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PARENTERAL PARENTERAL PRODUCTSPRODUCTS

PHC PHC 426426PHARMACY PRACTICE IIPHARMACY PRACTICE IIMeorMeor MohdMohd RedzuanRedzuan

PARENTERAL PRODUCTSPARENTERAL PRODUCTS

Definition (BP)Definition (BP) Parenteral preparations are sterile preparations Parenteral preparations are sterile preparations

intended for administration by injection,infusion or intended for administration by injection,infusion or implantation into human or animal bodyimplantation into human or animal body

May require the use of excipient, for eg to make the May require the use of excipient, for eg to make the preparation isotonic with blood, to adjust the pH, to preparation isotonic with blood, to adjust the pH, to increase solubility,to prevent deterioration of the active increase solubility,to prevent deterioration of the active ingredient or to provide adequate antimicrobial ingredient or to provide adequate antimicrobial properties but not to adversely affect the intended properties but not to adversely affect the intended medicinal action of the preparation or at the medicinal action of the preparation or at the concentrations used to cause toxicity or undue local concentrations used to cause toxicity or undue local irritation irritation

PARENTERAL PRODUCTSPARENTERAL PRODUCTS

ParenteralParenteral products are products that are products are products that are administered to the body by injection. administered to the body by injection. Because this route of administration Because this route of administration bypasses the normal body bypasses the normal body defencedefencemechanisms, it is essential that these mechanisms, it is essential that these products are prepared with a higher products are prepared with a higher degree of care and skills than degree of care and skills than utilisedutilised in in preparing conventional oral or topical preparing conventional oral or topical products products

PARENTERAL PRODUCTSPARENTERAL PRODUCTS

Sterile formulations must : Sterile formulations must : a. Sterilea. Sterile b. Particulate material b. Particulate material c. c. PyrogenPyrogen free free d. Stability d. Stability e. pH e. pH f. Osmotic pressure f. Osmotic pressure

PARENTERAL PRODUCTSPARENTERAL PRODUCTS

The The parenteralparenteral products is often used for drugs which products is often used for drugs which cannot given orally.cannot given orally.

due to patient …due to patient …intoleranceintolerance

instability of druginstability of drugpoor absorption poor absorption if given by oral routeif given by oral route

In practiceIn practice-- injectedinjected-- implantedimplanted-- infusedinfused

Directly into blood vessels, tissues, or other Directly into blood vessels, tissues, or other body compartments.body compartments. Usually admit at hospitalUsually admit at hospital Patient can admit their own medication Patient can admit their own medication

(insulin)(insulin)

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Parentral therapy is used to: (advantages)Parentral therapy is used to: (advantages)-- produce localized effectproduce localized effect-- administer drugs if the oral route administer drugs if the oral route cannot usedcannot used

-- deliver drugs to the unconscious deliver drugs to the unconscious patientpatient

-- rapidly correct fluid and elecrolyte rapidly correct fluid and elecrolyte imbalancesimbalances

-- ensure delivery of the drug to the ensure delivery of the drug to the target tissuestarget tissues

DisadvantagesDisadvantages•• ExpensiveExpensive•• Required trained personnelRequired trained personnel•• Difficult to remove if adverse or toxic Difficult to remove if adverse or toxic

reactionreaction•• Patient acceptabilityPatient acceptability--painpain•• Introduction of microorganism/toxic Introduction of microorganism/toxic ––

potentially fatal (especially as patient potentially fatal (especially as patient often already very sick)often already very sick)

•• Thrombosis,hemolysis,precipitate in the Thrombosis,hemolysis,precipitate in the vein tissue/nerve damagevein tissue/nerve damage

AdministrationAdministration The three major routes of administrationThe three major routes of administration SubcutaneousSubcutaneous IntramuscularIntramuscular IntravenousIntravenous

Other routesOther routes Intra dermalIntra dermal IntraIntra--arterial arterial Intra cardiacIntra cardiac IntraspinalIntraspinal IntraIntra--articulararticular

Subcutaneous Injection Subcutaneous Injection

Injected into the loose Injected into the loose connective and adipose connective and adipose tissue immediately beneath tissue immediately beneath to skinto skin

Typically volume not more Typically volume not more than 1 mlthan 1 ml

.. Abdomen, the upper back, .. Abdomen, the upper back, the upper arms and lateral the upper arms and lateral upper hipsupper hips

… more rapidly and … more rapidly and predictable adsorb than oralpredictable adsorb than oral

… less rapidly and … less rapidly and predictable than predictable than intramuscularintramuscular

drugs that cannot deliver drugs that cannot deliver orallyorally

Intramuscular InjectionIntramuscular Injection

Aqueous solution, solutions in oil and suspensionAqueous solution, solutions in oil and suspension Easier administration than IVEasier administration than IV Slower onset but prolonged action than IV, aqueous Slower onset but prolonged action than IV, aqueous

solution to be adsorb quickly should be slightly solution to be adsorb quickly should be slightly hipertonichipertonic

