Technical

Rubber & Plastics News ● June 29, 2009 15www.rubbernews.com

Characteristics of rubber used in pharmaceuticalsBy Daniel L. Norwood

Boehringer Ingelheim Pharmaceuticals Inc.

Michael RubertoMaterial Needs Consulting L.L.C.

Fran L. DeGrazioWest PharmaceuticalServices Inc.

Jim CastnerLantheus Medical Imaging

Wai Kueng WongExxonMobil Chemical Europe

and Dennis Jenke Baxter Healthcare Corp.

Pharmaceutical products produce adesirable therapeutic outcome whenthey are administered to a subject to ad-dress an issue related to health. In orderto produce this outcome, pharmaceuticalproducts must be manufactured, storedand administered.

Systems that accomplish these objec-tives do so because of their design andtheir materials of construction. In cer-tain situations, rubber materials pos-sess the required performance charac-teristics and thus are widely used in thepharmaceutical industry.

Pharmaceutical products are formu-lated, and administration regimens aredeveloped to maximize their therapeuticbenefit.

Any action that modifies the product’scomposition can adversely impact thederived benefit.

For example, contact between theproduct and its associated systems may

initiate an interaction, potentially re-sulting in a meaningful change in theproduct that could impact its ability toproduce the desired therapeutic out-come.

One such change could be the migra-tion of a compound out of the systemand into the pharmaceutical product.Such a compound could exert an unde-sirable influence on, or could impart anundesirable characteristic to, the phar-maceutical product, including:

● Reduction in product stability,● Alteration of the product’s impurity

profile,● Formation of extraneous (e.g., par-

ticulate) matter,● Inactivation of active ingredients,● Failure to meet established product

quality standards,● Development of undesirable esthetic

effects (e.g., smell, taste, discoloration,clarity),

● Increase in the risk that product usewould adversely affect the health and/orwell-being of the user (safety), and

● Interference with product testing.Such interactions between pharma-

ceutical products and their associatedsystems are well documented in the lit-erature.

The knowledge that such interactionscan and do occur and that they can anddo have documented product conse-quences has led to an increased aware-ness of this issue in the pharmaceuticalcommunity and is the driving force be-hind the issuance of regulations de-signed to ensure that suitability for useissues are readily and universally recog-nized, appropriately investigated andproperly assessed.

Specifically, regulatory agencies inthe U.S. and European Union have is-sued guidance and guidelines to specifi-cally address packaging (container clo-sure) systems (and their materials ofconstruction) used for pharmaceutical

Executive summaryRubber materials are widely used in systems used to manufacture, package

and deliver pharmaceutical products. While the rubber material’s nature and composition gives it its necessary and

desirable performance characteristics, these material properties can have im-portant and potentially detrimental consequences for the pharmaceutical prod-ucts.

Interactions between these materials and the pharmaceutical products theycontact are well known and documented and can result in a change in the prod-uct’s composition, which may adversely affect product safety (e.g., the productproduces an unanticipated and adverse user response) and/or efficacy (e.g., theproduct performs in a manner inconsistent with its labeling and indication).

Therefore, rubber materials used in pharmaceutical products must be evalu-ated to determine what material components can, and do, migrate from the ma-terials and accumulate in the pharmaceutical product, as it is through the pres-ence and actions of such substances that product safety and/or efficacy may becompromised.

The characterization of materials for their extractables (substances that canmigrate) and of products for their leachables (substances that do accumulate) isa necessary and complex part of the development, registration and manufactur-ing and distribution and therapeutic products.

This manuscript provides a general overview of the extractables and leach-ables issues associated with materials used with/in therapeutic products.

products. The relevant document in the U.S. is

the Food and Drug AdministrationGuidance for Industry, Container Clo-sure Systems for Packaging HumanDrugs and Biologics.1 In this document,the FDA establishes the concept of “suit-able for its intended use.” Specifically, insection II.B.1 of the Guidance, the FDAnotes that “every proposed packagingsystem should be shown to be suitablefor its intended use.”

The guidance goes on to establish fouraspects of suitability for use:

● Protection (that “a container closuresystem should provide the dosage formwith adequate protection from factors(e.g., temperature, light) that can causea degradation in the quality of thedosage form over its shelf-life”),

● Compatibility (that the product andcontainer closure “will not interact suffi-ciently to cause unacceptable changes inthe quality of either the dosage form orthe packaging component”),

● Safety (that the “packaging compo-nents should be constructed of materialsthat will not leach harmful or undesir-able amounts of substances to which apatient will be exposed when beingtreated with the drug product”), and

● Performance (that the container clo-sure system “functions in a manner forwhich it was designed”).

