PARENTERAL

BY

VIJAYA BHASKAR R RAMIREDDY

PARENTERAL

PARAOUTSIDE ENTERONINTESTINE Denotes Route of administration other than oral route Refers to injectable routes administration Necessity ? Poor Bioavailability & Narrow therapeutic index , Immediate physiologic response ex: cardiac arrest, asthma & shock

oral

VS parenteral
Oral Rapid onset of Action Less expensive Administrable to non responsive patients
Patient convenience & comfort Administrable directly to site of action Retrievable , if Necessary Better Absorption

Injectable

PARENTERAL ROUTES
Intra- articular Joints Intra spinal spinal column Intra arterial arteries Intravenous veins Intra dermal skin Intra synovial joint fluid Intra thecal spinal fluid

PROS N CONS
Quick onset of action Suitable for the drugs which are not administered by oral route Useful for unconscious or vomiting patients. Duration of action can be prolonged by modifying formulation. Suitable for nutritive like glucose & electrolyte. Suitable for the drugs which are inactivated in GIT or HCl (GI fluid)

PROS N CONS
Once injected cannot be controlled (retreat) Injections may cause pain at the site of injection Only trained person is required If given by wrong route, difficult to control adverse effect Difficult to save patient if overdose Sensitivity or allergic reaction at the site of injection Requires strict control of sterility & non pyrogenicity than other formulation.

Necessities of parenteral preparations

Sterility (must)
Pyrogen (must)

Free from particulate matter (must)

Clarity (must) Stability (must) Isotonicity (should)

Necessities of parenteral preparations

Solvents or vehicles used must meet special purity and other standards. Restrictions on buffers, stabilizers, antimicrobial preservative. Do not use coloring agents. Must be prepared under aseptic conditions. Specific and high quality packaging.

PARENTERAL ROUTES
Intra cardiac heart Intra muscular muscles Subcutaneous under the skin Intra cisternal Brain ventricles Intra peritonial Stomach Intra plueral Lungs

PARENTERAL TYPES
Powder for Injection Collidal solution Injectable emulsion Injectable suspension Oily injection (solution) Infusion fluid

Formulation of parenterals
1. Therapeutic agents 2. Vehicles i. Water ii. Water miscible vehicles iii.Non- aqueous vehicles 3. Added substances (Additives) i. Antimicrobials ii. Antioxidants iii.Buffers iv.Bulking agents

Formulation of parenterals
i. Chelating agents ii. Protectants iii.Solubilizing agents iv.Surfactants v. Tonicity- adjusting agents

General steps involved

1. Cleaning 2. Preparation of bulk products 3. Filtration

4. Filling of solution in or product in ampoule or vial

5.Sealing

6. Sterilization
7. Tests for Quality control

Formulation of Parenteral
1.Therapeutic ingredients: Insulin Antibiotics Anticancer Steroids Vaccines Antipyretic Analgesics Anti- inflammatory LVPs like Dextrose, NaCl or combination etc.

Formulation of Parenteral
2.Solvents:

o Water
o Should meet compendial requirements o Water miscible vehicles o Ethyl alcohol o PEG

o PG
o Non aqueous vehicles o Fixed oils

Formulation of Parenteral
Solvents Solvents used must be: Non-irritating Non-toxic Non-sensitizing No pharmacological activity of its own Not affect activity of medicinal

Formulation of Parenteral
3. Added

substances (Additives) Antimicrobials: Added for fungi static or bacteriostatic action or concentration Used to prevent the multiplication of micro-organisms Ex.. Benzyl alcohol -----0.5 10 % Benzethonium chloride -- 0.01 % Methyl paraben ---- 0.01 0.18 % Propyl paraben --0.005 0.035 % Phenol --0.065 0.5 %

Formulation of Parenteral
Preservatives: Multidose containers must have preservatives unless prohibited by monograph. Large volume parenteral must not contain preservative becoz it may be dangerous to human body if it contain in high doses.

