RPN20090629P015.
qxp 6/24/2009 2:59 PM Page 1
www.rubbernews.com
Characteristics of rubber used in pharmaceuticals
By Daniel L. Norwood
Boehringer Ingelheim Pharmaceuticals Inc.
Michael Ruberto
Material Needs Consulting L.L.C.
Fran L. DeGrazio
West PharmaceuticalServices Inc.
Jim Castner
Lantheus Medical Imaging
Wai Kueng Wong
ExxonMobil Chemical Europe
and Dennis Jenke
Baxter Healthcare Corp.
Pharmaceutical products produce a
desirable therapeutic outcome when
they are administered to a subject to ad-
dress an issue related to health. In order
to produce this outcome, pharmaceutical
products must be manufactured, stored
and administered.
Systems that accomplish these objec-
tives do so because of their design and
their materials of construction. In cer-
tain situations, rubber materials pos-
sess the required performance charac-
teristics and thus are widely used in the
pharmaceutical industry.
Pharmaceutical products are formu-
lated, and administration regimens are
developed to maximize their therapeutic
benefit.
Any action that modifies the product’s
composition can adversely impact the
derived benefit.
For example, contact between the
product and its associated systems may
TECHNICAL NOTEBOOK
Edited by Harold Herzlichh
initiate an interaction, potentially re-
sulting in a meaningful change in the
product that could impact its ability to
produce the desired therapeutic out-
come.
One such change could be the migra-
tion of a compound out of the system
and into the pharmaceutical product.
Such a compound could exert an unde-
sirable influence on, or could impart an
undesirable 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 use
would adversely affect the health and/or
well-being of the user (safety), and
● Interference with product testing.
Such interactions between pharma-
ceutical products and their associated
systems are well documented in the lit-
erature.
The knowledge that such interactions
can and do occur and that they can and
do have documented product conse-
quences has led to an increased aware-
ness of this issue in the pharmaceutical
community and is the driving force be-
hind the issuance of regulations de-
signed to ensure that suitability for use
issues are readily and universally recog-
nized, appropriately investigated and
properly assessed.
Specifically, regulatory agencies in
the U.S. and European Union have is-
sued guidance and guidelines to specifi-
cally address packaging (container clo-
sure) systems (and their materials of
construction) used for pharmaceutical
Rubber & Plastics News ● June 29, 2009 15
Technical
starts with scouting of the finished prod-
uct for leached substances.
Executive summary The primary reason that this is the
Rubber materials are widely used in systems used to manufacture, package case is the complexity of the analytical
and deliver pharmaceutical products. task involved in such a scouting process.
While the rubber material’s nature and composition gives it its necessary and In many cases the finished drug prod-
desirable performance characteristics, these material properties can have im- uct is a complex mixture of the active in-
portant and potentially detrimental consequences for the pharmaceutical prod- gredient, multiple formulation compo-
ucts. nents, impurities and decomposition
Interactions between these materials and the pharmaceutical products they products.
contact are well known and documented and can result in a change in the prod- The considerable analytical challenge
uct’s composition, which may adversely affect product safety (e.g., the product in performing a leachables assessment
produces an unanticipated and adverse user response) and/or efficacy (e.g., the is to uncover, identify and quantitate
product performs in a manner inconsistent with its labeling and indication). “unknown” leachables in trace quanti-
Therefore, rubber materials used in pharmaceutical products must be evalu- ties in the complex formulation matrix.
ated to determine what material components can, and do, migrate from the ma- This analytical challenge of “finding a
terials and accumulate in the pharmaceutical product, as it is through the pres- needle in the haystack when you don’t
ence and actions of such substances that product safety and/or efficacy may be even know what the needle looks like” is
compromised. greatly simplified if one is given the
The characterization of materials for their extractables (substances that can probable identity of the needle.
migrate) and of products for their leachables (substances that do accumulate) is In the case of leachables testing, this
a necessary and complex part of the development, registration and manufactur- means that it is far easier to determine
ing and distribution and therapeutic products. if a sample contains a known ex-
This manuscript provides a general overview of the extractables and leach- tractable than to determine if the sam-
ables issues associated with materials used with/in therapeutic products. ple contains any “unknown” compounds.
