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This guidance was written prior to the February 27, 1997 implementation of FDA’s Good Guidance Practices, GGP’s. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be updated in the next revision to include the standard elements of GGP’s.
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DRAFT GUIDANCE FOR PREPARATION OF PMA APPLICATIONS FOR TESTICULAR PROSTHESES |
 |
DRAFT GUIDANCE FOR PREPARATION OF PMA APPLICATIONS FOR
TESTICULAR PROSTHESES
Urology and Lithotripsy Devices Branch
Division of Reproductive, Abdominal, Ear, Nose and Throat, and
Radiological Devices
Office of Device Evaluation
Center for Devices and Radiological Health
March, 1993
TABLE OF CONTENTS
I. PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . 1
II. DEVICE DESCRIPTION. . . . . . . . . . . . . . . . . . . . 1
III. BACKGROUND. . . . . . . . . . . . . . . . . . . . . . . . 1
IV. GENERAL REQUIREMENTS OF PREMARKET APPROVAL (PMA)
APPLICATIONS FOR TESTICULAR PROSTHESES. . . . . . . . . . 1
1. Manufacturing Data . . . . . . . . . . . . . . . . . 2
1.1 Chemical Characterization of Device
Components. . . . . . . . . . . . . . . . . . . 2
1.1.1 Process tree. . . . . . . . . . . . . 2
1.1.2 Master List . . . . . . . . . . . . . 3
1.1.3 Chemical characterization of
Polymer Precursors. . . . . . . . . . 3
1.2 Sterilization processes.. . . . . . . . . . . . 4
1.3 Quality Assurance/control.. . . . . . . . . . . 4
2. Preclinical data . . . . . . . . . . . . . . . . . . 5
2.1 Device physical and chemical characterization. . 5
2.1.1 Tensile Testing . . . . . . . . . . . 5
2.1.2 Tear Resistance of Shells . . . . . . 6
2.1.3 Abrasion Resistance and Analysis. . . 8
2.1.4 Integrity of Adhered or Fused
Joints. . . . . . . . . . . . . . . . 10
2.1.5 Fatigue Life. . . . . . . . . . . . . 11
2.1.6 Silicone Bleed. . . . . . . . . . . . 13
2.1.7 Cohesivity of Gel . . . . . . . . . . 17
2.1.8 Valve Competence. . . . . . . . . . . 19
2.1.9 Testing of Explanted Materials
(Biodegradation). . . . . . . . . . . 19
2.1.10 Chemical characterization of the
Finished Device . . . . . . . . . . . 20
2.2 Toxicological Evaluations . . . . . . . . . . . 22
2.2.1 Pharmacokinetics Studies. . . . . . . 23
2.2.2 Mutagenicity Testing. . . . . . . . . 24
2.2.3 Acute, subchronic, and Chronic
Toxicity, Carcinogenicity,
Teratogenicity, and Immunotoxicity. . 24
3. Clinical data. . . . . . . . . . . . . . . . . . . . 25
4. Labeling . . . . . . . . . . . . . . . . . . . . . . 30
V. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . 33
APPENDIX I - EXTRACTION GUIDELINES FOR SILICONE IMPLANTS . . . .34
APPENDIX II - SELECTED BIBLIOGRAPHY OF ANALYTICAL
METHODOLOGIES . . . . . . . . . . . . . . . . . . . 39
DRAFT GUIDANCE FOR PREPARATION OF PMA APPLICATIONS
FOR
TESTICULAR PROSTHESES
I. PREFACE
This guidance document addresses the preparation of FDA
Premarket Approval (PMA) applications for testicular
prostheses. It may also be useful in the preparation of
Investigational Data Exemptions (IDE) applications,
reclassification petitions, and master files. Development of
this document is based upon scientific review and analysis
by the FDA and by published and unpublished studies.
II. DEVICE DESCRIPTION
A testicular prosthesis is an implanted device that consists
of a solid or gel-filled silicone rubber prosthesis that is
implanted surgically to resemble a testicle.
III. BACKGROUND
In the FEDERAL REGISTER of November 23, 1983 (48 FR 53023),
FDA issued a final rule classifying the testicular
prosthesis into class III (21 CFR 876.3750). In the FEDERAL
REGISTER of January 6, 1989, (54 FR 550), FDA published a
notice of intent to initiate proceedings to require
premarket approval of 31 preamendments Class III devices,
including testicular prostheses. In the Federal Register of
January 13, 1993 (58 FR 4116), FDA issued a proposed rule
requiring a PMA for testicular prostheses. These
proceedings were enacted on _____________________, requiring
a PMA for these devices be filed with the agency within 90
days.
IV. GENERAL REQUIREMENTS OF PREMARKET APPROVAL (PMA)
APPLICATIONS FOR TESTICULAR PROSTHESES
A PMA must be submitted by all distributors of testicular
prostheses. Any PMA submitted must meet the content
requirements contained in Section 515(c)(1) of the Federal
Food, Drug and Cosmetic Act (the act) and 21 CFR 814.20. A
PMA must also include a detailed discussion, with results of
preclinical and clinical studies, of the safety and
effectiveness of the device. In particular, the PMA shall
include all known or otherwise available data and other
information regarding: (1) any risks known to the applicant
that have not been identified in this document, and (2) the
effectiveness of the specific testicular prosthesis that is
the subject of the application (or, if adequate
justification can be provided, applicable effectiveness
information for other testicular prostheses). Valid
scientific evidence, as defined in 21 CFR 860.7, addressing
the safety and effectiveness of the device should be
presented, evaluated and summarized in a section or sections
of the PMA separate from known or otherwise available safety
and effectiveness information that does not constitute valid
scientific evidence (e.g., isolated case reports, random
experiences, etc.). This must include but not be limited
to:
1. Manufacturing Data:
Complete manufacturing information must be submitted in
accordance with the "Guidance for the Preparation of
PMA Manufacturing Information". This guidance is
available upon request from the Division of Small
Manufacturing Assistance (HFZ-220), Center for Devices
and Radiological Health, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857.
In addition, the following specific chemical
processing, sterilization, amd quality assurance
information is required to assess the safety and
effectivness of testicular prostheses.
1.1 Chemical Characterization of Device Components
Manufacturing and process tree information show
how the components of a device are made from
starting materials. This identifies potentially
leachable chemicals and immediate precursors of
crosslinked polymers. Only a limited amount of
chemical characterization can be done on highly
crosslinked polymers. For such polymers, it is
important to characterize the immediate precursors
to assure the quality of the base polymers and
crosslinking agents. The viscosity and molecular
weight distribution are very basic characteristics
of all polymers that greatly influence the
mechanical and physical properties of the device.
Determination of volatile content, extent of
chemical crosslinking, and the sol fraction of
components characterizes the curing processes that
are used. These determinations should be done on
10 or more lots to establish that control of the
chemical processing exists.
1.1.1 Process tree
Chemical formulation and manufacturing
information, presented in a step-by-step
process, from the starting materials to
composites to the final products, including,
but not limited to, all nonreactants and
reactants (including catalysts, curing
agents, and intermediate precursors) must be
provided for all device components. On
this tree, any substance or material
identified by some sort of company name or
code must also be identified by a
corresponding common chemical name.
1.1.2 Master List
A complete master list of common chemical
names and alternate names (company, trade and
code) for all nonreactants, reactants
(including intermediate precursors),
additives, catalysts, adjuvants, and products
should be provided. The same name for each
specific compound must be utilized throughout
the document.
1.1.3 Chemical characterization of Polymer
Precursors
Chemical characterization of the elastomer
intermediates (i.e., network precursors) of
the various components of the device
sufficient to demonstrate control of chemical
processing of the device materials should be
provided. This should be based on lot-to-lot
comparisons (minimum of 10 consecutive lots)
of the following information:
a. the molecular weight distribution,
expressed as weight average molecular
weight (Mw), number average molecular
weight (Mn), and polydispersity (MWD) of
these precursors.
b. analyses for volatile and nonvolatile
(if applicable) compounds, such as
cyclic oligomers, to establish the upper
limit of these compounds and to show
that they are being controlled.
c. if copolymers are being used, data to
show that the composition of these
copolymers is under control and that a
consistant product is being made.
Usually, such data would consist of
analyses of the group content of the
copolymer, for example, phenyl, fluoro,
vinyl, hydroxyl number, acid number,
peroxide, etc. as appropriate.
d. when viscosity is used as the variable
that is measured for production control,
a comparison of viscosity, Mn, and
volatile content should be given on a
lot-by-lot basis to show that viscosity
monitoring is sufficient to control the
chemical processing.
e. if composites or filled or reinforced
polymers are being used the fillers
should be characterized. The particle
size or surface area of any reinforcing
and nonreinforcing filler should be
given. If silica is being used the
percent crystallinity should be
provided.
1.2 Sterilization Processes
Standard operating procedures for sterilizing and
qualifying the sterilization process must be
provided. Provided information should include the
method of sterilization; the detailed
sterilization validation protocol/results; the
sterility assurance level; the type of packaging;
the packaging validation protocol/results;
residual levels of ethylene oxide, ethylene
glycol, and ethylene chlorhydrin remaining on the
device after the sterilization quarantine period,
if applicable; and the radiation dose, if
applicable.
