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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DRAFT GUIDANCE FOR PREPARATION OF PMA APPLICATIONS FOR PENILE INFLATABLE IMPLANTS |
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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 PENILE INFLATABLE IMPLANTS 2
1. Manufacturing Data: 2
1.1 Chemical Characterization of Device
Components 2
1.1.1 Process tree 3
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. 5
2. Preclinical Data 5
2.1 Finished product chemistry 6
2.1.1 Chemical characterization 6
2.1.2 Leachable Chemicals 6
2.1.3 Surface Composition 8
2.2 Toxicological Evaluation 8
2.2.1 Pharmacokinetics Studies 9
2.2.2 Mutagenicity Testing 9
2.2.3 Acute, subchronic, and chronic
toxicity,carcinogenicity,teratogenicity, and
immunotoxicity. 10
2.3 Physical, Mechanical and Reliability testing 10
2.3.1 General Requirements 10
2.3.2 Physical Material Characterization 12
2.3.3 Device/Component/Subassembly
Performance Testing 15
3. Clinical data 22
4. Labeling. 28
5. References (Risks and benefits associated with
penile implants) 31
Appendix I Extraction Guidelines for Polymers 38
Appendix II Selected bibliography of analytical methods 43
DRAFT GUIDANCE FOR PREPARATION OF PMA APPLICATIONS FOR
PENILE INFLATABLE IMPLANTS
Urology and Lithotripsy Devices Branch
Division of Reproductive, Abdominal, Ear, Nose and Throat
and Radiological Devices
I. PREFACE
This guidance document addresses the preparation of premarket
approval (PMA)applications for penile inflatable implants for the
treatment of erectile dysfunction. It may also be useful for the
preparation of Investigational Device 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 penile inflatable implant is a device that consists of two
inflatable cylinders implanted in the penis, connected to a reservoir
filled with radiopaque fluid implanted in the abdomen, and a subcutaneous
manual pump implanted in the scrotum. These devices have been constructed
from silicone or polyurethane elastomers and some models also contain
silicone gel. Also included within this device classification are those
models of the penile inflatable implant that have the reservoir and the
pump combined into one component that is implanted within the scrotum, or
that have a reservoir and pump combined within each of the two cylinders.
When the cylinders are inflated, they provide rigidity to the penis. These
devices are used in the treatment of erectile dysfunction.
III. BACKGROUND
In the FEDERAL REGISTER of November 23, 1983 (48 FR 53023), FDA issued
a final rule classifying the penile inflatable implant into class III (21
CFR 876.3350). 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. Although the
penile inflatable implant was not included in this list of 31 devices, the
agency has received more than 6,500 Medical Device Reports (MDRs) for this
device since 1984. Therefore, FDA has determined that the penile
inflatable implant identified in 21 CFR 876.3350 has a high priority for
initiating a proceeding to require premarket approval. In the FEDERAL
REGISTER of ____________________, FDA issued a proposed rule requiring a
PMA for these devices. 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
PENILE INFLATABLE IMPLANTS
A PMA must be submitted by all distributors of penile inflatable
implants. 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 penile inflatable
implant that is the subject of the application. 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 and quality assurance information is required to
assess the safety and effectiveness of penile inflatable implants.
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, including all adhesives, colorants and filling agents
(e.g., gel, saline contrast medium, etc.). 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
All physical and chemical properties of the device must be completely
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.
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 Finished product chemistry
2.1.1 Chemical characterization
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.
2.1.2 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.
2.1.3 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 Evaluation
The synthetic polymeric materials used in the penile inflatable
implant should not present any toxic risks upon long-term intimate
contact with the body. The high molecular weight polymeric
material used in silicone penile 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 testing 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
leachable substance. Thus, the chemicals recovered by extraction
of the final sterilized implant device, 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 penile prostheses.
