sterile dosage forms

STERILE DOSAGE FORMS

Prepared By :

Mr. Naresh Rajgor,

Assistant Professor,

M.P. Patel College of Pharmacy, Kapadwanj

STERILE DOSAGE FORMS PREPARED BY: MR. NARESH RAJGOR

PARENTERAL SUSPENSIONS

Parenteral suspensions are sterile, pyrogen free, biphasic (heterogeneous systems) containing dispersed drug particles suspended in a liquid phase(continuous phase).Advantages•Suitable for insoluble drugs •Increase chemical stability•Possible depot effect (provide prolong duration of action)

Disadvantages•Difficulty in formulation and in manufacturing •Difficult dose uniformity and maintenance of physical stability•Patient discomfort

Ideal characteristics of parenteral suspension•It should be sterile and pyrogen free.•It should be easily drawn into a syringe(syringeability) and readily ejected from the syringe(injectability)•Particle size should be small and uniform(less than 10 μm).•The solid content usually about 0.5-5%.•The dispersed particles do not settle rapidly after shaking.•It should be stable and elegance during its shelf life.•It should be isotonic and non irritating.

Formulationandpreparationofparenteralsuspensionincludes1.Formulationadditives2.Methodsofpreparation

Official products of Parenteral Suspension (IP 2010)•BenzathinePenicillin Injection•Fortified BenzathinePenicillin Injection•Cortisone Injection•Hydrocortisone Acetate Injection•Biphasic Insulin Injection•Biphasic IsophaneInsulin Injection•IsophaneInsulin Injection


•Insulin Zinc Suspension•MethylprednisoloneAcetate Injection•MetronidazoleSterile Suspension•Progesterone Injectable Suspension

PREFILLED SYRINGES

The first products presented in prefilled syringes were heparins, launched in Europe by Sanofi

and Rhone Poulenc-Rorer in the early 1980s.

•Conversions into a prefilled syringe system from a vial are widely accepted method of

packaging of products like antithrombotics, vaccines, antiinfectives, and other biotech drugs

indicated for chronic conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis and

Crohn’s disease.

The key advantages and driving factors of prefilled syringes are:

•Ease of administration and more convenient

•Easier for home use and in emergency situations

•Reduction of medication errors, misidentification

•Better dose accuracy

•Increased assurance of sterility

•Better use of controlled drugs such as narcotics

•Lower injection costs—less preparation, fewer materials and easy storage and disposal

•Elimination of vial over fill for product transferred to syringes for direct injection or addition to

primary diluents

•Product differentiation

•Reduced risk of needles tick injury

•Eliminates cross-infection from needle-use

•Needle safety regulations

Quality control of prefilled syringes

•The fixed dose in a prefilled syringe is filled mechanically and is checked electronically during

quality control.


•Major quality challenges for syringe filling include achievement to maintenance of sterility,

assurance of freedom from particulate contamination, and freedom from pyrogenic

contamination.

•Quality control also includes assurance of drug product potency, identity, safety, and stability.

One of the most challenging aspects of syringe quality control is the assurance of

container/closure integrity during and after filling and terminal sterilization.

Prefilled syringe components

•PFS are manufactured in much the same way as ampoules, tubing vials or syringe cartridges. A

syringe system generally consists of a barrel, a needle, and a rod with anel a stomeric plunger on

the tip. The plunger contacts the drug during administration. Selecting a plunger for a prefilled

syringe system is therefore an important consideration for pharmaceutical manufacturers.

Components Composition

arrel Glass or plastic

Piston Elastomer

Tip cap Elastomer

Plunger road Plastic

Lubricant Silicone oil

Staked needle Stainless steel

Needle shield Elastomer

Needle shield

cover

Plastic

Lever lock adapter Plastic

Tamper evident tip

cap

Plastic


TOTAL PARENTERAL NUTRITION

DefinitionTotal Parenteral Nutrition(TPN)may be defined as provision of nutrition for metabolic requirements and growth through the parenteral route (administered through intravenously).TPN also known as hyperalimentation solution.

This is a complete form of nutrition, containing protein, sugar, fat and added vitamins and minerals as needed for each individual.They are available as ready-to-mix kits.•The preferred method of delivering TPN is with a medical infusion pump. •A sterile bag of nutrient solution, between 500 mLand 4 L is provided. •The pump infuses a small amount (0.1 to 10 mL/hr) continuously in order to keep the vein open.