Limited volume 2Limited volume 2--5ml5ml Solutions, suspension,emulsion,oil base vehicleSolutions, suspension,emulsion,oil base vehicle Muscle sitesMuscle sites

The gluteal muscle in the buttock (larger volume can tolerate The gluteal muscle in the buttock (larger volume can tolerate for adult)for adult)

The deltoid muscle in the shoulder (rapid absorption)The deltoid muscle in the shoulder (rapid absorption) The vastus lateralis of the thigh (suitable for children and The vastus lateralis of the thigh (suitable for children and

infant)infant)

Intravenous Injection and Intravenous Injection and InfusionInfusion Small volume for IV to produce a rapid effect.Small volume for IV to produce a rapid effect. Complete bioavailabilityComplete bioavailability Less irritationLess irritation Volume Volume –– 50ml 50ml –– 1L infusion1L infusion Selection of veinSelection of vein

Size of needle or catheterSize of needle or catheter The type and volume of fluid to be admitThe type and volume of fluid to be admit The rate of admit of fluidsThe rate of admit of fluids

The fluids are admit into a superficial vein at the back of The fluids are admit into a superficial vein at the back of the hand or in the internal flexure of the elbow.the hand or in the internal flexure of the elbow.

It must not be used to admit emulsion and suspension.It must not be used to admit emulsion and suspension.

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IntraIntra--dermal Injectiondermal Injection

Small volume: 0.1 mlSmall volume: 0.1 ml Injected into the skin between the Injected into the skin between the

epidermis and the dermis.epidermis and the dermis. Absorption is slowAbsorption is slow < 0.1 < 0.1 –– 0.2ml0.2ml Used for diagnostic test for allergy and Used for diagnostic test for allergy and

immunityimmunity Administration of vaccinesAdministration of vaccines

IntraIntra--arterial Injectionsarterial Injections

The drug injected directly to the arteryThe drug injected directly to the artery Fast flow of blood, drug rapidly dispersed Fast flow of blood, drug rapidly dispersed

throughout blood system.throughout blood system. Manipulatives difficulties restrict the useManipulatives difficulties restrict the use To target specific organ/tissue served by To target specific organ/tissue served by

the arterythe artery Mainly for diagnostic proceduresMainly for diagnostic procedures

Intracardiac InjectionsIntracardiac Injections

Aqueous solutions are injected directly to Aqueous solutions are injected directly to cardiac or ventricle in emergency case cardiac or ventricle in emergency case only for local effect.only for local effect.

Intraspinal InjectionsIntraspinal Injections Less than 20 ml of Aqueous solutions are Less than 20 ml of Aqueous solutions are

injected into particular areas of the spinal injected into particular areas of the spinal column.column.

Use for spinal anaesthetics & antibioticsUse for spinal anaesthetics & antibiotics Must be isotonicMust be isotonic Categorized:Categorized: Intrathecal Intrathecal ––into spinal fluid into spinal fluid SubarachnoidSubarachnoid EpiduralEpidural PeriduralPeridural--into peridural spaceinto peridural space

Specific gratify of these injections may be Specific gratify of these injections may be adjusted to localize the site of action of drugadjusted to localize the site of action of drug

IntraIntra--articular Injectionsarticular Injections

Aqueous solutions or suspension injected Aqueous solutions or suspension injected into synovial fluid in a joint cavity.into synovial fluid in a joint cavity. Local administration of anti inflammatory Local administration of anti inflammatory

drugs. drugs.

Type of parenteralsType of parenterals

Large volume parenteralLarge volume parenteral Small volume parenteral Small volume parenteral Single dose ampoulesSingle dose ampoules Multiple dose vialsMultiple dose vials PrePre--filed syringesfiled syringes

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The British Pharmacopoeia (B.P.) The British Pharmacopoeia (B.P.) --DefinitionDefinition

SINGLE DOSE PREPARATIONS SINGLE DOSE PREPARATIONS single dose preparations as: single dose preparations as: ‘The volume of the injection in a single dose container ‘The volume of the injection in a single dose container

is sufficient to permit the withdrawal and administration is sufficient to permit the withdrawal and administration of the nominal dose using a normal technique’. of the nominal dose using a normal technique’.

MULTIPLE DOSE PREPARATIONS (BP 2004) MULTIPLE DOSE PREPARATIONS (BP 2004) MultidoseMultidose preparations are preparations are multidosemultidose aqueous aqueous

injections which contain a suitable antimicrobial injections which contain a suitable antimicrobial preservative at an appropriate concentration except preservative at an appropriate concentration except when the preparation itself has adequate antimicrobial when the preparation itself has adequate antimicrobial properties.properties.