The regulatory requirements for theproducts marketed in the EuropeanUnion are captured in the EuropeanMedicines Agency’s Guideline on PlasticImmediate Packaging Materials.2

While there are clear and meaningfuldifferences in the scope and specifics ofthe U.S. and EU guidance documents,the EU Guidelines are very much in linewith the suitability for intended use con-cepts in general and with the four di-mensions of suitability for use enumer-ated in the FDA guidance in particular.

The EMEA guidelines deal veryspecifically with the dimensions of safe-ty and certain aspects of compatibility(primarily drug sorption and altereddrug degradation) and consider the di-mensions of protection and performancemore by inference than substantivetext.

Extractables and leachables:General concepts

As noted previously, the migration of

an entity out of a system results in theaccumulation of an entity in the phar-maceutical product.

Thus the interaction between a sys-tem and a product can be assessed byconsidering either those substancespresent in the packaging which couldmigrate from the packaging or thosesubstances, derived from the packaging,that are present in the product.

Although these two sets of substancesmay be closely related (Fig. 1), therecan be clear differences between them,and thus the terms extractables andleachables were adopted to reflect thepopulations and emphasize their differ-ences. The rigorous definitions of thesetwo terms follow:

● Leachables: Those substances thatare present in the therapeutic productbecause of its contact with a material,component, system, etc.

● Extractables: Those substances thatare present in the material, component,system, etc, that can be extracted fromthat material by a solvent.

On the surface it seems logical thatthe best and most direct approach to as-sessing system—product interactions isto test the therapeutic product for leach-ables, as opposed to testing the systemfor extractables.

This is true because testing the prod-uct for leachables produces the exactdata that needs to be interpreted (thatis, what is actually in the product thatcould affect its safety and/or efficacy)while testing the system for extractablesstill leaves the question “to what extentwill these extractables accumulate inthe actual product?”

Despite this logic, it is rarely the casethat the suitability for use assessment

starts with scouting of the finished prod-uct for leached substances.

The primary reason that this is thecase is the complexity of the analyticaltask involved in such a scouting process.

In many cases the finished drug prod-uct is a complex mixture of the active in-gredient, multiple formulation compo-nents, impurities and decompositionproducts.

The considerable analytical challengein performing a leachables assessmentis to uncover, identify and quantitate“unknown” leachables in trace quanti-ties in the complex formulation matrix.

This analytical challenge of “finding aneedle in the haystack when you don’teven know what the needle looks like” isgreatly simplified if one is given theprobable identity of the needle.

In the case of leachables testing, thismeans that it is far easier to determineif a sample contains a known ex-tractable than to determine if the sam-ple contains any “unknown” compounds.

Thus, the extractables profile of thesystem establishes what the probableleachables are.

Test methods and procedures can bedeveloped and implemented to specifi-cally determine which of the extracta-bles do accumulate in the product atmeasurable quantities (and are thusleachables).

Extractables testing is also relevantin other facets of product quality assess-ment.

For example, extractables assess-ments may be a relevant means of exer-cising ongoing quality control.

It is reasonable to anticipate thatthere might be circumstances where it isnecessary to control, or demonstratecontrol of, the effect lot-to-lot variationin a system material on the product’sleachables profile. This objective can bemet by rigorous batch-to-batch testing ofthe system materials.

Because material testing is an ex-tractables assessment, extractablesstudies are frequently utilized in ongo-ing quality control.

Additionally, there are certain in-stances where it is required that thesystem and its components be “charac-terized.” An extractables assessment isa material characterization tool; a leach-ables assessment is not.

Extractables in pharmaceuticalrubber materials

It is an unfortunate circumstance thatthe performance characteristics re-quired in pharmaceutical applicationsare not intrinsic to the “pure” or “base”rubber but rather are imparted to theelastomer via its chemical modification.

In order to produce the actual materi-als used in pharmaceutical applications,the base elastomer is combined and/or

Table I. Examples of packaging concerns for common classes of drug products.

TECHNICAL NOTEBOOKEdited by Harold Herzlichh

See Rubber, page 16

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Technical

reacted with a number of chemicalagents or additives (e.g., vulcanizingagents, accelerators, activators, plasti-cizers, tackifiers, colorants, fillers, an-tioxidants, lubricants, see Table II) un-der harsh conditions of high temperatureand pressure.

These substances, their impuritiesand their processing-induced reaction ordecomposition products are all potentialextractables.

The more commonly utilized classes ofadditives are considered in greater de-tail as follows.

Curing and vulcanizing agents: Nat-ural rubber and synthetic analogs areoften processed (e.g., cured and/or vul-canized) to obtain a material with therequired physical and chemical proper-ties.