Components of TPN solutions(1)Protein as crystalline amino acids.(2)Fats as lipids.(3)Carbohydrate as glucose.(4)Electrolytes–Sodium, potassium,chloride, calcium and magnesium.(5)Metals/Trace elements–Zinc, copper, manganese, chromium, selenium.(6)Vitamins A,C,D,E,K, thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, choline and folic acid.

Why it is necessary?–A patient is severely under nourished and needs to have surgery, radiotherapy or chemotherapy;

–A patient suffers from chronic diarrhoea and vomiting;

–A baby's gut is too immature;

–A patient gastrointestinal tract is paralysed, for example after major surgery.

Normal Diet TPN– Protein…………Amino Acids– Carbohydrates…Dextrose– Fat……………..Lipid Emulsion


– Vitamins………Multivitamin Infusion– Minerals………Electrolytes & Trace Elements

Total Parenteral Nutrition Electrolytes

Electrolyte. Daily Requirement Standard Concentration

Na 60-150 meq 35-50 meq/L

K 40-240 meq 30-40 meq/L

Ca 3-30 meq 5 meq/L

Mg 10-45 meq 5-10 meq/L

Phos. 30-50 mM 12-15 mM/L

Indications for TPN

Short-term use

•Bowel (intestinal) injury /surgery•Bowel disease•Severe malnutrition•Nutritional preparation prior to surgery. •Mal absorption-bowel cancer

Long-term use

•Prolonged Intestinal Failure

•Crohn’sDisease

•Bowel resection


FREEZE DRIED PRODUCTS.

Definition:

Freeze-drying (also known as lyophilisation or cryodesication) is a dehydration process typically

used to preserve a material or make the material more convenient for transport, freeze-drying

works by freezing the material and then reducing the surrounding pressure to allow the frozen

water in the material to sublime directly from the solid phase to the gas phase.

Advantages of freeze dried products–Product is stored in dry state so avoidance of stability problems

–Product id dried without elevated temperatures

–Good for oxygen and/ or air sensitive drugs

–Rapid reconstitution time

–Constituents of the dried material remain homogenously dispersed

–Product is process in the liquid form

–Sterility of product can be achieved and maintained

Disadvantages of freeze dried products–Volatile compounds may be removed by high vacuum

–Single most expensive unit operation

–Stability problems associated with individual drugs

CharacteristicsThe desired characteristics of a freeze dried pharmaceutical dosage form include:

(1) an intact cake occupying the same shape and size as the original frozen mass


(2) Sufficient strength to prevent cracking, powdering, or collapse

(3) Uniform color and consistency

(4) Sufficient dryness to maintain stability (<2%)

(5) Sufficient porosity and surface area to permit a rapid reconstitution.

(6) Freedom from contamination such as:

-Micro -organisms(sterile),

-pyrogens (5EndotoxinsUnits/Kg), and particulates (less than 50 particles of 10μm per container

and less than 5 particles of 25μm per container result) is an essential attribute.

(7) Physically and chemically stable.

Introduction to Freeze drying cycle:

There are four stages in the complete drying process: pretreatment, freezing, primary drying, and

secondary drying.

Process

The process of freezing involves:

(1) Dissolving the drug and excipients in a suitable solvent, generally water.

(2) Sterilizing the bulk solution by passing it through bacteria-retentive filter (0.2microns).

(3) Filling into individual sterile containers.

(4) Freezing the solution by placing the open container on cooled shelves in a freeze drying

chamber or pre-freezing into another chamber.

(5) Applying a vacuum to the chamber and heating the shelves in order to sublime the water

from the frozen state.


NANOSUSPENSIONS

Definition

A pharmaceutical nanosuspension is defined as very finely dispersed solid drug particles in an aqueous vehicle for either or a land topical use or pararal and pulmonary administration. The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 00 and 600 nm.

Introduction:In nanosuspension technology, the drug is maintained in the required crystalline state with reduced particle size, leading to an increased dissolution rate and therefore improved bioavailability.Nanosuspensions can be administered via different parenteral administration routes ranging from intra-articular via intra peritoneal to intra venous injection.For administration by the parenteral route, the drug either has to be solubilised or has particle/globulesize below 5μm to avoid capillary blockage.