Thus, the extractables profile of the
system establishes what the probable
leachables are.
products. an entity out of a system results in the Test methods and procedures can be
The relevant document in the U.S. is accumulation of an entity in the phar- developed and implemented to specifi-
the Food and Drug Administration maceutical product. cally determine which of the extracta-
Guidance for Industry, Container Clo- Thus the interaction between a sys- bles do accumulate in the product at
sure Systems for Packaging Human tem and a product can be assessed by measurable quantities (and are thus
Drugs and Biologics.1 In this document, considering either those substances leachables).
the FDA establishes the concept of “suit- present in the packaging which could Extractables testing is also relevant
able for its intended use.” Specifically, in migrate from the packaging or those in other facets of product quality assess-
section II.B.1 of the Guidance, the FDA substances, derived from the packaging, ment.
notes that “every proposed packaging that are present in the product. For example, extractables assess-
system should be shown to be suitable Although these two sets of substances ments may be a relevant means of exer-
for its intended use.” may be closely related (Fig. 1), there cising ongoing quality control.
The guidance goes on to establish four can be clear differences between them, It is reasonable to anticipate that
aspects of suitability for use: and thus the terms extractables and there might be circumstances where it is
● Protection (that “a container closure leachables were adopted to reflect the necessary to control, or demonstrate
system should provide the dosage form populations and emphasize their differ- control of, the effect lot-to-lot variation
with adequate protection from factors ences. The rigorous definitions of these in a system material on the product’s
(e.g., temperature, light) that can cause two terms follow: leachables profile. This objective can be
a degradation in the quality of the ● Leachables: Those substances that met by rigorous batch-to-batch testing of
dosage form over its shelf-life”), are present in the therapeutic product the system materials.
● Compatibility (that the product and because of its contact with a material, Because material testing is an ex-
container closure “will not interact suffi- component, system, etc. tractables assessment, extractables
ciently to cause unacceptable changes in ● Extractables: Those substances that studies are frequently utilized in ongo-
the quality of either the dosage form or are present in the material, component, ing quality control.
the packaging component”), system, etc, that can be extracted from Additionally, there are certain in-
● Safety (that the “packaging compo- that material by a solvent. stances where it is required that the
nents should be constructed of materials On the surface it seems logical that system and its components be “charac-
that will not leach harmful or undesir- the best and most direct approach to as- terized.” An extractables assessment is
able amounts of substances to which a sessing system—product interactions is a material characterization tool; a leach-
patient will be exposed when being to test the therapeutic product for leach- ables assessment is not.
treated with the drug product”), and ables, as opposed to testing the system
● Performance (that the container clo- for extractables. Extractables in pharmaceutical
sure system “functions in a manner for This is true because testing the prod- rubber materials
which it was designed”). uct for leachables produces the exact It is an unfortunate circumstance that
The regulatory requirements for the data that needs to be interpreted (that the performance characteristics re-
products marketed in the European is, what is actually in the product that quired in pharmaceutical applications
Union are captured in the European could affect its safety and/or efficacy) are not intrinsic to the “pure” or “base”
Medicines Agency’s Guideline on Plastic while testing the system for extractables rubber but rather are imparted to the
Immediate Packaging Materials.2 still leaves the question “to what extent elastomer via its chemical modification.
While there are clear and meaningful will these extractables accumulate in In order to produce the actual materi-
differences in the scope and specifics of the actual product?” als used in pharmaceutical applications,
the U.S. and EU guidance documents, Despite this logic, it is rarely the case the base elastomer is combined and/or
the EU Guidelines are very much in line that the suitability for use assessment See Rubber, page 16
with the suitability for intended use con-
cepts in general and with the four di- Table I. Examples of packaging concerns for common classes of drug products.
mensions of suitability for use enumer-
ated in the FDA guidance in particular.
