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`PHARMACEUTICAL PACKAGING TECHNOLOGY
`PHARMACEUTICAL PACKAGING TECHNOLOGY
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`PHARMACEUTICAL PACKAGING
`TECHNOLOGY
`
`Edited by
`
`D.A.Dean
`Packaging Consultancy, Education and Training, Nottingham, UK
`
`E.R.Evans
`Pharmaceutical Quality Assurance Consultant, Wiltshire, UK
`
`I.H.Hall
`Packaging Consultant for Pharmaceuticals and Security,
`Buckinghamshire, UK
`
`London and New York
`
`

`
`First published 2000 by Taylor & Francis
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`Simultaneously published in the USA and Canada by Taylor & Francis,
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`Taylor & Francis is an imprint of the Taylor & Francis Group
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`© 2000 Taylor & Francis
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`known or hereafter invented, including photocopying and recording, or in
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`from the publishers.
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`Every effort has been made to ensure that the advice and information in this
`book is true and accurate at the time of going to press. However, neither the
`publisher nor the authors can accept any legal responsibility or liability for
`any errors or omissions that may be made. In the case of drug
`administration, any medical procedure or the use of technical equipment
`mentioned within this book, you are strongly advised to consult the
`manufacturer’s guidelines.
`
`British Library Cataloguing in Publication Data
`A catalogue record for this book is available from the British Library
`
`Library of Congress Cataloging in Publication Data
`Pharmaceutical packaging technology/edited by D.A.Dean, R.Evans, I.Hall.
`p.; cm.
`Includes bibliographical references and index.
`
`ISBN 0-203-30181-1 Master e-book ISBN
`
`ISBN 0-203-34225-9 (Adobe eReader Format)
`ISBN 0-7484-0440-6 (hardback)
`
`1. Drugs—Packaging. I. Dean, D.A. (Dixie A.), 1923—II. Evans, R. (Roy) III. Hall, I. (Ian)
`[DNLM: 1. Drug Packaging. 2. Technology, Pharmaceutical. QV 825 P536 2000]
`RS159.5 .P495 2000
`615’.8–dc21
`99–051910
`
`

`
`CONTENTS
`
` Contributors
` Preface
` Technical editor’s note
`
`4
`
`1 An introduction to pharmaceutical packaging
`D.A.DEAN
`2 The packaging function: management, development and product shelf life
`D.A.DEAN
`3 Regulatory aspects of pharmaceutical packaging
`J.GLASBY
`Specifications and quality
`E.R.EVANS
`5 Paper- and board-based packaging materials and their use in pack security systems
`I.H.HALL
`6 Glass containers
`D.A.DEAN
`7 PlasticsÐan introduction
`D.A.DEAN
`8 Development and approval of a plastic pack
`D.A.DEAN
`9 Films, foils and laminations (combination materials)
`D.A.DEAN
`10 Metal containers
`P.L.CORBYD.A.DEAN
`11 Closures and closure systems
`D.A.DEAN
`Sterile products and the role of rubber components
`N.FRAMPTOND.A.DEAN
`13 Blister, strip and sachet packaging
`D.A.DEAN
`14 The packaging line
`I.H.HALL
`15 Warehousing, handling and distribution
`I.H.HALL
`16 Printing and decoration
`D.A.DEAN
`17 Present and future trends
`D.A.DEAN
`
`12
`
` vii
`
` viii
`
` viii
`
` 1
`
` 24
`
` 50
`
` 73
`
` 106
`
` 147
`
` 185
`
` 229
`
` 258
`
` 285
`
` 311
`
` 345
`
` 363
`
` 385
`
` 398
`
` 411
`
` 434
`
`

`
`12
`STERILE PRODUCTS AND THE ROLE OF RUBBER COMPONENTS
`N.Frampton and D.A.Dean
`
`Introduction
`
`The selection of the appropriate packaging materials and processes for sterile products presents a series of challenges of
`considerably greater complexity than for non-sterile products. A sterile product may be defined as a product which is totally
`devoid of all forms of life, both vegetative and sporing. Most important in this area is contamination by bacteria, fungi or moulds
`and yeasts. In all pharmaceutical products it is also becoming highly desirable to work towards much lower bioburdens. This
`involves the application of microbiological standards to both raw materials and finished products. These normally exclude
`certain pathogens such as Salmonella typhi and Clostridium botulinum, but it should be noted that even some non-pathogens
`can also cause problems.
