Developing Polyisoprene Materials that Meet USP 381 Guidelines

ELECTRONICALLY REPRINTED FROM JULY 2014
Developing Polyisoprene Materials that
Meet USP 381 Guidelines
By Saman Nanayakkara, Shu Peng, and Gino G. Banco
A new grade of polyisoprene compounds complies with USP 381 guidelines for both
Type I and Type II elastomeric closures.
P
olyisoprne has been utilized in a variety of general
industrial and commercial
applications since the mid-1800s.
That time only available polyisoprene was natural rubber. In select
applications, it has also found favor
in the medical industry. Derived
from the latex of the Pará tree, it
is composed of long chains of isoprene monomers. However, the
recognition that certain proteins
in natural rubber can elicit allergic
reactions has posed a significant
hurdle for medical device developers interested in exploiting the
material’s mechanical and physical
properties in medical device applications, compelling them to search
for alternatives.
This quest has led to investigate
into synthetic rubber material options, including polyisoprene.
However, while polyisoprene compounds are viable alternatives to
natural rubber, traditional compounds of this synthetic polyiso-
prene did not meet all the requirements of U.S. Pharmacopeia’s USP
381, , “Elastomeric Closures for
Injections.1 This dillema has created the need for a new polyisoprene
compound that can meet the 2009
USP 381, Type I requirements.
Such a material would lessen the
regulatory burden facing medical
device developers while providing superior resealability and other
functional characteristics not typically achieved using other elastomeric materials
Why Polyisoprene?
In the mid-1950s, scientists discovered new types of catalyst systems that allowed for the development of synthetic polyisoprene
rubber. Commonly referred to as
polyisoprene, synthetic polyisoprene rubber is a cleaner, more consistent analog to its natural cousin.
It does not contain proteins, eliminating the allergen issue that has
limited the use of natural rubber in
the medical device industry. Additionally, polyisoprene has a similar
set of desirable mechanical, physical, and chemical characteristics as
its natural counterpart, providing
advantages for medical device applications.
Excellent material properties
such as tear resistance, rebound
resilience, elastic modulus, compression set, and stress relaxation
can be achieved by compounding
polyisoprene with carefully selected reinforcing fillers, plasticizers,
cure systems, and other specialty
ingredients. If formulated properly,
polyisoprene compounds can meet
USP Class VI and ISO 10993 biocompatibility guidelines.
Additionally, the material has the
unique ability to reseal itself after
being punctured, making it suitable
for septa, or closures for injection
fluid-transfer applications. When a
needle pierces an elastomeric septum such as a vial cap closure or
an IV bag port, it passes through
Table 1: USP <381> testing requirements.
Table 2: Physical and mechanical properties of RJ614-30, RJ649-40, and RJ651-30
polyisoprene compounds.
the seal that protects the inner sterile environment from the outer environment. A properly designed
elastomeric septum must allow easy
needle penetration while maintaining the integrity of the seal at all
times. It must also resist fragmenting, coring, or crumbling to prevent
contamination and occlusions while
exhibiting the ability to reestablish
the seal when the needle is removed.
USP 381–Compliant Polyisoprene
Despite polyisoprene’s many
beneficial properties, it is challenging to use traditional polyisoprene
materials to manufacture medical injection closures because of
stringent guidelines implemented
by various standards organizations.2–4 For example, in “Guidance for Industry: Container Closure Systems for Packaging Human
Drugs and Biologics,” FDA states
that the requirements presented in
“USP Elastomeric Closures for Injection” are typically a baseline for
demonstrating the safety of such
components.5 Hence, any injection
closure application submitted to
FDA after May 2009 is expected to
comply with the updated USP 381
guidelines.
The guidelines classify elastomeric closures into Type I devices
for aqueous preparations and Type
II devices for typically nonaqueous preparations. Type I closure requirements are more stringent than
Type II requirements, especially
for ultravoilet radiation absorbance
and reducing substances. While
certain traditional polyisoprene
compounds meet Type II requirements, they have had difficulty
meeting the updated physiochemical requirements for Type I closures.
After undergoing extensive biological, physicochemical, and functional testing, a new polyisoprene
compound, designated RJ651-30,
has been shown to comply with
USP 381 guidelines for both Type
I and Type II devices. The requirements for each test are presented in
Table 1.Table 2 compares the physical and mechanical properties of
RJ651-30 with those of two traditional polyisoprene compounds that
have historically been used in injection applications: RJ614-30 and
RJ649-40. While these traditional
compounds are USP 381 Type II
compliant, they can no longer be
21-gauge needles, as mandated in
the guidelines.
Since RJ651-30’s self-sealing capacity performance exceeded the
level required in USP 381, this test
was extended to further examine the
material’s limits. First, the material
was tested using needles measuring
Table 3: Physiochemical properties of RJ614-30, RJ649-40, and RJ651-30 polyisoprene
up to 16 gauge, the cross-sectional
compounds.
area of which is four times larger
than that of a 21-gauge needle. The
results of the self-sealing capacity
tests performed using larger needles
are presented in Table 5.