The EMEA guidelines deal very
specifically with the dimensions of safe-
ty and certain aspects of compatibility
(primarily drug sorption and altered
drug degradation) and consider the di-
mensions of protection and performance
more by inference than substantive
text.
Extractables and leachables:
General concepts
As noted previously, the migration of
RPN20090629P016.qxp 6/24/2009 3:01 PM
16 Rubber & Plastics News ● June 29, 2009
Rubber
Continued from page 15
reacted with a number of chemical
agents or additives (e.g., vulcanizing
agents, accelerators, activators, plasti-
cizers, tackifiers, colorants, fillers, an-
tioxidants, lubricants, see Table II) un-
der harsh conditions of high temperature
and pressure.
These substances, their impurities
and their processing-induced reaction or
decomposition products are all potential
extractables.
The more commonly utilized classes of
additives are considered in greater de-
tail as follows.
Curing and vulcanizing agents: Nat-
ural rubber and synthetic analogs are
often processed (e.g., cured and/or vul-
canized) to obtain a material with the
required physical and chemical proper-
ties.
These chemical agents, which typical-
ly contain either sulfur or peroxide, re-
act with active sites along the polymer
chain to produce cross-linking.
The processes of vulcanization and/or
curing may be facilitated by accelera-
tors (such as guanidines, thiazoles, thi-
urams and dithiocarbamates) and/or
activators (such as a metal oxide or fat-
ty acid).
Antioxidants: Rubber articles are ex-
posed to oxidation, flex, fatigue, ozone
and light during their shelf-life. Addi-
tionally, many rubber parts are steril-
ized by gamma irradiation prior to use
in pharmaceutical applications.
To improve their durability, they have
to be protected by different additives.
For example, the oxidation of rubber
can be considerably reduced by the addi-
tion of antioxidants, chemicals that de-
stroy and scavenge oxy radicals before
they have opportunity to react with rub-
ber chains.
The origins of degradation in poly-
mers are radical species such as:
R• Alkyl radical
RO • Alkoxy radical
ROO • Peroxy radical
ROOH Hydroperoxide
Therefore, radical scavengers such as
hindered phenols (e.g., Irganox-and Ir-
gafos-type compounds) are commonly
used in rubber formulations.
Fillers, such as metal silicates, silica,
calcium carbonate and carbon black, are
present in the rubber formulation to im-
pact certain of the material’s mechani-
cal properties, including hardness and
moisture sorption/desorption.
Light stabilizers are commonly used
to protect elastomers from sunlight as
well as artificial lighting. Many of these
chemistries include benzophenones,
benzotriazoles, or triazines. This topic
will be discussed in greater detail below.
Acid scavengers are used to neutralize
traces of halogen anions formed during
aging of halogen-containing rubbers. If
not neutralized, the anions would cause
premature aging of rubber and perform-
ance of rubber articles would signifi-
cantly deteriorate with time.
Effective acid scavengers include lead
oxides and lead salts (which are being
phased out because of environmental
concerns), magnesium oxide and moi-
eties such as Hycite 713.
Metal deactivators are used to control
metal-catalyzed hyperoxide decomposi-
tion. Hydroperoxides are species within
the “autoxidation cycle” that contribute
to the degradation of rubber vulcan-
izates.
Rubber poisons (such as copper, iron,
cobalt, nickel and other transition met-
Page 1
Technical
als) present in vulcanizates, even in
trace amounts (less than 5 parts per
million), increase the decomposition rate
of hydroperoxides and thus accelerate
oxidation and aging of rubber goods.
Therefore, rubber that contains or
could be in contact with rubber poisons
requires a specific stabilizer, a so-called
metal deactivator, for example, 2’,3-
bis[[3-[3,5-di-tert-butyl-4-hydroxyphenyl]
propionyl]]propionohydrazide (Irganox
MD 1024). The metal deactivator binds
ions 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 to
rubber formulations for the purpose of
identification, branding and protection.
