Hugo W.B., Russel A.D.(ed). Pharmaceutical Microbiology

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Ophthalmic preparations

Design philosophy

Medication intended for instillation on to the surface of the eye is formulated in aqueous

solution as eye-drops or lotion or in an oily base as an ointment. Because of the possibility

of eye infection occurring, particularly after abrasion or damage to the corneal surface,

all ophthalmic preparations must be sterile. Since there is a very poor blood supply to

the anterior chamber, defence against microbial invasion is minimal; furthermore, it

appears to provide a particularly good environment for growth of bacteria. As well as

being sterile, eye products should also be relatively free from particles which might

cause damage to the cornea. However, unlike aqueous injections, the recommended

vehicle is purified water since the presence of pyrogens (Chapter 1) is not clinically

significant.

Another type of sterile ophthalmic product is the contact lens solution (section

4.5); however, unlike the other types, this is not used for medication purposes but

merely as wetting, cleaning and soaking solutions for contact lenses.

Eye-drops

Eye-drops are presented for use in: (i) sterile single-dose plastic sachets containing

0.3-0.5 ml of liquid; (ii) multidose amber fluted eye-dropper bottles including the

rubber teat as part of the closed container or supplied separately (British Pharmacopoeia

1993); or (iii) plastic bottles with integral dropper. It should be covered with a

breakable seal to indicate that the dropper or cap has not been removed prior to initial

use. Although a standard design of bottle is used in hospitals, many proprietory products

are manufactured in plastic bottles designed to improve safety and care of use. The

maximum volume in each container is limited to 10 ml. Because of the likelihood of

microbial contamination of eye-dropper bottles during use (arising from repeated

opening or contact of the dropper with infected eye tissue or the hands of the patient),

it is essential to protect the product against inopportune contamination. Eye-drops for

surgical theatre use should be supplied in single-dose containers (British Pharmacopoeia

1993).

Examples of preservatives are: phenylmercuric nitrate or acetate (0.002% w/v),

chlorhexidine acetate (0.01 % w/v), thiomersal (0.01 % w/v) and benzalkonium chloride

(0.01 % w/v). Chlorocresol is too toxic to the corneal epithelium, but 8-hydroxyquinoline

and thiomersal may be used in specific instances. The principal consideration in relation

to antimicrobial properties is the activity of the bactericide against Pseudomonas

aeruginosa, a major source of serious nosocomial eye infections. Although benzal-

konium chloride is probably the most active of the recommended preservatives, it cannot

always be used because of its incompatibility with many compounds commonly used

to treat eye diseases, nor should it be used to preserve eye-drops containing anaesthetics.

Since benzalkonium chloride reacts with natural rubber, silicone or butyl rubber teats

should be substituted. Since silicone rubber is permeable to water vapour, products

should not be stored for more than 3 months after manufacture. As with all rubber

components, the rubber teat should be pre-equilibrated with the preservative prior to

Sterile pharmaceutical products 417

use. Thermostable eye-drops and lotions are sterilized at 121°C for 15 minutes. For

thermolabile drugs, filtration sterilization followed by aseptic filling into sterile

containers is necessary. Eye-drops in plastic bottles are prepared aseptically.

In order to lessen the risk of eye-drops becoming heavily contaminated either by

repeated inoculation or growth of resistant organisms in the solution, use is restricted,

after the container is first opened, to 1 month. This is usually reduced to 7 days for

hospital ward use on one eye of a single patient. The period is shorter in the hospital

environment because of the greater danger of contamination by potential pathogens,

particularly pseudomonads.

Finally, eye-drops for use during open-eye surgery must not contain a preservative

because of their cytotoxicity. Single-dose preparations are, therefore, ideally suited for

this purpose.