Potential benefits of nanosuspension technology•Intravenous: Rapid dissolution, Tissue targeting•Subcutaneous/intramuscular: Higher bioavailability, Rapid onset, Reduced tissue irritation-Nanosuspension formulation approaches most suitable for the compounds with low solubility, high log P value, high melting point and high dose.

Methods of preparation of nanosuspensions:

Mainly there are two methods for preparation of nanosuspensions.

1) The conventional methods of precipitation are called ‘Bottom Up technology’. Precipitation technique is not applicable to drugs, which are simultaneously poorly soluble in aqueous and non aqueous media.2) The ‘Top Down Technologies’ are the disintegration methods and are preferred over the precipitation methods.


The ‘Top Down Technologies’ include Media Milling (Nanocrystals), High Pressure Homogenization in water (Dissocubes), High Pressure Homogenization in nonaqueous media (Nanopure) and combination of Precipitation and High Pressure Homogenization (Nanoedege).Few other techniques used for preparing nanosuspensions are emulsion as templates, microemulsion as templates etc.

EVALUATION OF STERILE DOSAGE FORMS

•Sterile dosage forms include parenteral (i.e. Solution, suspension etc.,) and non parenteral (i.e. implant, ophthalmic etc.,) dosage forms.

All the dosage forms should meet their standard requirements of purity, identity, sterility and stability.

Quality control of sterile dosage forms

•The three general areas of quality control are incoming stock, manufacturing (in process) and the finished products.•For sterile products incoming stock control includes routine tests on all ingredients as well as special evaluations such as pyrogen tests on WFI, tests on packaging materials i.e. glass, plastic, rubber closures etc.,

Followings are the in process and finished products test for sterile dosage forms

1. Drug potency test: by assay method

2. pH: by digital calibrated pH meter

3. Syringeability (ability to drawn a solution into syringe) and injectability (ability to eject

a solution from the syringe)

4. Particle size distribution and sedimentation volume ratio (specific to parenteral

dispersion)

5. Extrudiability and spread ability (specific to ophthalmic gel and ointment)

6. Viscosity measurement : using rheometer


7. Isotonicity measurement: by RBC count method

8. Preservative effectiveness test

9. Sterility test: done by two methods

•Direct inoculation method

•Membrane filtration method

10. Leakage test: perform by two methods

•Dye immersion method

•High frequency spark test

11. Pyrogen test: perform by following methods

•Rabbit test (in vivo) includes

–sham test (for selection of animals for main test)

–main test

•LAL (Limulus amoebocyte lysate) test (in vitro)

12. Clarity test/ particulate matter test: perform by following methods

•Visual method: under white and black background•% transmittance: by UV detection

•Microscopic count method (or membrane filtration method)

•Light obstruction (obscuration) method

•Coulter counter method

13. Safety test (LD50toxicity test)

14. Package integrity test include container closure integrity test

15. Stability of dosage forms includes

•Accelerated stability study

•Long term stability


OPHTHALMIC PREPARATIONS

Definition:

Ophthalmics are defined as the dosage forms intended to be administered onto the external surface of the eye (known as topical preparations), inside (known as intra ocular preparations) or adjacent to the eye (known as periocular preparations) or those used in combination with ocular appliances.Ophthalmics are used therapeutically or prophylactically.•Therapeutically useful in the treatment of intraocular or surface conditions like conjunctivitis or inflammation, infections of the eye or eyelids etc.

•Prophylactically useful in post surgical and post trauma preparations.

Drug categories use in ophthalmic•Miotics e.g. pilocarpineHcl

•Mydriatics e.g. atropine

•Cycloplegicse.g. atropine

•Anti-inflammatoriese.g. corticosteroids

•Anti-infectives(antibiotics, antiviralsand antibacterials)

•Anti-glucomadrugs e.g. pilocarpineHcl

•Surgical adjuncts e.g. irrigating solutions

•Diagnostic drugs e.g. sodiumfluorescein

•Anestheticse.g. tetracaine

REQUIREMENTS OF OPHTHALMIC PREPARATIONS•Clarity


•Isotonicity

•pH

•Purity and stability

•Sterility

•Viscosity

•Surface activity

TYPES OF OPHTHALMIC DOSAGE FORM

1. Ophthalmic Solutions includes drops and lotions

2. Ophthalmic Suspensions

3. Ophthalmic Ointments

4. Ophthalmic Emulsions

5. Ophthalmic Gels

6. Ophthalmic Gel-forming solutions

7. Ophthalmic Injections

8. Irrigation Solutions (Intraocular)

9. Ocular Inserts

10. Sterile Powders

11. Contact Lenses Care Solutions

FORMULATION AND PREPARATION OF OPHTHALMIC PREPARATIONS•Ophthalmic solutions includes eye drops and eye lotions