The Tripartite Biocompatability 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 penile
inflatable 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 designs using polyurethane elastomers, FDA
believes that in vivo implant studies must be performed to
identify and determine the polyurethane elastomers (as well as
their 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 degradation products
generated by the breakdown of polyurethane elastomers after
prolonged exposure under physiological conditions in animals. The
agency suggests that these studies on polyurethane elastomers be
conducted as a separate subset of penile inflatable implant safety
studies.
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.
2.3 Physical, Mechanical and Reliability Testing
2.3.1 General Requirements
Physical, mechanical and reliability tests should be conducted on
components, subassemblies, and finished devices of each device
model proposed for marketing, as appropriate, and must examine all
aspects of device design, construction, and operation. All tests
should be performed on components and devices fabricated by
representative manufacturing processes and subjected to the final
validated sterilization procedures intended for the device.
A statistically valid number of samples of each model should be
tested. If sample devices of each available size are not tested,
it must be clearly indicated which device sizes were used for each
test. The absence of testing on each size must be justified by an
analysis demonstrating that the results from the tested devices
will accurately predict results for the untested device sizes.
Copies of typical original data sheets from all tests should be
included. For all tests that result in device failure, the
failure mode must be completely described. The significance of
all tests that result in failure of a device, component, or
subassembly to meet specification must be rationalized. If the
conditions under which the failed device, component, or
subassembly was tested (loads, environments, etc.) are likely to
occur in vivo, corrective actions taken to eliminate or minimize
further occurance must be identified and modified samples
retested.
The performance specifications for all components, subassembles,
and finished devices, and test conditions and acceptance criteria
for all tests should be completely explained and justified by
comparison to expected in vivo conditions. All tests should be
performed in an environment simulating the possible range of
anticipated in vivo conditions (temperatures, pressures, forces,
stresses, etc.), including capsular formation, where possible.
All methods used to determine the condition of the device after
testing, e.g., visual examination, electrical continuity, electron
microscope examination, functional testing, etc., should be
discussed and justified.
If accelerated aging is used to demonstrate device durability and
reliability, all processes used should be completely described,
and the calculations validating the expected aging should be
provided.
All data, collected from in vitro and animal testing, regarding
the useful lifetime or long term reliability of the device, must
be compared to data from clinical studies (prospective and/or
retrospective) where the useful lifetime of the device has been
determined. This comparison must validate the ability of the in
vitro and animal tests to accurately predict the useful lifetime
of an implanted device.
A failure mode and effects analysis (FMEA) should be conducted and
provided. Testing should demonstrate how the proposed device
design and manufacturing processes are consistent with the FMEA.
Additionally, the effects of implantation, including the stresses
of the biological environment, on device function and integrity
should be determined by appropriate animal testing. Complete
material, chemical and physical characterization and device/
component performance testing should be performed on devices
explanted from animals after an appropriate implantation duration.
Of special concern is the integrity of the cylinders, reservoir,
pump, tubing, joints, etc. 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.
2.3.2 Physical Material Characterization
Physical tests should include, but are not necessarily limited to,
the following, as appropriate. Suggested methodologies are listed
where available:
tensile strength and ultimate elongation of material specimens
taken from cylinders, pumps, reservoirs, and tubing of the
finished, sterilized product (ASTM D412). The device materials
must possess some minimum level of mechanical strength in order to
withstand ruptures from stresses and deformations applied to the
components of the device. Tensile strength and ultimate
elongation represent respectively the largest sustainable stress
and stretching deformation on a test specimen before rupture
occurs.
energy to rupture, i.e., strain energy to failure, for material
specimens taken from each of the above listed device components of
the finished, sterilized device. Energy to rupture, determined
from the total area under a generated stress-strain curve,
represents the total trauma, in units of energy, that a test
specimen can endure before rupturing.
tear resistance for material specimens taken from each of the
above listed device components of the finished, sterilized device
(ASTM D624). The device materials must possess some minimum level
of protection against the catastrophic propagation of a puncture
or small tear. Tear resistance is a measure of this capability.