Single dose ampoulesSingle dose ampoules

Small volumes in ampoules or small vialsSmall volumes in ampoules or small vials Glass ampoules are made of Type I borosilicate glass.Glass ampoules are made of Type I borosilicate glass. Packaging: filled and heat sealed.Packaging: filled and heat sealed. Prepared in clean room conditions and must be sterile and free of Prepared in clean room conditions and must be sterile and free of

particles.particles. Great concern relates to the hazards of opening the ampoules Great concern relates to the hazards of opening the ampoules

(contaminated by glass particle)(contaminated by glass particle) Ampoules neck have a painted dot marker (weakened neck).Ampoules neck have a painted dot marker (weakened neck). Plastic ampoules: BlowPlastic ampoules: Blow--fillfill--sealseal Have reliable sealHave reliable seal Single use without antimicrobial agents.Single use without antimicrobial agents. Must contain small excess of product.Must contain small excess of product.-- to allow nominal injection to allow nominal injection

volume to be drawn into a syringevolume to be drawn into a syringe

Multiple dose vialsMultiple dose vials

Thick walled class container is sealed with a rubber Thick walled class container is sealed with a rubber closure and held by an aluminum seal which is crimped closure and held by an aluminum seal which is crimped to the neck of the glass vial.to the neck of the glass vial.

These closures are then covered with a plastic capThese closures are then covered with a plastic cap Dose flexibility and economicalDose flexibility and economical Disadvantages: fragment of closure &Disadvantages: fragment of closure &Interaction between product & closureInteraction between product & closure Possibility of microbial contaminationPossibility of microbial contamination Antimicrobial agentsAntimicrobial agents Eg : InsulinEg : Insulin

Prefilled syringesPrefilled syringes

The injection solution is aseptically filled The injection solution is aseptically filled into sterile syringesinto sterile syringes It has high level of sterility insuranceIt has high level of sterility insurance Without any antimicrobial agents.Without any antimicrobial agents. Immediate useImmediate use Expensive.Expensive.

Advantages of PreAdvantages of Pre--filled Syringefilled Syringe For selfFor self--injecting patientsinjecting patients•• High degree of flexibility and independenceHigh degree of flexibility and independence•• Simple handling the discrete appearance of the injector Simple handling the discrete appearance of the injector

and reduction of injuriesand reduction of injuries Point of view of pharmaceutical companies and Point of view of pharmaceutical companies and

physiciansphysicians•• Product differentiation in the marketProduct differentiation in the market•• Cost savings from optimized drug use due to low Cost savings from optimized drug use due to low

overdosing requirements in preoverdosing requirements in pre--filled syringes in filled syringes in comparison to vialscomparison to vials

•• Reduced material requirement; simple storage and Reduced material requirement; simple storage and disposaldisposal

•• Better patient complianceBetter patient compliance

•• Simplified drug administrationSimplified drug administration•• Simple administration and great convenience Simple administration and great convenience

for hospital personnelfor hospital personnel•• Fewer needle injuriesFewer needle injuries•• Reduced risk of microbiological contaminationsReduced risk of microbiological contaminations•• Reduction of crossReduction of cross--infections (since reinfections (since re--use of use of

the needle is not necessary)the needle is not necessary)•• Reduction of misidentification since systems Reduction of misidentification since systems

are labelledare labelled•• High dosage accuracy and sterility assurance High dosage accuracy and sterility assurance

due to machine fillingdue to machine filling

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FORMULATION OF FORMULATION OF PARENTRAL PRODUCTSPARENTRAL PRODUCTS During the formulation of During the formulation of parenteralparenteral products, the following factors products, the following factors

are critical: are critical: (a) The vehicle in which the drug is dissolved or dispersed (a) The vehicle in which the drug is dissolved or dispersed (b) Volume (dose) of the injection (b) Volume (dose) of the injection (c) Adjustment to (c) Adjustment to isotonicityisotonicity (d) Adjustment of pH (d) Adjustment of pH (e) (e) StabilisersStabilisers (f) Preservatives (f) Preservatives (g) Adjustment of specific gravity (for spinal (g) Adjustment of specific gravity (for spinal anaesthesiaanaesthesia) ) (h) Concentration units (h) Concentration units

FORMULATION OF PARENTRAL FORMULATION OF PARENTRAL PRODUCTSPRODUCTS

Vehicle for injectionsVehicle for injections Provide higher proportionProvide higher proportion Should be inert, nonShould be inert, non--toxic & no therapeutic toxic & no therapeutic

activityactivity Mains water; always containing contaminant Mains water; always containing contaminant

such as electrolytes, organisms, particulate such as electrolytes, organisms, particulate matter and dissolved gases (COmatter and dissolved gases (CO22 and Cl)and Cl) Called water for injection.Called water for injection. It can be use for ophthalmic preparationIt can be use for ophthalmic preparation

Water for injectionsWater for injections Extensively use in parentral formulationExtensively use in parentral formulation It is well tolerated in the bodyIt is well tolerated in the body Ionazable electrolytes readily dissolve in Ionazable electrolytes readily dissolve in

waterwater It must bee free from pyrogenIt must bee free from pyrogen … a high level of chemical purity… a high level of chemical purity BP 1993; water from distillation processBP 1993; water from distillation process EP 1997; water prepared by distillation, EP 1997; water prepared by distillation,

reverse osmosis and ultrafiltrationreverse osmosis and ultrafiltration

Preparation of water for injectionsPreparation of water for injections The usual method is distillationThe usual method is distillation Consistent quality of productConsistent quality of product Source: potable waterSource: potable water Contaminated with suspended mineral and Contaminated with suspended mineral and

organic substances, mineral organic substances, mineral salts,m/o,endotoxin and chemicals.salts,m/o,endotoxin and chemicals.

