PHARMACEUTICALS Silicone tubing

for pharmaceuticals
published by srl
processing
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INTRODUCTION to gases than a comparable silicone

A. COLAS material (3). It is astonishing that silicone
R. MALCZEWSKI This article is about pharmaceutical tubing was already considered at that time,
K. ULMAN
processing and flexible tubing i.e. tubing since silicones in general were not
Dow Corning, Life Sciences made from various polymeric materials, in introduced to the market until around
Av. J. Bordet particular silicone polymers. Stainless steel 1943! Today silicone tubing is used in
B 7180 - Seneffe, Belgium and glass are also widely used in this many operations to assist in the production
application, but as they lie outside this of pharmaceuticals, including fluid transfer,
definition will not be considered further, peristaltic pumping and filling
despite their outstanding and unique operations (4,5).
mechanical properties and inertness (1).
Flexible tubing has gained more
acceptance in recent years as it offers low SILICONE PROPERTIES
costs and simplicity, particularly for single-
use applications where one can reduce Silicones have many interesting properties
costs associated with validation, cleaning-in- that make them suitable for tubing
place (CIP) or sterilisation-in-place (SIP) applications, some of which are listed
and disposal of contaminated waste waters. below (6).
Many of the articles about flexible
tubing for pharmaceutical processing are
generated by suppliers, each one Silicone Polymers
promoting their own attributes/advantages.
Specifiers are then left to build their Silicone is a commercial name describing
experience and search through a maze of many products but most are made from
data to make a final selection. Selecting a polydimethylsiloxanes or PDMS. These
suitable tubing is no simple task: suppliers polymers are characterized by strong
may not openly provide the composition of covalent bonds resistant to homolytic
their tubing (fluoro-elastomer, scission (silicones are UV stable; they are
polyurethane, polyvinylchloride, silicone, also thermally and chemically stable and so
polyolefin, or other), but rather, provide easy to sterilise). The polar backbone can
their opinion of what it is designed for. be susceptible to heterolytic scission but
It is interesting to note that Billmeyer's the methyl groups along the chain provide
textbook seems to offer few insights into the shielding (Figure 1).
general properties of silicones, other than Silicones are therefore hydrophobic and
The objective of this article is to citing their weather resistance (2). Indeed, the contact angle of water on a PDMS
ABSTRACT

give people involved in the silicone elastomers have limited mechanical model surface is high, 108 (7). Because
manufacturing of pharmaceuticals strength and only represent a fraction of the of this hydrophobicity, reactions between
a short, but scientific overview polymers used around us, yet some of their silicones and aqueous media are not
about tubing (in particular, properties make them unique in favoured in the absence of surfactants, and
pharmaceutical applications. This article then only in the presence of very strong
silicone tubing) currently used for
approach is to provide an exhaustive list of bases or acids.
fluid transfer, peristaltic pumping
relevant parameters for silicone tubing, Because of the low methyl-to-methyl
and filling operations. The article including what they can or cannot offer,
will present the benefits and to those who specify tubing.
limitations of such tubing and The first mention of silicone tubing
discuss the variables that need to appeared in 1948 when butyl rubber
be taken into consideration. was shown to have lower permeability