4.3 Eye lotions

Eye lotions are isotonic solutions used for washing or bathing the eyes. They are sterilized

in relatively large-volume containers (100ml or greater). Eye lotions are sterilized by

autoclaving in coloured fluted glass bottles with a rubber closure and screw cap, or

plastic container with screw cap or tear-off seal. They may contain a bactericide if

intended for intermittent domiciliary use for up to 7 days. If intended for first aid or

similar purposes, however, no bactericide is included and any remaining solution

discarded after 24 hours.

4.4 Eye ointments

Eye ointments are prepared in a semi-solid base (e.g. Simple Eye Ointment BP, which

consists of yellow soft paraffin, eight parts; liquid paraffin, one part; wool fat, one

part). The base is filtered when molten to remove particles and sterilized at 160°C for

2 hours. The drug is incorporated prior to sterilization if heat stable, or added aseptically

to the sterile base. Finally, the product is aseptically packed in clear sterile aluminium

or plastic tubes. Since the product contains virtually no water, the danger of bacteria

proliferating in the ointment is negligible. Therefore, there is no recommended maximum

period during which they can be used.

4.5 Contact-lens solutions

Most contact lenses are worn for optical reasons as an alternative to spectacles.

Contact lenses are of two types, namely hard lenses, which are hydrophobic, and soft

lenses, which may be either hydrophilic or hydrophobic. The surfaces of lenses must

be wetted before use, and wetting solutions (section 4.5.1) are used for this purpose.

Hard and, more especially, soft lenses become heavily contaminated with protein

material during use and must therefore be cleaned (section 4.5.2) before disinfection

(section 4.5.3). Contact lenses are potential sources of eye infection and consequently

microorganisms should be removed before the lens is again inserted into the eye.

Lenses must also be clean and easily wettable by the lacrimal secretions. Contact-lens

solutions are thus sterile solutions of the various types described below. Apart from

418 Chapter 21

achieving their stated functions, either singly or in combination, all solutions must

be non-irritating and must protect against microbial contamination during use and

storage.

4.5.1 Wetting solutions

These are used to hydrate the surfaces of hard lenses after disinfection. Since they must

also cope with chance contamination, they must contain a preservative as well as a

wetting agent. They may be isotonic with lacrimal secretions and be formulated to a

pH of about 7.2 for compatibility with normal tears.

4.5.2 Cleaning solutions

These are responsible for the removal of ocular debris and protein deposits, and contain

a cleaning agent that consists of a surfactant and/or an enzyme product. Since they

must also cope with chance contamination, they contain a preservative, are isotonic,

and have a pH of about 7.2.

4.5.3 Soaking solutions

These are responsible for disinfection of lenses but also maintain the lenses in a hydrated

state. The antimicrobial agents used for disinfecting hard lenses are those used in eye-

drops (benzalkonium, chlorhexidine, phenylmercuric acetate or nitrate, thiomersal and

chlorbutol). Ethylene diamine tetra-acetic acid (EDTA) is usually present as a synergist

(see Chapter 12). Benzalkonium chloride and chlorbutol are strongly bound to

hydrophilic soft contact lenses and therefore cannot be used in storage solutions for

these. Chlorhexidine and thiomersal are usually employed. It must be added that the

concentrations of all preservatives used in contact-lens solutions are lower than those

employed in eye-drops, in order to minimize irritancy. Hydrogen peroxide is now

becoming commonly used, but must be inactivated prior to lens insertion on to the

eye.

Finally, heat may be utilized as an alternative method to disinfect soft contact lenses,

especially the hydrophilic type. Lenses are boiled in isotonic saline.

5 Dressings

Dressings and surgical materials are used widely in medicine, both as a means of

protecting and providing comfort for wounds and for many associated activities such

as cleaning, swabbing, etc. They may or may not be used on areas of broken skin. If

there is a potential danger of infection arising from the use of a dressing then it must be

sterile. For instance, sterile dressings must be used on all open wounds, both surgical

and traumatic, on burns and during and after catheterization at a site of injection. It is

also important to appreciate that sterile dressings must be packaged in such a way that

they can be applied to the wound aseptically.