To improve the quality of the end product the To improve the quality of the end product the source of water may be pretreated bysource of water may be pretreated by Chemical softeningChemical softening FiltrationFiltration DeionisationDeionisation pH adjustmentpH adjustment Then treated by reverse osmosis Then treated by reverse osmosis This water was used as the feed water for distillationThis water was used as the feed water for distillation

Distillation setDistillation set A boiler containing feed waterA boiler containing feed water A heaterA heater A headspaces A headspaces A condenserA condenser

Conductivity of the water is not more Conductivity of the water is not more 2microS/cm.2microS/cm. Usually free of microbial contaminants.Usually free of microbial contaminants. It should contain fewer than 10 bacteria It should contain fewer than 10 bacteria

per 100 ml and no per 100 ml and no pseudomonaspseudomonas speciesspecies It must be free of pyrogens with less than It must be free of pyrogens with less than

0.25 endotoxin unit (EU) per ml 0.25 endotoxin unit (EU) per ml (endotoxin test)(endotoxin test) Chemical quality of the freshly collected Chemical quality of the freshly collected

distillate should be comply with the limit distillate should be comply with the limit tests for purified water.tests for purified water.

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Quality limits of water for injectionQuality limits of water for injection ChloridesChlorides less than 0.5 parts (ppm)less than 0.5 parts (ppm) AmmoniaAmmonia 0.1 ppm0.1 ppm Heavy metalsHeavy metals 0.1 ppm0.1 ppm OxidizableOxidizable

substancessubstances less than 5 ppmless than 5 ppm Residual on Residual on

evaporationevaporation less than 0.001%less than 0.001% pHpH 5.0 5.0 –– 7.07.0

Care is required in handling the freshly Care is required in handling the freshly collected distillate water as it subject to collected distillate water as it subject to microbial contamination during storage microbial contamination during storage and distribution.and distribution. Two systems are commonly used for the Two systems are commonly used for the

storage of water for injection:storage of water for injection: Batch storageBatch storage Dynamic storageDynamic storage

Batch storageBatch storage WFI stored as a batchWFI stored as a batch QC tests are performed on this batch.QC tests are performed on this batch. Batch release after identification.Batch release after identification. Provides maximum product accountability Provides maximum product accountability

before use.before use. Expensive storage systemExpensive storage system

Dynamic storageDynamic storage A surge tankA surge tank Quality polished stainless steel.Quality polished stainless steel. As the level of water falls more WFI produced and As the level of water falls more WFI produced and

filled into the tank. filled into the tank. Cheaper.Cheaper.Disadvantages:Disadvantages: Contamination through corrosion of the steel tank.Contamination through corrosion of the steel tank. Gram negative bacterial contamination.Gram negative bacterial contamination. Storage at 80 degree C to prevent bacteria Storage at 80 degree C to prevent bacteria

growth.(steam heated jacket)growth.(steam heated jacket) Surge tank need Surge tank need sterilisationsterilisation at interval of timeat interval of time

Distribution of water for injectionDistribution of water for injection The water in the stainless steel pipes is The water in the stainless steel pipes is

constantly circulated from the tank to avoid constantly circulated from the tank to avoid stagnation and to maintain the temperature.stagnation and to maintain the temperature. Disadvantage : Although water is constantly Disadvantage : Although water is constantly

circulated, POU normally will have dead leg circulated, POU normally will have dead leg (stagnant water) which can promote (stagnant water) which can promote m/o m/o growth.growth.

Sterilised water for injectionSterilised water for injection Packed in seal container, sterile and free Packed in seal container, sterile and free

from pyrogen.from pyrogen. It use to dissolve and dilute parentral It use to dissolve and dilute parentral

preparation before administration to the preparation before administration to the patient.patient.