`In order to limit or exclude microbiological contamination in pharmaceutical products, a number of approaches are
`possible:
`
`1 rigid (microbiological) specifications for all raw materials (especially water) and how they are ‘packed and stored’
`2 strict adherence to the code of good manufacturing practice (GMP) (facilities, personnel, procedures and documentation)
`3 use of special processing techniques, e.g. control of air quality, dedicated positive pressure production areas
`4 use of antimicrobial preservatives (where acceptable) which are essential to most multi-dose forms of product
`5 use of a sterilisation process which may involve a terminal sterilisation or an aseptic process
`6 the selection of the appropriate form of packaging, noting the advantages of certain (unpreserved sterile) forms of unit
`dose.
`
`Various guidelines, including those on general or current GMP (CGMP), are available related to specific aspects of the above
`from both official organisations, such as the FDA, and specialised societies such as the UK-based Parenteral Society and the
`US-based PDA.
`A terminal sterilisation process usually involves the filling and closing of product containers under conditions of a high-
`quality (low bioburden/particulate) environment where the product, container and closure are usually also of high
`microbiological quality but not sterile. This is followed by a final complete sterilisation process. In an aseptic processing
`operation, the drug product, container and closure are subjected to separate sterilisation processes and then brought together.
`Since maintenance of sterility relies on the processing, compliance with high standards is critical to any aseptic operation.
`Each function therefore requires thorough validation and control at every stage of the process.
`Antimicrobial preservatives can be added to many pharmaceutical products in order to give protection against microbial
`contamination. A wide range of preservatives is summarised in Table 12.1. It should be noted that preservatives should not be
`regarded as protection against poor processing techniques but as a means of minimising bioburden during poor storage and
`usage.
`There are a number of official tests for preservative challenge, i.e. preservative efficacy challenge tests, which can be found
`in the British Pharmacopoeia (BP), United States Pharmacopeia (USP), and European Pharmacopoeia (EP). There also are ‘in
`house’ challenges which may be more rigorous than the compendial tests.
`Since preservative efficacy may vary according to the product, analysis of preservative content often has to be supported by
`a preservative challenge test. This may also be relevant with certain emulsion systems where the preservative may partition
`between the different oil and water phases. For simple distribution phenomena, the partition or distribution law normally
`applies.
`Because of problems which include toxic hazards and sensitisation, some preservatives are under suspicion, while others
`have been withdrawn from use. This has often encouraged the use of non-preserved sterile unit dose presentations.
`Preservatives have also suffered from absorption, adsorption and, where soluble and volatile, subsequent loss by evaporation.
`
`

`
`346
`
`STERILE PRODUCTS AND RUBBER
`
`For example, preservatives suffering from adsorption include phenyl mercuric nitrate and acetate; benzalkonium chloride;
`thiomersal. Preservatives suffering from absorption include phenol; chlorocresol; cresol; and 2 phenyl ethanol.
`These preservatives have a solubility in certain rubbers and plastics and will continuously diffuse through the polymeric
`matrix due to their volatile nature. These
`
`Table 12.1 Antimicrobial preservatives
`
`Substance
`
`Phenyl mercuric nitrate
`(PMN) and acetate (PMA)
`Benzalkonium chloride
`Ethanol
`Benzoic acid
`Parabens
`Chlorhexidine
`2 Phenyl-ethanol
`Thiomersal
`Phenol
`Cresol
`Chlorocresol
`Benzyl Alcohol
`Bronopol
`
`Approx. % used
`
`Comments
`
`0.002
`
`0.01
`15.0
`0.1–0.5
`0.1–0.2
`0.01
`0.4
`0.1–0.2
`0.5
`0.3
`0.1
`1.0
`0.02–0.05
`
`Various usages but mercurials queried
`
`Oral, ophthalmic, topicals
`Oral, topicals
`Oral, topicals
`Creams, mixtures
`Eye products
`Eye products
`Eye/nasal products
`Certain multidose injections
`
`Creams
`
` problems illustrate the view that sterile products generally put greater stress on all packaging materials. Thermal processing
`can cause physical changes to plastics, glass and multilayer materials, as well as the increased potential of interaction,
`exchange and extraction. Thermal defects may arise from differential expansion and contraction, as well as instant or delayed
`cracking of glass-based materials due to the effects of thermal shock.