30 MARCH 2004 PHARMACEUTICALS

 Peroxide initiated, where a peroxide is short chain siloxane oligomers i.e.
used to produce radicals R and initiate HO(SiMe2O)nH, or silazanes i.e.
bonds between chains (Eqn. 1). This (Me3Si)2NH, which bond to the silica
works best when the siloxane chains surface and render the silica more easy to
carry some vinyl groups. disperse in the silicone polymer (13).
The peroxide of choice for extrusion,
and to minimize air inhibition, is bis
(2,4-dichlorobenzoyl) peroxide. But, this Silicone Tubing
peroxide gives rise to the formation of
by-products such as 2,4-dichloro- Silicone tubing is made by extrusion of the
Figure 1 3-d view of a short PDMS benzoic acid (10) or various polychloro- above compounded elastomers, known as
oligomer, Me3SiO(SiMe2O)4SiMe3, showing biphenyl congeners (PCB's) (11). high consistency silicone rubbers (HCR).
the shielding of the polysiloxane backbone by
These by-products can affect the These thermo-set materials are available as
the methyl groups.
stability of the tubing, diffuse and two-part products:
Picture courtesy of S. Grigoras, Dow Corning
concentrate at the surface or "bloom", Base plus a peroxide, usually in the
and/or lead to toxicological concerns. form of a paste (or masterbatch) for
intermolecular interactions between PDMS After extrusion of such tubing, and prior the peroxide initiated products; or
chains: to use, these by-products must be Part A and part B for the Pt catalysed
PDMS displays very products.
low Tg (146 K), a In both cases, the
Table I Comparison of the permeability of polydimethylsiloxane
property critical for two components are
with other polymers (9)
silicones to be mixed at the point of
elastomers (see use, for example
below); using a two-roll mill,
PDMS is compatible before extrusion at
with hydrocarbons room temperature
(polymers dissolves in followed by
such non-polar continuous curing in
solvents, while high temperature
elastomers absorb ovens. Different dies
and swell in these and mandrels are
solvents); eliminated by careful post-curing, which used to produce single-lumen tubing of
PDMS is highly permeable to many low may require several hours in ventilated various size and wall thickness (defined
molecular species/non polar ovens at elevated temperatures. by their Outside Diameter/Inside
substances, such as hydrocarbons as Platinum catalysed, where an organo- Diameter, or OD/ID, with specific
described above or gases (Table I). The metallic Pt complex catalyses the tolerances). Other tubing designs are also
latter property is useful for the addition of a SiH group to a vinyl group available (multi-lumens, side-by-side,
oxygenation of cell cultures, for (Eqn. 2). The etc), but these are
example, as used in the Corning advantages of this generally for use in
E-Cube (Figure 2) (8). reaction are that more specific
Silicone polymer synthesis has been there are no applications such as
reviewed elsewhere (6). With respect to by-products medical devices.
the application discussed here, and (addition reaction), Levels of remaining
specifically regarding impurities, it is worth only a low level of oligomers (see
noting that the synthesis of silicone catalyst (10 ppm above) will depend
polymers starts from distilled ingredients of Pt) is used, and on cure conditions
and does not involve solvents or heavy there is no need or further processing
metals. Impurities are essentially short for post-curing. steps, such as post-
linear or cyclic silicone oligomers of some As the cross-linking curing for the
volatility, and of the general formula points are few and the peroxide products,
-(SiMe2O)n-. Such species are either used polymer chains long, and storage. Tubing
as the starting oligomers or are generated cross-linked silicone Figure 2 Silicone tubing to oxygenate is packaged and
during the polymerisation reaction. networks retain the low the Corning E-Cube culture system. provided as
Tg displayed by silicone Picture courtesy Corning Inc extruded, usually in
polymers. So, silicones 50-foot long coils,
Silicone Elastomers are elastomeric at ambient temperature double-bagged in separately sealed
without the need for platicisers (12): polyethylene bags.
Silicone polymers are easily converted into this also allows them to maintain their It is worth mentioning that, as
three-dimensional networks or elastomers purity. silicones are thermo-set, they cannot be
using a cross-linking reaction (cure). For Note that as the chain-to-chain reprocessed as thermoplastics. For the
making tubing, two reactions are interactions are weak, silicone networks same reason, they cannot be heat-sealed;
preferred (6): have low mechanical properties in the therefore, to make connections, silicone
absence of fillers, such tubing is stretched over a hose barb
as fumed/amorphous connector and secured with two cable ties
silica. To ease the attached in opposite directions to hold the
compounding of such tubing in place (5). Over-moulding is
filler, various silica possible and sometimes used in the
surface treating agents medical device area.
are used, in particular Several considerations are important in
hydroxy end-blocked the selection of tubing, and the next