integrity of fused or adhered joints. ASTM F703 contains a
methodology, including geometries of test specimens. Unlike ASTM
F703, however, the testing should be conducted to and results
reported for the failure points of the specimens. The breaking
force at failure, normalized to the joint thickness, should be
reported for the test specimens. Failure of a fused or adhered
joint represents a potential source for leakage of gel-fill and/or
liquid-fill from the device. This testing provides a measure of
the resistance of the device to such failures.
cohesivity and/or penetration testing of gel in devices
containing gel. A methodology for gel cohesivity testing is given
in ASTM F703. Reported results for gel testing should include the
actual measurements of gel slump in gel cohesivity testing and/or
measurements of penetrometer fall in gel penetration testing. The
chosen test method(s) should be adequately sensitive to detect
significant variances in gel cohesivity and/or stiffness. Gel
cohesivity testing is designed to measure both the flow properties
and integrity, or connectivity, of the gel. In the event of
rupture of a gel-containing device component, it is important that
the gel maintain some degree of consistency and cohesiveness in
order to facilitate surgical removal.
Gel cohesivity 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 components, and
average degrees of functionality for precursors of cross-linked
components, is important in predicting the degree of cohesion in a
gel, as well as its relative tendency to bleed liquid components
of the gel. This information should be provided as well.
abrasion resistance and analysis of abraded surfaces of
silicone and polyurethane device components taken from the final
sterilized device. Some elastomeric components (particularly
silicone ones) of penile inflatable implants can be relatively
soft and prone to abrasive degradation at their surfaces. While
being placed in a patient, the prosthesis is rubbed against
tissue. When the patient moves, tissue or other anatomic
structures move over the prosthesis. Folds or hernias in device
components could conceivably cause device component surfaces to
rub against one another. Rubbing actions such as these can abrade
the surface of the device.
Abrasion can lead to weakening of the device component surface
making it more prone to mechanically induced trauma. Abrasion can
also release small particles of silicone or other elastomers into
the body, leading to the formation of granulomas. In addition,
abrasion of a silicone elastomer can expose the particles of
silica added to reinforce the elastomer. 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. 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 surfaces of elastomeric components
and the content and particle size distribution of the material
abraded from the elastomeric components must be known in order to
determine whether the implant is safe and effective. Reports on
abrasion resistance testing of elastomeric components of penile
inflatable implants should 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, should
be used to conduct the testing. A description of the test
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, should also be provided. The
material used to abrade specimens should be identified, and a
rationale for choosing this material should be provided as well.
Properties of the abrading medium including hardness, roughness,
etc., that are pertinent to the abrasion process, also should be
identified.
As usual, test specimens should be obtained from components of
finished sterilized devices. Significant weight losses in abraded
material should be induced, and the total number of passes (by the
abrasive medium) required to induce this observed weight loss
should be reported. Averages, standard deviations, detailed
protocols, cycling rates, and raw data should be reported.
Examinations for exposed silica (particularly crystalline silica)
of both the abraded surfaces and abraded particles from test
specimens should be conducted and reported. Percentages of
crystalline silica and the total content of crystalline silica in
these abraded particles should be analyzed for and reported.
Particle size distributions of abraded particles should be
reported.
The results of these tests must be compared to the energy,
stresses, etc., that the device will encounter in vivo.
2.3.3 Device/Component/Subassembly Performance Testing
General
Device/component/subassembly testing should demonstrate the
ability of the device to withstand the demands of use while
maintaining operational characteristics sufficient for intercourse
throughout the expected operational lifetime of the penile
inflatable implant, as stated in the physician and patient
labeling. Since in vivo loading histories are somewhat sporadic,
a discussion comparing the effects of the rate of cycling in each
in vitro test to actual usage conditions and to the expected
longevity of the implant should be included. Life tests should be
interrupted at appropriate intervals and devices/components/
subassemblies evaluated for relevant performance characteristics
and conformance to design specifications. Material
characteristics indicative of material degradation that could
induce device malfunction should be completely evaluated.