`Interaction between product and pack may involve:
`
`• surface interactions
`• leaching or migration of material from the pack into the product
`• loss of constituents in the product into the pack, i.e. container or closure.
`
`The history of injectables
`
`Injectable products are sterile liquid drug preparations that are administered parenterally, i.e. introduced into the patient’s
`body through the skin. Although injections are a relatively recent form of therapy, the history of the development of the
`technique can be traced back to the early seventeenth century. William Harvey described the circulation of blood in 1616, and
`later attributed death caused by snake bites to the distribution of the poison throughout the body via the blood.
`The first recorded attempt to inject medication intentionally was in 1665 by Sir Christopher Wren, then Professor of
`Astronomy at Oxford and later to become a famous architect. Wren worked on animals, but later attempts by a Johann Taylor
`were with humans. Unfortunately the crude nature of the apparatus, the absence of pure drugs and ignorance caused the
`practice to fall into disrepute.
`However, during the late eighteenth century and throughout the nineteenth century interest was spasmodically revived.
`Jenner used intradermal administration in the late eighteenth century for his smallpox vaccination and a Frenchman, Pravaz,
`introduced a plunger-type syringe in 1853 with leather components. Although the work of Pasteur and Lister pointed out the
`need for the development of aseptic techniques, it did not result in any immediate practical changes. Syringe materials were
`not suitable for heat sterilisation and the drugs were often heat sensitive, so by 1880 physicians were preparing their own
`injections at the time of use.
`By the 1890s progress had been made in the use of bacteriological filters towards sterilisation, and at about the same time a
`French pharmacist called Simousin developed the first ampoule. These changes resulted in the manufacture of parenteral
`solutions passing from the hands of the individual pharmacist or physician to pharmaceutical companies.
`Nevertheless, pyrogenic reactions continued to be associated with parenteral therapy. Florence Siebert demonstrated in
`1923 that the pyrogenic inducing bodies came from the water used to prepare the solutions, and care in using a pyrogen-free
`
`

`
`N.FRAMPTON AND D.A.DEAN 347
`
`water eliminated the fever problem. This lead to the official acceptance by the American Formulary in 1926 of injectable
`solutions, which is the true beginning of universal parenteral therapy.
`Today parenteral products are divided into two types, namely large and small volume parenterals. Large volume solutions
`in containers of 100 ml or more are essentially for intravenous use, usually over an extended period of time. Such solutions
`are also for irrigation and dialysis. Small volume parenterals are for immediate injection by various routes, such as
`subcutaneous, intramuscular and intravenous.
`Injections are often the most efficient way of administering a wide variety of essential drugs. There are of course both
`advantages and disadvantages associated with this method of drug administration over the oral form; these are detailed in
`Table 12.2.
`
`Sterilisation of parenteral products
`
`The basic pharmacopoeial accepted sterilisation processes include:
`
`1 dry heat
`2 moist heat
`3 irradiation, including gamma irradiation and beta irradiation
`4 gases
`5 product and air filtration.
`
`Dry heat
`
`Dry heat sterilisation involves high temperatures such as 160°C for 3 h; 170°C for 2 h; 180°C for 1 h; 300–320°C for 3–4 min.
`Although glass and metal can withstand these temperatures, the use of dry heat sterilisation for rubber and plastics needs to be
`considered with care. There are relatively few ‘engineering’ type plastics and a limited number of rubbers that can meet these
`high dry temperatures and retain satisfactory physical properties.
`
`Temperatures of above 100°C can be achieved by moist heat under pressure in an autoclave and, as with dry heat, there is a
`time—temperature relationship:
`
`Moist heat
`
`• 106–108°C (6–8 h)
`• 115–118°C (30 min)
`• 121–124°C (15 min)
`• 134–138°C (3 min).