•Ophthalmic suspensions

•Ophthalmic ointments

•Ophthalmic gels

•Ophthalmic emulsions

TYPES OF ADDITIVES USED IN OPHTHALMIC PREPARATIONS

•The additives used in different types of formulation for ophthalmic preparations are as below.


–Vehicles: it may aqueous and/or non aqueous

–Stabilizers includes

-Preservatives

-Antioxidants

-Buffers

-Chelating agents

–Thickening agents (Viscosifiers)

–Tonicity adjusting agents

–Suspending agents

–Wetting agents

–Flocculating agents

–Ointment base

–Emulsifying agents

–Emulsion stabilizer

–Gelling agent etc.

EVALUATION OF OPHTHALMIC PREPARATIONS•They can be evaluated by performing the following tests.

A. General tests includes

•Test for sterility

•Test for ocular toxicity and irritation

•Test for preservative efficacy

•Drug potency measurement

•Isotonicity measurement

•pH determination

•Drug release studyincluding ocular penetration

•Container closure integrity test

B. Specific tests for ophthalmics


1) For ophthalmic suspensions

–Physical appearance

–Sedimentation rate

–Redispersibility

–Rheological properties include viscosity, Extrudiability

–Particle size and size distribution

2) For ophthalmic solutions

–Clarity test–Rheological properties like viscosity, density, specific gravity

3) For Ophthalmic ointments

–Rheological properties include viscosity, Extrudiability, Spreadiability

–Mean retention time

4) For ophthalmics emulsion(include micro emulsion)

–Physical appearance

–Identification

–Globule size and size distribution

–Rate of creaming

–Rheological properties include viscosity, Extrudiability

5) For ophthalmic gels–Rheological properties include viscosity, Extrudiability, spreadiability

–Mean retention time

–Mucoadhesive strength

6) For ophthalmic injections–Test for pyrogen

–Test for particulate matter

–Leak test


CONTAINERS The containers used for packing ophthalmics should have the following requirements:–Facilitate easy handling.

–Do not absorb the medicament or release any substance into the preparation.

–Do not alter the stability or therapeutic activity of the preparation.

–Withstand the sterilization procedure.

Volume of Packing

Usually 10-25 ml of liquid preparation or less than 5 g of semi-solid preparation is packed in each container.

Types of containers

1. Based on Number of Doses Present:

A. Single-dose Containers: They consist of only one dose of the ophthalmic preparation . Usually preparations which do not contain preservatives are packed in single-dose containers in order to maintain the sterility until administered. Generally intraocular preparations & ophthalmic injections are packed in Single-dose containers.

B. Multiple-dose containers: The preparations containing preservatives are packed in multiple-dose containers.

2. Based on the form the container: (I)Bottles:

(a) Bottle: Generally low-density polyethylene (LDPE) type of plastic, either without or with pacifying agents or other colorants to afford protection from light, isused in making the bottles. Propylene or high density propylene (HDPE) rising can also be used.

(b) Fitment: The size of adropof the ophthalmic products depends upon the fitment. The fitment may also prevent gushing of product from the bottle at the time of use.

(c) Cap: It is also called as closer. It closes the bottle and prevents leakage or contamination of the products. Caps are made from propylene type of plastic.Small plastic bottles used for packing ophthalmic solution, suspension and emulsion are called as plastic squeeze bottles or drop container.

(II) Tubes: Semisolid ophthalmic like ointments and gels are packed in small metal and plastic collapsible tubes with a narrow tip. If required tubes coated with epoxy or vinyl plastic may be used.


Testing the Containers:

Uniformity of volume: The entire container should be of same volume.

Leakage Test: All the containers should be leak proof. Otherwise, there will be loss of the

ingredients.

Collapsibility Test: This test is evaluated the collapsibility of metal or plastic tubes.

STERILE DOSAGE FORMS

• Sterile products are dosage forms of therapeutic agents that are free of viable microorganism.

