Sterile ions

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Sterile preparations

STERILE PHARMACEUTICALS

1. PARENTERALS

Parenteral products are products that are administered to the body by injection.

Because this route of administration bypasses the normal body defencemechanisms, it is essential that these products are prepared with a higher degreeof care and skills than utilised in preparing conventional oral or topical products.The finished product must be sterile, non-pyrogenic and free from extraneousinsoluble materials. These products must satisfy a number of requirements forparenteral products.

Formulation of Parenteral products

Sterile formulations must meet a number of special criteria such as:a. Sterility

b. Particulate materialc. Pyrogen freed. Stabilitye. pHf. Osmotic pressure

During the formulation of parenteral products, the following factors are critical:(a) The vehicle in which the drug is dissolved or dispersed(b) Volume (dose) of the injection(c) Adjustment to isotonicity(d) Adjustment of pH(e) Stabilisers(f) Preservatives(g) Adjustment of specific gravity (for spinal anaesthesia)(h) Concentration units

The formulation of injections are not different to the formulation of products byother routes except for certain requirements which parenteral products mustsatisfy. The major ones are limits to the level of pyrogens present and ofparticulate matter. For formulation of injections, the injection route dictates thevolume of the formulation. Hence the solubility of the drug in the selected vehicle iscritical in the formulation. The preferred vehicle is water as it is well tolerated bythe body, is easy to administer and has a large solvent capacity. Due to the widevariety of contaminants in mains water, water for injections must be used as thevehicle for parenteral products. Water for injections (WFI) must be sterile and freefrom pyrogens.

Solutions for parenteral use and injections with a volume of 100mL or more mustcomply with the BP test for the absence of particulate matter. Particles >50

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microns can be detected by visual inspection. Examples of such particulatematerials are cellulose, glass, rubber cores, cloth or cotton fibres.Suitable filtration media for removal of particulate materials are sintered glass

filters or membrane filters with a pore size of 0.45-1.2m.

As parenteral formulations are administered directly to tissues and systemiccirculation, formulations prepared should not vary significantly from physiologicalpH, which is about 7.4. In certain cases however, acidic or alkaline solutions maybe needed to solubilize drugs. The acceptable pH range is 3-10.5 for IVpreparations and 4-9 for other routes. Buffers are included in injections to maintainthe pH of the packaged product. However, the buffer used in the injection mustallow the body fluids to change the product pH after injection. Acetate, citrate andphosphate buffers are commonly used in parenteral products.

The osmotic pressure of blood is approximately 300 milliOsmoles/L and ideally anysterile solution would be formulated to have the same osmolarity e.g., 0.9%

w/v

Sodium Chloride iv solution has an osmolarity of 308 mOsmole/L and 5%

w

/vDextrose iv solution has an osmolarity of 280 mOsmol/L. Intravenous solutions thathave larger osmolarity values (hypertonic) or smaller osmolarity values (hypotonic)may cause damage to red blood cells, pain, and tissue irritation. Parenteralsolutions which are hypotonic need to be adjusted to isotonicity. Osmolarityadjustment is made usually by using sodium chloride, glucose or mannitol usingone of the following methods;

The freezing point depression method

Sodium chloride equivalent

Molar concentrations

Serum osmolarity

Adjustment of tonicity using the Freezing Point DepressionInjection solutions are often made isotonic with 0.9% w/v sodium chloride solutions.The amount of solute, to the required dilution necessary to make a solutionisotonic, can be determined from the freezing point depression. The freezing pointdepression of blood plasma and tears is 0.52C. Thus solutions which freeze at 0.52C have the same osmotic pressure as body fluids. Hypotonic solutions havea freezing point depression higher than 0.52C and require the addition of asolute to depress the freezing point to 0.52C.

The amount of adjusting substance added to these solutions may be calculatedfrom the equation:

W = 0.52 - ab

where:

W = percentage concentration of adjusting substance in the

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final solutiona = freezing point depression of the unadjusted hypotonic

solutionb = freezing point depression of a 1% w/v concentration of

the adjusting substance

A list of freezing point depression values is detailed in Table 6, page 53 of thePharmaceutical Codex.

Note: that some components of injections, such as buffers and antioxidants, affectthe tonicity and these have to be accounted for when adjusting the tonicity ofparenteral formulations. Other components, such as preservatives, which arepresent in low concentration, have little effect on the tonicity.

Antimicrobial agents

Aqueous preparations which are prepared using aseptic precautions and which

cannot be terminally sterilised may contain a suitable antimicrobial preservative inan appropriate concentration. No antimicrobial preservative is added when:

The volume to be injected in a single dose exceeds 15mL unless otherwisejustified

The preparation is intended for administration by routes where for medicalreasons an antimicrobial preservative is not acceptable

If the drug formulation itself has sufficient antimicrobial activity

Antimicrobial agents are added to multiple dose vials to inhibit the growth ofmicrobial organisms which may occur accidentally and contaminate the productduring use. The antimicrobial agents selected must be stable and effective in theparenteral formulation. Because they are effective in the free form, their activitycan be greatly reduced by interaction with components of the injection. Rubberclosures have been shown to take up antimicrobial preservatives from the injectionsolution.