Cyclical testing beyond the expected longevity of the implant and
recording of failure mode should be included as part of the life
tests.
Complete Device testing
Testing to demonstrate the operational characteristics of the
device should include but not necessarily be limited to:
amount of pressure generated in the penile cylinder during
inflation;
rate of pressure rise during inflation and pressure drop during
deflation;
range of time and number of strokes required for full
inflation;
ability to maintain the cylinder in a functional inflated
condition for the specified duration (valve leakage);
symmetry of geometry between cylinder pairs while inflated;
time to fully deflate cylinder from fully inflated pressure;
all bonds within the device and between components should
undergo appropriate testing to include but not be limited to
measurement of bond shear and tensile strength. Bond strength
should exceed the loads expected during device handling and after
implantation;
cyclic inflation/deflation tests to demonstrate appropriate
functional durability.
Filling Agent Permeability
The permeability of the filling agent through the reservoir and
body of the device must be evaluated to demonstrate that fluid
loss due to osmosis will be acceptable over the expected life of
the penile inflatable implant.
Component Specific Testing
Proper component operation, conformance to predetermined
operational specifications, and reliability over the expected life
of the device must be demonstrated. Resistance of each component
to tears, crazing, fracture, material fatigue (including wear
between mating components), change of position (e.g., valve
seats), and permanent deformation also must be demonstrated.
Component characterization and testing should include but not be
limited to:
Pumps
Pump characterization and testing should include but not
necessarily be limited to:
minimum force required to affect fluid displacement;
range of volumes displaced per stroke;
squeeze force vs. fluid displacement (volume);
inflation effort, defined as pump force times number of strokes
required for full inflation;
objective confirmation of uniform pump discharge to both penile
cylinders.
Valves
Valve characterization and testing should include but not
necessarily be limited to:
pump output pressure required to affect valve opening for
inflation;
tactile pressure/force required to affect valve opening,
against fully inflated cylinders, for deflation;
back pressure required for valve failure;
maximum pressure differential across closed valve at full
inflation and leakage rate at this pressure;
prevention of spontaneous inflation and deflation under
movements and loads simulating those expected to be sustained by
the implanted device in both inflated and deflated states;
potential for valve failure which could result in an inability
to deflate cylinders.
Cylinders
Cylinder characterization and testing should include but not
necessarily be limited to:
maximum expansion capability (length and girth);
stiffness or rigidity, including resistance to buckling at
maximum inflation pressure;
resistance to aneurysms;
confirmation of concentricity;
wear characteristics if a fold in the cylinder develops;
burst strength of the cylinder, including all joints and seams,
or proof testing demonstrating an adequate margin of safety
relative to the maximum inflation pressure;
durability tests demonstrating adequate resistance to fatigue
caused by cyclic external compression applied radially to the
inflated cylinder;
durability tests demonstrating adequate resistance to fatigue
caused by cyclic oscillation (bending and/or axial buckling) of
both inflated and deflated cylinders;
applied force at the rate of 1 Hertz versus number of cycles to
rupture (AF/N) curve, constructed on the basis of cyclical
externally applied radial compression on a fully inflated
cylinder. 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.
Horizontal and vertical motions of inflated and deflated
devices over the expected operational lifetime of the device must
also be evaluated.
Reservoirs
Reservoir characterization and testing should include but not
necessarily be limited to:
capacity (volume);
pressures experienced over the inflation/deflation cycle;
rate of maximum fluid outflow and inflow;
wear characteristics if a fold in the reservoir envelope
occurs;
durability tests demonstrating adequate resistance to fatigue
caused by cyclic external compression applied radially to inflated
reservoir.
Tubing
Tubing characterization and testing should include but not
necessarily be limited to:
tensile characteristics (with and without tubing connectors, if
any);
tear or rupture resistance;
kink resistance;
wear characteristics if a fold in the tubing develops.