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PYROGENPYROGEN

Water Water –– source of pyrogen( fever source of pyrogen( fever producing substance) .producing substance) . Pyrogens must be removed from the water Pyrogens must be removed from the water

before use as water for injection.before use as water for injection. It can be achieved by distillation process.It can be achieved by distillation process. After injection water contains pyrogens can After injection water contains pyrogens can

increase body temperature. increase body temperature. Free pyrogen water describe as Free pyrogen water describe as

apyrogenicapyrogenic

Microbial Microbial pyrogenspyrogens arise from arise from components of Gramcomponents of Gram--negative and negative and positive bacterial, fungi and viruses.positive bacterial, fungi and viruses. NonNon--microbial microbial pyrogenspyrogens; steroid and ; steroid and

plasma components.plasma components. The most important The most important pyrogenpyrogen in in

pharmaceutical product is high pharmaceutical product is high molecular weight molecular weight endotoxinsendotoxins.. They are found in the outer membrane of They are found in the outer membrane of

gram negative bacteria.gram negative bacteria.

Freshly prepared parenteral products must not Freshly prepared parenteral products must not be contaminated with microorganism that could be contaminated with microorganism that could produce pyrogen.produce pyrogen.

Contaminated solutions will become more Contaminated solutions will become more pyrogenic with the passage of time.pyrogenic with the passage of time.

These products must be sterilised shortly after These products must be sterilised shortly after preparation.preparation.

Endotoxins produce significant physiological Endotoxins produce significant physiological changes when injected.changes when injected.

Their detection and elimination are very Their detection and elimination are very important for manufacturers of parenteral important for manufacturers of parenteral products.products.

Nature of EndotoxinsNature of Endotoxins Endotoxins isolated from the outer Endotoxins isolated from the outer

membranes of Gram negative membranes of Gram negative bacteria are compose of three bacteria are compose of three areas.areas. The inner region is composed of lipid The inner region is composed of lipid

A that is linked to a central A that is linked to a central polysaccharide core. polysaccharide core.

Polysaccharides core is joined to long Polysaccharides core is joined to long projections known as the Oprojections known as the O--antigenic antigenic side chains.side chains.

Lipid A responsible for most of the Lipid A responsible for most of the biological activity of endotoxin.biological activity of endotoxin.

It is not soluble in water, however, it is It is not soluble in water, however, it is joined to a core polysaccharide by an joined to a core polysaccharide by an eight carbon sugar that acts as a eight carbon sugar that acts as a solute carriers for the lipid A in solute carriers for the lipid A in aqueous solutions. aqueous solutions.

The molecular weight of endotoxin is important The molecular weight of endotoxin is important to determine the biological activity.to determine the biological activity.

In a pure aqueous solutions, endotoxin has a In a pure aqueous solutions, endotoxin has a relative molecule mass of about 10relative molecule mass of about 1066..

Equivalent to a virus RMM.Equivalent to a virus RMM. In the presence of Mg and Ca, the endotoxin In the presence of Mg and Ca, the endotoxin

form a bilayer or vesicles with diameter 0.1 form a bilayer or vesicles with diameter 0.1 micron.micron.

Can easily pass through 0.22 micron Can easily pass through 0.22 micron filter.(commonly used in parenteral product filter.(commonly used in parenteral product preparation) preparation)

Biological activity of PyrogensBiological activity of Pyrogens

The injections of endotoxins and pyrogens The injections of endotoxins and pyrogens can produce many physiological effects. can produce many physiological effects. The most important effect from parentral The most important effect from parentral

products contaminated with pyrogen is products contaminated with pyrogen is pyrogenic effect.pyrogenic effect. Lipid A directly affect the thermoregulatory Lipid A directly affect the thermoregulatory

centres in the brain.centres in the brain.

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At high dose levels of endotoxin will also:At high dose levels of endotoxin will also: Activate the coagulation system.Activate the coagulation system. Alter carbohydrate and lipid metabolism.Alter carbohydrate and lipid metabolism. Produce platelet aggregation.Produce platelet aggregation. Produce shock and ultimately death.Produce shock and ultimately death. The effect is serious. Therefore the The effect is serious. Therefore the

detection & elimination are very importantdetection & elimination are very important

NonNon--aqueous solventsaqueous solvents

Water miscible coWater miscible co--solventssolvents Glycerin and propylene glycol are use as Glycerin and propylene glycol are use as

vehicle in small volume parenteral fluids.vehicle in small volume parenteral fluids. They are use to increase solubility of drugs They are use to increase solubility of drugs

and stabilised drug from degradation and stabilised drug from degradation (hydrolysis)(hydrolysis)

Metabolizable oils are used to dissolve Metabolizable oils are used to dissolve drugs that are insoluble in water.drugs that are insoluble in water. Hormones and vitamins (IM)Hormones and vitamins (IM)

Particulate matterParticulate matter

Solutions for Solutions for parenteralparenteral use and injections with a use and injections with a volume of 100mL or more must comply with the BP volume of 100mL or more must comply with the BP test for the absence of particulate matter. test for the absence of particulate matter.

Particles >50 microns can be detected by visual Particles >50 microns can be detected by visual inspection. Examples of such particulate materials inspection. Examples of such particulate materials are cellulose, glass, rubber cores, cloth or cotton are cellulose, glass, rubber cores, cloth or cotton fibresfibres. .

