contributes an critical role in pharmaceutical world. Hence to pharmaceutical world. Hence to understand ‘washing’, first lets understand ‘washing’, first lets understand the term “Clean”.understand the term “Clean”.

CleanClean

►Today, most glass vials are of high Today, most glass vials are of high quality and require little if any cleaning. quality and require little if any cleaning. However after the manufacturing However after the manufacturing process, vials are subject to uncontrolled process, vials are subject to uncontrolled environments and are likely to become environments and are likely to become contaminated with particulates and contaminated with particulates and micro-organisms. For this purpose, vial micro-organisms. For this purpose, vial washers are used throughout the washers are used throughout the Pharmaceutical and Biotech Industry.Pharmaceutical and Biotech Industry.

CleanClean

► The performance of a vial washer can be The performance of a vial washer can be validated through two studies:validated through two studies:

► Particulate RemovalParticulate Removal To determine the effectiveness of the vial To determine the effectiveness of the vial

washer, it is recommended to spike vials with washer, it is recommended to spike vials with a styrene polymer bead suspension prior to a styrene polymer bead suspension prior to washing. The vial washer should be able to washing. The vial washer should be able to remove all particulates.remove all particulates.

► Chemical Contaminants RemovalChemical Contaminants Removal To test the ability to remove chemical To test the ability to remove chemical

contaminants, vials are spiked with a Sodium contaminants, vials are spiked with a Sodium Chloride (NaCl) solution. After washing, no Chloride (NaCl) solution. After washing, no traces of NaCl should be detected.traces of NaCl should be detected.

PrinciplePrinciple

► The most effective way to remove The most effective way to remove contaminants from vials is through contaminants from vials is through "scrubbing" action with utilities. Most "scrubbing" action with utilities. Most commonly used utilities for washing of vials commonly used utilities for washing of vials are Purified Water and Water For Injection are Purified Water and Water For Injection (WFI), which is not only without particulates, (WFI), which is not only without particulates, but also without microorganisms and but also without microorganisms and pyrogenes. The "scrubbing" action is pyrogenes. The "scrubbing" action is accomplished by high pressure water jets. accomplished by high pressure water jets. The effectiveness of this "scrubbing" is a The effectiveness of this "scrubbing" is a function of the following factors:function of the following factors:1) The energy level of the WFI 1) The energy level of the WFI 2) The amount of WFI used per vial.2) The amount of WFI used per vial.

PrinciplePrinciple

►Energy Level Of WFIEnergy Level Of WFI The higher the WFI temperature, the The higher the WFI temperature, the

higher the energy level. High higher the energy level. High temperature temperature

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

PrinciplePrinciple

► Amount Of WFIAmount Of WFI The amount of WFI is subject to the size of The amount of WFI is subject to the size of

the vial. Obviously, larger vials require more the vial. Obviously, larger vials require more WFI than smaller vials. WFI than smaller vials.

In a vial washing machine, the amount of WFI In a vial washing machine, the amount of WFI is determined by:is determined by: 1) The cycle time (or speed setting) of the 1) The cycle time (or speed setting) of the machine, machine, 2) The number of spraying stations 2) The number of spraying stations 3) The orifice of the spraying opening.3) The orifice of the spraying opening.

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

Sterilizing And Sterilizing And DepyrogenationDepyrogenation►Cleaning plays an important role Cleaning plays an important role

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

Sterilizing And Sterilizing And DepyrogenationDepyrogenation► SterileSterile► Vials can be sterilized in dry-heat ovens and sterilization Vials can be sterilized in dry-heat ovens and sterilization

tunnels. Dry-heat ovens are designed to sterilize at a tunnels. Dry-heat ovens are designed to sterilize at a temperature of 170°C. Sterilizing tunnels are designed to temperature of 170°C. Sterilizing tunnels are designed to sterilize at twice that temperature.sterilize at twice that temperature.

► Heat destroys microorganisms. The destruction process of Heat destroys microorganisms. The destruction process of micro-organisms is a function of time and temperature. The micro-organisms is a function of time and temperature. The rate of destruction is more or less logarithmic, meaning that in rate of destruction is more or less logarithmic, meaning that in a given time interval and at a given temperature, the same a given time interval and at a given temperature, the same percentage of the bacterial population will be destroyed. For percentage of the bacterial population will be destroyed. For example, if the time required to destroy 1-log cycle (90%) is example, if the time required to destroy 1-log cycle (90%) is known, and the desired thermal reduction has been decided known, and the desired thermal reduction has been decided (e.g. 4-log), then the time required can be calculated.(e.g. 4-log), then the time required can be calculated.