Next, the self-sealing capacity test
Table 4: Functionality tests for RJ651-30 using a 21-gauge needle, per USP <381>
guidelines.
was performed by piercing the vials 10 times using 20-gauge needles
and then placing them under vacuum. Subsequently, the vials were
stressed further by piercing them
once, placing them immediately under vacuum, piercing them again,
Table 5: Self-sealing capacity tests for RJ651-30 using 16- to 20-gauge needles.
and placing them immediately under vacuum again. By repeating
used to manufacture closures for compression set resistance tests at these steps with each vial until a
failure was observed, more vial-toaqueous preparations because they 70°C.
cannot meet Type I physiochemiTable 3 presents selected re- vial resolution was achieved in the
cal requirements. Since compound sults of physiochemical testing. In data, enabling the researchers to unRJ651-30 is Type I compliant, it is particular, the absorbance testing derstand how many times the septa
by definition Type II compliant as highlights the difference between could be punctured and resealed
well, rendering it suitable for use in the traditional compounds and the before failure occurs. All but one
both aqueous and nonaqueous prep- newly developed material. While of the 10 vials tested in this manner
arations.
the traditional compounds satisfy survived 20 cycles, while the failed
Ranging from 30 to 40 Shore A Type II guidelines for absorbance, vial succumbed at five cycles.
durometer, the hardness of the three they fail to meet Type I absorbance
compounds is typical for such ma- guidelines. In contrast, the newly Conclusion
Polyisoprene compounds are well
terials. RJ614-30 and RJ651-30 both developed compound meets Type I
exhibit excellent tensile strength, absorbance guidelines, with UV ab- suited for use in medical septa because of their superior resealability
high elongation, and very good tear sorbance of 0.1 (50% of the limit).
strength. Compound RJ649-40,
Table 4 shows the results of func- and desirable mechanical, physiwhich exhibits the best compression tionality testing for RJ651-30, indi- cal, and chemical characteristics.
set resistance, has slightly lower ten- cating that the material performs However, stringent USP guidelines
sile properties and tear strength than exceptionally well according to the have made it difficult to use tradithe other two materials. All three functionality guidelines described tional polyisoprene compounds in
compounds demonstrate compara- in USP 381. The penetrability, elastomeric closures used for aqueble mechanical and physical proper- fragmentation, and self-sealing ca- ous preparations. While traditional
ties and perform especially well in pacity tests were conducted using compounds can be formulated to
Saman Nanayakkara is laboratory
meet Type II guidelines for non- References
manager
and senior chemist at Parker
1. USP 381, “Elastomeric Closures
aqueous preparations, they do not
for Injections” (Rockville, MD: Hannifin Corp’s Medical Systems Div. He
pass the absorbance requirements
joined the company in 2009. He has over
U.S. Pharmacopeia, 2009).
during physiochemical testing.
2. EP 3.2.9, “Rubber Closures for 25 years of experience in elastomer comIn contrast to traditional polyisoContainers for Aqueous Parenteral pounding, characterization, testing, and
prene compounds, a new polyisoPreparations, for Powders, and for processing. Contact him at saman.nanayprene compound provides proper
Freeze-Dried Powders,” European akkara@parker.com.
Shu Peng is engineering manager at
Pharmacopeia 5.0 (Strasbourg,
mechanical and physical properties
Parker
Hannifin Corp.’s Medical Systems
France: European Pharmacopeia,
while complying with USP 381
Div. He joined the company as a senior
2005).
Type I guidelines. The new com3. JP 7.03, “Test for Rubber Closure development engineer in 1992. He spepound exhibits such good properfor Aqueous Infusions,” Japanese cializes in polymer engineering, rubber
ties as low needle penetration rePharmacopeia, XV General Tests elasticity, and finite element analysis.
sistance, unlikelihood of fragment(Tokyo: Pharmaceuticals and Medi- Contact him at speng@parker.com.
Gino Banco serves as principal R&D
cal Devices Agency, 2006).
ing or coring, and high resealabilengineer
in Parker Hannifin Corp.’s En4. ISO 8871, “Elastomeric Parts for
ity, making it suitable for injection
gineered
Materials
Group. He joined the
Parenterals and for Devices for
septa applications. Because of its
Pharmaceutical Use” (Geneva: In- company in 2010. His focus is on the deability to comply with USP 381,
ternational Organization for Stan- velopment of products and technologies
its excellent mechanical and physifor the life sciences market. In this cadardization, 2005). cal properties, and its ability to
5. “Guidance for Industry: Container pacity, Banco works with the Engineered
incorporate properties from other
Closure Systems for Packaging Hu- Materials Group’s 14 divisions, including
man Drugs and Biologics” (Silver the Medical Systems Div., leading global
polyisoprene compounds such as
Spring, MD: U.S. Food and Drug teams in new materials development,
self-lubrication and antimicrobial
manufacturing, and medical device iniAdministration, 1999).
agents, this compound shows that
tiatives. Contact him at gino.banco@
polyisoprene can still be used in inparker.com
jection septa.
Posted with permission from July 2014. Medical Products Manufacturing News, UBM Canon, Copyright 2014. All rights reserved.
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