1.3 Quality Assurance/control
A QA/QC plan that demonstrates how raw materials,
components, subassemblies, and any filling agents
will be received, stored, and handled in a manner
designed to prevent damage, mixup, contamination,
and other adverse effects must be provided. This
plan shall specifically include, but not
necessarily be limited to, a record of raw
material, component, subassembly, and filling
agent acceptance and rejection, visual examination
for damage, and inspection, sampling and testing
for conformance to specifications.
Written procedures for finished device inspection
to assure that device specifications are met must
be provided. These procedures shall include, but
are not limited to, that each production run, lot
or batch be evaluated and, where necessary, tested
for conformance with device specifications prior
to release for distribution. A representative
number of samples shall be selected from a
production run, lot or batch and tested under
simulated use conditions and to any extremes to
which the device may be exposed.
Furthermore, the QA/QC procedures should include
appropriate visual testing of the packaging,
packaging seal, and product. Sampling plans for
checking, testing, and release of the device shall
be based on an acceptable statistical rationale
(21 CFR 820.80 and 820.160).
2. Preclinical Data
2.1 Device Physical and Chemical Characterization
Appropriate physical and chemical properties of
the device must be characterized. Each item must
be supported by complete reports (i.e., protocols
with a full description of test methods and raw
data). These reports must be from the testing of
an adequate number of samples obtained from
sterilized devices produced by the standard
manufacturing procedures. Each and every distinct
type of shell, patch, gel, and all other
components critical to the integrity of the
devices must be tested separately to account for
any variations in chemical composition, physical
texturing, component thickness, sterilization
method, etc. (but not simple variations in size of
devices or device components).
2.1.1 Tensile Testing (Determination of
Uniaxial Tensile Strength, Ultimate
Elongation, and Energy to Rupture) of
shells and patches of liquid-filled or
filled testicular prostheses
Shell rupture and subsequent liquid or gel
leakage are anticipated outcomes in some
unknown percentage of implanted filled
testicular prostheses. Whether this rupture
is primarily caused by externally-induced
damage, by biodegradation, or by fatigue of
the materials due to repeated loading is
unknown. It is clear, however, that the
shell and patch materials (and any other
elastomeric materials that comprise a lumen
of the finished device) must possess a
minimum level of mechanical strength and
energy absorbing capacity in order for the
implant to be able to withstand anticipated
service loads without rupture. As a minimum
baseline data set, the uniaxial tensile
properties of the shell and patch materials,
in the form and configuration representative
of as-implanted devices, must be known.
Because the morphology of the materials can
be affected by processing, and because liquid
or gel absorption into the shell and patch
material can affect tensile properties, test
samples must be cut from finished devices
rather than from specially-cast material or
unplaced shells or patches. Also, because
tensile properties can be significantly
affected by various sterilization cycles and
by the existence of fold flaws in the
material, these parameters must be studied as
well. Measured tensile properties of the
elastomeric components of the devices must
include tensile strength, elongation at
failure, and strain energy at failure. The
methodology of tensile testing should be in
accordance with ASTM Method D412. Because
test-to-test variability appears to be
significant in some cases, statistical
assessment of variability and raw data must
be reported.
2.1.2 Tear Resistance of Shells and Patches of
Liquid Filled or Gel-Filled Testicular
Prostheses
Shell rupture and subsequent liquid or gel
leakage are anticipated outcomes in some
unknown percentage of implanted filled
testicular prostheses. Whether this rupture
is primarily caused by externally-induced
damage, by biodegradation, or by fatigue of
the materials due to repeated loading is
unknown. It is clear, however, that the
shell and patch materials (and any other
elastomeric materials that comprise a lumen
of the finished device) must possess a
minimum level of mechanical strength and
energy absorbing capacity in order for the
implant to be able to withstand anticipated
service loads without rupture.
The exact mechanism of failure in elastomeric
materials is difficult, if not impossible, to
determine based on morphological changes.
Thus, it is not known whether fatigue, creep,
tensile overload, or some other mechanism is
involved. Whether losses in shell integrity
are initiated by material failure or
externally induced puncture, the shell
material must provide some protection against
catastrophic propagation of a tear or
puncture with consequent loss of liquid or
gel from the lumen. This material
characteristic is generally called tear
resistance, and the methodology is covered in
ASTM Method D624.
Because the morphology of the material can be
affected by processing, and because liquid or
gel absorption into the shell material can
affect properties, test samples must be cut
from finished devices rather than from
specially-cast material or unplaced shells.
Also, because material properties can be
significantly affected by various
sterilization cycles, effects of these
treatment(s) on tear resistance must be
studied. Because test-to-test variability
appears to be significant in some cases,
statistical assessment of variability and raw
data must be reported.
In addition to shell materials, tear
resistance of patches and any other
elastomeric components comprising a lumen of
the finished device must be determined. As
is the case with shells, a propagated tear in
any of these other components could
conceivably lead to loss of liquid or gel
from the lumen.
2.1.3 Abrasion Resistance and Analysis of
Abraded Surfaces of Solid Silicone and
Silicone Liquid-Filled or Gel-Filled
Testicular Prostheses
Silicone elastomers used in testicular
prostheses are relatively soft and are prone
to abrasive degradation at their surfaces.
While being placed in the incision in the
scrotum of a patient, a prosthesis is rubbed
against scrotal tissue. When the patient
moves, tissue or other anatomic structures
move over the prosthesis and/or its fibrous
capsule. Formation of a hernia or fold in
the shell in a filled device could
conceivably cause portions of the shell to
rub against itself. Rubbing actions such as
these can abrade the surface of the device.
Concern over abrasion is heightened when the
surface of the device is textured. Depending
upon the nature of the texturing process, the
topography of the surface may be either
regular or irregular. In either case, some
portion of the surface material will project
from the bulk material of the shell. Shear
stresses exerted on this projected surface
material will be greater since the shear
forces will be distributed over smaller
areas. Thus, when compared to smooth surface
material, textured surface material is more
prone to crack formation, tearing, and
abrasion for a given shear force.
Abrasion can lead to weakening of the device
surface making it more prone to mechanically
induced trauma. Abrasion can also release
small particles of silicone elastomer into
the body. These small particles can be
attacked by white blood cells which try to
digest the particles. However, because of
the relative inertness of the silicone
particles, they cannot be digested by the
white blood cells. Instead, the white blood
cells are destroyed (lysed) by the attempt to
digest the silicone, which can then result in
the formation of a mass of chronically
inflamed tissue (i.e., a silicone granuloma),
which must be surgically removed (Ref. 1).
If the particles are sufficiently small, they
can be transported to other regions of the
body where the same processes can produce
distant silicone granulomas.
In addition, the literature reports that
abrasion of a silicone elastomer can expose
the particles of silica added to reinforce
the elastomer (Ref. 2). Crystalline silica
is recognized as a sclerogen, i.e., an agent
which produces hard or sclerotic tissue,
capable of causing adverse reactions when
placed in the body (Ref. 3). Amorphous
fumed, rather than crystalline, silica is
typically used to reinforce the silicone
elastomers of these devices. However, there
are still concerns over the presence of
minute crystalline silica impurities in the
reinforcer and whether there is any
significant in vivo conversion of amorphous
silica into crystalline silica.
The abrasion resistance of the surface of the
silicone testicular prosthesis and the
particle size distribution of the material
abraded from the prosthesis must be known in
order to determine whether the device is safe
and effective. In order to respond to
unanswered questions concerning the adverse
effects of exposing silica in the body,
abrasion resistance testing, followed by
examination of the abraded surface for the
presence or absence of silica, must be
performed to determine whether a testicular
prosthesis is safe and effective.
Reports on abrasion resistance testing of
solid silicone testicular prostheses and
shell materials of liquid filled or silicone
gel-filled testicular prostheses must contain
relevant information on the equipment and
abrader used, identification and dimensions
of specimens, and detailed protocols. In
particular, a standard abrasion test machine,
or equivalent specialized equipment, must be
used to conduct the testing. In addition, a
complete description of the test apparatus
must be provided. A description of the
apparatus used, including the number of
specimens that can be tested simultaneously,
the dimensions (width and length) of both the
maximum sample size and the maximum abrading
area, and the manner in which specimens are
held, must also be provided. The material
used to abrade specimens must be identified,
and a rationale for choosing this material
must be provided as well. Properties of the
abrading medium including hardness,
roughness, etc., that are pertinent to the
abrasion process, also must be identified.
As usual, test specimens must be obtained
from shells of sterilized finished devices
manufactured according to the sponsor's
standard methods. Testing must be conducted
on each and every silicone elastomer
(comprising the outer surface of the device)
of all varieties of composition and surface
texture. Significant weight losses in
abraded material must be induced, and the
total number of passes (by the abrasive
medium) required to induce this observed
weight loss must be reported. Averages,
standard deviations, detailed protocols,
cycling rates, and raw data must be reported.
Examinations for exposed silica (particularly
crystalline silica) of both the abraded
surfaces and abraded particles from test
specimens must be conducted and reported.
Percentanges of crystalline silica and the
total content of crystalline silica in these
abraded particles must be analyzed for and
reported. Particle size distributions of
abraded particles must be reported.
2.1.4 Integrity of Adhered or Fused Joints of
Liquid-Filled or Gel-Filled Testicular
Prostheses.