► Example: If the bacterial population is 1 million CFU (Colony Example: If the bacterial population is 1 million CFU (Colony Forming Units), and it takes 5 minutes to destroy 1-log cycle at Forming Units), and it takes 5 minutes to destroy 1-log cycle at a certain temperature, then the remaining population after 5 a certain temperature, then the remaining population after 5 minutes is 100,000 CFU, after 10 minutes 10,000 CFU, after 15 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). minutes 1,000 CFU and after 20 minutes 100 CFU (4-log cycles).

Sterilizing And Sterilizing And DepyrogenationDepyrogenation► Pyrogene FreePyrogene Free► During the destruction of the cell-wall of bacteria (also During the destruction of the cell-wall of bacteria (also

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

► Pyrogenes are too small to be eliminated by filtration. Pyrogenes are too small to be eliminated by filtration. However, heat will disintegrate pyrogenes (high-However, heat will disintegrate pyrogenes (high-molecular lipo-polysaccharides) to harmless molecules. molecular lipo-polysaccharides) to harmless molecules.

► At 250°C, the time required to disintegrate pyrogenes At 250°C, the time required to disintegrate pyrogenes 1-log cycle, is 5 minutes (D-value). Empirically has 1-log cycle, is 5 minutes (D-value). Empirically has been determined that for every 46.4°C. increase in been determined that for every 46.4°C. increase in temperature, the D-value will be reduced by 1-log temperature, the D-value will be reduced by 1-log cycle.cycle.

Sterilizing And Sterilizing And DepyrogenationDepyrogenation► In other words, at a temperature of 296.4°C, a In other words, at a temperature of 296.4°C, a

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

► Refer the table given below:Refer the table given below:

Tunnel SterilizerTunnel Sterilizer

Technical SpecificationsTechnical 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 SterilizersTypes Of Tunnel Sterilizers

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

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

► Sterilizing/Depyrogenation tunnels consist of three Sterilizing/Depyrogenation tunnels consist of three chambers:chambers: 1) The infeed chamber1) The infeed chamber2) The sterilizing chamber2) The sterilizing chamber3) The cooling chamber3) The cooling chamber

Advantages Of Hot Air Tunnels Over Advantages Of Hot Air Tunnels Over Radiant Heat TunnelsRadiant Heat Tunnels

► Heat transfer by convection is faster than by Heat transfer by convection is faster than by radiation. The sterilizing chamber of a Hot Air radiation. The sterilizing chamber of a Hot Air tunnel can therefore be shorter that of a tunnel can therefore be shorter that of a radiant heat tunnel. This results in a smaller radiant heat tunnel. This results in a smaller foot print.foot print.

► Particulates generated by the vials and the Particulates generated by the vials and the tunnel itself (transport belt) are continuously tunnel itself (transport belt) are continuously removed by HEPA filters. Hot Air tunnels are removed by HEPA filters. Hot Air tunnels are "cleaner" than Radiant heat tunnels."cleaner" than Radiant heat tunnels.

► Better control of air over-pressure in the clean Better control of air over-pressure in the clean room by balancing the air pressures in the room by balancing the air pressures in the three sections of the tunnel.three sections of the tunnel.

► Better process control by automatically Better process control by automatically adjusting the air pressure and air velocity per adjusting the air pressure and air velocity per section.section.

Advantages Of Hot Air Tunnels Over Advantages Of Hot Air Tunnels Over Radiant Heat TunnelsRadiant Heat Tunnels

►Note 1:Note 1: Glass vials can be safely exposed to 350°C. Glass vials can be safely exposed to 350°C.

Higher temperatures should be avoided as Higher temperatures should be avoided as the surface of the vials is subject to change. the surface of the vials is subject to change. The result is increased friction between vials The result is increased friction between vials which may adversely affect down stream which may adversely affect down stream vial handling. The optimum working vial handling. The optimum working temperature of a sterilizing tunnel is temperature of a sterilizing tunnel is therefore 350°C. therefore 350°C.

►Note 2:Note 2: Typically, sterilization/depyrogenation Typically, sterilization/depyrogenation

tunnels are validated at no less than 4-log tunnels are validated at no less than 4-log pyrogene reduction. This includes a 1-log pyrogene reduction. This includes a 1-log cycle safety margin.cycle safety margin.

FiltersFilters

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

DOP TestingDOP Testing

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

Automatic Door SettingAutomatic Door Setting

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

Vial LoadingVial Loading

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

►The tunnel conveyor is moved by an The tunnel conveyor is moved by an AC motor with frequency control. The AC motor with frequency control. The conveyor travel distance per loading conveyor travel distance per loading stroke is subject to the vial diameter stroke is subject to the vial diameter and is controlled by the PLC.and is controlled by the PLC.

Infeed AreaInfeed Area

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

Sterilizing ChamberSterilizing Chamber

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

Cooling ChamberCooling Chamber

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

HMI (Humane Machine HMI (Humane Machine Interface)Interface)

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

Documents

Parenterals & CGMP. What are parenterals? ► Sterile, pyrogen free preparations injected through skin or mucous membrane into internal body compartments