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Sterile Product . . . . . . . . . Are dosage forms of therapeutic agents that are free of viable microorganisms. Parenterals Opthalmics Irrigating preparations

What are perenterals ? Are sterile, pyrogen free preparations injected through skin or mucous membrane into internal body compartments. •

Para Enteron: Para means without Enteron means Intestine

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 1946: Organization of Parenteral drug Association 1965: Development of Total Parenteralnutrition(TPN)

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• 1982: Insulin and biotechnology products •

Infusion pumps

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.

Intracardiac: -Injections into heart chamber. Intrathecal (spinal fluid): Injection into spinal fluid. Intrasynovial:- (joint fluid area): Injection into a joint fluid area. 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

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Manufacturing and Packaging requirements Cost

Advantages Of Parenteral Administration Fastest method of drug delivery (e.g. cardiac arrest, asthama, shock) Viable alternative to unsuccessful oral therapy 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)

General Requirements Production in clean areas Separate areas for operations component preparation product preparation filling etc Level of cleanliness Filtered air Laminar air flow: air speed (horizontal versus vertical flow)

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number of air changes air samples

Premises Design avoid unnecessary entry Clean areas smooth, unbroken surfaces permit cleaning no uncleanable cupboards, equipment ceilings sinks and drains Changing rooms designed as airlocks flushed with filtered air separate for entry and exit desirable hand washing facilities visual and/or audible warning system

Personnel Outdoor clothing

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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 Regular training manufacture hygiene microbiology outside staff Hygiene and cleanliness contaminants SOPs : Changing and washing

Equipment 73

Air supply:(HVAC) Generation and supply of filtered air Airflow patterns Pressure differentials monitored and recorded Conveyer belts Effective sterilisation of equipment Maintenance and repairs Planned maintenance, validation and monitoring

Processing Minimise contamination No unsuitable materials e.g. live microbiological organisms Minimise activities staff movement

Temperature Control

Finishing Of Products Checks for integrity Maintenance of vacuum (where applicable) checked Parenteral products: Individual inspection background eyesight checks

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breaks

Vehicles For Injection AQEOUS VEHICLE Frequently, isotonic (to blood) to which drug may be added at the time of use.

Water-miscible Vehicle Portion of the vehicle in the formulation Used primarily to effect solubility of drugs

and / or reduce

hydrolysis Ethyl alcohol; polyethylene glycol(liquid) and propylene glycol

Non Aqueous vehicles: Fixed oils (Vegetable origin ,liquid , and

rancid

resistance ,

unsaturation, free fatty acid content) used in hormone preparations Examples of Water-Miscible Vehicles

Aqueous Co solvent vehicles: ethyl alcohol (Alcohol USP) propylene glycol Glycerin USP Polyethylene glycol 300 NF Examples of Non aqueous vehicles

Oleoginous Vehicles

Peanut Oil

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

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

Antibacterial agents Limited concentration of agents Phenylmercuric Nitrate 0.01%. Benzalkonium chloride 0.01%

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Phenol or cresol 0.5% Chlorobutanol 0.5% Refrigeration slows the growth, does not prevent Antibacterial agents testing.

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)

Buffers Added to maintain the pH Result in stability 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

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Tonicity Agents Reduce pain of Injection Can include buffers Sodium chloride Potassium chloride Dextrose Mannitol Sorbitol lactose

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 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)

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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.

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.

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Available Injections Small Volume Parentrals (25-50ml) Large volume Parentrals

Parenteral Incompatibility Physical Chemical Therapeutic:

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