It is anticipated that leakage of liquid or
gel from filled testicular prostheses occurs
in some unknown percentage of implanted
devices. In addition to rupture of the
primary shell material, failure of a joint
associated with a seal of the filling hole
patch or valve is a potential source for
liquid or gel leakage. Consequently, it is
necessary that the joints between the various
components comprising the shell of the device
be as strong as possible so that the strength
of the shell is not compromised. At the very
least, the breaking force, normalized to
joint thickness, must be provided for tensile
specimens containing each and every type of
joint critical to the integrity of a lumen in
the device. In addition, because it is known
that shells of filled testicular prostheses
are perfused by swelling agents from the
liquid or gel contained in the devices, and
because sterilization could affect the
integrity of a seal, the specimens used for
joint testing must be obtained from finished,
manufactured devices that have been
sterilized. Raw data, including joint
thicknesses of each and every test specimen,
must be provided. (It is noted that unlike
the test methods outlined in section 7.2 of
ASTM standard F703, testing of adhered and
fused joints must be conducted to the failure
points of the specimens.)
2.1.5 Fatigue Life of Solid Silicone and
Liquid-Filled or Silicone Gel-Filled
Testicular Prostheses (Construction of
Applied Force/Number of Cycles to
Failure Curve for Device)
Most materials are subject to a finite
fatigue life when repeatedly stressed or
flexed. Repeated compression, folding,
bending, or flexing of the device, with time,
weakens the silicone elastomer of a device
and may eventually lead to failure of the
device. Rupture or failure of the shell of a
silicone gel-filled testicular prosthesis can
cause release of the silicone gel into the
body, possibly leading to migration of
silicone to regional lymph nodes and other
organs. (Thus, from the standpoint of
safety, it is much more important that
fatigue testing be conducted on silicone gel-filled
devices as opposed to testing of solid
silicone devices.) Rupture of the shell can
also lead to deflation of a liquid-filled or
gel-filled testicular prosthesis, producing a
deformity requiring surgical intervention in
order to be corrected.
Failure mechanisms of these devices are
addressed by compressive fatigue testing in
which a constant compressive force is
cyclically applied to an intact silicone
(solid or filled) prosthesis until the device
fails. The number of cycles the prosthesis
can endure prior to shell failure is an
indirect estimate of the maximum amount of
time the device can remain intact in the
body. Other effects of immersion in a
biological system may reduce this estimated
lifetime, but the fatigue life of the
prosthesis is a good measure of the absolute
maximum working life a patient can expect
from a testicular prosthesis.
Full characterization of the compressive
fatigue life of a filled testicular
prosthesis is more involved and time-consuming
than simple uniaxial (i.e., one-dimensional) tensile
testing of the device's
shell material. However, the results of
compressive fatigue testing are much more
pertinent to an assessment of the safety and
effectiveness of a testicular prosthesis. A
prosthesis subjected to compressive fatigue
testing experiences a complex combination of
tensile, torsional, compressive, and radial
forces not experienced by shell specimens in
uniaxial tensile testing. Thus, the mode of
testing closely mimics the one, two, and
three-dimensional forces which are likely to
be experienced by an actual implanted
testicular prosthesis.
Compressive fatigue testing is also
advantageous over uniaxial tensile testing in
that the test device remains intact (until
the point of rupture) for the duration of the
testing. In compressive fatigue testing,
unlike uniaxial tensile testing, the tested
shell material of a filled device maintains
contact with the liquid-fill or gel-fill of
the device. This is not the case for
specimens for tensile testing excised from
the shells of gel-filled testicular
prostheses.
Implanted testicular prostheses are subjected
to a variety of compressive loads of
differing magnitudes and differing
frequencies of occurrence. Given the
variability in frequency and magnitude of
compressive loadings on implanted testicular
prostheses, it is important that a full range
of compressive forces be used in fatigue
testing of the devices.
Thus, an applied force versus number of
cycles to rupture of the device (AF/N) curve
must be constructed for each and every model
of testicular prosthesis. The resultant data
points used to construct each curve must be
sufficient to plot the asymptotic endurance,
or "fatigue force" limit, of the device and
to approximately determine the "elbow point",
i.e., the location of the maximum change in
curvature of the AF/N plot, if any exists.
Each curve must also contain an average value
for failure of the device due to a single
blow, i.e., a single stroke of loading.
Data from the AF/N plot should be used to
calculate and report the applied force
corresponding to 6.5 million cycles times the
anticipated and/or labelled lifetime of the
device in years. (6.5 million cycles per
year corresponds to an adult male walking 5
hours per day at one step per second, i.e., 1
hertz.) The theoretical applied force,
experienced during walking, on an actual
implanted testicular prosthesis should be
calculated (along with a suitable safety
factor) and reported. A comparison of the
theoretical in vivo and experimentally
determined applied forces to the testicular
prosthesis should be reported.
A frequency of 1 Hertz must be used for the
cycling rate of the testing. This frequency
approximates the frequency of loading
experienced in walking and also avoids
undesirable heating effects which can occur
at higher testing frequencies.
2.1.6 Silicone Bleed of the Shell and Patch
Materials of Silicone Gel-Filled
Testicular Prostheses
Silicone bleed permeation, which is the
seepage of silicone fluid components of the
internal gel fill through an intact shell of
a silicone gel-filled testicular prosthesis,
is one means by which the device can release
silicone into the human body. The body is
essentially a fluid receptacle for the liquid
silicone released by the device. As the
liquid silicone emerges from the shell, it
can dissipate into the body by at least two
mechanisms. The silicone bleed product can
be transported away from the device by simple
diffusion, that is, liquid flow in the
extracellular fluid as this fluid perfuses
the region adjacent to the surface of the
prosthesis. The bleed product can also be
taken up by white blood cells, primarily
macrophages in the tissues, and carried to
lymph nodes or other organs. Because the
liquid silicone is constantly removed from
the region of the prosthesis, the bleed
process cannot come to a halt. This results
in the body acting as an "infinite sink" for
the liquid silicone.
Determination of liquid silicone bleed rates
is particularly important in the case of
silicone gel testicular prostheses. A large
percentage of these devices are implanted in
infants. Thus, small quantities of silicone
bleed products may have proportionately
larger effects when body weights are small
and immune systems are not as fully developed
as in adults.
Steady-state diffusion coefficients for
silicone bleed permeation rates from silicone
gel-filled testicular prostheses must be
determined so that sound estimates can be
made of long-term accumulations of silicone
into a patient's body. These steady-state
diffusion coefficients must be determined for
individual components of the silicone bleed
as well. Silicone molecules in gel bleed
product have a range of molecular weights,
which cannot be assumed to be representative
of the range of molecular weights found for
molecules of silicone fluid in the gel inside
the device.
In fact, it is likely that silicone molecules
of smaller molecular weight possess higher
permeability rates through intact shells of
testicular prostheses than do silicone
molecules of higher molecular weight. Thus,
the composition of the bleed product is
likely, at any given time, to be skewed
toward lower molecular weight components in
comparison to the composition of the fluid
components of the gel inside the device.
These lower molecular weight silicone
molecules are also more likely to stimulate
biological activity. Therefore, accurate
assessments of the likelihood of long-term
toxicological response to an implanted
prosthesis (that remains intact) require
accurate dose rates of individual liquid
silicone components in the bleed, especially
those of the lowest molecular weights.
Various methodologies for performing liquid
silicone bleed permeation testing have been
used or proposed. Measured coefficients for
diffusion of components of liquid silicone
through a prosthesis are largely dependent
upon the receptacle medium used to collect
the bleed. It is possible to conduct the
experiment using either a solid-state medium
or a liquid-state medium. While, in general,
solid-state receptacles are easier to use,
there are major drawbacks associated with
them.
The major drawback to using a solid-state
medium is the potential for significant loss
of volatile silicones of low molecular
weight. Unlike a liquid receptacle diffusion
cell, the placement of a testicular
prosthesis on a disk or a filter is an
experimental system open to air or vacuum.
Substantial amounts of volatile silicones may
be lost (during the bleed experiment and/or
during subsequent extraction of the disk or
filter) and thus excluded from compositional
analysis of the bleed product. Yet, as
explained earlier, it is vital that accurate
short-term and long-term dose rates of these
low molecular weight, volatile silicones be
established. Therefore, a liquid-state
receptacle medium must be used to conduct
liquid silicone bleed experiments in order to
adequately assess the potential risks
attributable to liquid silicone bleed from
silicone gel-filled testicular prostheses.
A stirred receptacle medium of physiological
saline is the best means of emulating actual
in vivo bleed rates. Stirring of the saline
medium is necessary to more accurately
account for the "infinite sink" conditions
which, as discussed earlier, exist in the
body. Stirring of the saline medium
transports a portion of the poorly soluble
silicones from the membrane surface such that
a concentration gradient in the vicinity of
the surface is maintained.
In summary, bleed permeation experiments must
be conducted as following: A standard liquid
diffusion cell, maintained at a temperature
simulating physiologic conditions must be
employed. The upper compartment must consist
of gel obtained from a sterilized, finished,
and manufactured testicular prosthesis. The
membrane must consist of shell and/or patch
material obtained from the same sterilized,
finished, and manufactured device from which
the gel sample was obtained. The bottom
compartment must consist of the receptacle
medium for the liquid silicone bleed product.
The outer-most gel contacting shell material
must be tested, as well as any patch material
comprising the same lumen as this shell.
Each variety of shell and/or patch material
varying significantly in thickness or design
must be tested separately. Each variation in
gel must be tested separately. Control cells
must also be employed to correct measurements
for background levels of silicone.