PHARMACEUTICALS MARCH 2004 31

sections attempt to Table II Typical mechanical properties of materials used stress required to bend to a
address them by as flexible tubing (2,14-16) specified radius) (18).
comparing the properties Silicone tubing can by
of various tubing materials marked by external printing
as well as their but, because of its low
performance in transfer surface energy, inks do not
operations and pumping adhere well and can be
operations. removed during cleaning
with solvents, which are
sometimes used. Silicone is
TUBING also pigmentable. Barium
PERFORMANCE sulphate has long been
used as white filler for bulk
Brand pigmentation or in
co-extrusion stripes for
Although branding is not really a attract dusts; their operating temperature medical devices where X-ray radio-opacity
property, it is still worthy of some range is wider than PVC. is important.
consideration as it occurs in literature For silicone tubing, various types of defects
and can be confusing. What exactly a may exist, including:
brand is intended to represent in terms Extrusion lines or gels (probably Service Temperatures
of performance is somewhat of a resulting from premature cure in the
mystery, especially when one single extruder); Because of their low Tg and high thermal
brand name encompasses materials Bubbles (evolution of water vapour stability, silicones can operate over a wide
with very different compositions. Of during cure from moisture that may range of temperatures. Perhaps not
special concern to Dow Corning is the have been absorbed onto the cooled relevant to manufacturers of
use of their silicone elastomer brand, cylinders of the two-roll mill or pharmaceutical or biotechnology products,
Silastic, which is often used to mean hydrogen evolution from a side reaction silicones are quoted with a temperature
any silicone used in a medical between H-Si and hydroxyl species in operating range from -80C to +215C, the
application. A practical approach would Pt cured product) (6); widest operating range for any commercial
be to understand the owner and Particulate contamination. elastomer (2).
meaning of a brand before relying on it. Establishing limits for such defects is not an
easy task, yet they should be detailed in a
supplier's sales specifications. Some of Chemical Resistance
Appearance and Mechanical these visual tests are even referenced in
Properties ISO standards about silicone elastomers Although they are unlikely to be present in
used for tubing extrusion (17). pharmaceutical processing, such as
Silicone clarity is at best described as Other issues associated with fermentations or filling operations, two
translucent when compared to some mechanical properties, relate to floor space factors limit the chemical resistance of
organic thermoplastics. This results because and handling. Concerns here are silicones: swelling by certain organic
silicone elastomer, from which the tubing is managing the tubing in the production of solvents, and chemical degradation by
made, is comprised of silicone polymers pharmaceuticals, utilising the smallest strong bases or acids.
and amorphous silica (see above). Since possible floor space, while avoiding Swelling of silicones occurs in
these two materials have different refractive problems such as kinking. Variables to hydrocarbon non polar organic solvents
indices, and as there is no specific consider here include bend radius (the such as toluene. Up to 200% w/w gain can
compounding to match them, silicone radius of a bent section of tubing measured occur, thus resulting in a mechanically
tubing is translucent. to the innermost surface of the curved weaker elastomer where bonds are not
After cure, silicone elastomers display portion) and force to bend (the amount of actually broken but where the elastomer is
interesting diluted. Swelling is
mechanical Table III Silicone tubing/elastomer resistance to various ingredients and conditions both time and
properties molecular weight
(Table II): high dependent as
elongation at diffusion controlled:
break, although silicone tubing swells
with lower tensile quickly in low Mw
strength than silicone but less in
polyurethane high Mw silicones
(PU); medium (Table III).
hardness, with a On the other
"tacky" surface and hand, degradation
a high coefficient can occur in the
of friction when presence of strong
compared to bases or strong acids,
polytetrafluoro- which hydrolyse the
ethylene (PTFE), siloxane bonds and
yet far less rigid cause
than PTFE, and de-polymerisation of
being hydrophobic the siloxane
and excellent backbone.
electrical This leads to
insulators, they can various trade tables