• These include parenteral, ophthalmic and irrigating preparation.• Sterile products are more frequently solutions or suspensions, but may even be solid

pellets for tissue implantation.

Advantages– 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)

Disadvantages– 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.

Ideal Requirements– Sterility (must)– Pyrogen (must)– Free from particulate matter (must) – Clarity (must)– Stability (must)


– Isotonicity – 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.

• Formulation of sterile dosage form

• Sterile dosage forms are formulated as solutions, suspension, emulsion, liposomes, microspheres, nano systems and powders to be reconstituted as solution.

• Solvent system suitable for sterile products are limited to those that produce little or no tissue irritation, water is the most common.

• All components must be pure.

Sr. No Name of the agent

1 Vehicles WaterWater Miscible vehiclesNon aqueous vehicles

2 Excipient/solutes

2.A Antimicrobial Preservatives Benzyl alcoholBezethonium chlorideButyl Paraben Chlorobutanol Metacresol Methylparaben PhenolPhenylmercuric citratePropyl paraben Thimersol

2.b. Solubilizers, wetting agents or emulsifiers Dimethylacetamide Dioctyl sodium sulfosuccinate Egg yolk phospholipid Ethyl alcoholEthyl lactate, Glycerin, Lecithin, PEG40 castor oilPEG 300Polysorbate 20,40, 80


Povidone, propylene glycol

2.C Buffers Acetic acid, adipic acid,Benzoic acid and sodium benzoateCitric acid, ;lactic acid, maleic acid, potassium phosphate, sodium actate, sodium citrate and tartrate, tartaric acid

2.D Bulking agents or tonicity modifiers Glycerin, lactose, mannitol, dextrose, NaCl, sodium sulfate, sorbitol

2.E Suspending Agents Helatin, methyl cellulose, pectin, PEG 4000, Na CMC, Sorbitol solution

2.F Chelating Agents EDTA disodium, Edetate calcium disodium, EDTA tetrasodium

2.G Local Anaesthetics Procaine HCl, Benzyl alcohol

2.H Stabilizers Creatinine, glycine, naicinamide, sodium acetyltryptophanate, sodium caprylate, sodium saccharine

2.I Antioxidants Ascorbic acidSodium bisulfateSodium metabisulfate, thiourea, BHT, Tocopherol


biofilm formation.

inactivate the fauling bacteria.


CONTAINERS AND CLOSURES

• A. GLASS CONTAINER

• Glass is the choice of container for most of SVP.• It is composed of silicon dioxide, with varying amounts of other oxides such as sodium,

potassium, calcium, magnesium, aluminium, boron and iron.• The basic structural network of glass is formed by silicon oxide tetrahedron.• Boric oxide will enter into this structure, but most of the other oxides do bot.• The latter are only loosely bound and relatively free to migrate.• These migratory oxides may leached into a solution in contact with the glass.• The oxides thus dissolved may hydrolysed to raise pH of the solution and catalyse or

enter into reaction.• Such occurrences can be minimize by proper selection of glass composition.

• TYPES:Type I : A borosilicate glassType II: a soda lime treated glassType III: a soda lime glassNP: General Purpose soda lime glass, not for parenteral.

• Type I glass is composed of silicon dioxide (81%) and boric oxide (13%) with low level of non-network forming oxides.

• While Type II and type III glass compounds are composed of relatively high proportion of sodium oxide (14%) and calcium oxide (8%).


• B. PLASTIC COTAINERS

• Principle ingredient of plastic containers are thermoplastic polymers like polyethylene,

polypropylene, PVC, polycarbonate, polyamide, polystyrene, teflon.

• Plastic materials used in the medical field have less other additives.

• In certain cases, some amount of plasticizer, fillers, antistatic agents, antioxidents and

other ingredients may be added.

• Most of the plastic containers melt at elevated temperatures except polyethylene and

polystyrene.

• Plastic materials used mainly because they are light weight, no breakable and with low

additives have low toxicity and low reactivity with products.

• Reactivity can be occur with sorption of the polymer in some cases.

• Additive leached and may react with the products.

• Most polymers are adversely affected by elevated temperatures required for thermal

sterilization and have a relatively high permeability for water vapor.

• Significant permeation of gases like oxygen may occur with some plastic containers.

• C. Rubber closures:

• Rubber closures are used to seal the openings of cartridges, vials and bottles and

permeate and withdrawal of needle without loss of integrity of the sealed containers.