Suitable filtration media for removal of particulate Suitable filtration media for removal of particulate materials are sintered glass filters or membrane materials are sintered glass filters or membrane filters with a pore size of 0.45filters with a pore size of 0.45--1.2µm. 1.2µm.

ADDITIVESADDITIVES

The purpose additive required in The purpose additive required in parenteral formulation is to produce a parenteral formulation is to produce a safe and elegant product.safe and elegant product. Antimicrobial agentsAntimicrobial agents AntioxidantsAntioxidants BuffersBuffers Tonicity adjusting agentsTonicity adjusting agents

Antimicrobial agentsAntimicrobial agents MultidoseMultidose parentralparentral product.product.

MultidoseMultidose vialsvials AA are not use in large volume injection or if the drug AA are not use in large volume injection or if the drug

formulation itself has sufficient antimicrobial activityformulation itself has sufficient antimicrobial activity MethohexitalMethohexital sodium injectionsodium injection

AA must be stable and effective in the AA must be stable and effective in the parentralparentralformulation.formulation.

AA was added to inhibit microbial growth AA was added to inhibit microbial growth ––accidently accidently contaminated during use.contaminated during use.

PrecautionsPrecautions AA are more effective in free form and their activity AA are more effective in free form and their activity

greatly reduce by interaction with components of greatly reduce by interaction with components of injection.injection.

Rubber closure can take up AA from the solutionRubber closure can take up AA from the solution

AA uptake is more on natural and AA uptake is more on natural and neoprene rubber and less with butyl neoprene rubber and less with butyl rubber closure.rubber closure.

AimsAims Small amount and effective use of AA is Small amount and effective use of AA is

necessary.necessary. AA effectiveness AA effectiveness ––challenge test with challenge test with

selected m/o.selected m/o. The test procedure in BP (2001)The test procedure in BP (2001)

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Examples of antimicrobial preservatives used in Examples of antimicrobial preservatives used in aqueous multiple dose injectionaqueous multiple dose injection

AntimicrobialAntimicrobial ConcentrationConcentrationpreservativepreservative (%w/v)(%w/v)Benzyl alcoholBenzyl alcohol 1 1 -- 22ChlorocresolChlorocresol 0.1 0.1 –– 0.30.3CresolCresol 0.25 0.25 –– 0.50.5Methyl hydroxybenzoateMethyl hydroxybenzoate 0.10.1PhenolPhenol 0.25 0.25 –– 0.60.6ThiomersalThiomersal 0.010.01

AntioxidantsAntioxidants

Many drugs easily degrade (oxidation) in aqueous Many drugs easily degrade (oxidation) in aqueous solutionsolution

Small volume of Small volume of parentralparentral product of unstable drugs product of unstable drugs in aqueous often contain antioxidant.in aqueous often contain antioxidant.

EgEg of antioxidants: of antioxidants: BisulphitesBisulphites and and metabisulphitesmetabisulphites Avoid interaction with drugs.Avoid interaction with drugs. ParenteralParenteral product also contain chelating agents; to product also contain chelating agents; to

remove trace elements which can remove trace elements which can catalysecatalyseoxidative degradation oxidative degradation egeg: EDTA or citric acid : EDTA or citric acid

BuffersBuffers The ideal pH for The ideal pH for parenteralparenteral product is 7.4product is 7.4 > pH 9; tissue necrosis> pH 9; tissue necrosis < pH 3; pain and phlebitis in tissue < pH 3; pain and phlebitis in tissue In certain cases however, acidic or alkaline solutions In certain cases however, acidic or alkaline solutions

may be needed to may be needed to solubilizesolubilize drugs. The acceptable pH drugs. The acceptable pH range is 3range is 3--9 for IV preparations and 49 for IV preparations and 4--9 for other routes 9 for other routes

The function : to maintain pH in The function : to maintain pH in parenteralparenteral products.products. Precautions : pH change can arise through interaction Precautions : pH change can arise through interaction

between the product and the container.between the product and the container. The buffer used in the injection must allow the body The buffer used in the injection must allow the body

fluid to change the product pH after injection.fluid to change the product pH after injection. EgEg of buffer used: Acetate, citrate and phosphate of buffer used: Acetate, citrate and phosphate

buffers.buffers.

TonicityTonicity--adjusting agentsadjusting agents Isotonic solution have the same osmotic Isotonic solution have the same osmotic

pressure as blood plasma and do not damage pressure as blood plasma and do not damage the membrane of red blood cellsthe membrane of red blood cells

Hypotonic solutions have a lower osmotic Hypotonic solutions have a lower osmotic pressure than blood plasma and cause blood pressure than blood plasma and cause blood cells swell and burst.cells swell and burst.

Hypertonic solutions have a higher osmotic Hypertonic solutions have a higher osmotic than plasma; as a result the red blood cells than plasma; as a result the red blood cells lose fluids and shrink.lose fluids and shrink.