32 MARCH 2004 PHARMACEUTICALS

(Table III), which sometimes contain Understanding the tubing composition is (28). This phenomenon has been linked to
conflicting information since test conditions therefore a consideration in selecting the its hydrophobicity and high water contact
and ratings are not always comparable. best way to study extractables. Ultimately, angle (1). Some authors interpret these
Moreover, combinations of ingredients may the goal is to detect and assay specific results as a lower reactivity and inherently a
prove to be much more potent than single impurities and correlate them to better compatibility (28). Note that similarly
ingredients. For example, silicones can be toxicological studies (see below). to PTFE, PDMS also yields a high water
cleaned from laboratory glassware with a contact angle (7). There are probably some
mixture of water / alcohol / strong base, limitations to such compatibility claims: low
while none of the ingredients on their own Cleaning and Sterilisation water contact angle appears to be
will affect it. Not surprisingly, therefore, important, but this alone is not sufficient to
compatibility is to be assessed on a case- Tubing is packaged as extruded. The make conclusions regarding low chemical
by-case basis. importance of cleaning prior to use is reactivity and for tubing selection other
mentioned in an article comparing silicone criteria also need to be considered.
with other tubing, with regards to Another interesting aspect concerns
Purity and Extractables incubation of natural plankton (22): silicone rugosity: PTFE, despite its rugosity, results in
exerted no significant effect while some a lower pressure drop than stainless steel
Extractables is a broad topic, ranging from other tubing decreased the phytoplankton tubing; this allows retrofitting with
what can be leached? (selecting the best growth rate, an effect which in some cases perfluoropolymers as pressure losses can
chemical solvent to give a maximum was removed after washing. Prior to use, be minimised and allow for lower diameter
response) to what is likely to be leached? cleaning with Water for Injection (WFI), tubing (1). Such a study does not yet seem
(selecting the most representative followed by compressed air drying in to exist for silicone tubing.
biological solvent corresponding to the controlled atmosphere rooms is practiced
application). Extreme examples may by some, though few details are available.
include tubing elastomers with or without Because of its stability, silicone is easy Burst Resistance
plasticizers. to sterilise. Common sterilisation
Silicones inherently do not require procedures include (23): Silicone tubing is highly flexible and will
plasticizers, stabilizers, UV absorbers or Autoclave (steam) in a standard gravity expand with increased intraluminal
anti-oxidants. Because of how they are steam sterilisation cycle (30 minutes at pressure, for example, when pumping high
produced, silicones often contain very low 15 psi and 121C), or in a high-speed viscosity fluids or when short bend radii
levels of heavy metals, usually less than flash steam sterilisation cycle make kinking a concern there is a risk that
10 ppm. Pt complexes are used as catalyst (15 minutes at 30 psi and 132C). the tubing may "balloon" and ultimately
for cross-linking but at low levels (10 ppm Note that silicone materials are more burst. A recent study details burst resistance
of Pt); once cured, quantifiable levels of difficult to heat than materials such as for both standard and braid reinforced Dow
platinum are not found in extractables, thermoplastics because they have Corning silicone elastomer tubing (the latter
even when rigorous solvents are thermal insulating properties and so is made from silicone elastomer overlaid
employed (21). may require more time to heat; with a polyester braid and then another
For silicones, extractables consist of Gamma radiation where doses up to layer of silicone elastomer) (29). The
short chain oligomers (6), -(SiMe2O)n-, for 2.5 Mrad (25 kGy) do not adversely results indicate (30):
which acceptable residual level may be affect mechanical properties (higher Lot-to-lot variation appears greater with
defined by different monographs (see doses may lead to some changes); smaller dimension tubing, most
below). Ethylene oxide (ETO) with sufficient probably because small defects are
A recent article reviewed how best to time to allow for complete degassing of likely to be more critical here;
analyse for extractables from silicone residual ETO. Residual levels of ETO For tubing of a given dimension, burst
elastomers (21). The article focuses on after sterilisation have been investigated strength increases with increasing
obtaining the maximum potential with different tubing, and silicone was elastomer hardness (50 to 80
extractables in one single extraction test. shown to absorb less and release ETO Shore A);
Exaggerated conditions are described with faster than PVC or polyester- Depending on dimensions, the burst
precautions taken not to lose significant polyurethane tubing (24); strength (at room temperature) of
volatiles, as could occur during storage or Sterilisation by e-beam has also been standard silicone tubing lies in the
sterilisation and to minimize degradation of mentioned (25). range 30 to 250 psi, while that for
the elastomer. Repeated sterilisations, up to 10 cycles for reinforced/braided tubing can be
This allowed separation of extracts from ETO (25) and 25 cycles with steam (26), five-fold greater for the corresponding
the product and minimized swelling, which have been shown to have no significant dimensions.
could impact the extractant due to poor effect on the mechanical properties of Note that since silicone mechanical
solvent recovery and extractables being silicone elastomers. properties are strain rate-dependant, burst
trapped in the swollen elastomer network. resistance may be affected by the rate of
The observations were as follows: pressure change (30). Some suppliers
Among the solvents used, highest levels TUBING PERFORMANCES IN quote a maximum working pressure, often
of extractables were observed with TRANSFER OPERATIONS between 1/5 and 1/3 of the burst
acetone (around 2% w/w), while low pressure, yet apparently without published
levels of extractables were obtained Surface Smoothness data to support this or explanations about
with ethanol, water or other aqueous the process variables to be considered. So,
media. Acetone may be an ideal Inner surface smoothness is sometimes setting limits here is left with the user.
solvent for "exaggerated" studies as per promoted to reduce risk of particle
the purpose of this study; entrapment and build-ups (27). Probably
Sample size is critical, as extraction more important is poor wetting to improve Sorption
yields will decrease with thicker drainage and limit bio-film adhesion. PTFE,
samples; despite a higher rugosity than electro- Over time tubing can selectively absorb
Extractables, as expected, decrease polished stainless steel (1), has been certain ingredients from the solution it
upon storage or after sterilisation. shown to be amenable to biofilm removal comes into contact with, in particular low