Dressings are described in the British Pharmacopoeia (1993). Methods for their

sterilization include autoclaving, dry heat, ethylene oxide and ionizing radiation. Any

Sterile pharmaceutical products 419

other effective method may be used. The choice is governed principally by the stability

of the dressing constituents to the stress applied and the nature of their components.

Most cellulosic and synthetic fibres withstand autoclaving but there are exceptions.

For instance, boric acid tenderizes cellulose fibres during autoclaving, and dressings

containing waxes cannot be sterilized by moist heat. Certain constituents are also

adversely affected on exposure to large doses of gamma-radiation. Those dressings

that are required to be sterile are listed in Table 21.1, together with other dressings and

materials that may be sterilized when required.

A very important aspect of dressings production is packaging. The packaging

material must allow correct sterilization conditions (for example permeation of moisture

or ethylene oxide), retain the dressing in a sterile condition and allow for its removal

without contamination prior to use. All dressings intended for aseptic handling and

application must be double-wrapped. For steam sterilization they may be individually

wrapped in fabric, paper or nylon and sterilized in metal drums, cardboard boxes or

bleached Kraft paper. The choice of method also determines the design of the autoclave

cycle. Dressings may be sterilized in downward displacement autoclaves, which rely

Table 21.1 Uses of surgical

Dressing

Required to be sterile

Chlorhexidine gauze

dressing

Framycetin gauze

dressing

Knitted viscose primary

dressing

Paraffin gauze dressing

Perforated film absorbent

dressing

Polyurethane foam

dressing

Semi-permeable adhesive

film

Sodium fusidate gauze

dressing

May be sterile for use in

certain circumstances

Absorbent cotton wool

Elastic adhesive dressing

Plastic wound dressings

Absorbent cotton gauze

Gauze pads

Absorbent viscose

wadding

dressings and methods of sterilization

Uses

Medicated open-wound

dressing, burns, grafts

Medicated open wound

dressing, burns, grafts

Ulcerative and granulating

wounds

Burns, scalds, grafts

Postoperative wounds

Burns, ulcers, grafts,

granulating wounds

Adhesive dressing for open

wounds, i.v. sites, stoma

care, etc.

Medicated open wound

dressing, burns, grafts

Swabbing, cleaning,

medication application

Protective wound dressing

Protective dressing

(permeable or occlusive)

Absorbent wound dressing

Swabbing, dressing, wound

packing

Wound cleaning, swabbing,

skin antiseptic application

Method of sterilization

Any combination of dry

heat, gamma-radiation

and ethylene oxide

Any method

Ethylene oxide or

gamma-radiation

Ethylene oxide or

gamma-radiation

Any method

on displacement of air by steam, or in the more modern high prevacuum autoclaves in

which virtually all the air is removed before the admission of steam. This method

ensures rapid heating-up of the dressings, reduces the time needed to achieve sterilization

(e.g. 134°C for 3 minutes) and shortens the overall sterilization cycle.

A recent development is the use of spray-on dressings. A convenient type is an

acrylic polymer dissolved in ethyl acetate and packed as an aerosol. This should be

self-sterilizing. The film after application is able to maintain the sterility of a clean

wound for up to 2 weeks. However, they can only be used on clean, relatively dry

wounds.

6 Implants

Implants are small, sterile cylinders of drug, inserted beneath the skin or into muscle

tissue to provide slow absorption and prolonged action therapy. This is principally

based on the fact that such drugs, invariably hormones, are almost insoluble in water

and yet the implant provides a rate of dissolution sufficient for a therapeutic effect. The

British Pharmacopoeia (1993) describes one implant, testosterone. The United States

National Formulary (1990) also includes oestradiol. Implants are made from the pure

drug into tablet form by compression or fusion. No other ingredient can be included

since this may be insoluble or toxic or, most importantly, may influence the rate of

drug release.