Stirred physiological saline should be used
as a receptacle medium. While CDRH believes
that useful information (as to a "worst
possible case" scenario) can still be
obtained from a bleed experiment into a
hydrocarbon solvent, the priority for testing
into stirred saline is much greater. In any
case, if a manufacturer believes that a
different solvent is more suitable to the
bleed experiment, full justification must be
provided to CDRH as to the choice of solvent.
Sufficient amounts of liquid silicone bleed
must be collected and analyzed on a time-course
basis such that both short-term
accumulation amounts and long-term, i.e.,
steady-state, diffusion coefficients of both
total bleed and individual components of
liquid silicone bleed can be estimated.
Analyses of bleed permeation data indicate
that limiting steady-state coefficients can
be obtained from properly conducted
experiments provided sufficient time is
allowed to establish equilibrium bleed rates.
The intervals at which bleed product is
analyzed for chemical identity and molecular
weight shall be determined by the
manufacturer, but must be such that steady-state
diffusion coefficients, particularly of
low molecular weight silicones, can be
determined with sufficient accuracy.
It is not sufficient for a manufacturer to
simply measure the total weight of liquid
silicone bleed as a function of time. The
bleed product must be adequately analyzed and
resolved in order to determine accurate dose
rates of smaller linear and cyclical
silicones of, e.g., molecular weights of 1500
or less. All extraction procedures for these
low molecular weight silicones must be
validated for percent recovery.
Additional parameters needed to estimate
long-term in vivo accumulation rates of
liquid siicone components must also be
provided. These parameters include the
normalized cross-sectional area of each and
every membrane tested, the average thickness
of each and every membrane tested, estimates
of the total surface area (for the intact
device) of each testicular prosthesis tested,
and estimates of the minimum and maximum
surface areas for the size range of each type
of silicone gel-filled testicular prosthesis
tested. As with all other physical and
chemical testing reports, detailed protocols,
calculation methods, all raw data (on a time-course
basis), and calculated averages with
standard deviations must be provided.
2.1.7 Cohesivity of Gel in Silicone Gel-Filled
Testicular Prostheses
Gel cohesivity testing is designed to measure
both the rheological, or flow, properties of
the gel and the integrity, or connectivity,
of the gel. In the event of device (and
enclosing capsular tissue) rupture, it is
important that the gel maintain some degree
of consistency and cohesiveness in order to
facilitate surgical removal. A less cohesive
gel may thwart substantial recovery of the
gel, and portions of it may be more prone to
migrate throughout the body.
A desired consistency of silicone gel is
obtained by blending several polymeric
components together. Cohesivity tests are
designed to measure the inseparability of
these various components as well as to
indicate the flow characteristics of the gel
by looking at the extrusion of the gel
through a specified orifice under the
influence of gravity. Since it is possible
for the rheological properties of the gel to
change as a function of sterilization
cycle(s), the materials used in gel
cohesivity testing must be from finished,
sterilized manufactured devices.
Specifications for cohesivity testing in the
ASTM F703 Standard for gel-filled breast
prostheses state that the silicone gel
contained in the finished product is to be
considered acceptable if there is no total
separation of any component of the pendant
gel, and if the pendant portion does not
exceed 4.5 cm after 30 minutes at room
temperature in a die with specified
dimensions and tolerances. A similar
methodology of testing would be appropriate
for silicone gel-filled testicular
prostheses.
Reported results for gel testing must include
the actual measurements of gel slump in gel
cohesivity testing and/or measurements of
penetrometer fall in gel penetration testing.
Detailed protocols, raw data, averages and
standard deviations, and the manufacturer's
specific pass-fail criteria must be provided.
The chosen test method(s) must be adequately
sensitive to detect significant variances in
gel cohesivity and/or stiffness.
Cohesivity of the gel can, in many respects,
be predicted from detailed chemical
characterization of the gel product.
Knowledge of information such as molecular
weight averages of gel components,
percentages of cross-linked and uncross-linked
silicones, and average degrees of
functionality for precursors of cross-linked
silicones, is important in predicting the
degree of cohesion in a silicone gel, as well
as its relative tendency to bleed liquid
silicone components. This information must
be provided as well.
2.1.8 Valve Competence
Leakage via a partially or fully failed valve
of a fluid-filled testicular prosthesis may
or may not (depending upon the degree of
toxicity of the fill) pose a safety concern
to the patient. In any case, however,
maintenance of valve integrity is necessary
to the efficacy of fluid-filled testicular
prostheses employing valves.
Manufacturers must demonstrate that valve
integrity is maintained at actual anticipated
maximum service loads (with an appropriate
safety factor). The most informative means
of performing this testing is to gradually
increase the induced pressure in the test
devices until valve failure occurs and a
maximum service pressure can be defined for
the device. It should also be determined
whether the failed test valves reseal upon
removal of the excess failure-inducing
pressures.
2.1.9 Testing of Explanted Materials
(Biodegradation)
The effects of implantation, including the
stresses of the biological environment, on
device materials and integrity should be
determined by appropriate animal testing.
Complete material, chemical and physical
characterization should be performed on
devices explanted from animals after an
appropriate implantation duration. Results on
tests of explants should be compared to
results on unimplanted devices and
conclusions about degradation of materials or
components drawn. The results of this
testing should also be compared to failure
rates determined in in-vitro tests and
clinical studies, in order to demonstrate
that the animal model and study duration are
appropriate.
2.1.10 Chemical characterization of the
Finished Device
2.1.10.1 Crosslinking
If fabrication of the device involves
curing of polymeric components by
chemical crosslinking, then data
establishing the extent and
reproducibility of the crosslinking
should be provided. This may be done by
a various methods, for example;
a. Measurement of Young's modulus
at low strain as this is
approximately proportional to
crosslink density.
b. Measurement of equilibrium
swelling of the polymeric component
by a good solvent.
c. Measurement of the soluble (sol
fraction) content of a gel.
Determination of total extractables
using a good solvent could
accomplish this.
d. Determination of the amount of
unreacted crosslinker from its
concentration in the total
extractables.
2.1.10.2 Leachable Chemicals
Determination of the extractable or
releasable chemicals in an implant
device are necessary for assessment of
the safety of the device. Chemical
identification and quantification of
releasable chemicals is necessary to
facilitate the determination of safe
levels by dose-response toxicological
methods. Migration rates of the
releasable chemicals from various
components of the device may also be
evaluated when providing toxicology
data. Knowledge of the levels of
volatiles and residues in the device
provides an upper limit to the amount of
releasable chemicals from the various
components as they are found in the
final sterilized device. This is
necessary to relate amounts of
releasable chemicals back to device
characteristics as these are factors
that should and can be controlled in the
manufacturing process.
Complete identification and
quantification of all chemicals, such
as;
a. residual monomers, cyclics, and
oligomers;
b. known toxic residues such as
polychlorinated biphenyls (PCBs) if
dichlorobenzoyl peroxides are used,
heavy metals, aromatic amines if
polyurethanes are used, and
residues of transition metal
catalysts;
c. residues of ethylene oxide if
that is used for sterilization;
d. additives and adjuvants used in
the manufacture of the device, such
as plasticizers, antioxidants,etc.;
below a molecular weight of 1500,
exhaustively extracted from each of the
individual structural components as they
are found in the final sterilized device
should be reported. The solvents used
for extraction should have varying
polarities and should include, but not
be limited to dichloromethane and
ethanol/saline (1:9). Other, more
contemporary extraction techniques such
as supercritical fluid extraction, may
also be useful - at least for exhaustive
extraction of the silicone materials.
Experimental evidence must be provided
to show that exhaustive extraction has
been achieved with one of the solvents,
and the percent recovery, especially for
the more volatile components, be
reported. Extracts that may contain
oligomeric or polymeric species must
have the molecular weight distribution
provided, along with the number and
weight average molecular weights and the
polydispersity.
Guidelines for extraction and a selected
bibliography of analytical methodologies
are included as Appendix I and II
respectively.
All experimental methodology must be
described, and raw data (including
instrument reports) provided along with
all chromatograms, spectrograms, etc.
The practical quantitation limit (PQL)
(see "Compilation of EPA's sampling and
analysis methods, Lewis publishers 1992)
must be provided when the analyte of
interest is not detected. Laboratory
test methods and animal experiments used
in the characterization of the physical,
chemical (other than exhaustive
extraction), and mechanical properties
of the device should be applicable to
the intended use of the device in
humans.
2.1.10.3 Surface Composition
Infrared measurements of the surface of
device components as they occur in the
final sterilized product should be
provided. This establishes the major
chemical characteristics of the surface
which may differ from the bulk. This
information will provide baseline
characterization for comparison with
explants.
2.2 Toxicological Evaluations
The synthetic polymeric materials used in
testicular prostheses should not present a toxic
risk upon long-term intimate contact with the
body. The high molecular weight polymeric
material used in silicone testicular prostheses
contains low molecular weight components, such as
monomers, oligomers, and catalysts which can leach
out into the body. Therefore, one important
requirement of the preclinical toxicology testing
of the device is to determine the potential
toxicity of these releasable chemicals as they
appear in the final sterilized device. These
tests should reveal the potential for local as
well as systemic toxicity (including genotoxicity,
carcinogenicity, adverse reproductive effects,
teratogenicity, and immunotoxicity) of any
leacable substance. Thus, the chemicals recovered
by extraction of the final sterilized implant
material, when appropriate, should be used as the
test article in animal studies after they are
separated, quantified and identified.