PHARMACEUTICALS MARCH 2004 33

molecular weight Table IV Spallation weight Spallation refers to specific impurities, extractable or volatile
substances. A recent during pumping (5 l/min degradation and the substances, heavy metals, resistance to
study on the sorption of with saline) (40) amount of particles specific chemicals and some biological
parabens shows that if being generated and parameters.
filling lines are left idle for released from the tubing It is interesting to note that tubing is
extended periods of time, wall during peristaltic sometimes promoted in the EU as
perfluoro tubing performs pumping but well before carrying a CE Mark. This is irrelevant for
better than many other catastrophic failure or pharmaceutical applications, and even in
tubing products, including leakage. Spallation is medical device applications, as the
silicone tubing which can dependant on the tubing tubing alone is only a component,
absorb up to 40% of the composition: low perhaps essential, but not yet a finished
preservatives over a 6 h spallation has been product requiring compliance with the
period (static condition reported for fluoro- Medical Device Directive (93/42/EEC)
no flow) (31-34). elastomers (30) and the and so to carry a CE Mark. The Directive
Sorption of other issue has been much does however require that the tubing
substances has been reported, for example studied in blood pumping applications. In user be responsible for establishing the
liposomal formulations (35). addition, pump settings have been shown quality and suitability of the tubing he
to be critical: when occlusion forces where selects.
reduced, spallation from silicone tubing was
TUBING PERFORMANCES largely reduced (39). Interestingly enough,
IN PUMPING OPERATIONS platinum cured silicone elastomer with TOXICOLOGY, IMPACT
lower hysteresis, as described above, once ON THE ENVIRONMENT
The advantages of peristaltic pumping again appears to perform better than AND DISPOSAL
are obvious (closed system with no risk standard grades of platinum tubing
of outside contamination by air or (Table IV). Interesting trade claims are made here
lubricant from the pump). The by some suppliers, such as contains no
technique is used not only for toxic extractables (non-PVC, non-latex,
processing pharmaceuticals, but also for STANDARDS non-silicone) (36). Data from a recent
blood pumping in extra-corporeal blood study, based on clinical trials on tubing
circulation in cardiopulmonary by-pass Relevant standards that should be used in extra-corporeal circulation during
surgery or hemo-dialysis. These are considered when selecting tubing for cardio-pulmonary bypass, showed that
some of the most demanding tubing pharmaceutical processing might platinum cured silicone tubing induced
applications since they not only require include: lower leukocyte adhesion than any other
resistance to chemicals, but also FDA G95-1 Memorandum Required tubing (41). Although it is not the
resistance to distortion during use which Biocompatibility Training and purpose of this article to provide a
could reduce flow rates as the tubing Toxicology Profiles for Evaluation of detailed review of this topic, there is
flattens and resistance to catastrophic Medical Devices; growing attention in this area, both at a
failure/leakage (pump life). Pump life International Standard ISO 10993: product level and along the entire supply
depends on many factors like pump Biological Evaluation of Medical chain, from raw materials thought
settings, the product being pumped, and Devices, Part 1: Evaluation and products generation and disposal.
the tubing material itself. Overall, certain Testing, and idem, Part 11: Tests For raw materials, even process
organic thermoplastics seem to perform for Systemic Toxicity; ingredients can be critical, especially if
better than silicones when only United States Pharmacopeia 27 they are potentially toxic and/or
considering pump life (36), although (USP 27), Monograph c88: hazardous. For example, there is currently
there are much conflicting data. Biological Reactivity Tests, In Vivo, much discussion about perfluorooctanoic
The recovery capability or resilience Classification of Plastics: Class V acid (PFOA) or its salts, which are used as
of the elastomer is critical and can be and VI; essential processing aids in the
measured by tests such as compression ASTM F748-98: Standard Practice polymerisation of fluoropolymers, even if
set (how much memory will remain in for Selecting Generic Biological Test the finished products are not expected to
an elastomer after it has been subjected Methods for Materials and Devices; contain PFOA (42). The material from
to a permanent compression) or FDA 21 CFR 177.2600: Rubber which the tubing is made can also be
hysteresis (how much energy is being articles intended for repeated use; important, for example in the case of
dissipated between a low stress and 3-A Sanitary standards, Standards polyvinylchloride (PVC), phthalate
relax cycle). and practices for the sanitary design, plasticisers may be present. Silicones too
Regarding silicone, peroxide initiated fabrication, installation and have been in the limelight following the
elastomers perform better than those cleanability of dairy and food breast implant controversy. As a result,
cured with platinum. An interesting equipment or systems used to manufacturer associations are
correlation has been established handle, process and package coordinating efforts and sharing costs to
between hysteresis, a simpler test to run consumable products where a high address such issues. One example is the
than compression set, and tubing pump degree of sanitation is required; 35-million dollars Siloxane Research
life. It has been found that the extended National Sanitation Foundation Program, which, under Dow Corning's
pump life of peroxide initiated silicone (NSF51): Materials and leadership is further investigating the
elastomers may be explained by their Components used in Food toxicology of six silicone model
lower compression set and lower Equipment; compounds.
hysteresis when compared with platinum European Pharmacopoeia 3.1.9: Silicone and the environment are
cured elastomers (37). As a result of this Silicone elastomers for closures and addressed in a recent book (43). Regarding
observation, platinum cured elastomers tubing. silicone tubing disposal, incineration is
with lower hysteresis have been Each of these standards address different probably the most likely method.
developed for use in pumping properties that could impact tubing Incineration of silicone tubing will lead to
applications (38). selection, such as identification, presence of the formation of CO2, SiO2 and water; thus,