These chemical agents, which typical-ly contain either sulfur or peroxide, re-act with active sites along the polymerchain to produce cross-linking.

The processes of vulcanization and/orcuring may be facilitated by accelera-tors (such as guanidines, thiazoles, thi-urams and dithiocarbamates) and/oractivators (such as a metal oxide or fat-ty acid).

Antioxidants: Rubber articles are ex-posed to oxidation, flex, fatigue, ozoneand light during their shelf-life. Addi-tionally, many rubber parts are steril-ized by gamma irradiation prior to usein pharmaceutical applications.

To improve their durability, they haveto be protected by different additives.

For example, the oxidation of rubbercan be considerably reduced by the addi-tion of antioxidants, chemicals that de-stroy and scavenge oxy radicals beforethey have opportunity to react with rub-ber chains.

The origins of degradation in poly-mers are radical species such as:

R • Alkyl radicalRO • Alkoxy radicalROO • Peroxy radicalROOH Hydroperoxide Therefore, radical scavengers such as

hindered phenols (e.g., Irganox-and Ir-gafos-type compounds) are commonlyused in rubber formulations.

Fillers, such as metal silicates, silica,calcium carbonate and carbon black, arepresent in the rubber formulation to im-pact certain of the material’s mechani-cal properties, including hardness andmoisture sorption/desorption.

Light stabilizers are commonly usedto protect elastomers from sunlight aswell as artificial lighting. Many of thesechemistries include benzophenones,benzotriazoles, or triazines. This topicwill be discussed in greater detail below.

Acid scavengers are used to neutralizetraces of halogen anions formed duringaging of halogen-containing rubbers. Ifnot neutralized, the anions would causepremature aging of rubber and perform-ance of rubber articles would signifi-cantly deteriorate with time.

Effective acid scavengers include leadoxides and lead salts (which are beingphased out because of environmentalconcerns), magnesium oxide and moi-eties such as Hycite 713.

Metal deactivators are used to controlmetal-catalyzed hyperoxide decomposi-tion. Hydroperoxides are species withinthe “autoxidation cycle” that contributeto the degradation of rubber vulcan-izates.

Rubber poisons (such as copper, iron,cobalt, nickel and other transition met-

als) present in vulcanizates, even intrace amounts (less than 5 parts permillion), increase the decomposition rateof hydroperoxides and thus accelerateoxidation and aging of rubber goods.

Therefore, rubber that contains orcould be in contact with rubber poisonsrequires a specific stabilizer, a so-calledmetal deactivator, for example, 2’,3-bis[[3-[3,5-di-tert-butyl-4-hydroxyphenyl]propionyl]]propionohydrazide (IrganoxMD 1024). The metal deactivator bindsions into stable complexes and “deacti-vates” them.

Pigments, including carbon black, in-organic substances (e.g., oxides of titani-um and iron) and organic substances(e.g., pyrazolone, ultramarine, phthalo-cyanine and diarylide) may be added torubber formulations for the purpose ofidentification, branding and protection.

Antimicrobials and fungicides: Mi-crobial growth on the rubber surfacecan lead to discoloration, staining, odordevelopment or the formation ofbiofilms that ultimately, result in dete-rioration of mechanical properties ofthe product. Antimicrobials and fungi-cides may be used by resin manufactur-ers and molders to maintain the fresh-ness, durability and aesthetics of theelastomer.

Additional rubber additives includeplasticizers, processing aids, slip agents,clarifiers, antistats and others.

Utilization of rubber materials inpharmaceutical systems

The use of elastomers in the medicalindustry is nearly as old as the rubberindustry itself.

The potential utility of elastomers ascomponents of packaging and deliverydevices was recognized shortly after thediscovery of the vulcanization process.

The unique properties of processedrubber, including elasticity, penetrabili-ty, resiliency, ability to act as a gas/val-or barrier and general chemical compat-ibility were the driving force behind itsready adoption in early 21st centurypharmaceutical applications (primarilyas closures for glass vials), and it is thefact that these properties are largely un-matched by today’s polymers and plas-tics that ensures rubber’s continued usein modern pharmaceutical practice (clo-sures, O-rings, plungers, seals, etc.).

Considering the conditions of contactbetween an elastomer and a therapeuticproduct, which can include elevatedtemperatures, long contact times andaggressive pharmaceutical products

(e.g., products whose composition issuch that they are effective “solubilizingagents”) and the nature of the elas-tomer (e.g., relatively high amounts ofnumerous additives, some of which arepoorly bound by the base material andsome of which are exposed to the phar-maceutical product because they havebloomed to the contact surface), it notsurprising that consequential interac-tions between elastomeric parts andpharmaceutical products occur withsome regularity.