The effectiveness of antimicrobial agents can be tested by challenging the productwith selected organisms. The test procedure will evaluate the antimicrobial activityof the preservative in the packaged product (refer BP 1998).

Table 1 lists anti-microbial agents commonly utilised in parenteral formulations

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Table 1: Commonly utilised anti-microbial agents in parenteralpreparations

Anti-microbial agent Concentration used (% w/v)

Benzalkonium Chloride* 0.01

Benzyl alcohol 1-2

Chlorobutol 0.25-0.5

Phenol 0.5

Chlorocresol 0.1-0.3

Phenylmercuric salts 0.002

Methylhydroxybenzoate 0.1-0.2

Antioxidants

Many drugs in aqueous solutions are easily degraded by oxidation. Small volumeparenteral containing these drugs often contain an antioxidant. Bisulphites andmetabisulphites are the commonly used antioxidants in aqueous injections.Antioxidants must be carefully selected for use in injections to avoid interactionwith the active. Antioxidants have a lower oxidation potential than the active and

hence are either preferentially oxidized or block oxidative chain reactions. Injectionformulations may, in addition also contain chelating agents, such as EDTA or citricacid, to remove trace elements, which catalyse oxidative degradation.

SINGLE DOSE PREPARATIONS

The British Pharmacopoeia (B.P.) 1998 define single dose preparations as:The volume of the injection in a single dose container is sufficient to permit thewithdrawal and administration of the nominal dose using a normal technique.

MULTIPLE DOSE PREPARATIONS (BP 2004)

Multidose preparations are multidose aqueous injections which contain a suitableantimicrobial preservative at an appropriate concentration except when thepreparation itself has adequate antimicrobial properties.

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CONTAINERS

Containers for parenteral products are produced from one of 3 types of glass orfrom one of a variety of plastic materials.

Types of glass

Type I: Commonly known as neutral glass. It has a high resistance to hydrolysisand withstands autoclaving, weathering and solution of pH of up to 8.

Type II (sulphated glass): Containers may be treated with moist sulphur dioxideat high temperature to create a neutral surface film with high hydrolytic resistance.Lower resistance to autoclaving than for type I glass.

Type III (soda glass): This offers very little resistance to hydrolysis and shouldonly be used for powders for reconstitution prior to injection and for non aqueous

preparations.

Type II and Type III glass containers should be used once only for parenteralpreparations.

Types of containers

Glass ampoules (Fig. 1(a)) are the most commonly used single dose containersand can range from sizes of 1 to 50mL. For aqueous solutions, neutral glass isused. After filling, glass ampoules are sealed by fusion of the glass and hencethere is no danger of entry of micro-organisms. Amber glass ampoules areavailable for light sensitive products. Clear ampoules may be used provided thatthe ampoules are packaged in a light-resistant box.

Glass vials sealed by rubber closures (Fig. 2(b)) are commonly used as multi-dosecontainers. The rubber closure is held in place by an aluminium sealing ring. Therubber closure permits the penetration of a syringe needle to allow the withdrawalof a dose of injection.

Filling and hand sealing of glass ampoules

Ampoules must first be rinsed out using water for injections to remove any dust,particulate matter and/ or glass fragments. Using a syringe, gently draw the volumerequired to be filled plus an excess volume. Invert the syringe to allow the air torise towards the needle and push up the plunger to remove all air. Attach themembrane filter and needle to the syringe (Fig. 1(c)). Discard the first 0.5-1mL offiltrate. Invert the ampoule over the needle and expel the required volume of liquidinto the ampoule taking care not to splash the liquid into the neck of the ampoule.

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Each ampoule must also contain a slight excess volume of product. This isnecessary to allow the nominal injection volume to be drawn into a syringe. Referto table 1 for excess volumes required.

Using a twin-jet burner (Fig. 2), adjust the platform height and flame intensity. Tryan empty ampoule first before sealing your products. Position the ampoulebetween the flames. Grip the end of the neck with a blunt-nosed forceps and whenthe glass is soft enough, pull off the top of the ampoule vertically and gently. Leavethe tip in the flame for a second or two longer and then remove. The tip should nowbe smoothly and evenly rounded (Fig. 3a) Ampoules should have a reliable sealwhich can be readily leak tested. A good seal will not deteriorate during thelifetime of the product.