BP stated : large volume infusion liquid, BP stated : large volume infusion liquid, aqueous fluid for SC,ID,IM, intra thecal aqueous fluid for SC,ID,IM, intra thecal ––must must be isotonic be isotonic

Sodium chloride, glucose, or mannitolSodium chloride, glucose, or mannitol Additive that could effect the tonicity;Additive that could effect the tonicity; Buffers and antioxidantsBuffers and antioxidants Another additive which are presence in low Another additive which are presence in low

concentration, have a little effect on the concentration, have a little effect on the tonicity.tonicity.

Isotonic solution; 0.9% NaCl.Isotonic solution; 0.9% NaCl. Freezing point depression. Freezing point depression. ––to determine to determine

required dilution required dilution

Isotonic calculationIsotonic calculation

W = 0.52-ab

W = percentage concentration of adjusting substance in the final solution

a = Freezing point depression of the unadjusted hypotonic solution

b = freezing point depression of a 1% w/v concentration of the adjusting substance

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Special InjectionSpecial Injection

Complex formulationsComplex formulations SuspensionsSuspensions Contain less than 5% of drug solid with a mean particle Contain less than 5% of drug solid with a mean particle

diameter within the range 5 diameter within the range 5 –– 10 micrometer.10 micrometer. More difficult to More difficult to sterilisedsterilised than solutionthan solution Components Components sterilisesterilise separately during separately during

manufacture, and then aseptically combined.manufacture, and then aseptically combined. The final product cannot be filter The final product cannot be filter sterilisedsterilised due to due to

the presence particle in the formulationthe presence particle in the formulation Powder can be Powder can be sterilisedsterilised by gas, but the gas by gas, but the gas

residues must be avoided.residues must be avoided.

DRIED INJECTIONDRIED INJECTION Dried powder /granules aseptically added to Dried powder /granules aseptically added to

a sterile viala sterile vial Drug reconstitute with water for injection Drug reconstitute with water for injection

before use. (make sure all of the powder before use. (make sure all of the powder dissolve before use)dissolve before use)

NONNON--AQUEOUS INJECTIONAQUEOUS INJECTION Formulated in Formulated in arachisarachis and sesame oil, which and sesame oil, which

are easily metabolizedare easily metabolized

LARGELARGE--VOLUME VOLUME PARENTRAL PRODUCTSPARENTRAL PRODUCTS Single dose injections that are administered by Single dose injections that are administered by

IV infusionIV infusion Sterile aqueous solution or emulsions with water Sterile aqueous solution or emulsions with water

for injection as the main componentfor injection as the main component Free particleFree particle During administration of this fluids additional During administration of this fluids additional

drugs are often added to the fluids.drugs are often added to the fluids. Small volume parentral productsSmall volume parentral products Small volume infusion productSmall volume infusion product

LargeLarge--volume parentral products include:volume parentral products include: Infusion fluidsInfusion fluids TPN solutionTPN solution IV antibioticsIV antibiotics PatientPatient--controlled analgesiacontrolled analgesia Dialysis fluidsDialysis fluids Irrigation solutionsIrrigation solutions

LargeLarge--volume parentrals are variously volume parentrals are variously formulated and packaged and have been use formulated and packaged and have been use to:to: Restore fluids and electrolyte imbalance in patients Restore fluids and electrolyte imbalance in patients

suffering from dehydration, shock or injurysuffering from dehydration, shock or injury Provide nutrition in circumstances where patients Provide nutrition in circumstances where patients

are malnourished, e.g. TPNare malnourished, e.g. TPN Act as a vehicle for administration of medicinesAct as a vehicle for administration of medicines Perform dialysisPerform dialysis Allow irrigation of body partsAllow irrigation of body parts

LargeLarge--volume parentrals must be terminally volume parentrals must be terminally heat sterilised.heat sterilised.

While water for injections is the main While water for injections is the main component of these products they also component of these products they also incorporate other ingredients including:incorporate other ingredients including: Carbohydrates (dextrose, sucrose and dextran)Carbohydrates (dextrose, sucrose and dextran) Amino acidsAmino acids Lipid emulsions which contain vegetable or semi Lipid emulsions which contain vegetable or semi

synthetic oilsynthetic oil Electrolytes such as sodium chlorideElectrolytes such as sodium chloride Polyols, (glycerol, sorbitol and mannitol)Polyols, (glycerol, sorbitol and mannitol)

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Most of large volume Most of large volume parentralparentral products products are clear solution, except for O/W are clear solution, except for O/W emulsions.emulsions. O/W emulsions production is specialized O/W emulsions production is specialized

as they as they destabiliseddestabilised by heat.by heat. Heat can affect droplet size of emulsionsHeat can affect droplet size of emulsions Therefore have to use other Therefore have to use other sterilazationsterilazation

methodmethod

Production of largeProduction of large--volume parentral productsvolume parentral products Manufactured in highManufactured in high--standard clean room.standard clean room. Automation filling machine system in the productionAutomation filling machine system in the production In line membrane filter (to remove particulate matter) In line membrane filter (to remove particulate matter)

before fill in the bottle (glass or plastic)before fill in the bottle (glass or plastic) After filling sealed with rubber closure crimped with After filling sealed with rubber closure crimped with

aluminiumaluminium Plastic bag aseptically filled and heat sealed or blowPlastic bag aseptically filled and heat sealed or blow--fillfill--

seal systemseal system Products are examined for particulate matter and the Products are examined for particulate matter and the

integrity of container closure established.integrity of container closure established. Moist heat should be use to Moist heat should be use to sterilisedsterilised parentralparentral products, products,

irrigation solutions and dialysis fluids wherever possible.irrigation solutions and dialysis fluids wherever possible.