• Rubber closures are compounded of several ingredients like natural rubber or synthetic

polymers usually sulfur and 2 mercaptobenzothiazole.

• Closure should be completely nonrective with the products.

• Testing:

• The physicochemical tests on aquous extracts includes pH, turbidity, residue on drying,

iodine number and heavy metal content.

• The biological tests on saline, polyethylene glycol 400 and cottonseed oil extracts

includes acute and chronic toxicity on mice and rabbits.


LAMINAR AIR FLOW (LAF) BENCH:• The underlying principle of a laminar air flow hood is that a constant flow of HEPA filtered

air at a rate of approximately 90 linear feet per minute physically sweeps the work area and prevents the entry of contaminated air

• The hood workspace is used to prevent the contamination of compounded sterile products and parenteral preparations

• The space between the HEPA filter and sterile product being prepared is referred to as the critical work surface

• HEPA filter - High Efficiency Particulate Air filter removes 99.97% of all air particles 0.3mm or larger.

•

Types of Laminar Air Flow:

• Horizontal Flow (Laminar Flow Hood)

– Air blows towards worker

– Used for non-chemotherapy preparations


• Vertical Flow (Biological Safety Cabinet or Chemotherapy Hood)

– Air blows from top down to maintain sterility and protect the worker

– Used to make chemotherapy


• All aseptic manipulations should be performed at least SIX inches within the hood to

prevent the possibility of contamination from room air entering the hood.

• A laminar flow hood should be left operating continuously

• If hood is turned off it must run for 30 minutes to reestablish laminar air flow and then be

cleaned prior to use

• Before use, all interior working surfaces of the laminar flow hood should be cleaned from

back to front away from the HEPA filter.

• The HEPA filter is located in the fragile mesh between thin metal strips at the back of the

hood behind the HEPA filter screen

• Nothing should be permitted to come in contact with the HEPA filter

• NO cleaning solution

• NO aspirate from syringes

• NO glass from ampules

• NO fluids, even if sterile

• DO NOT touch HEPA filter

• No Paper, Pens, Calculators or Labels in the Hood

• Only products essential to product preparation should be placed in the laminar flow hood

to minimize the potential for contamination.

• Eating, drinking, and smoking is always prohibited

• Talking or coughing should be directed away from the hood to minimize air flow

turbulence

• A mask covering mouth and nose must be worn while working in the hood

• The use of a laminar flow hood alone without the observance of aseptic technique, cannot

insure product sterility


ASEPTIC TECHNIQUES• Aseptic technique is the technique for manipulations of compounded sterile products and

parenteral preparations that prevents contamination

• Aseptic technique requires specific manipulations for:

1. Syringes

2. Needles

3. Vials

4. Ampules

5. Removal of packaging

6. Assembling of sterile products

7. Hand placement

1. Syringe:

• Syringes are available in sizes ranging from 0.5 to 60 milliliters (ml)

• Graduation marks on syringes represent different increments depending on size of

syringe

• DO NOT use syringes whose gradations are greater than twice the volume being

measured

• To maintain sterility, neither the syringe tip or plunger should be touched

2. Needles:

3. Hub

a. Where the needle attaches to the syringe tip and allows the fluid in the syringe

barrel

4. Bevel

a. The tip of needle is slanted to a point and the slanted part of the needle is the

bevel. The bevel allows for smooth insertions through stoppers and ports with

minimal coring

• Coring

– The development of a core or hole in the rubber of a vial

– To prevent coring insert needle as shown


– Insert the bevel tip first, then pressing downward and toward the bevel so the

bevel tip and heel enter at the same point

• Needle size is determined by two numbers

– Gauge

– Length

• The larger the gauge number the finer the diameter of the needle’s bore

– 27 gauge needle finer than 13 gauge needle

– Common needle sizes at UK include

• 16G 1&1/2 inch

• 18G 1&1/2 inch

• 20G 1 inch

• Needle length is measured in inches

• Never touch any part of the needle

• Open needle package within hood to maintain sterility

• It is important that when using needles and syringes in product preparation that they not

be removed from the hood workspace

• Needles and syringes must be properly disposed in a sharps container located near the

hood to prevent injury to others

• Never dispose of needles or syringes in regular trash.