`
`Moist heat sterilisation can be used to sterilise packaging components for aseptic filling or to terminally sterilise both the
`product and the pack. Because of this, various factors have to be noted.
`
`Table 12.2 Parenteral products administration
`
`Advantages
`
`Faster effect
`Maintenance of high drug levels
`Little or no inactivation
`Injected directly into target
`
`
`
`Disadvantages
`
`More expensive
`Professional administration
`Unpleasant for patient
`
`1 The product expands according to its coefficient of expansion as the temperature rises (note that alcohol expands more
`than water).
`2 The air space or ullage above the product also expands according to its nature (air or nitrogen) and its pressure.
`3 The combined expansion will depend on the product/ullage ratio and the pressure build-up will depend on whether the
`pack is rigid with limited expansion (e.g. glass) or flexible and extensible (e.g. various relatively thin-walled plastics).
`
`

`
`348
`
`STERILE PRODUCTS AND RUBBER
`
`4 Whether the packaging material is resistant to moisture (metal, glass) or absorbs and loses moisture according to the
`temperature and level of moisture present (e.g. certain plastic materials).
`
`The above invariably means that closures may dimensionally change during the sterilisation process (especially screw-based
`systems). Also, certain materials may extend during the heating cycle (plastics) and hence become distorted when recooled.
`To minimise this distortion, an overpressure or balanced pressure autoclave is essential for some materials, i.e. bottles or
`bags. Control of this distortion depends on the plastic involved, the design of the pack, the nature of the product, the volume
`to ullage (air space) ratio, the time-temperature cycle involved, the overpressure and when and how it is applied. These have
`to be optimised by trial and error experimentation, as other factors (i.e. how the autoclave is loaded and the items spaced etc.)
`also play a part. This always assumes that the closure remains effective throughout the cycle and does not ‘vent’. In this
`context this cannot happen with welded packs and, in general, closures made by effectively applying an aluminium overseal
`over a rubber stopper are superior to the older systems based on metal screw caps (older glass IV packs).
`As indicated above, the properties of certain plastics may be temporarily modified by the combination effects of moisture
`and temperature during the autoclaving cycle. In general, the physical properties of rubber formulations are not affected by
`the moist heat sterilisation other than the fact that closure systems may absorb moisture (depending on the rubber formulation/
`materials employed) during the autoclave cycle. This can be an issue for lyophilised products or aseptically filled dry powders
`where long drying cycles for the rubber closures are sometimes employed to prevent desorption of moisture from the closure
`into the product.
`
`Irradiation
`
`Sterilisation by irradiation typically uses either gamma or beta radiation (electron beam). These two processes are
`significantly different in that gamma irradiation is a lengthy process involving penetrating rays, whereas beta irradiation is in
`comparison a short exposure process where the rays are much less penetrating, i.e. it tends to be a surface sterilising process.
`Typically gamma irradiation is achieved by a cobalt 60 source at a dose of 25 kGy. The items to be sterilised are slowly
`passed through the process, over a period of up to 24 h. These rays will penetrate most materials, including aluminium foil,
`paper, board, glass, rubber and plastics. Gamma irradiation has increased in popularity for the terminal sterilisation of medical
`devices and the sterilisation of packaging components for aseptic process.
`
`Gaseous sterilisation
`
`Although various gases can be employed, e.g. formaldehyde, ethylene oxide, most pharmaceutical processes relate to the
`latter. Since ethylene oxide (and its residues) are toxic and it forms explosive mixtures with air/oxygen, special precautions
`are essential to safe handling. Ethylene oxide is therefore mixed with an inert gas (usually CO2) and needs a certain temperature
`(usually 55°C) and the presence of moisture to be effective, together with materials which are either porous (paper, Tyvek,
`board) or permeable to the gas (PVC, PS, PE, etc.). This means that there is a solubility or retention factor related to their use
`and a period must be allowed to reduce residues (by degassing).