Formulation of Parenteral
Antioxidants: Used to protect product from oxidation Acts as reducing agent or prevents oxidation Ex: A) Reducing agent: Ascorbic acid -0.02 0.1 % Sodium bisulphite-0.1 0.15 % Sodium metabisulphite-- 0.1 0.15 % Thiourea 0.005 % B) Blocking agents: Ascorbic acid esters0.01 0.015% BHT0.005 0.02 % C) Synergistic: Ascorbic acid , Citric acid , Tartaric acid D) Chelating agent: EDTA0.01- 0.075 %

Formulation of Parenteral

Buffers: Added to maintain pH, Change in pH may causes degradation of the products Acetates, citrates, phosphates are generally used. Factors affecting selection of buffers: Effective range, Concentration Chemical effect on the total product EXAMPLES: Acetic acid ,adipic acid, benzoic acid, citric acid, lactic acid Used in the conc. of 0.1 to 5.0 %

Formulation of Parenteral

Chelating agents: Used to form the complex with the metallic ions present in the formulation so that the ions will not interfere during mfg. of formulation. They form a complex which gets dissolved in the solvents. Examples: Disodium edetate 0.00368 - .05 % Disodium calcium edetate - 0.04 % Tetrasodium edetate 0.01 %

Formulation of Parenteral

Stabilizers: As parenterals are available in solution form they are most prone to unstabilize Used to stabilize the formulation Maintain stable Examples: Creatinine 0.5- 0.8 % Glycerin 1.5 2.25 % Niacinamide 1.25 -2.5 % Sodium saccharin 0.03 %

Formulation of Parenteral
Solubilizing agents: Used to increase solubility of slightly soluble drugs they acts by any one of the following: solubilizers, emulsifiers or wetting agents. Examples: Dimethylacetamide, Ethyl alcohol Glycerin Lecithin PEG 40 castor oil PEG 300 Polysorbate 20, 40, 80

Formulation of Parenteral

Tonicity- adjusting agents: Used to reduce the pain of injection. Buffers may acts as tonicity contributor as well as stabilizers for the pH. Isotonicity depends on permeability of a living semipermaeable membrane Hypotonic : swelling of cells (enlargement) Hypertonic: shrinking of cells (reduction) Example: Glycerin Lactose Mannitol Dextrose Sodium chloride Sorbitol

LABELLING
Name of product Quantity of the product % of drug or amount of drug in specified volume of amount of drug and volume of liquid to be added Name and quantity of all added substances Mfg. license no. Batch no. Manufacturer/Distributor Mfg. & Expiration date Retail price (incl. of all taxes) Mfger. address Veterinary product should be so labeled

LABELLING
Must check each individual monogram for: Type of container:
Glass Plastic Rubber closure
Type I Type II Type III NP

Type of glass

Tests for glass containers

Package size Special storage instructions
Powdered Glass test Water Attack test

Mixer/Homogenizer

Filtration assembly

Bottling/Filling machinery

PERSONNEL

Clothing of appropriate quality: Grade D hair, beard, moustache covered Protective clothing and shoes Grade C Hair, beard, moustache covered Single or 2-piece suit (covering wrists, high neck), shoes no fibres to be shed Grade A and B Headgear, beard and moustache covered, masks, gloves No shedding of fibres, and retain particles shed by operators

Sterile area

Production facilities:
Clean- up area
Preparation area

Aseptic area
Quarantine area Finishing and packaging area

LAY OUT

S T O C K
R O O M

COMPOUNDING AREA

ASEPTIC AREA

QUARANTINE AREA

STORAGE AND TRANSPORT

PACKING CLEAN UP AREA STERILIZATION AND LABELLING

Clean- up area:
Non aseptic area Free from dust ,fibres & micro-organisms

Constructed in such a way that should withstand moisture, steam & detergent
Ceiling & walls are coated with material to prevent

accumulation of dust & micro-organisms

Exhaust fans are fitted to remove heat & humidity The area should be kept clean so that to avoid contamination to aseptic area The containers & closures are washed & dried in this area.

Preparation area:
The ingredients are mixed & preparation is prepared for filling

Not essential that the area is aseptic

Strict precaution is taken to prevent contamination from outside

Cabinets & counters: SS

Ceiling & walls : sealed & painted

Aseptic area:
Filtration & filling into final containers & sealing is done The entry of outside person is strictly prohibited To maintain sterility, special trained persons are only allowed to enter & work Person who worked should wear sterile cloths Should be subjected for physical examination to ensure the fitness Minimum movement should be there in this area Ceiling & walls & floors : sealed & painted or treated with aseptic solution and there should not be any toxic effect of this treatment

Aseptic area:
Cabinets & counters: SS Mechanical equipments : SS AIR:
Free from fibres, dust & micro organisms

HEPA filters are used which removes particles upto 0.3 micron
Fitted in laminar air flow system, in which air is free from dust & micro organisms flows with uniform velocity Air supplied is under positive pressure which prevents particulate contamination from sweeping

UV lamps are fitted to maintain sterility

Quarantine area:
After filling, sealing & sterilization the products or batch is kept in this area The random samples are chosen and given for analysis to QC dept. The batch is send to packing after issuing satisfactory reports of analysis from QC If any problem is observed in above analysis the decision is to be taken for reprocessing or others..