In addition, the primary concern for any implanted
device is its potential to cause cancer. This
potential may arise not only from chemical
leachables and degradation products from the
device, but also from physical effects of the
device at the implanted site. Therefore, adequate
long-term studies with implantation of device
materials should be conducted to evaluate the
carcinogenic potential of testicular implants.
The Tripartite Biocompatibility Guidance for
Medical Devices (September 1986) lists suggested
short-term (irritation tests, sensitization assay,
cytotoxicity, acute systemic toxicity,
hemocompatibility/hemolysis, pyrogenicity
(material-mediated), implantation tests,
pharmacokinetics studies, mutagenicity
(genotoxicity)) and long-term (subchronic
toxicity, chronic toxicity, carcinogenesis
bioassay, reproductive and developmental toxicity)
biological tests that might be applied to
evaluating the safety of medical devices. The
guidance may also be used in selecting appropriate
tests for the evaluation of testicular implants.
2.2.1 Pharmacokinetics Studies
Pharmacokinetic/biodegradation studies of all
materials contained in the finished
sterilized device must be reported. Of
special concern are questions regarding the
ultimate fate, quantities, sites/organs of
deposition, routes of excretion, and
potential clinical significance of silicone
shedding, retention and migration. For the
polyurethane foam covered designs, FDA
believes that in vivo implant studies must be
performed to identify and determine the
bioabsorption, distribution, and elimination
of the polyurethane coating (as well as its
degradation products) in experimental
animals. It is also important to identify
and determine the mechanism and rate of
degradation, as well as the quantity of
toluene diamine (TDA) generated by the
breakdown of polyurethane foam covered
testicular prostheses after prolonged
exposure under physiological conditions in
animals.
2.2.2 Mutagenicity Testing
Complete reports from the mutagenicity
testing of chemicals extracted from the
finished, sterilized components of the device
must be provided. The testing must, at
minimum, consist of bacterial mutagenicity,
mammalian mutagenicity, DNA damage, and cell
transformation assays.
2.2.3 Acute, Subchronic and Chronic Toxicity,
Carcinogenicity, Teratogenicity, and
Immunotoxicity
Acute, subchronic, and chronic toxicity,
carcinogenicity*, reproductive and
teratological effects* and immunotoxicity*
studies should be conducted on the final
sterilized product, using either device
materials and/or appropriate extracts of the
device materials. In particular, studies
should assess compounds extracted from the
materials of the final sterilized device for
estrogen-like antigonadotropic activity in an
appropriate animal model using scientifically
valid methods. Complete reports from acute
and subchronic toxicity testing of
extractable chemicals contained in the final
sterilized device should include gross and
histopathological studies in appropriate
tissues both surrounding and remote from the
implanted site.
*For specific and detailed guidance on these
studies, please contact the urology and
Lithotripsy Devices Branch at (301) 427-1194.
3. Clinical data
Valid scientific evidence, as defined in 21 CFR 860.7,
should include well-controlled, prospective, clinical
studies, with statistically justified sample size and
detailed long-term follow-up, in order to provide
reasonable assurance of the safety and effectiveness of
the testicular prosthesis. A detailed protocol for the
clinical trial, with explicit patient
inclusion/exclusion criteria, clear study objectives,
and a well-defined follow-up schedule, should be
specified. FDA believes that at least five year
follow-up data (or until physical maturity of the
subject, whichever occurs later) are necessary in order
to characterize the safety and effectiveness of the
device over its expected lifetime; however,
appropriately justified alternate follow-up schedules
will be considered. Any deviations from the protocol
should be stated and justified.
Time course presentations of patient satisfaction with
and psychological benefit from the implantation of this
device, as well as information on the anatomical
effects of the testicular prosthesis (including all
adverse events), should be provided. Full patient
accounting should be reported, including: (1)
theoretical follow-up (the number of patients that
would have been examined if all patients were examined
according to their follow-up schedules); (2) patients
lost to follow-up, including measures taken to minimize
such events (with all information obtained on patients
lost to follow-up); (3) time course of revisions,
including all explant data; and (4) time course of
deaths (stating the cause of death, including the
reports from any postmortem examinations). As part of
this, each clinical report should clearly state the
date that the database was closed to the addition of
new information. Detailed patient demographic analyses
and characterizations should be presented, and should
show that the patients included in the study are
representative of the population for whom the device is
intended.
A statistical demonstration, based on the number of
patients who complete the required study period, should
show that the sample size of the clinical study is
adequate to provide accurate measures of the safety and
effectiveness of the device. The statistical
demonstration should identify the effect criteria;
reasonable levels for Type I (alpha) and Type II (beta)
errors; anticipated variances of the response
variables; and provide any assumptions or statistical
formulas with copies of any references used and all
calculations made. A complete description of any
patient randomization techniques used, and how these
techniques were employed to exclude potential sources
of bias, should be provided. Statistical
justifications for pooling across several variables
such as the etiology and duration of scrotal
abnormality, patient age, anatomical abnormalities of
the genitalia, device usage (initial implantation
versus revision), type of device (solid or silicone
gel-filled, polyurethane foam coated or uncoated, size,
etc.), type of device surface, investigational site,
surgeon experience and technique, and incision site
should be provided. The data collected and reported
should include all possible relevant variables in order
to permit stratification and analysis of the study
data. This is necessary in order to evaluate the
risk/benefit ratio for each unique subpopulation of
patients.
Appropriate control/comparison groups should be
included and justified and, if not, their absence must
be justified. All hypotheses to be tested must be
clearly stated. Appropriate statistical techniques
must be employed to test these hypotheses and support
claims of safety and effectiveness. For each relevant
subgroup, a sufficient number of patients needs to be
followed for a sufficient length of time to adequately
support all claims (explicit and implied) in any PMA
submission.
To evaluate the risks to the patient from the
testicular prosthesis, such studies should include time
course presentations of clinical data demonstrating the
presence or absence of device migration, skin erosion,
implant extrusion, rupture/leakage, fibrous capsular
contracture, infection, patient dissatisfaction leading
to removal, or any other device malfunction or adverse
health event, including any effects on the immune
system (both local to the device and systemic) and the
reproductive system, without regard to the device
relatedness of the event. The diagnostic criteria for
each type of immunological and allergic phenomenon
should be defined at the beginning of the study, and
all cases should be well documented utilizing these
criteria. Patients must be regularly monitored for the
occurrence of such adverse events for a minimum of five
years post-implantation, or until physical maturity of
the subject (whichever occurs later).
FDA recognizes that the primary benefit of the
testicular prosthesis is cosmetic in nature. The
effectiveness of the device can probably be measured by
assessing: (1) the degree of maintenance or
enhancement of a male's psychological well-being
post-implantation; and (2) the anatomical effect provided by
the device in vivo; both of which can be balanced
against any illness or injury from the use of the
device. FDA understands that evaluation of the degree
of benefit, in part, involves an assessment of patient
satisfaction and psychological well-being, particularly
in light of the function of the device. Such
evaluation includes subjective factors, relates to
patient expectations, and may be transient in nature.
Assessments of the implant's anatomical presence
post-implantation, on the other hand, should provide some
objective measure of device effectiveness.
The evaluation parameters for this portion of the
clinical study should be structured for an objective
and standardized recording/measurement of: (1) the
psychological benefit of the device to the implant
recipient, including any improvement in quality of
life; and (2) the anatomical effect of the implant.
The primary requirements for an acceptable scientific
documentation of psychological benefits of the device
are the use of (1) prospective research designs,
including pre- and post-surgical repeated measures; (2)
appropriate control/comparison groups; and (3)
standardized test instruments rather than informal,
yet-validated questionnaires.
Any questionnaire utilized in the documentation of the
psychological consequences of testicular prostheses
must be shown to provide a scientifically valid measure
of the psychological effects of testicular loss/absence
upon males. Documentation of these psychological
consequences shall include (1) pre-surgical baseline
assessments of psychological status, including measures
of the perceived loss that these subjects experience
and their expectations for improvement with the device;
(2) regular post-surgical follow-up of any changes in
psychological status for at least five years, or until
physical maturity of the subject (whichever occurs
later); (3) statistical comparison of post-surgical
psychological test scores versus pre-surgical test
scores within the group of treated patients; (4)
statistical comparison of psychological test scores of
treated patients versus untreated control patients at
all pre-surgical and post-surgical assessment
intervals; and (5) correlation of the psychological
data with the physical outcomes of the implantation
procedure.
Documentation of the anatomical outcome of implantation
of a testicular prosthesis shall include: (1) regular
post-surgical evaluations of the stiffness and
dimensional characteristics of the device, as well as
assessments of the status of the device's anatomical
position, for at least five years post-implantation;
(or until physical maturity of the subject, whichever
occurs later) and (2) patient assessments of the
physical presence of the implant during this follow-up
period.
Any PMA for the testicular prosthesis should separately
analyze the degree of device safety and efficacy by the
following variables: (1) etiology and duration of
testicular loss/absence; (2) age of implant recipient;
(3) anatomical abnormalities of the genitalia; (4)
device usage (initial implantation versus revision);
(5) type of device (solid or silicone gel-filled,
polyurethane foam coated or uncoated, size, etc.); (6)
type of device surface; (7) investigational site; (8)
surgeon experience and technique; and (9) incision
site. Furthermore, for each explantation procedure
performed on the study subjects, the following
information must be provided: (1) the mode of failure
of the removed device; and (2) whether or not the
explanted device was replaced with a new device (and,
if a new device was implanted, the manufacturer, type,
and model of the new device must be provided).