`
`Filtration
`
`Finally, filtration should be mentioned as a means of producing sterile products or gases. In the case of aqueous-based liquids
`(of low viscosity), terminal filtration usually employs a special filter of 0.2 m (or minimum 0.22 m) pore size. Although a
`single filter can achieve effective sterility, there is a general trend towards a two filter process, i.e. 0.45 m then 0.22 m, where
`applicable. In the case of more viscous products, filtration may need an increase in temperature (which usually reduces the
`viscosity) and/or additional pressure. Filtration techniques generally assume that the product can be produced with low
`bioburden products.
`
`The efficacy, stability and safety of a parenteral drug on storage and administration depends largely on the nature and
`performance of the packaging components. In general the requirements of a modern parenteral product can be summarised as
`follows:
`
`Packaging materials
`
`• the drug is medically effective
`• the complete item is easy and quick to use
`• the inside of the container and its contents must be sterile
`
`

`
`• the drug and inside of the container must be free from pyrogens and toxic substances
`• there must not be excessive contamination by particulates
`• minimum interaction or exchange between product and pack.
`
`All the above requirements must be maintained throughout the product shelf life.
`Four main materials are used for the primary (direct contact with drug) or secondary packaging (part of the container or
`administration set but not in direct contact with the drug):
`
`N.FRAMPTON AND D.A.DEAN 349
`
`1 glass
`2 plastics
`3 aluminium
`4 rubber.
`
`The first three materials will only be touched on briefly since they are covered in full in earlier chapters.
`
`Glass
`
`Glass is available in four types, i.e. types I, II, III, NP (USA) or I, II, III, IV (Europe), the different grades relating mainly to
`their chemical ‘neutrality’. Applications include:
`
`• ampoules—single or double ended, open or closed (always single use containers)
`• vials—normally produced from pregraded tubing and used as single dose or multidose containers, in sizes of 2.5 ml to 100
`ml, with neck sizes of 13 mm to 20 mm
`• bottles—various sizes and closure systems, produced by conventional glass moulding techniques.
`
`Plastics
`
`There are many different types of plastics and an even greater number of grades to meet virtually every product requirement.
`The main economical plastics used in pharmaceutical applications are the economical ‘four’ i.e. polyethylene, polypropylene,
`polystyrene and polyvinylchloride.
`Plastics are used in virtually every pharmaceutical application (oral, topical, ophlthalmic, parenteral applications), either as
`a single material or in combination with other materials, as coatings or laminations.
`
`Aluminium
`
`Aluminium is used as an overseal to effect a seal between the rubber disc or plug and vial. An overseal must be rigid, yet
`sufficiently ductile and malleable to be clamped onto the vial. Since the overseal is a secondary closure, problems of drug
`compatibility do not occur. The aluminium itself is usually coated on the outer surface with an epoxy resin-based lacquer.
`This protects the aluminium from oxidisation, or from slight surface corrosion during autoclaving. Alternatively, the product
`may be coloured by using coloured anodised aluminium and a clear lacquer. The range of colours enable coding of products
`and further differentiation can be achieved using a D-I-D overseal (decoration-identification-differentiation) which enables
`instructions, logos or product names to be printed on the overseal.
`
`Rubber and elastomers
`
`Rubber components are now used extensively for many parenteral packaging and administration applications including
`injection vials and prefilled syringes. Because of its varied chemical nature and risk of extractables, rubber is regarded by
`many as the most critical of the primary packaging materials, especially as a wide range of constituents can be involved (see
`below).
`Up to the beginning of the twentieth century, closures were typically made from cork or glass stoppers. In the early 1900s
`solid rubber ‘corks’ or bungs, made using natural rubber as the base elastomer, replaced the cork and glass stoppers. The use
`of rubber bungs (a popular nomenclature used to describe rubber closures) provided a number of specific advantages
`summarised in Table 12.3.
`
`

`
`350
`
`STERILE PRODUCTS AND RUBBER
`
`Rubber formulations
`
`In this chapter the word ‘elastomer’ is used to describe the base polymer and ‘rubber’ to describe the fully compounded
`finished component. A rubber formulation is a complex blend of ingredients, and a typical high extract sulphur cured natural
`rubber formulation is given in Table 12.4.