Filling and hand sealing of glass vials

Glass vials are filled using the same rinsing and filling procedure as for ampoules.In the case of vials containing a fixed number of dose units, an excess volumeis required to allow the stated number of doses to be withdrawn (Table 2). Vials aresealed using rubber closures which are held in place by an aluminium sealing. Ahand crimper is available in the laboratory to seal the rubber closures andaluminium sealing onto the vials.

INSPECTION OF FILLED INJECTABLE PRODUCTS

Injection ampoules and vials should be checked for defects, cracks, chips, damageto the seals and closures. Injection solutions when examined under suitableconditions of visibility should be free from particles. BP1998 Appendix XIII A & Bdescribes tests for particulate contamination.

STORAGE AND LABELLING

Previously ampoules were labelled by use of paper labels. Presently this has beensuperseded by direct printing on the glass. For dispensing purposes in thepractical lab, a paper label is used and should contain the following information.

The strength expressed in terms of the amount of active ingredient in asuitable dose volume

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

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

Special labelling requirements for particular product e.g., powders forreconstitution prior to use, concentrated solutions requiring dilutions prior touse

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

The conditions under which the preparation should be stored

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Note: In practice, the expiry date should be determined for each product byconducting suitable stability studies. In hospital, sterile preparations are often givenan expiry date of 1 week from date of manufacture/ reconstitution.

Units of concentration

The concentration of the components in parenteral products may be expressed invarious ways:

Percentage weight/volume. Examples include: Magnesium sulphateinjection 50%w/v, sodium chloride intravenous infusion 0.9% w/v

Weight per unit volume. Examples include: Atropine sulphate 600g/mlor ephedrine hydrochloride injection 30mg/ml

Millimoles per unit volume. Examples include: Potassium chloridesolution, strong (sterile) contains 2mmol each of K+and Cl

- per ml; Calciumchloride injection BP contains 2.5 mmol of Ca2+and 10mmol of Cl

- in 5ml.

ESSENTIAL READING B. P. 1998/2004

The Pharmaceutical Codex

Pharmaceutical Dosage Forms and Drug Delivery Systems, H C Ansel, LV Allen Jr and N G Popovich

Fig. 1 (a) Fig. 1 (b) Fig. 1(c)

glass ampoule Multi dose glass vial Syringe with membranefilter and needle attachment

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Fig. 2 Twin jet burner

Fig. 3 sealed ampoules with good seal (a) and faulty seals (b-e)

Table 2: Recommended overages for official injectable products

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2. OPHTHALMIC PREPARATIONS

Ophthalmic preparations are sterile, liquid, semi-solid or solid preparationsintended for administration upon the eyeball and/or to the conjunctiva or to beinserted in the conjunctival sac. Several categories of eye preparations may be

distinguished:-eye drops-eye lotions-semi-solid eye preparations-ophthalmic inserts

PREPARATION OF EYE DROPS

Extemporaneous preparation of eye drops involves the following:

Preparation of the solution Clarification Filling and sterilization

Preparation of the solution

The aqueous eye drop vehicle containing any necessary preservative, antioxidant,stabilizer, tonicity modifier, viscosity modifier or buffer should be prepared first.Then the active ingredient is added and the vehicle made up to volume.

Clarification

The BP has stringent requirements for the absence of particulate matter in eyedrop solutions. Sintered glass filters or membrane filters of 0.45 1.2 m poresizes are suitable. The clarified solution is either filled directly into the finalcontainers which are sealed prior to heat sterilization or filled into a suitablecontainer prior to filtration sterilization. Clarified vehicle is used to prepare eyedrop suspensions which are filled into final containers and sealed prior tosterilization.

Sterilization

This can take the form of:

Autoclaving at 115C for 30 minutes or 121C for 15 minutes Heating at 98 - 100C for 30 minutes together with either benzalkonium

chloride 0.01% w/v or chlorhexidine acetate 0.01% w/v or phenylmercuricacetate or nitrate 0.002% w/v or thiomersal 0.01% w/v. This method isdescribed in the BP (1980) but is no longer a pharmacopoeialrecommended method.

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Filtration through a membrane filter having a 0.22m pore size into sterilecontainers using strict aseptic technique. Filling should take place underGrade A laminar airflow conditions. A suitable filter holder forextemporaneous preparation is illustrated in Figure 4. The filter assembly issterilized by autoclaving before use.

Dry heat sterilization at 160C for 2 hours is employed for non-aqueouspreparations such as liquid paraffin eye drops. Silicone rubber teats mustbe used.

Immediately following sterilization the eye drop containers must be converted withreadily breakable seal, such as a viskring, to distinguish between opened andunopened containers.