Compression of sterile drugs must be conducted under aseptic conditions using

sterile machine parts and materials. After manufacture, the outer surface of the implant

is sterilized by immersion in 0.002% w/v phenylmercuric nitrate at 75°C for 12 hours.

After the surface has been dried, each implant is placed aseptically into a sterile glass

phial with a cotton-wool plug at both ends. This prevents damage and reduces the risk

of glass spicules, formed when the phial is opened, adhering to the implant. This

compression process is not ideal. The absence of a lubricant increases the difficulties

of making tablets; the hardness of the implant is difficult to regulate, which consequently

leads to variations in the rate of drug release. The alternative method, fusion, can be

used provided the drug is heat-stable. The pure drug is melted at 5-10°C above its

melting temperature and poured into moulds. Note that if the melting temperature is

high enough the interior of the implant will automatically be sterilized by this process.

It is also possible to sterilize the implant after packaging, by dry heat, provided the

melting temperature is above 160°C. Clearly, it is easier to manufacture sterile implants

by fusion since the process does not require presterilized ingredients or aseptic

processing. The implant hardness is also very consistent.

7 Absorbable haemostats

The reduction of blood loss during or after surgical procedures where suturing or ligature

is either impractical or impossible can often be accomplished by the use of sterile,

absorbable haemostats. These consist of a soft pad of solid material packed around and

over the wound which can be left in situ, being absorbed by body tissues over a period

of time, usually up to 6 weeks. The principal mechanism of action of these is the ability

to encourage platelet fracture because of their fibrous or rough surfaces, and to act as a

Sterile pharmaceutical products 421

matrix for complete blood clotting. Four products commonly used are: oxidized

cellulose, absorbable gelatin sponge, human fibrin foam and calcium alginate.

7.1 Oxidized cellulose

This consists of cellulosic material which has been partially oxidized. White gauze is

the most common form, although lint is also used. It can be absorbed by the body in 2-

7 weeks, depending on the size. Its action is based principally on a mechanical effect

and it is used in the dry state. Since it inactivates thrombin, its activity cannot be enhanced

by thrombin incorporation.

7.2 Absorbable gelatin foam

This is an insoluble gelatin foam produced by whisking warm gelatin solution to a

uniform foam, which is then dried. It can be cut into suitable shapes, packed in metal or

paper containers and sterilized by dry heat (150°C for 1 hour). Moist heat destroys the

physical properties of the material. Immediately before use, it can be moistened with

normal saline containing thrombin. It behaves as a mechanical haemostat providing

the framework on which blood clotting can occur.

7.3 Human fibrin foam

This is a dry sponge of human fibrin prepared by clotting a foam of human fibrinogen

solution with human thrombin. It is then freeze-dried, cut into shapes and sterilized by

dry heat at 130°C for 3 hours. Before use, it is saturated with thrombin solution. Blood

coagulation occurs in contact with the thrombin in the interstices of the foam.

7.4 Calcium alginate

This is composed of the sodium and calcium salts of alginic acid formed into a powder

or fibrous material and sterilized by autoclaving. It aids clotting by forming a sodium-

calcium alginate complex in contact with tissue fluids, acting principally as a mechanical

haemostat. It is relatively slowly absorbed and some residues may occasionally remain

in the tissues.

8 Surgical ligatures and sutures

The use of strands of material to tie off blood or other vessels (ligature) and to stitch

wounds (suture) is an essential part of surgery. Both absorbable and non-absorbable

materials are available for this purpose.

8.1 Sterilized surgical catgut

This consists of absorbable strands of collagen derived from mammalian tissue,

particularly the intestine of sheep. Because of its source, it is particularly prone to

bacterial contamination, and even anaerobic spores may be found in such material.