`
`The choice of elastomer has the greatest effect on a formulation. The most common elastomers that can be used for closures
`for injectable products are given in Table 12.5. Of these elastomers, natural rubber, synthetic polyisoprene, butyl, chlorobutyl
`and bromobutyl rubber are typically used for the manufacture of rubber closures and stoppers used in the packaging and
`administration of parenterals.
`
`Elastomer
`
`Table 12.3 Special properties of rubber
`
`Property
`
`Advantage gained
`
`Flexible
`Resilient
`Non-thermoplastic
`Good compression set
`Can be varied by ingredient choice
`
`Conforms to shape of vial etc.
`Reseals after needle puncture
`Tolerates most heat sterilising and other processes
`Retains seal throughout product life
`Formulations can usually be developed compatible with most drugs
`
`Table 12.4 Typical sulphur cured natural rubber formulation
`
`Category
`
`Ingredient
`
`Elastomer
`Filler
`Pigment
`Plasticiser
`Processing aid/activator
`Activator
`Vulcanisation system
`
`Natural rubber
`Calcium carbonate
`Red iron oxide
`Paraffin oil
`Stearic acid
`Zinc oxide
`Accelerator (e.g. sulphonamide, dithiocarbamate, thiuram)
`Elemental sulphur
`
`Table 12.5 Elastomer characteristics
`
`Mass % (w/w)
`
`60.00
`25.0
`4.0
`5.0
`1.0
`2.5
`1.5
`1.0
`
`Polymer
`
`Natural rubber
`Synthetic polyisoprene
`Butyl
`Halobutyl
`Nitrile
`EDPM
`Silicone rubber
`Neoprene
`
`
`
`Characteristic
`
`Good physical properties
`Good physical properties
`Low permeability
`As butyl, but with lower water extractables
`Mineral oil resistance
`Resistance to high pH solutions
`High permeability
`Lower oil resistance than nitrile
`
`Natural rubber
`
`This was the first type of polymer used in pharmaceutical applications, and was found to have desirable characteristics in that
`its resilience provided sealing properties and this resilience could be developed to allow the rubber to be pierced by a
`hypodermic needle, resealing after removal. This high level of resilience is partially due to its chemical structure, it being a
`straight chain elastomer (Figure 12.1).
`
`

`
`N.FRAMPTON AND D.A.DEAN 351
`
`Figure 12.1 Natural rubber
`
`
`During the curing or cross-linking process only 10–20% of the available double bonds react and this gives rise to the
`potential for breaking of the chemical chains upon exposure to factors such as heat, oxygen or ozone. This can result in
`surface tackiness, crazing and ultimately total degradation of the rubber.
`Although natural rubber has been used for many years, there is an increasing awareness of an issue described as ‘latex
`protein allergy’ whereby naturally occurring proteins and natural rubber latex can cause allergic reactions and, in the most
`severe cases, anaphylactic shock. Items made from latex natural rubber typically include surgical and examination gloves,
`anaesthesia masks, and dental dams. During the period 1989–1993 the US Food and Drug Administration (FDA) received
`reports of over 1000 cases of injury and fifteen cases of death associated with latex allergy (Dillard and MacCollum, 1992).
`The cases of death related to a single supply of barium enema catheters which were believed to have been produced using poor
`manufacturing conditions. These were recalled and subsequently replaced by catheters made using synthetic rubber.
`Rubber closures and components for the packaging and administration of parenterals are normally made from so-called dry
`rubber. Where such closures have been produced using dry natural rubber, the bioavailability of proteins has not been proved
`(Slater, 1993). It is postulated that the difference between latex and dry natural rubber is related to the processing of the base
`elastomer and rubber compound (Russell-Fell, 1993). The processing of dry natural rubber involves acid coagulation followed
`by a crumbling/creeping operation with extensive washing in water and drying at 100–130°C. During manufacture dry natural
`rubber compounds are typically compression moulded at high temperatures up to 160°C. A study of the extractable protein
`content of fourteen dry natural rubber samples and five dry natural rubber products found limits so low as to be at the limit of
`detection of the Lowry method (Yip et al., 1995). There has been one reported case (Towse et al., 1995) of an allergic
`reaction involving local erythema following an injection of insulin. The paper concluded that there was strong circumstantial
`evidence that the patient’s allergic response was caused by latex antigens contained in the insulin vial and/or syringe. Reputable
`suppliers have been pursuing alternatives to dry natural rubber: one common approach is to introduce synthetic polyisoprene
`and to describe such materials as natural rubber latex free.