Incompatibility issues associated withthe use of rubber closures in pharma-ceutical products were observed in theearly days of rubber utilization.

For example, the loss of preservativessuch as stabilizers like cresol or phenolfrom pharmaceutical products was re-ported as early as 1923 and was the sub-ject of extensive investigation in the1950s.3-8

Issues such a haze formation andleaching of zinc from closures and sy-ringe plungers were quantitatively in-vestigated in the middle 1950s as viableanalytical methodologies were devel-oped.9,10

The identification of 2-(methythio)benzothiazole in water extracts ofplungers from disposable syringes wasreported in 1965.11

In a review published in 1966, Capperdiscusses various types of interactionsbetween rubber and medicants, includ-ing the deposition of particulates intothe drug product, the adsorption ofpreservatives and medicants, “yieldinginto the solution the various materialsadded as accelerators or antioxidants, ormaterials derived from vulcanizingagents, and water absorption.”12

Included in this review is the report ofthe formation of a stearate-containingdeposit in eyedrops because of leaching

of these substances from the rubbercomponent, and of the “deactivation” ofpenicillin by rubber tubing by mercap-tans leached from the tubing. The uti-lization of a Teflon liner to retard theleaching of extractives was repoted byLachman in 1964.13

The development of modern chro-matographic and spectroscopic analyti-cal methods facilitated the investigationof rubber materials for organic extracta-bles.

The period of time between the early1970s to the present was one of activeresearch in this area.14-32

Given the long and active history ofinvestigation into rubber and productinteractions, one might conclude that inthe current environment all the issueshave been resolved and that rubber ma-terials used in pharmaceutical applica-tions are inherently and eminently suit-able for use.

While it is certainly the case that in-creased awareness of, and knowledgeabout, suitability for use issues has driv-en developments in rubber composition,processing and utilization, such a desir-able state of affairs has not been fullyrealized.

On one hand development of the per-fectly suitable rubber is limited by thefact that there are limited choices interms of material composition and pro-cessing.

The dual requirements of functionali-ty and suitability are, to some extent, in-herently mutually exclusive, and thusthere is a limited amount of “wiggleroom” in the composition and processingdesign space that defines a viable prod-uct.

On the other hand, pharmaceuticalproducts, especially biopharmaceuticals,are becoming more compositionally com-plex and “sensitive” to perturbations re-

Table II. Additives used in rubber formulations.

Fig. 1. The relationship between ex-tractables and leachables. Althoughthese two populations of entities typi-cally share members in common, withleachables being a subset of extracta-bles, there are many reasons and manycases where the extractable does notequal leachables and leachables arenot equivalent to extractables.

RubberContinued from page 15

The authorsDaniel L. Norwood is a distinguished research fellow in the Analytical Sci-

ences Department at Boehringer Ingelheim Pharmaceuticals Inc. He has heldpositions at Magellan Laboratories, Glaxo Research Institute, Duke UniversityMedical Center and the University of North Carolina School of Public Health.He chairs the PQRI Working Group on Leachables and Extractables for orallyinhaled and nasal drug products.

Michael Ruberto is the president of Material Needs Consulting L.L.C., whichprovides consulting services to manage the development and commercializationof medical devices and packaging, with a special emphasis on material selec-tion, extractables and leachables, and supply chain management. Ruberto alsowas employed by Ciba Specialty Chemicals for 15 years..

Fran DeGrazio has been in the pharmaceutical packaging industry for 25years with expertise in delivery of injectable drug products. In 2006 she movedinto her current role as vice president of marketing and strategic business de-velopment at West Pharmaceutical Services.

Jim Castner is a senior principal research scientist at Lantheus MedicalImaging (formerly Bristol-Myers Squibb Medical Imaging Division) with morethan 16 years experience in the pharmaceutical industry. He had also workedfor more than 10 years at DuPont in the Medical Products and the AgricultureCrop Protection units as a primary investigator.

John Wong, senior staff scientist with ExxonMobil Chemical Europe, joinedthe company in 1987 and was involved in various application developments onpolyolefins and elastomers. He is currently technical coordinator of butyl poly-mers in pharmaceutical stopper and seal applications.

Dennis Jenke is a principal scientist in the Technology Resources Division ofBaxter Healthcare Corp. In this role, he works with a team of analytical chem-istry professionals who are responsible for the development, validation and ap-plication of diverse analytical strategies and methods for the discovery, identifi-cation and quantification of trace constituents in pharmaceutically relevantsolutions and samples.