422 Chapter 21

Therefore, sterilization is a particularly difficult process. Since collagen is converted

to gelatin when exposed to moist heat, autoclaving cannot be used. The official method

is to pack the 'plain' catgut strands (up to 350 cm) on a metal spindle in a glass or other

suitable container with a tubing fluid, the purpose of which is to maintain both flexibility

and tensile strength after sterilization. Probably the most suitable method is to expose

the material to gamma-radiation. There is minimal loss of tensile strength and the

container can be overwrapped prior to sterilization to provide a sterile container surface

for opening aseptically. The alternative method involves placing the coiled suture

immersed in a tubing fluid (commonly 96% ethyl alcohol with or without 0.002% w/v

phenylmercuric nitrate) and stored for sufficient time to ensure sterilization. The outer

surface of the phial must be sterilized before opening to avoid contamination of the

suture when removed. Therefore, the phial is immersed in 1% w/v formaldehyde in

ethanol for 24 hours prior to use. It cannot be heated. A non-official method of

sterilization is to immerse the catgut in a non-aqueous solvent (naphthalene or toluene)

and heat at 160°C for 2 hours. The catgut becomes hard and brittle during this process,

and is aseptically transferred to an aqueous tubing fluid to restore its flexibility and

tensile strength.

Catgut is packed in single threads, up to 350 cm in length, of various thicknesses

related to tensile strength, in single-use glass or plastic containers which cannot be

resealed after use. Any remaining material should be discarded. Hardened catgut is

prepared by treating strands with certain agents to prolong resistance to digestion. If

hardened with chromium compounds, the material is known as 'chromicized' catgut.

Non-absorbable types

Sutures and ligatures are also made from many materials not absorbed by the body

tissues. These consist of uniform strands of metal or organic material which will not

cause any tissue reactions and are capable of sterilization. Depending on the physical

stability of each material, they are preferably sterilized by autoclaving or gamma-

radiation. They are packed in single-use glass or plastic containers which may contain

a tubing fluid with or without a bactericide. The different materials are described in the

British Pharmacopoeia (1993). These include linen (adversely affected by gamma-

rays), nylon (either monofilament or plaited), silk and stainless steel (monofilament or

twisted).

Instruments and equipment

The method chosen for sterilization of instruments (see also Table 21.2) depends on

the nature of the components and the design of the item. The wide range of instruments

that may be required in a sterile condition includes syringes (glass and plastic disposable),

needles, giving sets, metal surgical instruments (scalpels, scissors, forceps, etc.), rubber

gloves, catheters, etc. Relatively complicated equipment, such as pressure transducers,

pacemakers, kidney dialysis equipment, incubators and aerosol machine parts may

also be sterilized. Artificial joints could also be included in the vast range of items

required in modern medical practice in a sterile condition. The choice of method depends

largely on the physical stability of the items and the appropriate technique in particular

Sterile pharmaceutical products 423

Table 21.2 Methods* commonly used to sterilize or disinfect equipment

Equipment

Syringes (glass)

Syringes (glass),

dismantled

Syringes

(disposable)

Needles (all

metal)

Needles

(disposable)

Metal

instruments

(including

scalpels)

Disposable

instruments

Rubber gloves

Administration

(giving) sets

Respirator

parts

Dialysis

machines

Fragile, heat-

sensitive

equipment

Method of

treatment

Dry heat

Moist heat

Gamma-radiation

Ethylene oxide

Dry heat

Gamma-radiation

Ethylene oxide

Autoclave

Dry heat

Gamma-radiation

Ethylene oxide

Autoclave

Gamma-radiation

Ethylene

oxide

Gamma-radiation

Ethylene oxide

Moist heat

(autoclave)

Moist heat

(low-

temperature

steam, or hot

water at

80°C)

Chemical

Ethylene oxide

Chemical

Disinfection or

sterilization

Sterilization

Disinfection

Sterilization

Disinfection

Preferred

method

Dry heat using

assembled

syringes

Gamma-radiation

Dry heat

Gamma-radiation

Dry heat

Gamma-radiation

Sterilization by

steam where

possible

Formalin

Ethylene oxide

under expert

supervision

Comments

Autoclave not recommended:

difficulty with steam

penetration unless plungers

and barrels sterilized

separately

Possibility of 'crazing' of

syringes after ethylene oxide

Cutting edges should be

protected from mechanical

damage during the process

If autoclave used, care with

drying at end of process.