34 MARCH 2004 PHARMACEUTICALS

there are no toxicity concerns with its treated as component articles of drug Safety for the ultimate user, the patient,
degradation products. In addition, the products and therefore come under the with an understanding of the purity and
toxicity of silicone elastomers is not a same control regulations as the drugs extractable profile, and links between
concern: in addition to their use in themselves. Traceability and change these and toxicological studies.
pharmaceutical processing, they are often control are two important factor to
used in many long-term medical devices, consider and today many extrusion In conclusion, silicones appear to be well
for example hydrocephalic shunts, or houses are relying on detailed suited to meet the above. In making a final
pacemaker leads. documentation for raw materials, tubing selection, one must consider their
Another environmental impact to cleaning agents and packaging benefits, as well as their limitations. It is
consider here is single versus multiple-use components as well as change control important to remember that silicone tubing
tubing, the latter requiring a significant level and notification of changes for materials has now been used successfully for more
of validation, WFI and disposal of CIP produced upstream on their suppliers. than 30 years in various fluid transfer
contaminated streams (5). Other critical variables that may be operations.
important include environmental control
in the extrusion area, cross-
COST contamination resulting from other ACKNOWLEDGMENTS
materials produced on site, and rework
Cost-to-acquire tubing is only one practices. A recent publication highlights The authors wish to thank D. Anderson
element to consider as there is a various requirements designed to insure and C. Sn for their helpful comments.
spectrum of options here from a fixed compliance and management for
asset made of a stainless steel and/or risk (45).
glass for multiple uses, to a simpler Based on the above trends, Dow The following are registered trade marks:
asset including re-useable or Corning is unique as a supplier of tubing C-FLEX (Consolidated Polymer
disposable tubing, to a single-use flexible because of its integrated supply chain Technologies); USP (The United States
approach made of both disposable bags and the fact that it produces both Pharmacopeial Convention); SILASTIC
and tubing. A recent article addresses silicone elastomers and silicone tubing (Dow Corning Corporation).
the issue and concludes that single-use at sites registered and audited by the
options offer much capital savings as United States FDA. This provides
expected, improve manufacturing complete traceability from polymer
flexibility but also offers opportunities to compounding through tubing REFERENCES
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PHARMACEUTICALS MARCH 2004 35

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