Antimicrobials and fungicides: Mi-
crobial growth on the rubber surface
can lead to discoloration, staining, odor
development or the formation of
biofilms that ultimately, result in dete-
rioration of mechanical properties of
the product. Antimicrobials and fungi-
cides may be used by resin manufactur-
ers and molders to maintain the fresh-
ness, durability and aesthetics of the
elastomer.
Additional rubber additives include
plasticizers, processing aids, slip agents,
clarifiers, antistats and others.
Utilization of rubber materials in
pharmaceutical systems
The use of elastomers in the medical
industry is nearly as old as the rubber
industry itself.
The potential utility of elastomers as
components of packaging and delivery
devices was recognized shortly after the
discovery of the vulcanization process.
The unique properties of processed
rubber, including elasticity, penetrabili-
ty, resiliency, ability to act as a gas/val-
or barrier and general chemical compat-
ibility were the driving force behind its
ready adoption in early 21st century
pharmaceutical applications (primarily
as closures for glass vials), and it is the
fact that these properties are largely un-
matched by today’s polymers and plas-
tics that ensures rubber’s continued use
in modern pharmaceutical practice (clo-
sures, O-rings, plungers, seals, etc.).
Considering the conditions of contact
between an elastomer and a therapeutic
product, which can include elevated
temperatures, long contact times and
aggressive pharmaceutical products
Fig. 1. The relationship between ex-
tractables and leachables. Although
these two populations of entities typi-
cally share members in common, with
leachables being a subset of extracta-
bles, there are many reasons and many
cases where the extractable does not
equal leachables and leachables are
not equivalent to extractables.
www.rubbernews.com
(e.g., products whose composition is of these substances from the rubber
such that they are effective “solubilizing component, and of the “deactivation” of
agents”) and the nature of the elas- penicillin by rubber tubing by mercap-
tomer (e.g., relatively high amounts of tans leached from the tubing. The uti-
numerous additives, some of which are lization of a Teflon liner to retard the
poorly bound by the base material and leaching of extractives was repoted by
some of which are exposed to the phar- Lachman in 1964.13
maceutical product because they have The development of modern chro-
bloomed to the contact surface), it not matographic and spectroscopic analyti-
surprising that consequential interac- cal methods facilitated the investigation
tions between elastomeric parts and of rubber materials for organic extracta-
pharmaceutical products occur with bles.
some regularity. The period of time between the early
Incompatibility issues associated with 1970s to the present was one of active
the use of rubber closures in pharma- research in this area.14-32
ceutical products were observed in the Given the long and active history of
early days of rubber utilization. investigation into rubber and product
For example, the loss of preservatives interactions, one might conclude that in
such as stabilizers like cresol or phenol the current environment all the issues
from pharmaceutical products was re- have been resolved and that rubber ma-
ported as early as 1923 and was the sub- terials used in pharmaceutical applica-
ject of extensive investigation in the tions are inherently and eminently suit-
1950s.3-8 able for use.
Issues such a haze formation and While it is certainly the case that in-
leaching of zinc from closures and sy- creased awareness of, and knowledge
ringe plungers were quantitatively in- about, suitability for use issues has driv-
vestigated in the middle 1950s as viable en developments in rubber composition,
analytical methodologies were devel- processing and utilization, such a desir-
oped.9,10 able state of affairs has not been fully
The identification of 2-(methythio) realized.
benzothiazole in water extracts of On one hand development of the per-
plungers from disposable syringes was fectly suitable rubber is limited by the
reported in 1965.11 fact that there are limited choices in
In a review published in 1966, Capper terms of material composition and pro-
discusses various types of interactions cessing.
between rubber and medicants, includ- The dual requirements of functionali-
ing the deposition of particulates into ty and suitability are, to some extent, in-
the drug product, the adsorption of herently mutually exclusive, and thus
preservatives and medicants, “yielding there is a limited amount of “wiggle
into the solution the various materials room” in the composition and processing
added as accelerators or antioxidants, or design space that defines a viable prod-
materials derived from vulcanizing uct.
agents, and water absorption.”12 On the other hand, pharmaceutical
Included in this review is the report of products, especially biopharmaceuticals,
the formation of a stearate-containing are becoming more compositionally com-
deposit in eyedrops because of leaching plex and “sensitive” to perturbations re-
Table II. Additives used in rubber formulations.