Additionally, the effect of the presence of these
implants upon future medical diagnoses/treatments
involving the scrotum in testicular implant recipients
must be analyzed. Any accessories that are sold with
the testicular implant must be shown to have been
effectively used in implant procedures without adverse
effects. Finally, the clinical investigation should
validate the physician and patient instructions for use
(labeling) that were utilized.
For the polyurethane foam covered prosthesis, the
following information needs to be presented: (1) the
kinetics of the end products generated from the
degradation of the polyurethane foam (in vivo); (2) the
frequency and incidence of infection and complication
of retrieval of the implant by surgeons using both
polyurethane foam covered and uncoated prostheses in a
retrospective cohort study; and (3) the neoplasticity
of the material as well as its general toxicity,
including neurological, physiological, biochemical, and
hematological effects, as well as pathology following
prolonged and repeated exposure to polyurethane foam
covered testicular prostheses.
Any epidemiological studies should contain enough
subjects to detect a small but significant increase in
one or more connective tissue diseases (especially
scleroderma) that may be associated with the use of the
device.
The agency believes that insufficient time has elapsed
to permit a direct evaluation of the risks of cancer
and immune related connective tissue disorders posed by
the presence of silicone in the human body and that
sufficient epidemiological data or experimental animal
data are not available to make a reasonable and fair
judgement. Therefore, the agency will require long-term
postapproval follow-up for any testicular
prosthesis permitted to continue in commercial
distribution. Well-designed clinical prospective
studies with long-term follow-up together with
experimental animal studies will be considered as
essential in the determination of safety and
effectiveness of the device. Further, these clinical
studies must collect long-term data on the
teratogenic/reproductive effects of the device as well
as later effects on offspring (from those patients with
a unilateral, functional testicle).
The risk/benefit assessment (as with the entire PMA)
must rely on valid scientific evidence as defined in 21
CFR 860.7(c)(2) from well-controlled studies as
described in 21 CFR 860.7(f) in order to provide
reasonable assurance of the safety and effectiveness of
the testicular prosthesis in the surgical correction,
restoration, or construction of the male scrotal
anatomy.
4. Labeling
Copies of all proposed labeling for the device,
including any information, literature, or advertising
that constitutes labeling under section 201(m) of the
act (21 U.S.C. 321(m)), should be provided. The
general labeling requirements for medical devices are
contained in 21 CFR Part 801. These regulations
specify the minimum requirements for all devices.
Additional guidance regarding device labeling can be
obtained from FDA's publication "Labeling: Regulatory
Requirements for Medical Devices," and from the Office
of Device Evaluation's "Device Labeling Guidance"; both
documents are available upon request from the Division
of Small Manufacturers Assistance (HFZ-220), Center for
Devices and Radiological Health, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD
20857. Highlighted below is additional guidance for
some of the specific labeling requirements for
testicular prostheses.
The intended use statement should include the specific
indications for use and identification of the target
populations. Specific indications and target
populations must be completely supported by the
clinical data described above. For example, it may be
necessary to restrict the intended use to the specific
subpopulations of patients in whom safety and
effectiveness have been demonstrated.
The directions for use should contain comprehensive
instructions regarding the preoperative, perioperative
and postoperative procedures to be followed. This
information includes, but is not necessarily limited
to, (1) a description of any preimplant training
necessary for the surgical team; (2) a description of
how to prepare the patient (e.g., prophylactic
antibiotics), operating room (e.g., what supplies must
be on hand), and testicular prosthesis (e.g., handling
instructions, resterilization instructions) for
prosthesis implantation; (3) instructions for
implantation, including surgical approach, sizing,
device handling, and any intraoperative test procedures
to ensure implant integrity and proper placement; (4)
and instructions for follow-up, including whether
antibiotic prophylaxis is recommended during the
postimplant period and/or during any subsequent dental
or other surgical procedures, how to determine when
patients are ready to resume normal activities, and how
to evaluate, and how often to evaluate, implant
integrity and placement. The directions should
instruct caregivers to specifically question patients
prior to surgery for any history of allergic reaction
to any of the device materials. Troubleshooting
procedures should be completely described. The
directions for use should incorporate the clinical
experience with the implant, and should be consistent
with those provided in other company-provided labeling.
The labeling should include both implant and explant
forms to allow the sponsor to adequately monitor device
experience. The explant form should allow collection
of all relevant data, including the reason for the
explant, any complications experienced and their
resolution, and any action planned (e.g., replacement
with another implant).
Patient labeling must be provided which includes the
information needed to give prospective patients (or
their parents/guardians) realistic expectations of the
benefits and risks of device implantation. Such
information should be written and formatted so as to be
easily read and understood by most patients and should
be provided to patients prior to scheduling
implantation, so that each patient has sufficient time
to review the information and discuss it with his
physician(s). Technical terms should be kept to a
minimum and should be defined if they must be used.
Patient information labeling, if possible, should not
exceed the seventh grade reading comprehension level.
The patient labeling should provide the patient (or
parents/guardians) with the following information: (1)
The indications for use and relevant contraindications,
warnings, precautions and adverse effects/
complications should be described using terminology
well known and understood by the average layman; (2)
the anticipated benefits and risks associated with the
device must be provided to give patients realistic
expectations of device performance and potential
complications. The known, suspected and potential
risks of device implantation should be identified and
the consequences, including possible methods of
resolution, should be described; (3) any alternatives
available to the use of the device, including no
treatment, should be identified, along with a
description of the associated benefits and risks of
each. The patient should be advised to contact his
physician for more information on which of these
alternatives might be appropriate given his specific
condition; (4) instructions for how to care for the
device must be provided to the patient. This
information should include the expected length of
recovery from surgery and when to resume normal
activities following implantation, warnings against
certain actions that could damage or rupture the
device, how to identify conditions that require
physician intervention, who to contact if questions
arise, and other relevant information; (5) the fact
that the implant may not be a "lifetime" implant must
be emphasized. Where possible, the patient labeling
should provide information on the approximate number of
revisions necessary for the average patient, and
indicate the average longevity of each implant so
patients are fully aware that additional surgery for
device replacement or removal may be necessary. This
information must be supported by the clinical
experience (i.e., not merely bench studies) with the
implant or by published reports of experience with
similar devices.
The physician's labeling should instruct the urologist
or implanting surgeon to provide the implant candidate
with the patient labeling prior to implantation to
allow each patient (or his parents/guardians)
sufficient time to review and discuss this information
with his physician(s).
The adequacy and appropriateness of the instructions
for use provided to physicians and patients should be
verified as part of the clinical investigations.
Applicants should submit any PMA in accordance with
FDA's "Premarket Approval (PMA) Manual." The guidance
is available upon request from the Division of Small
Manufacturers Assistance (HFZ-220), Center for Devices
and Radiological Health, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD. 20857.
V. REFERENCES
1. Travis, W.D., Balogh, K. and Abraham, J. L.; Silicone
Granulomas; Report of Three Cases and Review of the
Literature: Human Pathology, Vol. 16: No. 1, pp. 19-27,
January 1985.
2. Benjamin, E., Ahmed, A., Rashid, A.T.M.F., and Wright,
D.H.; Silicone Lymphadenopathy., A report of two cases, one
with concomitant malignant lymphoma", Diagnostic
Histopathologv, 5:133-141, 1982.
3. Transcript of FDA GPS Device Panel Meeting, November
12, 13, 14, 1991. Vol. II, pp. 109-111, (115-120).
APPENDIX I - EXTRACTION GUIDELINES FOR SILICONE IMPLANTS
I. Leachables
Most polymeric materials contain in addition to the relatively
inert, high molecular weight polymer, other components such as
residual monomers, oligomers, catalysts, processing aids, etc.
These are present at varying levels depending on the raw material
sources, the manufacturing processes, and intended function of
additives. Also, additional chemical species may be generated
during manufacturing processes such as heat sealing, welding, or
sterilization of the device. All of these may migrate from the
device into the human body and should be the subject of risk
assessments.
The rate of migration from the shell itself will very likely be
controlled by diffusion processes in the shell elastomer itself
unless there is partitioning in the external phase, in this case,
body fluids and tissues. The latter cannot hold if metabolic
processes convert the migrant into another chemical species or if
it is eliminated. In either case, the situation is equivalent to
migration into infinite volume and corresponds to exhaustive
extraction. The effect of the external phase is treated in a
paper by R. C. Reid, K. R. Sidman, A. D. Schwope and D. E. Till,
Ind. Eng. Chem. Prod. Res. Dev., 19(4), 1980, p. 580-587.
The rates of migration may be very slow so that the levels of
migrants in short term animal studies may not be high enough to
elucidate any responses. Toxicological testing of migrants
allows for determination of dose response curves and "no adverse
effect levels." For the shell, initial levels plus migration
rates would allow calculation of dose rates. In order to carry
out such risk assessments, the identity and levels of the
potential migrants must be established. Presently, exhaustive
extractive experiments are the best approach for accomplishing
this.
II. Samples
Each of the individual structural components (shell, outer
patches, sealants, etc.) as they are found in the final
sterilized device should be subjected to extractions. No
additional processing or curing should be performed on these
samples. A major fraction of each structural component as it is
in the final device should be subjected to extractions. Two
approaches are possible;
1. Several replicate samples can be taken from each of the
structural components of the finished devices and these
samples can be subjected to extractions.
2. Several replicate samples can be taken from the
structural components before final assembly, but the
components must have undergone all processing, curing and
sterilization treatments that the finished device receives.
