Definition
Antiseptic: A substances that arrests or prevents the growth of micro organisms by inhibiting their activity without necessarily destroying them.
Aseptic processing:
Those operations performed between the sterilization of an object or preparation and the final sealing of its package. These operations are, by definition are carried out in the complete absence of microorganisms.
Bactericide: Any agent that destroys microorganism
Bacteriostat: Any agent that arrests or retards the growth of microorganisms
Bioburden: The no of viable microorganisms in or on an object or preperation entering a sterilization step.
Disinfection: A process that decreses the probability of infection by destroying vegetative microorganisms, but not ordinarily bacterial spores.
Germicide: An agent that destroys microorganisms, but not necessarily bacterial spores.
Sterility: The absence of viable microorganisms.
Sterilization: A process by which all viable microorganisms are removed or destroyed.
Terminal sterilization: A process by which all viable microorganisms are destroyed within the final, sealed package.
Sterilization assurance level: A term related to the probability of finding a non sterile unit following a sterilizaion step. Usully expressed in negative power of 10 i.e 1 in 1 million= 10 -6
Viricide: An agent that will destroy viruses.
Parenteral-Preparations
Introduction:
Parenteral preparations or injections are the sterile solution or suspensions of drugs in aqueous or oily vehicles meant for introduction into the body by means of an injection under or through one or more layers of the skin or mucous membrane.
Essential qualities of a parenteral products
Free from living microorganisms and microbial products
Free from pyrogens
Free from foreign particles such as dust fibers etc.
Free from chemical contaminants
It should be isotonic with body fluids
It should have matching specific gravity with respect to some body fluids
Multidose injections must contain preservatives
Container/closure must not effect the product
Advantages
Route of administration used when rapid onset of action of the drug is required
This route is preferred when the drugs are inactivated in the G.I.T or not absored after oral administration
Prolonged action of a drug can be successfully produced by this route
Must sutible route for patients who are non-coperative, un conscious or are otherwise unable to take the medicine orally.
Disadvantages
This mode of treatment is more expensive because it requires a technical and trained person for administration
Sterilization is of utmost importance
Technical person required for drug administration, wrong route of injection may prove fatal.
Daily or frequent administration of injections may pose difficulties to the patients.
Route of administration of injections:
- Intramuscular injection: the injection are given into the muscular tissues of shoulder, thigh or buttock are usually selected. Generally volume of 2 to 4ml is administered at one site.
- Intravenous injections: these injections are given into the vein therefore directly reach the blood stream. Large volume of solution ranging from 1ml to 500ml or even more can be injected but volumes of more the 15ml should be isotonic with blood.
Note: oily injections and suspensions cannot be injected by this route.
- Intracutaneous or intradermal injections: these injections are given in between dermis and epidermis, this route is used for the testing sensitivity of the injections and for diagnostic purpose, usually small volume from 0.1to 0.2ml is injected.
- Subcutaneous or hypodermic injections: these injections are given in the subcutaneous tissue under the skin of the upper arm. The volume of 1ml or less can be injected by this route.
- Intra arterial injections: these injections are given directly into the artery when an immediate effect in peripheral area is required.
- Intracardiac injections: they are given directly into the heart muscles or ventricle and are used in emergency only.
- Intrathecal injections: they are given into the subarachonid space surrounding the spinal card. This route is used for spinal anesthesia.
- Intracisternal injections: they are given in between the first and second cervical vertebrae. This route is used to withdraw cerebrospinal fluid for diagnostic purpose.
- Intra articular injections: these injections are given into the liquid that lubricates the joints.
- Peridural injections: these injections are given between the duramater and the inner aspects of the vertebra. This route is some time used for giving anesthesia in spinal.
- Intracerebral injections: these injections are given into the cerebrum.
Types of parenteral preparations:
- Solution
- Suspensions
- Emulsions
- Dry, souluble products ( dissolved in suitable solvent immediately before its administration)
- Dry insoluble products ( combined with suitable vehicle just before its administration)
WASHING AND DE CORTNING
DE-CORTNING AREA:
Procedure:
Clean the outer corrugated carton of the packed vial / ampoules with lint free cloth before opening.
Remove the shrink-wrap packed Vials / Ampoules from the master carton in the de-cartoning room.
Place the Vials / Ampoules on the MS pallet and check for any breakage.
If any one of the vial is observed broken, treat the full pack as rejected and return it to the Ware house.
Cut the shrink wrap film (Vials / Ampoules) using a cutter and remove the film.
Transfer the Vials / Ampoules into the S.S. box for washing.
Washing:
Procedure:
Washing of ampoules and vials is done by using filtered RO water either RO1, RO2 or both or deionized water at temperature 60 ± 10°C in combination with compressed air Oil Free Moisture Free.Particle Free.
- On receiving the Ampoules, these are de-cartoned in the de-cartoning room.
- Transfer the De-cartoned ampoules in S.S washed boxes to washing section for washing.