The authors
Daniel L. Norwood is a distinguished research fellow in the Analytical Sci-
ences Department at Boehringer Ingelheim Pharmaceuticals Inc. He has held
positions at Magellan Laboratories, Glaxo Research Institute, Duke University
Medical Center and the University of North Carolina School of Public Health.
He chairs the PQRI Working Group on Leachables and Extractables for orally
inhaled and nasal drug products.
Michael Ruberto is the president of Material Needs Consulting L.L.C., which
provides consulting services to manage the development and commercialization
of medical devices and packaging, with a special emphasis on material selec-
tion, extractables and leachables, and supply chain management. Ruberto also
was employed by Ciba Specialty Chemicals for 15 years..
Fran DeGrazio has been in the pharmaceutical packaging industry for 25
years with expertise in delivery of injectable drug products. In 2006 she moved
into 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 Medical
Imaging (formerly Bristol-Myers Squibb Medical Imaging Division) with more
than 16 years experience in the pharmaceutical industry. He had also worked
for more than 10 years at DuPont in the Medical Products and the Agriculture
Crop Protection units as a primary investigator.
John Wong, senior staff scientist with ExxonMobil Chemical Europe, joined
the company in 1987 and was involved in various application developments on
polyolefins 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 of
Baxter 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 relevant
solutions and samples.
RPN20090629P017.qxp 6/25/2009 2:43 PM Page 1

www.rubbernews.com Rubber & Plastics News ● June 29, 2009 17

lated to material interactions. The jux-
taposition of these two trends means
that rubber/product interactions are
still an important product design consid-
eration and constraint.
This observation is supported by re-
cent reported adverse events that have
been associated with rubber/product in-
teractions.
For example, one of the most widely
documented instances of an unanticipat-
ed incompatibility between a rubber
Technical
component of a container closure system
and a protein drug product is that of
Eprex (epoetinum alfa) and its pre-filled
syringe 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 a
formulation stabilizer.
Shortly after this change, the inci-
dence of anti-body mediated pure red
cell aplasia (PCRA) with Eprex use by
chronic renal failure patients increased.
The cause of PCRA was directly linked
to the formation of neutralizing antibod-
ies to both recombinant and endogenous
erythropoietin in patients administered
Eprex. A considerable, cross-functional
technical effort was undertaken to es-
tablish the root cause of this phenome-
non. One potential root cause involved
leached substances.
The presence of previously unidenti-
fied leachables was suggested as new
peaks in the tryptic map of Eprex.
Leaching studies determined that the
polysorbate 80 extracted low levels of
vulcanizing agents (and related sub-
stances) from the uncoated rubber com-
ponents of the pre-filled syringe.
This leaching issue was addressed by
replacing the rubber components with
components coated with a fluoropoly-
mer.
See Rubber, page 18

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6/09
RPN20090629P018.qxp 6/25/2009 2:47 PM
18 Rubber & Plastics News ● June 29, 2009
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 epoetin
products. This is strong circumstantial
evidence that leaching of the vulcaniz-
ing agent was, in fact, the root cause of
the observed effect.
Orally inhaled and nasal drug
products as example of extracta-
bles and leachables issues
Orally inhaled and nasal drug prod-
ucts (OINDP) are a drug product class
used for the treatment of asthma, chron-
ic obstructive pulmonary diseases
(COPD), and systemic conditions such
as diabetes. OINDP include metered
dose inhalers (MDIs), dry powder in-
halers (DPIs), nasal sprays, inhalation
solutions and inhalation sprays.