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Technicallated to material interactions. The jux-taposition of these two trends meansthat rubber/product interactions arestill an important product design consid-eration and constraint.

This observation is supported by re-cent reported adverse events that havebeen associated with rubber/product in-teractions.

For example, one of the most widelydocumented instances of an unanticipat-ed incompatibility between a rubber

component of a container closure systemand a protein drug product is that ofEprex (epoetinum alfa) and its pre-filledsyringe packaging system.33-35

At some point in its product lifetime(ca. 1998), Eprex, a product of recombi-nant human erythropoietin, was refor-mulated with polysorbate 80, which re-placed human serum albumin as aformulation stabilizer.

Shortly after this change, the inci-dence of anti-body mediated pure red

cell aplasia (PCRA) with Eprex use bychronic renal failure patients increased.The cause of PCRA was directly linkedto the formation of neutralizing antibod-ies to both recombinant and endogenouserythropoietin in patients administeredEprex. A considerable, cross-functionaltechnical effort was undertaken to es-tablish the root cause of this phenome-non. One potential root cause involvedleached substances.

The presence of previously unidenti-

fied leachables was suggested as newpeaks in the tryptic map of Eprex.Leaching studies determined that thepolysorbate 80 extracted low levels ofvulcanizing agents (and related sub-stances) from the uncoated rubber com-ponents of the pre-filled syringe.

This leaching issue was addressed byreplacing the rubber components withcomponents coated with a fluoropoly-mer.

See Rubber, page 18

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Technical

18 Rubber & Plastics News ● June 29, 2009 www.rubbernews.com

As the fluoropolymer is an effective bar-rier to migration, the leaching of the rub-ber’s components was greatly reduced.

Since the conversion from the uncoat-ed to the coated components, the inci-dence of PRCA has returned to the base-line rate seen for all marketed epoetinproducts. This is strong circumstantialevidence that leaching of the vulcaniz-ing agent was, in fact, the root cause ofthe observed effect.

Orally inhaled and nasal drugproducts as example of extracta-bles and leachables issues

Orally inhaled and nasal drug prod-ucts (OINDP) are a drug product classused for the treatment of asthma, chron-ic obstructive pulmonary diseases(COPD), and systemic conditions suchas diabetes. OINDP include metereddose inhalers (MDIs), dry powder in-halers (DPIs), nasal sprays, inhalationsolutions and inhalation sprays.

OINDP are unique among drug prod-uct types in that the container closuresystem is an integral part of the drugproduct and critical for drug productperformance. Container closure systemscan include rubber, plastic, metal andother components.

Rubber components are most oftenused as seals, especially in metered doseinhalers (Fig. 2), which include an or-ganic propellant under pressure as partof the formulation.

Because rubber and plastic incorporatechemical additives and processing aidsand metal components often have organicresidues on their surfaces, the potentialexists for leaching of these chemicals fromthe components into the formulation.

The degree of regulatory concern re-garding organic leachables in OINDP issummarized in Table I, which is adapt-ed from the FDA’s so-called “PackagingGuidance.”1 In Table 1, the “Likelihoodof Packaging Component-Dosage FormInteraction” (e.g. the likelihood of leach-ing) is linked with the “Degree of Con-

cern Associated with the Route of Ad-ministration.”

The inhalation route of administra-tion is of high concern because:36-39

● The patient population is sensitiveand compromised. OINDP patients in-clude individuals with asthma and vari-ous COPD (chronic obstructive pulmonarydiseases, such as chronic bronchitis andemphysema) who by definition have com-promised lung function and can show in-creased sensitivity to irritants.

● Paradoxical bronchospasm is an is-sue. Paradoxical bronchospasm is a rela-tively rare event in which a medicine pre-scribed to treat bronchospasm (a suddennarrowing of the airway, as in an asthmaattack) or the underlying condition, hasthe effect of inducing bronchospasm.40

Paradoxical bronchospasm is a potential-ly life threatening event.

Although the causes of paradoxicalbronchospasm are not well understood,it is advisable to reduce to the extentpractical any potential irritant.

● OINDP tend to be for chronic admin-istration, and therefore long-term use.OINDP are designed for the treatmentof asthma, COPD and other systemicdisease conditions such as diabetes. It istherefore likely that patients will takeOINDP for many years if not decades.

Additionally, because MDI drug prod-ucts include organic solvents underpressure in direct contact with rubberand plastic container closure systemcomponents, there is a high likelihoodfor interaction and leaching.

