Parenterals & CGMP.

Parenterals & CGMP

What are parenterals? 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 Parenterals? Parenterals : Besides the intestine Circumvents:
Gastero Intestinal instability Low absorption Variable absorption

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? 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

Routes Of Parenteral Administration
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 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

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

General Requirements Laminar air flow: Conformity to standards
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 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

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

Premises Design Clean areas avoid unnecessary entry
smooth, impervious, unbroken surfaces permit cleaning no uncleanable recesses, ledges, cupboards, equipment no sliding doors Ceilings pipes and ducts sinks and drains

Premises 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

Sanitation Clean areas Disinfectants Fumigation Monitoring 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 Laundry and changes Minimum number in clean areas aseptic processing inspection and control

Personnel 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) Conveyer belts
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
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 monitoring records action taken

Processing 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

Processing 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

Processing 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 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 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

Vehicles For Injection
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 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. Higher solids specification to allow leaching from glass packaging during sterilization (22 – 40 ppm)

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 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 albicans, 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

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

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 Anti inflammatory Agents: Hydrocrtisone Anti –clotting agents: Heparin Vasoconstrictors (prolong action); epinephrine increase tissue permeability: Hyaluronidase (enzyme)

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.

Unique Characteristics Of Parenterals
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 Parenterals
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 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

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 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.

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 effect e.g. Cortisone antagonizing heparin.

Vial Washing and Tunnel sterilizer

Technical Specifications
MAKE HAMISH ENGINEERING INDUSTRIES PVT. LTD. MODEL CMW 15 X 3 SERIAL No. 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 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”.

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.

Clean 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.

Principle 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.

Principle 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. 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. 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.

Tunnel Sterilizer

Technical Specifications
MAKE HAMISH ENGINEERING INDUSTRIES PVT. LTD. MODEL V-450 SERIAL No 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: Radiant heat tunnels 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. 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
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. 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. Better control of air over-pressure in the clean room by balancing the air pressures in the three sections of the tunnel. Better process control by automatically adjusting the air pressure and air velocity per section.

Advantages Of Hot Air Tunnels Over Radiant Heat Tunnels
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.

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 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 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).

Parenterals & CGMP.

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