OINDP are unique among drug prod-
uct types in that the container closure
system is an integral part of the drug
product and critical for drug product
performance. Container closure systems
can include rubber, plastic, metal and
other components.
Rubber components are most often
used as seals, especially in metered dose
inhalers (Fig. 2), which include an or-
ganic propellant under pressure as part
of the formulation.
Because rubber and plastic incorporate
chemical additives and processing aids
and metal components often have organic
residues on their surfaces, the potential
exists for leaching of these chemicals from
the components into the formulation.
The degree of regulatory concern re-
garding organic leachables in OINDP is
summarized in Table I, which is adapt-
ed from the FDA’s so-called “Packaging
Guidance.”1 In Table 1, the “Likelihood
of Packaging Component-Dosage Form
Interaction” (e.g. the likelihood of leach-
ing) is linked with the “Degree of Con-
Fig. 2. Schematic diagram of a metered dose inhaler, from Bespak P.L.C.
Page 1
Technical
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 sensitive
and compromised. OINDP patients in-
clude individuals with asthma and vari-
ous COPD (chronic obstructive pulmonary
diseases, such as chronic bronchitis and
emphysema) 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 sudden
narrowing of the airway, as in an asthma
attack) or the underlying condition, has
the effect of inducing bronchospasm.40
Paradoxical bronchospasm is a potential-
ly life threatening event.
Although the causes of paradoxical
bronchospasm are not well understood,
it is advisable to reduce to the extent
practical any potential irritant.
● OINDP tend to be for chronic admin-
istration, and therefore long-term use.
OINDP are designed for the treatment
of asthma, COPD and other systemic
disease conditions such as diabetes. It is
therefore likely that patients will take
OINDP for many years if not decades.
Additionally, because MDI drug prod-
ucts include organic solvents under
pressure in direct contact with rubber
and plastic container closure system
components, there is a high likelihood
for interaction and leaching.
Because of this high level of concern,
two specific guidance documents dealing
with OINDP were issued by the FDA,
one of which is related to “Nasal Spray
and Inhalation Solution, Suspension
and Spray Drug Products”37 and the oth-
er (still at the time of this writing in
draft form) related to “Metered Dose In-
haler and Dry Powder Inhaler Drug
Products.”38
These guidance documents, along with
the “Packaging Guidance,”1 describe
what is generally expected for regulatory
submissions related to inhalation drug
products. Specifically, for MDI drug
products the guidance suggests:38
“Since inhalation aerosol formulations
include organic liquids as the propel-
lants or the vehicle (e.g. chlorofluorocar-
bons, hydrofluorocarbons, alcohols), po-
tential leaching of compounds from the
elastomeric and plastic components of
the container and closure system into
the formulation is a serious concern that
should be addressed.
“Therefore, the composition and quali-
ty of the materials used in the manufac-
ture of the container and closure system
components should be carefully selected.
“For safety considerations, materials
should be chosen that minimize or elimi-
nate leachables without compromising
the integrity or the performance of the
drug product.”
Further, the guidance says:
“Identity and concentration profiles of
the leachables in the drug product or
placebo formulation (e.g. drug product
formulation without drug substance)
should be determined through the end of
the drug product’s shelf life and corre-
lated, if possible, with the extractables
profile(s) of the container and closure
components determined under the vari-
ous control extraction study conditions.”
To increase efficiency in the pharma-
ceutical development process, as well as
increase the likelihood of earlier regula-
tory approvals for new inhalation drug
products, the developers of inhalation
drug products desired even greater clar-
ification regarding the regulatory re-
quirements for extractables/leachables
testing, qualification and control.
In late 2001, a Leachables and Ex-
tractables Working Group was formed
by the Product Quality Research Insti-
tute to address the issue of leachables
safety qualification thresholds in in-
halation drug products.