Finishing and packaging area:

After proper label, the product is given for packing Packing is done to protect the product from external environment The ideal Packing is that which protects the product during transportation, storage, shipping & handling. The labeled container should be packed in cardboard or plastic containers Ampoules should be packed in partitioned boxes.

LVP
LVPs which are administered by IV route are commonly called as IV fluids. Purposes :

Body fluids, Electrolyte replenisher

Volume supplied:
100 to 1000 ml

Precautions / necessities in mfg.:

Free from foreign particles Free from micro organisms Isotonic with body fluids As they are in LVP no bacteriostatic agents are added Free from pyrogens

Examples:
Dextrose injection IP : available in 2 , 5 , 10 , 25 & 50 % w/v solution. Used for
Fluids replenisher, Electrolyte replenisher

Sodium chloride & Dextrose injection IP: (DNS)

Contains
0.11 to 0.9 % Sodium chloride 2.5 to 5.0 % Dextrose

Used for
Fluids replenisher, Electrolyte replenisher Nutrient replenisher

Examples:

Sodium chloride injection IP:

0.9 % conc. Also known as normal saline solution Used as
Isotonic vehicle Fluids replenisher, Electrolyte replenisher

Sodium lactate injection IP:

Contains 1.75 to 1.95 % w/v of sodium lactate Used as
Fluids replenisher, Electrolyte replenisher

Examples:

Mannitol injection IP:

Contains 5, 10 , 15, 20 % of mannitol Used as :
Diagnostic aid Renal function determination As a diuretic

Mannitol & Sodium chloride injection IP:

Contains 5, 10 , 15, 20 % of mannitol & 0.45 % of Sodium chloride Used as :
As a diuretic

Examples:

Other solutions:
Ringer injection IP Ringer lactate solution for injection IP

Common uses :
Used in surgery patients In replacement therapy Providing basic nutrition For providing TPN As a vehicle for other drug subs.

IV ADMIXTURES

Definition:
When two or more sterile products are added to an IV fluid for their administration, the resulting combination is known as IV admixture. In hospitals, prepared by nurses by combining or mixing drugs to the transfusion fluids. The drugs are incorporated in to bottles of LV transfusion fluids.

Care :
Microbial contamination Incompatibility
Physical : change in color Chemical : hydrolysis, oxidation, reduction etc.. Therapeutic: undesirable antagonistic or synergistic effect

Methods for safe & effective use of IV admixture:

Proper training to nurses & pharmacist Instruction regarding labeling Information for stability & compatibility to the hospital pharmacy dept. Information for the formulation skills to the pharmacist.

QC TESTS
Quality control testing and evaluation of parenterals is concerned with: I. Incoming raw materials including: routine testing on all drugs, additives, and packaging materials. II. The manufacturing process control including:

QC TESTS
1. Daily testing of water for injection. 2. Confirmation of fill volume and yields of containers. 3. Checking label identity and count.

QC TESTS

III. The Finished product. 1. Tests necessary to insure the potency of the product. 2. Tests for volume in container. 3. Sterility test. 4. Pyrogen test. 5. Clarity and particulate analysis. 6. Glass-seal of ampoules leaker testing.

QC TESTS

Sterility Testing: It is a test to estimate the probability of presence of microorganisms. Since the test is destructive, it is not possible to examine the whole product batch to assure sterility. Adequate sampling of the batch must be tested. A sterility test may be done in two ways: Direct inoculation method: The specified volume of the parenteral product is transferred aseptically to different culture media which expected to support the growth of both aerobic and anaerobic micro-organisms and media are tested for growth after suitable incubation period.

QC TESTS

Thioglycollate medium
(to assure anaerobic growth)

soybean-casein digest medium

( to assure aerobic growth)

QC TESTS
The membrane filtration method: The solution is passed through a membrane having a pore size sufficiently small to retain bacteria. A membrane generally suitable for sterility testing has a porosity of 0.45 0.02 .The membrane and the retained bacteria on it are transferred to liquid media and media are tested for growth after suitable incubation period. Before conducting the sterility test it is necessary to inactivate any antimicrobial agent which will interfere with the results of the experiment. This may be the active drug it self as in case of antibiotic products or it could be a preservative.