Because of this high level of concern,two specific guidance documents dealingwith OINDP were issued by the FDA,one of which is related to “Nasal Sprayand Inhalation Solution, Suspensionand Spray Drug Products”37 and the oth-er (still at the time of this writing indraft form) related to “Metered Dose In-haler and Dry Powder Inhaler DrugProducts.”38

These guidance documents, along withthe “Packaging Guidance,”1 describe

what is generally expected for regulatorysubmissions related to inhalation drugproducts. Specifically, for MDI drugproducts the guidance suggests:38

“Since inhalation aerosol formulationsinclude organic liquids as the propel-lants or the vehicle (e.g. chlorofluorocar-bons, hydrofluorocarbons, alcohols), po-tential leaching of compounds from theelastomeric and plastic components ofthe container and closure system intothe formulation is a serious concern thatshould be addressed.

“Therefore, the composition and quali-ty of the materials used in the manufac-ture of the container and closure systemcomponents should be carefully selected.

“For safety considerations, materialsshould be chosen that minimize or elimi-nate leachables without compromisingthe integrity or the performance of thedrug product.”

Further, the guidance says:“Identity and concentration profiles of

the leachables in the drug product orplacebo formulation (e.g. drug productformulation without drug substance)should be determined through the end ofthe drug product’s shelf life and corre-lated, if possible, with the extractablesprofile(s) of the container and closurecomponents determined under the vari-ous control extraction study conditions.”

To increase efficiency in the pharma-ceutical development process, as well asincrease the likelihood of earlier regula-tory approvals for new inhalation drugproducts, the developers of inhalationdrug products desired even greater clar-ification regarding the regulatory re-quirements for extractables/leachablestesting, qualification and control.

In late 2001, a Leachables and Ex-tractables Working Group was formedby the Product Quality Research Insti-tute to address the issue of leachablessafety qualification thresholds in in-halation drug products.

Based on a developed hypothesis andstep-wise investigative plan, which in-cluded both literature investigationsand laboratory work, the PQRI L&EWorking Group produced a “Recommen-dation Document” in 2006 which wassubmitted to the FDA.36

The PQRI recommendations includetwo safety thresholds for leachables in in-halation drug products: “QualificationThreshold” (QT) at 5 µg/day total daily in-take for an individual organic leachable,and the “Safety Concern Threshold” (SCT)at 0.15 µg/day total daily intake for an in-dividual organic leachable.

The qualification threshold is definedas “the threshold below which a givenleachable is not considered for safetyqualification (toxicological assessments)unless the leachable presents structureactivity relationship concerns,” whereasthe concern threshold is defined as “thethreshold below which a leachable wouldhave a dose so low as to present negligiblesafety concerns from carcinogenic andnoncarcinogenic toxic effects.”36

The threshold at or above which achemist should begin to identify a par-ticular leachable and/or extractable andreport it for potential toxicological as-sessment, was defined as the “Analyti-cal Evaluation Threshold,”36 which is de-rived from the concern threshold withconsideration of an individual drugproduct’s dosing requirements.

It is noted that the safety thresholdsdo not apply to the so-called “specialcase” compounds and compound classes(PAHs, N-nitrosamines, and 2-mercap-tobenzothiazole), which are deemed bythe regulatory authorities to have spe-cial safety concern and therefore shouldbe evaluated and controlled with tech-

nology-based thresholds. The PQRI recommendations also in-

cluded “Best Practices” for inhalationdrug product development with regardto extractables and leachables.

The best practice recommendationscover the areas of selection of compo-nents, controlled extraction studies,leachables studies and routine extracta-bles testing. Both the safety thresholdsand best practice recommendationshave been independently reported in thescientific literature.41, 42

Developments in elastomers usedin pharmaceutical applications

While the ultimate objective of havingcost effective, broadly applicable, func-tional and suitable pharmaceutical rub-ber materials has only been partially re-alized, ongoing developments and futureinnovations in rubber composition, rub-ber compounding, rubber processing andrubber utilization have the potential toclose the gap between the utopia of to-morrow and the reality of today.

Vendors of rubber materials and partsused in pharmaceutical applicationshave been actively engaged in address-ing extractables and leachables issues.

The development and utilization ofperoxide-cure systems to replace sulfur-based curing processes is an importantexample of this engagement.

Additionally, many vendors of rubbermaterials to the pharmaceutical indus-try have developed grades of such mate-rials that can generically be described asbeing “low in extractables.”

One such example is brominatedisobutylene paramethylstyrene tere-polymer (BIMSM) has been reported tobe a very clean material that can be vul-canized effectively by a low level of cleancuratives.43

Finally, the use of coated rubber parts(e.g., rubber parts coated with a migra-tion barrier such as polytetrafluo-roethane) in pharmaceutical applica-tions is increasing.