Based on a developed hypothesis and
step-wise investigative plan, which in-
cluded both literature investigations
and laboratory work, the PQRI L&E
Working Group produced a “Recommen-
dation Document” in 2006 which was
submitted to the FDA.36
The PQRI recommendations include
two safety thresholds for leachables in in-
halation drug products: “Qualification
Threshold” (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 defined
as “the threshold below which a given
leachable is not considered for safety
qualification (toxicological assessments)
unless the leachable presents structure
activity relationship concerns,” whereas
the concern threshold is defined as “the
threshold below which a leachable would
have a dose so low as to present negligible
safety concerns from carcinogenic and
noncarcinogenic toxic effects.”36
The threshold at or above which a
chemist should begin to identify a par-
ticular leachable and/or extractable and
report it for potential toxicological as-
sessment, was defined as the “Analyti-
cal Evaluation Threshold,”36 which is de-
rived from the concern threshold with
consideration of an individual drug
product’s dosing requirements.
It is noted that the safety thresholds
do not apply to the so-called “special
case” compounds and compound classes
(PAHs, N-nitrosamines, and 2-mercap-
tobenzothiazole), which are deemed by
the regulatory authorities to have spe-
cial safety concern and therefore should
be evaluated and controlled with tech-
www.rubbernews.com
nology-based thresholds.
The PQRI recommendations also in-
cluded “Best Practices” for inhalation
drug product development with regard
to extractables and leachables.
The best practice recommendations
cover the areas of selection of compo-
nents, controlled extraction studies,
leachables studies and routine extracta-
bles testing. Both the safety thresholds
and best practice recommendations
have been independently reported in the
scientific literature.41, 42
Developments in elastomers used
in pharmaceutical applications
While the ultimate objective of having
cost effective, broadly applicable, func-
tional and suitable pharmaceutical rub-
ber materials has only been partially re-
alized, ongoing developments and future
innovations in rubber composition, rub-
ber compounding, rubber processing and
rubber utilization have the potential to
close the gap between the utopia of to-
morrow and the reality of today.
Vendors of rubber materials and parts
used in pharmaceutical applications
have been actively engaged in address-
ing extractables and leachables issues.
The development and utilization of
peroxide-cure systems to replace sulfur-
based curing processes is an important
example of this engagement.
Additionally, many vendors of rubber
materials to the pharmaceutical indus-
try have developed grades of such mate-
rials that can generically be described as
being “low in extractables.”
One such example is brominated
isobutylene paramethylstyrene tere-
polymer (BIMSM) has been reported to
be a very clean material that can be vul-
canized effectively by a low level of clean
curatives.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 users
of rubber materials.
An extreme example of the vendor’s
increasing willingness to provide such
information is the VeriSure product line
offered by West Pharmaceuticals.
VeriSure products are certified on a
lot-to-lot basis for extractables and the
individual material lots are supported by
comprehensive extractables documenta-
tion including an extractable “finger-
print” and an extractables specification.43
The aforementioned advances in the
strategies for designing, performing and
interpreting extractables and leachables
safety assessments, in the composition
of the materials themselves and in the
level of vendor participation in the as-
sessment process are further augmented
in advances in the tactics (e.g., analyti-
cal approaches) utilized in the various
facets 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 timely
product development, registration, mar-
keting and stewardship, supported by
the principles of good science and Quali-
ty by Design.
Acknowledgements
This manuscript is a compilation of
presentations made by the authors at
the Fall 174th Technical Meeting of the
Rubber Division of the American Chemi-
cal Society, held in Louisville, Ky., in
October 2008.
The individual authors wish to ac-
See Rubber, page 19
RPN20090629P019.qxp 6/25/2009 2:57 PM Page 1

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

IAC purchases pieces of supplier Stankiewicz

By Douglas Bolduc
Automotive News
KREFELD, Germany—International
Automotive Components Group has ex-
panded its global automotive carpets
and 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 leader
globally, as it has been in North Ameri-
ca, said IAC Chairman Wilbur L. Ross.