QC TESTS

Inactivation procedures:

A suitable inactivators may be added to the liquid test media to neutralize the antimicrobial substance, e.g. B-Lactamase which hydrolyses penicillins and cephalosporins.The solution is passed through a membrane of pore size small enough to retain bacteria. The membrane and the bacteria on it are washed using saline solution to remove the last traces of antimicrobial substance then inoculated.If solid materials are present they will be retained on the filter with the microorganisms, so they should be dissolved in suitable solvent before filtration.

QC TESTS
If there is no suitable solvent for the solid material, the parenteral preparation is diluted to a concentration less than the MIC of the antimicrobial by using a large volume of medium.

QC TESTS
Sterility testing of different parenteral products: 1. Aqueous solutions are tested by direct inoculation or membrane filtration. 2. Solids are dissolved in suitable solvent which has no antimicrobial activity then tested by direct inoculation. 3. Oily solution of low viscosity are filtered on membrane and membrane is inoculated. Those of high viscosity are diluted first with suitable diluent which has no antimicrobial activity then filtered.

QC TESTS
4. For oily solution if we used direct inoculation method we should add emulsifying agent to facilitate mixing of oil with the aqueous medium and the medium should be shaken every day and the emulsifying agent should has no antimicrobial activity.

QC TESTS
Pyrogen Testing: According to the old technique, the USP test is carried out by injecting in an ear vein of each of 3 rabbits 10 ml of the test solution per kg body weight, over 10 min. The rabbits should be healthy and mature and show temperature change of not more than 1C from each other and each must not exceed 39.8C.

QC TESTS
The rectal temperature of the rabbits is recorded at 1, 2 and 3 hours subsequent to injection. The solution is apyrogenic if no rabbit shows an individual rise in temperature of 0.6C or the sum of the temperature rise of the three rabbits does not exceed 1.4C.

QC TESTS
If the temperature rise exceeds these limits, continue the test using another 5 rabbits. The sample is considered acceptable if no temperature rise of more than 0.6C for each individual rabbit or the sum of temperature rise does not exceed 3.7C for the whole 8 rabbits.

QC TESTS
A new method for pyrogen detection is known as theLimulus test (LAL).The amebocytes, or circulating blood cells, of the horseshoe crab (Limulus polyphemus) contain a protein that clots in the presence of bacterial pyrogens. A test sample is incubated with amebocytes lysate from the horseshoe crab for 60 min.

QC TESTS
Pyrogenic substance will give A positive LALtest characterized by the formation of a solid gel that remains intact in the bottom of the tube on inversion. This method showed to be more sensitive, more rapid and easier to perform.

QC TESTS

Weight variation or content uniformity test

This test is intended for sterile solids used for parenteral preparation. The weight of 10 individual sterile units is noted and the content is removed from them and empty individual sterile unit is weighed intern. Then net weight is calculated by subtracting empty sterile unit weight form gross weight. The content of active ingredient in each sterile unit is calculated by performing the assay according to the individual monographs. The content in 10 sterile units is calculated by performing the assay. The dose uniformity is met if the amount of active ingredient is within the range of 85-115.0% of label claim as determine by the content uniformity method or weight variation method..

QC TESTS

The dose uniformity is also met if the potency value is 100% in the individual monograph or less of label claim multiplied by average of limits specified for potency in individual monograph divided by 100 provided that the relative standard deviation in both the cases is equal to or less than 6.0%.If one unit is outside the range of 85115.0%, and none of the sterile unit is outside the range of 75125.0% and if the relative standard deviation of the resultant is greater than 6.0% then, the fore mentioned test is carried for 20 more sterile units. The sterile units meet the requirements if not more than one unit is out side the range of 85-115%, no unit is outside the range of 75-125.0% and the calculated relative standard deviation is NMT 7.8%

QC TESTS
Particulate matter in injections
The preparations intended for parenteral use should be free form particulate matter and should be clear when inspected visually. Two methods are described by USP according to the filled volume of the product to be tested. For large volume parenterals (LVP's), a filtration followed by microscopical examination procedure is used. For small volume parenterals (SVP's)a light obscuration based sensor containing electronic liquid-borne particle counter system is used. The USP standards are met if the LVP's under test contain NMT 50 particles per ml of 10 m, and NMT 5 particles per ml of 25m in an effective linear dimensional fashion.

QC TESTS

The USP standards are met if the SVP's under test contain NMT 10,000 particles per container of 10 m, and NMT 1000 particles per container of 25m in an effective spherical diameter.

QC TESTS