Another area of increased vendor par-ticipation is in the area of providing ex-tractables information to potential usersof rubber materials.

An extreme example of the vendor’sincreasing willingness to provide suchinformation is the VeriSure product lineoffered by West Pharmaceuticals.

VeriSure products are certified on alot-to-lot basis for extractables and theindividual material lots are supported bycomprehensive extractables documenta-tion including an extractable “finger-print” and an extractables specification.43

The aforementioned advances in thestrategies for designing, performing andinterpreting extractables and leachablessafety assessments, in the compositionof the materials themselves and in thelevel of vendor participation in the as-sessment process are further augmentedin advances in the tactics (e.g., analyti-cal approaches) utilized in the variousfacets of the E&L assessment.45

The combined impact of all these ad-vances is an environment that is charac-terized by effective, efficient and timelyproduct development, registration, mar-keting and stewardship, supported bythe principles of good science and Quali-ty by Design.

AcknowledgementsThis manuscript is a compilation of

presentations made by the authors atthe Fall 174th Technical Meeting of theRubber Division of the American Chemi-cal Society, held in Louisville, Ky., inOctober 2008.

The individual authors wish to ac-

Fig. 2. Schematic diagram of a metered dose inhaler, from Bespak P.L.C.

See Rubber, page 19

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Rubber & Plastics News ● June 29, 2009 19www.rubbernews.com

ProductsElastocon TPE Technologies Inc. has published a

brochure for its full line of custom and standard SEBSand non-SEBS series of thermoplastic elastomers, ther-moplastic olefins and machine-side compounding solu-tions. The literature is enhanced with a variety of end-use product application photos.

For a copy of the brochure, call 888-644-8732 or visitwww.elastocontpe.com.

ExxonMobil Chemical Co. has introduced a high-flow thermoplastic vulcanizate for automotive interi-ors. Santoprene TPV M350 can be processed using two-component injection molding or mono-sandwichmolding onto a rigid polypropylene substrate to pro-duce an unfoamed structure that does not indent. Alsocolorable, Santoprene TPV M350 offers low- and stable-gloss level, high scratch and mar resistance, good abra-sion and chemical resistance, low fogging and odoremission, the company said.

For more information, call 281-870-6007 or visitwww.exxonchemical.com.

3M Co. has introduced a high-tack electrical insulat-ing tape for hard-to-hold applications.

3M Electrical Tape 44HT is a polyester composite in-sulating tape with a durable backing providing atough, puncture-resistant protective layer, the firmsaid. Specific applications include stick-woundcoils/transformers and bobbin-wound coils for banding,anchoring, insulating and protecting start wires,leads, terminal strips, insulation strips, insulation pa-per, end turns and connections in motors and trans-formers, 3M said.

Visit www.3M.com/electrical or call 800-676-8381 fordetails.

Sartomer Co. has come out with improved retardertechnology for the company’s crosslinking coagents.The retarder systems are less volatile, odorless andpersist in the compound even at high processing tem-peratures, the company said. Sartomer products usingthe proprietary retarder packages are designated withan R suffix in the product code.

For details, call 610-363-4100 or visit www.sar-tomer.com.

GLS Corp. has introduced halogen-free, flame retar-

dant thermoplastic elastomers that provide an alterna-tive to traditional flexible vinyl jacketing and insula-tion for consumer electronics applications. GLS’ OnFlexTPE materials comprises five groups of high-perform-ance compounds. All grades are made without the useof halogenated flame retardants and do not containphthalates, GLS said.

Visit www.glscorporation.com or call 800-457-8777for more information.

DSM N.V. has introduced Keltan 1200A, an ultra-low viscosity EPDM for the petroleum additives marketor processing additive for rubber applications. DSMsaid key processing benefits include excellent wettingproperties for fibers and fillers and improved adhesionin rubber compounds.

For information, visit www.dsm.com.

B&H Tool Co. has added to its line of plastic extru-sion tooling for cable, hose, pipe and profiles. Includedare: the Wedge Ring Remover, which enables operatorsto instantly pop out the wedge ring after each extrusionrun; the Core Tube Remover that allows for removal ofthe core tube from the front end of the crosshead with-out damaging the front end; and a striping attachment,enabling the co-extrusion of a single, dual, triple orquad stripe, B&H said.

Call 800-272-8878 or visit www.bhtool.com for de-tails.

Bluestar Silicones USA Corp. has come out withSilcolease Poly 366, a solventless silicone polymer thatoffers a flat release coating system for liners and lami-nators. Designed to be used with Silcolease Optima se-ries technology, the company said the multifunctionalpolymer can be customized for fast cure, low-tempera-ture cure or platinum formulation reduction.