This approach can be used provided that the content and
chemical identity of the extracts is the same as (or closely
represents) that found using approach 1.
Both of these approaches require that the ratio of the sample
weight to the device structural component weight be known so that
levels of extractants can be referred back to the entire device
as implanted. That is, the grams of migrant per grams of the
specific structural component is then multiplied by the total
weight of the structural component to give the total amount per
device. For the shell material, because the weight ratios may be
inaccurate, the sample area should be reported so that the
fraction of the shell area can be calculated to give the
multiplier.
III. Selection of Extracting Solvents
Solvents should be chosen that are expected to solubilize the low
molecular weight migrants thus facilitating exhaustive
extraction. Inasmuch as the chemical nature of all of the
migrants is not known, it is advisable to use solvents with
different chemical characteristics such as polarity, aromaticity,
etc. Both polar and non-polar solvents should be used. Charged
or very polar species such as heavy metals, catalyst complexes,
and inorganic chemicals may also migrate from the polymers and
would not be soluble in non-polar solvents.
Initial experiments should use a solvent of mixed polarity such
as methylene dichloride. For highly crosslinked elastomers as
are used in the shells, solvents which swell the polymer are
desirable as they would enable completion of the experiments
sooner.
IV. Design of the Extraction Experiment
A. Extraction vessel.
An extraction cell should be used in which a sample of known
weight and known geometric surface area is extracted by a
known volume of solvent. An example of such a cell is
described in an article by Snyder, R. C. and Breder, C. V.,
J. Assoc. Off. Anal. Chem., 68(4) 1985, p 770f. Such a cell
may work for polymer plates such as cut from the shell.
Mild agitation of the solvent is recommended. Although
immersion of samples allows for two-sided extraction,
calculation should be based on the sample weight or the area
of one side when doing exhaustive extractions. Additional
considerations and helpful comments are given in the section
"Design of the Extraction Experiment, part D.1.a, Extraction
Vessel" of the Recommendations for Chemistry Data for
Indirect Food Additive Petitions obtainable from the
Division of Food Chemistry and Technology, CFSAN, FDA,
Harvey W. Wiley Federal Building, Room 1B-018, 5100 Paint Branch Parkway
College Park, MD 20740-3835.
B. Extraction Sample
General considerations on sampling are given above. Because
migration is a diffusive process plate geometry is
desirable; the experimental time can be further minimized by
using thin samples. The sample geometry, thickness, weight
and solvent volume must be reported. The ratio of volume of
solvent to the area of the sample is not so important for
exhaustive extraction as described below. However, if
cloudy solutions or precipitation is noticed during the
first time interval, then the solvent volume to sample
surface area is too low.
C. Temperature and Time of Extractions
For the determination of residual levels of low-molecular
weight components of polymeric materials, experiments can be
accelerated since only the levels are of interest here and
not the kinetics. Exhaustive extractions should be carried
out as described below in order to determine residue levels.
This will also provide the maximum amount of migrants per
sample which should be used for further chemical
characterization and for toxicological tests. Extractions
can be done at 37 C or at elevated temperatures in order to
accelerate the experiment. However, the petitioner is
advised that elevated temperatures may cause chemical
reactions to produce additional extractants. Also, if
elevated temperatures are used they should be chosen so that
no additional curing or crosslinking of the polymers takes
place during the extraction experiment.
For exhaustive extractions, the duration of the extraction
cannot be prescribed in advance but can be dealt with in the
following manner. A series of successive extractions is
carried out by exposing the sample to the solvent for a
period of time, analyzing the solvent for extractants,
replacing with fresh solvent and again exposing the sample
for a period of time, analyzing and repeating the process.
When the level of the analyte for the ith successive
extraction is one-tenth (.1) of the level in the first
extraction the extraction may be deemed complete. It is
possible that this condition may not occur because of
extremely slow migration of the higher molecular weight
material. The test can be applied to the contents of the
extract with molecular weights below 1500. All the separate
analyte levels are added up to give the cumulative value and
via the sample/solvent ratio referred back to sample levels
and finally back to device levels.
In order to minimize experimental time and provide for
analysis choosing unequal time periods is desirable.
Intervals based on a log or half-log scale generally work
out well and minimizes the number of chemical analyses. For
shells, this should also allow determination of migration
rates by log-log plots of cumulative migration against time.
V. Characterization of the Extracts
A. Analytical Methodology
Specific or non-specific analytical methods may be required
depending on the situation. For example, size exclusion
chromatography (SEC), high pressure liquid chromatography
(HPLC) or some other chromatographic or separation methods
may show that the extractants in a given solvent consist of
several chemical species. Appropriate methodologies, such
as atomic absorption (AA), ion chromatography, etc., should
be employed to assess the presence of metallic, inorganic,
organometallic, etc., leachables in polar solvents. For the
purposes of performing the exhaustive extraction,
determination of the total concentration of extractants by
gravimetric or some other method would suffice. A
bibliography of representative analytical methodologies
which may be useful is given in Appendix II.
It is necessary for the purposes of toxicological testing to
identify the individual components in terms of their
molecular composition and to determine the concentration of
the individual components of the extract. Following
separation and isolation, identification of the individual
components in terms of chemical composition can be done by
any number of chemical identification methods such as
infrared, UV-visible (including diode array), NMR, or mass
spectrometries (See Appendix II). Comparison to known
structures will be beneficial. Determination of the
individual concentrations may require a specific analytical
method unless relative concentrations of the components can
be determined and used together with the total concentration
to give the individual concentrations.
B. Description of Analytical Methods
All analytical methods must be completely described.
Calibration or standard curves should be supplied. The
calibration curve should bracket the concentration of the
migrant in the extract. All analytical methods should be
validated. An excellent discussion of these points is given
in the Section D.3 entitled "Analytical Methodology" in the
Recommendations for Chemistry Data for Indirect Food
Additive Petitions already cited above. Additional
information with accompanying references concerning
validation procedures can be found in papers by Vanderwielen
and Hardwidge (Guidelines for Assay Validation,
Pharmaceutical Technology, March 1982, pp 66-76) and by
Ficarro and Shah (Validation of High-Performance Liquid
Chromatography and Gas Chromatography Assays, Pharmaceutical
Manufacturing, Sept 1984, pp 25-27). We agree with the
recommendations given in those Guidelines.
(2/18/93)
Appendix II Selected bibliography of analytical methods
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Wims, A.M., Swarin, S., "Determination of Antioxidants in
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19, 1243-1256, (1975).
Lichenthaler, R.G., Ranfelt, F., "Determination of Antioxidants
and their Transformation Products in Polyethylene by High-Performance
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Schabron, J.F., Fenska, L.E., "Determination of BHT, Irganox
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Haney, M.A., W.A. Dark, "A Reversed-Phase High Pressure Liquid
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J. Chromatogr. Sci., 18, 655-659, (1980).
Lehotay, J., Danecek, J., Lisa, O., Lesko, J., Brandsteterova,
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Schabron, J.F., Bradfield, D.Z., "Determination of the Hindered
Amine Additive CGL-144 in Polypropylene by High-Performance
Liquid Chromatography, J. Appl. Polym. Sci., 26, 2479-2483,
(1981).
Francis, V.C., Sharma, Y.N., Bhardwaj, I.S., "Quantitative
Determination of Antioxidants and Ultraviolet Stabilizers in
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Makromol. Chem., 113, 219-225, (1983).
Choudhary, V., Varshney, S., Varma, I.K., "Degradation of
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150, 137-150, (1987).
Munteanu, D., Isfan, A., Isfan, C., Tincul, I., "High-Performance
Liquid Chromatographic Separation of Polyolefin Antioxidants and
Light-Stabilisers", Chromatographia, 23 (1), 7-14, (1987).
Padron, A.J.C., Colmenares, M.A., Rubinztain, Z., Albornoz, L.A.,
"Influence of Additives on Some Physical Properties of High
Density Polyethylene - I. Commercial Antioxidants", Eur. Polym.
J., 23 (9), 723-727, (1987).
Padron, A.J.C., Rubinztain, Z., Colmenares, M.A., "Influence of
Additives on Some Physical Properties of High Density
Polyethylene - II. Commercial u.v. Stabilisers", Eur. Polym. J.,
23 (9), 729-732, (1987).
Raynor, M.W., Bartle, K.D., Davies, I.L., Williams, A., Clifford,
A.A., "Polymer Additive Characterization by Capillary
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"Deformulating Polypropylene by HPLC", Polymer Notes, Waters
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Neilson, R. C., "Extraction and Quantitation of Polyolefin
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Waters Polymer Update, applications Brief No. RN101, "The
Analysis of Additives in Polyolefins by Reverse Phase Gradient
Chromatography", date unknown.
POLYVINYL CHLORIDE (PVC)
Pedersen, H.L., Lyngaae-Jorgensen, J., "Gel Permeation
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Systems", J. Chromatogr., 55, 15-24, (1971).
Liao, J.C., Browner, R.F., "Determination of Polynuclear Aromatic
Hydrocarbons in Poly(vinyl chloride) Smoke Particulates by High
Pressure Liquid Chromatography and Gas Chromatography-Mass
Spectrometry", Anal. Chem., 50,(12), 1683-1686, (1978).
Shepherd, M.J., Gilbert, "Simple and Inexpensive Application of
Steric Exclusion Chromatography for the Isolation of Low-Molecular
Weight
Additives form Polymer Systems", J. Chromatogr.,
435-441, (1979).