IAC bought Stankiewicz’s nine plants
in Germany, Belgium, Poland and the
Czech Republic for an undisclosed
amount. The deal is expected to be com-
pleted by early to mid-July, at which time
Stankiewicz 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. After
it filed for insolvency on Dec. 29, 2008,
key customers such as BMW A.G. and
Daimler A.G. provided the 64-year-old
company unspecified support to prevent
disruption 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 in
Vance, Ala., and its factory in Sauzet,
France, are not part of the deal.
The Stankiewicz facilities will be ab-
sorbed into IAC’s European business
unit, which is made up of operations once
owned by U.S. suppliers Lear Corp., Vis-
teon Corp. and Collins & Aikman Corp.

Elastocon TPE Technologies Inc. has published a
brochure for its full line of custom and standard SEBS
and 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 visit
www.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-sandwich
molding onto a rigid polypropylene substrate to pro-
duce an unfoamed structure that does not indent. Also
colorable, Santoprene TPV M350 offers low- and stable-
gloss level, high scratch and mar resistance, good abra-
sion and chemical resistance, low fogging and odor
emission, the company said.
For more information, call 281-870-6007 or visit
www.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 a
tough, puncture-resistant protective layer, the firm
said. Specific applications include stick-wound
coils/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 for
details.
Sartomer Co. has come out with improved retarder
technology for the company’s crosslinking coagents.
The retarder systems are less volatile, odorless and
persist in the compound even at high processing tem-
peratures, the company said. Sartomer products using
the proprietary retarder packages are designated with
an 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-
Products
dant thermoplastic elastomers that provide an alterna-
tive to traditional flexible vinyl jacketing and insula-
tion for consumer electronics applications. GLS’ OnFlex
TPE materials comprises five groups of high-perform-
ance compounds. All grades are made without the use
of halogenated flame retardants and do not contain
phthalates, GLS said.
Visit www.glscorporation.com or call 800-457-8777
for more information.
DSM N.V. has introduced Keltan 1200A, an ultra-
low viscosity EPDM for the petroleum additives market
or processing additive for rubber applications. DSM
said key processing benefits include excellent wetting
properties for fibers and fillers and improved adhesion
in 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. Included
are: the Wedge Ring Remover, which enables operators
to instantly pop out the wedge ring after each extrusion
run; the Core Tube Remover that allows for removal of
the 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 or
quad stripe, B&H said.
Call 800-272-8878 or visit www.bhtool.com for de-
tails.
Bluestar Silicones USA Corp. has come out with
Silcolease Poly 366, a solventless silicone polymer that
offers a flat release coating system for liners and lami- Pallmann Maschinenfabrik GmbH & Co. K.G. has de-
nators. Designed to be used with Silcolease Optima se- veloped the Ultra-Granulator PS-C for the economical
ries technology, the company said the multifunctional size reduction of natural and synthetic rubber of any
polymer can be customized for fast cure, low-tempera- kind. A guillotine integrated into the infeed chute that
ture cure or platinum formulation reduction. cuts the rubber bales into size-reduced slices elimi-
For more information, call 866-474-6342 or visit nates a separate processing step outside the machine
www.bluestarsilicones.com. and makes any precutting unnecessary, according to
the firm. Built of welded steel construction, the mill is
Dr. Boy GmbH & Co. K.G. has introduced the designed for rough continuous operation. For more
BOY XS, a compact injection molding machine with a information call 973-471-1450 or visit www.pallman-
clamping force of 100kN. npulverizers.com.
The machine is also available as an insert-molding
machine with vertically arranged clamping and injec- finished and packaged molded part, the company
tion units, called the BOY XS V. The two models are said.
suited for automation solutions from granules to the Visit www.dr-boy.de for more information.

Rubber 9. S. Reznek, J. Am. Pharm. Assoc. 42, 288 (1953).

Continued from page 29
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