`
`Butyl and halobutyl rubber (chlorobutyl/bromobutyl)
`
`Butyl rubber shown in Figure 12.2, has been commercially available since 1942, and chlorobutyl and bromobutyl have been
`commercially available since 1960 and the 1970s respectively. All three polymers offer very low permeability to gases. The
`vulcanisation of butyl rubber requires a high level of curatives to effect cross-linking; the introduction of halogenated butyl
`rubber resulted in greater reactivity of the base polymer. As a direct result it was possible to use a lower level of curatives for
`halobutyl polymers and also to explore so-called unconventional vulcanisation systems that yielded a significantly lower level
`of extractables.
`In certain cases it is desirable to combine the properties of the previously described natural rubber with those of the
`halobutyls. With straight butyl rubbers this was impossible due to the prolonged cure time of butyl which meant that the
`natural rubber would be overcured, resulting in an unusable ‘non-homogeneous’ mix.
`
`Cure ingredients
`
`During cure (or vulcanisation), the individual polymer chains become chemically linked together to form a three-dimensional
`structure. This minimises the tendency for permanent distortion under load at room temperature or for the rubber to ‘melt’ at
`high temperatures, such as at steam sterilisation. Certain additives are necessary as vulcanisation agents to provide the
`chemical cross-links, which are created at elevated temperatures, typically from 140°C to 200°C. Heat is applied to the rubber
`while it is being compressed in metal moulds, so that the forming and vulcanisation processes occur simultaneously. The
`most commonly used vulcanisation system in the general rubber industry is based on sulphur. Sulphur systems can be devised
`to fit most rubber processing conditions and can be applied to most polymers commonly used for pharmaceutical
`applications. Activators, usually zinc oxide and stearic acid, are necessary to activate the accelerators, but here the precise
`quantity is less critical. The detailed mechanism of the rubber curing process is complicated, but it is generally accepted that
`the sulphur combines with a zinc salt of the accelerator to produce a thio-intermediate which, in turn, reacts with the rubber.
`The inevitable residue of zinc-accelerator salts is slightly water soluble and can be extracted by aqueous solutions, if only at
`
`

`
`352
`
`STERILE PRODUCTS AND RUBBER
`
`Figure 12.2 Butyl rubber
`
`the level of a few parts per million. This tendency to contaminate is a significant disadvantage of a sulphur cure, although
`many sulphur cured rubbers have a long history of satisfactory use with aqueous injectables.
`the organic accelerator 2-
`One such contaminant associated with sulphur-based vulcanisation systems
`is
`mercaptobenzothiazole (2-MCBT) and associated derivatives. In 1981 (Petersen et al., 1981) the presence of 2-(2-
`hydroxyethylmercapto) benzothiazole (HEB) was detected in the contents of a disposable hypodermic syringe. It was
`identified that the extractant was a reaction product formed between a 2-MCBT derivative and ethylene oxide used for
`sterilisation. Subsequently the oxidation product of HEB, 2-(carboxymethylthio)benzothiazole (CMB), was detected in the
`serum of premature babies receiving prolonged intravenous therapy (Meek and Pettit, 1985). So-called modem vulcanisation
`systems do not use sulphur as the cross-linking agent nor use 2-MCBT or derivatives, and are consequently free from this
`particular problem. These new vulcanisation systems show a considerable reduction in aqueous extractable matter and are
`often described as having low water extractables.
`
`Fillers
`
`Fillers are added to the elastomer in order to add bulk, lower cost and/or to improve physical properties such as hardness,
`strength and abrasion resistance. Typical fillers are materials such as carbon black, talc, china clay and whiting. Carbon black
`has been shown to contain polynuclear aromatics (PNAs) and there is concern regarding their carcinogenicity (Lee and Hites,
`1976). However, despite extra controls there has been a move away from the use of carbon black as a filler in applications
`involving the primary packaging o