- Feed ampoules in ampoule washing machine horizontally on conveyer belt from feeding side.
Washing and cleaning of containers closures and equipment : all the containers, closures, and glass equipments used are thoroughly cleaned with detergent and then washed with RO water or De ionized water and finally rinse with water for injection. Same procedure is adaped for all
Filtration Unit, Pyrex Glass Flasks, Silicone Tubes with Glass Filters POR-2 and NRV’S, Machine Parts i.e. Pumps, Needles and Uniforms etc.
And then sterilized through autoclaving process (if used in filling area).
STERILIZATION
Depyrogenation:
It refers to the removal of pyrogens from solution, most commonly from injectable pharmaceuticals.
Pyrogen:
A pyrogen is defined as any substance that can cause a fever. A pyrogen can either be an endotoxin or an exotoxin, although most pyrogens are endogenous. Endotoxins are lipopolysaccharide (LPS) molecules found as part of the cell wall of gram-negative bacteria (see right), and are released primarily upon cell lysis. Endotoxins are typically only toxic when found in the bloodstream, and gram-negative bacteria exist routinely in human intestines, but do not cause a pyrogenic effect.
The FDA has set the following maximum permissible endotoxin levels for drugs distributed in the
- Drug (injectable, intrathecal) - 0.2 EU/kg product
- Drug (injectable, non-intrathecal) - 5 EU/kg product
- Sterile water - 0.25-0.5 EU/ml (depends on intended use)
Pyrogen detection:
Rabbit Test: Early endotoxin detection was accomplished by injecting rabbits with the sample and observing the response in their body temperature. Rabbits have similar endotoxin tolerance to humans.
LAL Test:Currently, the method of choice for endotoxin detection is the Limulus Amebocyte Lysate (LAL) test. This test is based on Dr. Frederik Bang's observation that horseshoe crab blood forms clots when exposed to endotoxins. Amoebocyte extract from horseshoe crab blood is mixed with a sample suspected of endotoxin contamination, and a reaction is observed if endotoxins are present. The FDA has approved four variations of the LAL test: gel-clot, turbidimetric, colorimetric, and chromogenic assay. The differences in these variations refer to the characteristics of the amoebocyte/endtoxin reaction (e.g. gel-clot produces a precipitate and colorimetric changes color). This test is fast (approx. 30 minutes) and highly sensitive (up to 0.005 EU/ml sensitivity).
Sterility testing
Parenteral preparations are required to be sterile, they should be tested for sterility and must comply with the official test for sterility described in U.S.P. These test are performed on all lots of their final containers.
According to U.S.P there are two basic methods for sterile testing
1.Direct inoculation of test samples on culture media :
In this method an aliquot quantity of the material under test is transferred to culture tubes (pre sterilized ) containg a measured volume of a sutible culture medium like fluid thioglycolate medium or thioglycolate broth medium. This whole operation done under aseptic conditions. These tubes are plugged with sterilized cotton wool and incubated for seven days at temperature of 30 to 35 0c. positive and negative control tubes containing the culter media must be incubated under same conditions to confirm sterility and growth promoting properties of the medium. In case of repeat ( turbidity or growth) test must be repeated 2nd time with fresh sample and in case of more the three times of sterility test fails product rejected.
2.Filtration technique:
If the product has antimicrobial properties must be neutralized or eliminated by dilution. In case of oily or solid preparations which make the culture medium turbid and difficult to identify, the normal test may have to be modified by sub culturing the medium. If turbidity appears it is due to microbial growth and shows that the material is not sterile.
Optical checking:
Clarity test
The presence of particular matter in the finished product particularly those which are given intravenously are of serious concern. The particle larger than the size of red blood cells are dangerous, they may block blood vessels with serious results.
For checking the clarity of single or multiple dosage form the unlabelled containers are held by the neck against strongly illuminated screen of which white surface is used for dark colored particles and black surface for the detection of light colored particles. The contents of the containers are slowly inverted and rotated and the solution examined for the presence of turbidity, dust or any other foreign particles.
Note= particle more than 50micron seen with necked eye
Foreign particles rejections and its reasons:
- Black particle= due to heater problem (carbon shedding ) of dry heat sterilizer
- Fiber = area rejection due to disturb area or shedding from the clothes of persons, ceilings, walls and furniture of the room from glass and rubber apparatus etc.
- Glass pieces = mostly due to break ampoules or improper washing of ampoules
- Charing = Filling machine rejection ( solution burns on flame when machine needles drop the solution on ampoule neck before ejection from ampoule)
- Tip rejection = filling machine problem due to sealing capture adjustment problem or burner flame problem ( cause extra melting or less melting of glass ampoules)
- White particle= mostly due to formulation problem or improper mixing of material during compounding
- Turbid solution = variations in the water temperature during batch manufacturing or abrupt change in temperature of solution during batch manufacturing
- Color variation= due to formulation problem or extra heating of solution during manufacturing or in final products
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