Container and ClosuresContainer and Closures

Large volume parentral fluids are package Large volume parentral fluids are package into:into:

Glass bottles Glass bottles PVC collapsible bagsPVC collapsible bags SemiSemi--rigid polythene containerrigid polythene container

The containers and closures that are The containers and closures that are used for packaging parentral products used for packaging parentral products must:must: Maintain the sterility of the packaged fluidsMaintain the sterility of the packaged fluids Withstand sterilisationWithstand sterilisation Be compatible with the packed fluidBe compatible with the packed fluid Allow withdrawal of the contents.Allow withdrawal of the contents.

Type I glassType I glass Type I glass for products that have a high pHType I glass for products that have a high pH Transparent and chemically inert.Transparent and chemically inert. It can be use for drugs that incompatible with It can be use for drugs that incompatible with

plastic bags.plastic bags. Disadvantage are heavy and brittle, and also Disadvantage are heavy and brittle, and also

require an air inlet during the administration. To require an air inlet during the administration. To equal inside and outside of the bottle.equal inside and outside of the bottle.

Problem; Problem; contamination.bycontamination.by glass glass particle,pressureparticle,pressure imbalance between internal imbalance between internal and external environmentand external environment

PVC plastic bags are widely used to PVC plastic bags are widely used to package infusion fluids.package infusion fluids. They are design with a port for the They are design with a port for the

attachment of the administration set and attachment of the administration set and additive port for the addition of smalladditive port for the addition of small--volume parentral fluids.volume parentral fluids.

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PVC collapsible bags are:PVC collapsible bags are: Resistance to impactResistance to impact Flexible and collapse during fluid Flexible and collapse during fluid

administration and so do not require an air administration and so do not require an air inlet systeminlet system

The disadvantages of the plastic bags The disadvantages of the plastic bags are:are: They are a high moisture penetrationThey are a high moisture penetration They are adsorb some drugsThey are adsorb some drugs They are require and extended sterilization They are require and extended sterilization

time due to the heat resistance of the PVCtime due to the heat resistance of the PVC Moist heat sterilization requires air ballasting Moist heat sterilization requires air ballasting

to avoid pouch explosion.to avoid pouch explosion.

Semi rigid plastic containers are use for are use for 100 ml for electrolyte solutions100 ml for electrolyte solutions 3 L for TPN3 L for TPN Up to 5 L for dialysis solutionsUp to 5 L for dialysis solutions

Semi rigid plastic containers Semi rigid containersSemi rigid containers

Are more drug compatible than PVC Are more drug compatible than PVC containercontainer Are difficult to breakAre difficult to break Do not fully collapseDo not fully collapse Need extended heat sterilisationNeed extended heat sterilisation Need air equilibrationNeed air equilibration

Semi rigid are design with two ports;Semi rigid are design with two ports; One for attachment of administration setOne for attachment of administration set The other port permits the addition of The other port permits the addition of

small volume parenteral product or small small volume parenteral product or small infusion fluids.infusion fluids. Single use.Single use. They have graduated scaleThey have graduated scale

LabellingLabelling

Product identityProduct identity Solution strength in terms of the amount of Solution strength in terms of the amount of

active ingredient in a suitable doseactive ingredient in a suitable dose--volumevolume Batch number and product expiry dateBatch number and product expiry date Storage requirementsStorage requirements For TPN solutions, the name of the For TPN solutions, the name of the

patient, the unit number, ward and infusion patient, the unit number, ward and infusion rate.rate.

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LabellingLabelling

The name and concentration of any added substance The name and concentration of any added substance e.g., antioxidant, antie.g., antioxidant, anti--microbial preservative microbial preservative

• Indication that a single dose preparation should be • Indication that a single dose preparation should be discarded after first use discarded after first use

• Special • Special labellinglabelling requirements for particular product requirements for particular product e.g., powders for reconstitution prior to use, e.g., powders for reconstitution prior to use, concentrated solutions requiring dilutions prior to use concentrated solutions requiring dilutions prior to use

• The date after which the preparation is not intended • The date after which the preparation is not intended to be used to be used (expiry date) (expiry date)

• The conditions under which the preparation should be • The conditions under which the preparation should be stored stored