Little oxidative degradation

when high-vacuum autoclave

used

Chemicals not recommended:

may be microbiplogically

ineffective, may present

hazard to patient safety by

compromising the safety

devices on the machine

Ethylene oxide not

recommended in NHS for

practical reasons

*1 Disposable equipment should not be resterilized or re-used.

2 Ethylene oxide is a difficult process to control, and the Department of Health discourages its use in hospitals.

3 Low-temperature steam with formaldehyde is of value in the disinfection/sterilization of some heat-sensitive materials

(see also Chapter 20).

4 Chemical agents, e.g. glutaraldehyde, hypochlorite.

424 Chapter 21

situations. For instance, incubators necessitate a chemical method of sterilization. On

the other hand, even delicate instruments like pressure transducers are now available

that can withstand autoclaving. This is a new and developing field of medical technology

in which many factors may have to be considered before the choice is made as to the

most appropriate method of sterilization in any particular situation.

10 Further reading

Allwood M.C. (1990) Package design and product integrity. In: Guide to Microbiological Control in

Pharmaceuticals (eds S. Denyer & R. Baird), pp. 341-355. Chichester: Ellis Horwood.

Allwood M.C. (1990) Adverse reactions to parenterals. In: Topics in Pharmacy: Formulation Factors

in Adverse Reactions (eds A.T. Florence & A.G. Salole). London: Wright.

British Pharmacopoeia (1993) and Addenda. London: HMSO.

Denyer S. & Baird R. (eds) (1990) Guide to Microbiological Control in Pharmaceuticals. London:

Ellis Horwood.

Pharmaceutical Codex (1993) London: Pharmaceutical Press.

European Pharmacopoeia (1997) 3rd edn. Strasbourg: Council of Europe.

Phillips I., Meers P.D. & D'Arcy P.F. (1976) Microbiological Hazards of Infusion Therapy. Lancaster:

MTP Press.

Russell A.D., Hugo W.B. & Ayliffe G.A.J. (1998) Principles and Practice of Disinfection, Preservation

and Sterilization, 3rd edn. Oxford: Blackwell Science.

Turco S. & Young R.E. (1987) Sterile Dosage Forms, 3rd edn. Easton, Philadelphia: Lea and Febiger.

United States Pharmacopoeia (1995) 23rd revision. Rockville, MD: US Pharmacopoeia Convention.

Sterile pharmaceutical products 425

Factory and hospital hygiene and

good manufacturing practice

1.1

1.1.1

1.1.2

1.1.3

1.1.4

1.1.5

2.1

2.2

2.3

2.4

2.5

3.1

3.1.1

Introduction

Definitions

Manufacture

Quality assurance

Good manufacturing practice (GMP)

Quality control

In-process control

Control of microbial contamination

during manufacture: general aspects

Environmental cleanliness and hygiene

Quality of starting materials

Process design

Quality control and documentation

Packaging, storage and transport

Manufacture of sterile products

Clean and aseptic areas: general

requirements

Design of premises

3.1.2

3.1.3

3.1.4

3.1.5

3.1.6

3.1.7

3.1.8

3.2

3.2.1

3.2.2

3.2.3

3.2.4

Internal surfaces, fittings and

equipment

Services

Air supply

Clothing

Changing facilities

Cleaning and disinfection

Operation

Aseptic areas: additional requirements

Clothing

Entry to aseptic areas

Equipment and operation

Isolator and blow/fill/seal technology

Guide to Good Pharmaceutical

Manufacturing Practice

Conclusions