For more information, call 866-474-6342 or visitwww.bluestarsilicones.com.

Dr. Boy GmbH & Co. K.G. has introduced theBOY XS, a compact injection molding machine with aclamping force of 100kN.

The machine is also available as an insert-moldingmachine with vertically arranged clamping and injec-tion units, called the BOY XS V. The two models aresuited for automation solutions from granules to the

finished and packaged molded part, the companysaid.

Visit www.dr-boy.de for more information.

Pallmann Maschinenfabrik GmbH & Co. K.G. has de-veloped the Ultra-Granulator PS-C for the economicalsize reduction of natural and synthetic rubber of anykind. A guillotine integrated into the infeed chute thatcuts the rubber bales into size-reduced slices elimi-nates a separate processing step outside the machineand makes any precutting unnecessary, according tothe firm. Built of welded steel construction, the mill isdesigned for rough continuous operation. For moreinformation call 973-471-1450 or visit www.pallman-npulverizers.com.

knowledge the various contributionsmade by individuals within their respec-tive organizations to those presenta-tions and this manuscript.

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34 (1993).27. D.L. Norwood, D. Prime, B.P. Downey, J.Creasey, S.K. Sethi and P. Haywood, J. Pharm. Bio-med. Anal. 13, 293 (1995). 28. X.K. Zhang, R.C. Dutky and H.M. Fales, Anal.Chem. 68, 3288 (1996).29. D.M. Paskiet, PDA J. Pharm. Sci. Technol. 51,248 (1997).30. F. Zhang, A. Chang, K. Karaisz, R. Feng and J.Cai, J. Pharm. Biomed. Aqnal. 34, 841 (2004).31. J. Castner, N. Williams and M. Bresnick, Am.Pharm. Rev. 7, 70 (2004). 32. B. Xiao, S.K. Gozo and L. Herz, J. Pharm. Bio-med. Anal. 43, 558 (2007).33. B. Sharma, F. Bader, T. Templeman, P. Lisi, M.Ryan and G.A. Heavner, Eur. J. Hosp. Pharm. 5, 86(2004).34. K. Boven, J. Knight, F. Bader, J. Rossert, K.Eckardt and N. Casadevail, Nephr. Dialy. Trans.20, ii30 (2005).35. J. Pang, T. Blanc, J. Brown, S. Labrenz, A. Vil-lalobos, A. Depaolis, S. Gunturi, S. Grossman, P.Lisi and G.A. Heavner, PDA J. Pharm. Sci. Tech.61, 423 (2007).36. Product Quality Research Institute Leachablesand Extractables Working Group, D.L. Norwood(Chair), “Safety Thresholds and Best Practices ForExtractables and Leachables in Orally Inhaled andNasal Drug Products,” Product Quality ResearchInstitute, http://pqri.org/pdfs/LE_Recommenda-tions_to_FDA_09-29-06.pdf , Sept. 2006.37. Nasal Spray and Inhalation Solution, Suspen-sion, and Spray Drug Products – Chemistry, Manu-

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RubberContinued from page 29

IAC purchases pieces of supplier StankiewiczBy Douglas Bolduc

Automotive News

KREFELD, Germany—InternationalAutomotive Components Group has ex-panded its global automotive carpetsand acoustic parts business by purchas-ing key pieces of insolvent German sup-plier Stankiewicz GmbH.

The acquisition strengthens IAC’s op-erational capability and technical know-

how in those areas, making it a leaderglobally, as it has been in North Ameri-ca, said IAC Chairman Wilbur L. Ross.

IAC bought Stankiewicz’s nine plantsin Germany, Belgium, Poland and theCzech Republic for an undisclosedamount. The deal is expected to be com-pleted by early to mid-July, at which timeStankiewicz will emerge from insolvency.

The plants generate about $208 mil-

lion in annual sales, IAC said.Stankiewicz supplies insulation,

dampening products, sound absorbers,floor coverings and other coverings. Afterit filed for insolvency on Dec. 29, 2008,key customers such as BMW A.G. andDaimler A.G. provided the 64-year-oldcompany unspecified support to preventdisruption of their assembly lines.

Stankiewicz’s other customers include

Audi, Renault and General Motors Corp.The company’s two U.S. factories, one

in Spartanburg, S.C., the other inVance, Ala., and its factory in Sauzet,France, are not part of the deal.

The Stankiewicz facilities will be ab-sorbed into IAC’s European businessunit, which is made up of operations onceowned by U.S. suppliers Lear Corp., Vis-teon Corp. and Collins & Aikman Corp.

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