Perlstein, P., "The Determination of Light Stabilisers in
Plastics by High-Performance Liquid Chromatography", Anal. Chim.
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Gradient Elution for the Characterization of Phenol-Formaldehyde
Resins", Angew. Makromol. Chem., 150, 179-187, (1987).
POLYMETHYLMETHACRYLATE (PMMA)
Pasteur, G.A., "Qunatitative Determination of Stabilizers in
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Methacrylate in Soft Contact Lenses by High Performance Liquid
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POLYURETHANES
Spagnolo, F., "Quantitative Determination of Small Amounts of
Toluene Diisocyanate Monomer in Urethane Adhesives by Gel
Permeation Chromatography", J. Chromatogr. Sci., 14, 52-56,
(1976).
McFadyen, P., "Determination of Free Toluene Diisocyanate in
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Guthrie, J.L. and McKinney, R.W., "Determination of 2,4- and
2,6-Diaminotoluene in Flexible Urethane Foams", Anal. Chem., 49(12),
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Toluene Diisocyanate (TDI) and 4,4 -diisocyanatodiphenylmethane
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Richards, J.M., Meuzelaar, H.L.C., Bunger, J.A., "Spectrometric
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Materials", J. Biomed. Mater. Res., 23, 321-335, (1989).
Richards, J.M., McClennen, W.H., Meuzelaar, H.L.C.,
"Determination of Additives in Biomer and Lycra Spandex by
Pyrolysis Tandem Mass Spectrometry and Time Temperature Resolved
Pyrolysis Mass Spectrometry", J. Appl. Polym. Sci., 40, 1-12,
(1990).
Belisle, J., Maier, S.K., Tucker, J.A., "Compositional Analysis
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572, 41-49, (1991).
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RUBBERS
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J. Chromatogr. Sci., 25, 506-509, (1987).
NYLONS
Caldwell, J., Perenich, T., "Recovery and Analysis by HPLC of
Benzoyl Peroxide Residues in Nylon Carpet Fibers", Textile Res.
J., June, 1987.
CELLULOSE ACETATE
Floyd, Th.R., "Use of Two-Dimensional Liquid Chromatography in
the Analysis of Additives in Cellulose Acetate Polymer",
Chromatographia, 25(9), 791-796, (1988).
SILICONES
Horner, H.J., Weiler, J.E., Angelotti, "Visible and Infrared
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Neal, P., "Note on the Atomic Absorption Analysis of
Dimethylpolysiloxanes in the Presence of Silicates", J. Assoc.
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Neal, P., Campbell, A.D., Firestone, D., "Low Temperature
Separation of Trace Amounts of Dimethylpolysiloxanes from Food",
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Sinclair, A., Hallam, T.R., "The Determination of
Dimethylsiloxane in Beer and Yeast, Analyst, 96, 149-154, 1971.
Howard, J.W., "Report on Food Additives", J. Assoc. Off. Anal.
Chem., 55(2), 262, (1972).
Frick, R., Baudisch, H., "Physico-chemical Determination of
Intravascular Silicone in Brain and Kidney", Beitr. Path. Bd.,
149, 39-46, (1973).
Cassidy, R.M., Hurteau, M.T., Mislan, J.P., Ashley, R.W.,
"Preconcentration of Organosilicons on Porous Polymers and
Separation by Molecular-Seive and REversed-Phase Chromatography
with an Atomic Absorption Detection System", J. Chromatog. Sci.,
14, 444-447, (1976).
Vessman, J., Hammar, C., Lindeke, B., Stromberg, S., LeVier, R.,
Robinson, R., Spielvogel, D., Hanneman, L., "Analysis of Some
Organosilicone Compounds in Biological Material", In Biochemistry
of Silicon and Related Problems; Bendz, G, Lindqvist, I., Eds.;
Plenum: New York, 1977; pp 535-558.
Pellenbarg, R., "Enviromental Poly(organosiloxanes) (Silicones)",
Environmental Science and Technology, 13(5), 565-569, (1979).
Abraham, J.L., Etz, E.S., "Molecular Microanalysis of
Pathological Specimens in situ with a Laser-Raman Microprobe",
Science, 206, 716-718, (1979).
Buch, R.R., Ingebrightson, D.N., "Rearrangement of
Poly(dimethylsiloxane) Fluids on Soil", Environmental Science and
Technology, 13(6), 676-679, (1979).
Doeden, W.G., Kushibab, E.M., Ingala, A.C., "Determination of
Dimethylpolysiloxanes in Fats and Oils", J. Amer. Oil Chemists
Soc., 57(2), 73-74, (1980).
Abe, Y., Butler, G.B., Hogen-Esch, T.E., "Photolytic Oxidative
Degradation of Octamethylcyclotetrasiloxane and Related
Compounds", J. Macromol. Sci., Chem., A16(2), 461-471, (1981).
Leong, A.S.-Y., Disney, A.P.S., Grove, D.W., "Spallation and
Migration of Silicone from Blood-Pump Tubing in Patients on
Hemodialysis", N. Engl. J. Med., 306(3), 135-140, (1982).
Baker, J.L., LeVier, R.R., Spielvogel, D.E., "Positive
Identification of Silicone in Human Mammary Capsular Tissue",
Plast. Reconst. Surg., 69(1), 56-60, (1982).
Kacprzak, J.L., "Atomic Absorption Spectroscopic Determination of
Dimethylpolysiloxane in Juices and Beer", J. Assoc. Off. Anal.
Chem., 65(1), 148-150, (1982).
Mahone, L.G., Garner, P.J., Buch, R.R., Lane, T.H., Tatera, J.F.,
Smith, R.C., Frye, C.L., "A Method for the Qualitative and
Quantitative Characterization of Waterborne Organosilicon
Substances", Environ. Toxicol. Chem., 2, 307-313, (1983).
Buch, R.R., Lane, T.H., Annelin, R.B., Frye, C.L., "Photolytic
Oxidative Demethylation of Aqueous Dimethylsiloxanols", Environ.
Toxicol. Chem., 3, 215-222, (1984).
Watanabe, N., Yasuda, Y., Kato, K., Nakamura, T., "Determination
of Trace Amounts of Siloxanes in Water, Sediments and Fish
Tissues by Inductively Coupled Plasma Emission Spectrometry", The
Science of the Total Environment, 34, 169-176, (1984).
Bruggeman, W.A., Weber-Fung, D., Opperhuizen, A., Van der Steen,
J., Wijbenga, A., Hutzinger, O., "Absorption and Retention of
Polydimethylsiloxanes (Silicones) in Fish: Preliminary
Experiments", Toxicol. Environ. Chem., 7, 287-296, (1984).
McCamey, D.A., Iannelli, D.P., Bryson, L.J., Thorpe, T.M.,
"Determination of Silicone in Fats and Oils by Electrothermal
Atomic Absorption Spectrometry with In-Furnace Air Oxidation",
Anal. Chim. Acta., 188, 119-126, (1986).
Anderson, C., Hochgeschwender, K., Weidemann, H., Wilmes, R.,
"Studies of the Oxidative Photoinduced Degradation of Silicones
in the Aquatic Environment", Chemosphere, 16(10-12), 2567-2577,
(1987).
Watanabe, N., Nagase, H., Ose, Y., "Distribution of Silicones in
Water, Sediment and Fish in Japanese Rivers", The Science of the
Total Enviroment, 73, 1-9, (1988).
Winding, O., Christensen, L., Thomsen, J.L., Nielsen, M.,
Breiting, V., Brandt, B., "Silicon in Human Breast Tissue
Surrounding Silicone Gel Prostheses", Scand. J. Plast. Reconstr.
Surg., 22, 127-130, (1988).
Annelin, R.B., Frye, C.L., "The Piscine Bioconcentration
Characteristics of Cyclic and Linear Oligomeric
Permethylsiloxanes", The Science of the Total Environment, 83, 1-11,
(1989).
Parker, R.D., "Atomic Absorption Spectrophotometric Method for
Determination of Polydimethylsiloxane Residues in Pineapple
Juice: Collaborative Study", J. Assoc. Off. Anal. Chem., 73(5),
721-723, (1990).
Nakamura, K., Refojo, M.F., Crabtree, D.V., "Factors Contributing
to the Emulsification of Intraocular Silicone and Fluorosilicone
Oils", Invest. Ophth. Vis. Sci., 31(4), 647-656, (1990).
Nakamura, K., Refojo, M.F., Crabtree, D.V., Leong, F., "Analysis
and Fractionation of Silicone and Fluorosilicone Oils for
Intraocular Use", Invest. Ophth. Vis. Sci., 31(10), 2059-2069,
(1990).
Gaboury, S.R., Urban, M.W., "Spectroscopic Evidence for Si-H
Formation During Microwave Plasma Modification of
Poly(dimethylsiloxane) Elastomer Surfaces", Polym. Commun.,
32(13), 390-392, (1991).
Israeli, Y., Philippart, J.-L., Cavezzan, J., Lacoste, J.,
Lemaire, J., "Photo-oxidation of Polydimethylsiloxane Oils: Part
I - Effect of Silicon Hydride Groups", Polym. Degradation. Stab.,
36, 179-185, (1992).
"Selective Detection of Cyclic Silicon Compounds Extracted from
Silicone Breast Implants"; DET Report No. 22, March, 1992;
DETector Engineering & Technology, Inc., Walnut Creek, CA.
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