Fig. 4: Filter holders for bacterial filters(A) 13mm and 25mm types fitted to syringes(B) Cutaway view of 25mm type

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Labelling requirements are summarised in Tables 3 and 4

Table 3: General Labelling requirements for eye drop containers

Requirement Include on labelFully identify the product Title;either name and concentration ofactive ingredients or reference toofficial monograph giving thesedetails. If monograph allows morethan one concentration then state theone used

Specify storage conditions Store in a cool place or Protectfrom light

State product expiry date Month and year of expiry

Warning label Not to be taken

Specify volume e.g. 5mLEnsure correct use e.g. Shake the bottle for a

suspension

Table 4: Additional labelling requirements for use in specific locations

All locations Include concentration of active ingredient and name andconcentration of any antimicrobial present

HospitalWards

OperatingTheatres

Clinics

Patients name. The eye to be treated. Date of opening ofbottle and/or date to discard

Single dose for once-only use. Marked with indication andconcentration of active ingredient. No preservative. Outerpackage fully labelled

Single dose or multidose used once only

Domiciliary Avoid contamination of contents during useDiscard 4 weeks after openingKeep out of reach of childrenPlus instructions on how to use

PREPARATION OF EYE LOTIONS

The purpose of eye lotions is to assist in the cleaning of the external surfaces ofthe eye. This might be to help remove a non-impacted foreign body or to cleanaway conjunctival discharge. Eye lotions intended for use in surgical or first-aidprocedures should not contain antimicrobial preservatives and should be in single-use containers. There is no intention to use an eye lotion to deliver any activeingredient to the eye but rather to remove unwanted gross contaminants from the

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eye. Thus these preparations should be very simple and the most common eyelotion consists of sterile normal saline. This preparation typifies the requirements ofan eye lotion which are:

Sterile and usually containing no preservative

Isotonic with lachrymal fluid Neutral pH Large volume but not greater than 200mL Non-irritant to ocular tissue

Labelling

These should include:

Title identifying the product and concentration of contents Sterile until opened

Not to be taken Use once and discard remaining solution Expiry date

Preserved eye lotion would need the additional labelling:

Avoid contamination of contents during use Discard remaining solutions not more than 4 weeks after first opening

The lotions should be supplied in coloured fluted bottles and sealed to excludemicroorganisms.

PREPARATION OF EYE OINTMENTS

Eye ointments are popular and duplicate many of the therapeutic options offeredby eye drops. Ointments have the disadvantage of temporarily interfering withvision, but have the advantage over liquids of providing greater total drugbioavailability. However, ointments take a longer time to reach peak absorption.

Eye ointments must be sterile and may contain suitable antimicrobialpreservatives, antioxidants and stabilizers. USP ophthalmic ointments packagedin multi-dose containers are to contain an antimicrobial substance unless otherwise

directed in the monograph or if the formulation itself is bacteriostatic. The mostcommonly used agents include the two mercurials, phenylmercuric nitrate andthiomersal, the parabens and chlorobutanol. It is necessary also that suchointments are free from particulate matter that could be harmful to the tissues ofthe eye. The EP and BP have limits for the particle size of incorporated solidswhich will be met if all particles have been reduced to


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The basic components of an eye ointment are given below:

Liquid paraffin 1 part Wool fat 1 part (to facilitate incorporation of water) Yellow soft paraffin 8 parts

Hard paraffin as required to produce required consistency in hot climates

Preparation of eye ointments

Eye ointments are normally prepared using aseptic techniques to incorporate thefinely powdered active ingredient or a sterilized concentrated solution of themedicament into the sterile eye ointment basis. Immediately after preparation theeye ointment is filled into the sterile containers which are then sealed so as toexclude microorganisms. The screw cap should be covered with a readilybreakable seal.

All apparatus used in the preparation of eye ointments must be scrupulously cleanand sterile.

Certain commercial eye ointments may be sterilized in their final containers usingionising radiation.

Preparation of eye ointment basis

The paraffins and the wool fat are heated together and filtered, while molten,through a coarse filter paper in a heated funnel into a container which canwithstand dry heat sterilization temperatures. The container is closed to exclude

microorganisms and together with contents is maintained at 160C for 2 hours.

Containers for eye ointments

Eye ointments should be supplied in small sterilized collapsible tubes made ofmetal or in a suitable plastic. The tube should not contain more than 5g ofpreparation and must be fitted or provided with a nozzle of a suitable shape tofacilitate application to the eye and surrounds without allowing contamination of thecontents. The tubes must be suitably sealed to prevent microbial contamination.Eye ointment may also be packed in suitably designed single-dose containers.

Labelling

This includes the following:

The names and percentages of the active ingredients The date after which the eye ointment is not intended to be used

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The conditions under which the eye ointment should be stored normally ata temperature not exceeding 25C

The name and concentration of any antimicrobial preservative or othersubstance added to the preparation

A statement to the effect that the contents are sterile providing the container

has not been opened

Essential Reading

BP 1998 Section on Eye Preparations page 1428-1431

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Sterile ions

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