3. Ampoule and Vials

• To break ampule

• Clean ampule neck with alcohol swab

• Leave swab in place

• Grasp ampule neck with thumb and index finger

• Use quick, firm, snapping motion away from body towards side wall of hood

• DO NOT BREAK TOWARD HEPA FILTER

• To withdraw medication from ampule

• Tilt ampule

• Place needle bevel in corner space near opening

• Pull back syringe plunger


• Do NOT use a filter needle to remove ampule contents

• To avoid glass contamination of ampule solution

• Use 5 micron filter needle to filter glass as solution is pushed out of the syringe

• A filter needle can only be used in one direction, otherwise glass particles originally

filtered are reintroduced

• For UK consistency always use the filter needle as the second needle

4. Removal of packaging

• Any sterile component or supply (e.g., syringes, needles, and ampules) should only be

opened and/or removed from their packaging within the laminar-flow workspace.

• When opening the wrapper on a needle, it should be peeled open.

• Tearing paper introduces paper particles into the hood which could lead to product

contamination.

5. Assembling of sterile products

Great care must be exercised to prevent any touch contamination of critical edges or

component surfaces.

The syringe tip and plunger and all parts of the needle are critical surfaces.

6. Hand placement

It is important that hand placement during any aseptic manipulation is such that

laminar airflow is not interrupted around any of the critical sterile fluid pathways.

Great care should be taken to avoid contact with the syringe plunger, especially

during multiple manipulations using the same syringe. Since the plunger enters the

barrel of the syringe during repeated uses, contamination can be accidentally

introduced into the barrel.


WATER FOR INJECTION

PREPARATION:

The source water can be expected to be contaminated with the natural suspended

minerals and organic substances, dissolved mineral salts, colloidal material, viable

bacteria, bacterial endotoxins, industrial or agricultural chemicals and others particulate

matter.

The degree of contamination will vary with the source and will be markedly different,

whether obtained from a well or from surface source such as a stream or lake.

Hence the source water usually must be pretreated by one or a combination of the

following treatments: chemical softening, filtration, deionization, carbon adsorption or

reverse osmosis.

A schematic of a typical process used to convert potable water to water for injection is

shown below:

City water Sand filter Primary softener Polisher

Storage Tank Reverse Osmosis Dechlorinator

Clean Steam

Generator Multiple Effect Still

Cool Loop Hot Loop

The EP only permits distillation as the process for producing WFI. The USP and JP allow all these technologies to be applied.

In general distillation and reverse osmosis are widely used methods for producing WFI.

Distillation:


Distillation is a process of converting water from a liquid to its gaseous form. Since steam is pure gaseous water, all other contaminations in the feed water are removed.

In general, a conventional still consists of a boiler containing feed water (distillant), a source of heat to vaporize the water in condensing surfaces for refluxing the vapor, thereby returning volatile impurities to the distillant, a means of eliminating volatile impurities before the hot water vapor is condensed and a condenser for removing the heat of vaporization, thereby converting the water vapor to a liquid distillate.

The specific construction of still and the process specification may produce the quality of water and prevent the contamination of water.Types:

1. COMPRESSION DISTILLATION2. MULTIPLE EFFECT STILLS

Reverse Osmosis: As the name suggests, the natural process of osmosis is reverse due to the

application of high pressure. Pressure, usually between 200 to 400 psig, is applied to overcome osmotic

pressure and force pure water to permeate through the membrane. Membrane usually composed of cellulose esters or polyamides. The molecules most difficult to remove are small organic molecules like sodium

chloride.

Schematic diagram of reverse osmosis process


STORAGE AND DISTRIBUTION

The rate of production of WFI usually is not sufficiently to meet the production demands. Therefore it is collected in holding tanks for subsequent use and the temp of 80 C should be maintaining to prevent microbial contamination.

The USP also permits the WFI to store at room temp. for maximum of 24 hours.

PURITY OR QUALITY CONTROL TEST:

Various chemical and physical tests have been performed to check the purity of WFI. Total organic carbon (TOC), with a limit of 0.5 mg/L and conductivity with a limit of 1.3

uS/ cm at 25 C or 1.1. uS/cm at 20 C. The wet chemistry tests are still used for WFI. Biological requirements continue to be for WFI not more than 10 colony forming units

(CFUs)/100 ml and 0.25 USP endotoxin units/ml. Sterility test has also been performed WFI must passes the sterility test.


sterile dosage forms

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