Accessory Components
Other components of the penile inflatable implant or accessories
such as tubing connectors, extension adapters, and specialized
tools used during the insertion procedure should be evaluated
appropriately. Testing of these components or accessories should
reflect the anticipated conditions of use. For example, extension
adapters and tubing connectors should be demonstrated to be able
to maintain connection to the device for the expected life of the
device.
Gel Bleed Testing
Silicone bleed permeation, which is the seepage of silicone fluid
components of any gel used in a penile 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
component, 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.
Steady-state diffusion coefficients for silicone bleed permeation
rates from penile 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 penile
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 responses 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 penile 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 penile 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 penile prosthesis. The
membrane must consist of component materials 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.
Each variety of gel-containing component 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 silicone 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 gel-containing component
tested, and estimates of the minimum and maximum surface areas for
the size range of each type of gel-containing component 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.
3. Clinical data
Valid scientific evidence, as defined in 21 CFR 860.7, should include
information from 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 penile inflatable implant. 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 5-year follow-up data 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/partner satisfaction with and
psychological benefit from the implantation of this device as well as
information on the anatomical and physiological effects of the penile
inflatable implant (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 the measures taken to minimize such events (with all
information obtained on patients lost to follow-up); (3) time course of
revisions, including all explant and repair 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 enrolled 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 this device. The statistical demonstration should
identify the effect criteria, reasonable levels for Type I (alpha) and Type
II (beta) errors, and anticipated variances of the response variables and
provide any assumptions or statistical formulas with copies of any
references used and all calculations used. A complete description of any
patient randomization technique 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 impotence, anatomical abnormalities of the
genitalia, the number and type of treatments (if any) attempted to restore
potency prior to device implantation, device usage (initial implantation
versus revision), the frequency of device use post-implantation, degree of
manual dexterity, 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 penile inflatable
implant, such studies should include time course presentations of clinical
data demonstrating the presence or absence of device leakage, tubing
bending/kinking or disconnection, cylinder aneurysm or rupture, valve
failure, spontaneous inflation/deflation, component migration, extrusion,
skin erosion, infection, iatrogenic injury, hematoma, excessive fibrous
capsular growth, pain, sensory loss, patient dissatisfaction leading to
surgical 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 5 years post-implantation.
FDA recognizes that the primary benefit of the penile inflatable
implant is the restoration of penile erectile function. The effectiveness
of the device can probably be measured by assessing (1) the ability of the
device in vivo to provide adequate rigidity (as well as length/girth
enhancement, if such claims are made) to the penis to permit coitus; (2)
the degree of maintenance or enhancement of a male's psychological well-
being post-implantation; (3) partner satisfaction with the device; and (4)
the enhancement of the male's ability to conceive naturally, as a result of
the improved intromission provided by the implant (provided that the
patient's semen quality was sufficient for conception prior to
implantation); all 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. Device effectiveness is also dependent
upon the degree of partner satisfaction with the implant's performance,
since this can directly relate to the patient's own perception of self
image. Assessments of enhanced fertility and penile rigidity, length, and
girth 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 (as well as to his sexual partner), including any
improvement in quality of life; (2) the quality of the erection provided by
the implant; and (3) an increase in the rate of conception (in those
patients interested in future fertility). The primary requirements for an
acceptable scientific documentation of psychological benefits of the device
(to both the implant recipient and his partner) are the use of (1)
prospective research designs, including pre- and post-surgical repeated
measures; (2) appropriate control/comparison groups; and (3) standardized
test questions rather than informal, yet-validated questionnaires.
Any questionnaire utilized in the documentation of the psychological
consequences of penile inflatable implants must be shown to provide a
scientifically valid measure of the psychological effects of impotency upon
males and their partners. Documentation of these psychological
consequences shall include (1) pre-surgical baseline assessment 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 5 years; (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 implant procedure.
Documentation of the anatomical and physiologic outcomes of
implantation of a penile inflatable implant shall include: (1) regular
post-surgical evaluations of the inflation, dimensional,
rigidity/stiffness, and deflation characteristics provided by the device
for at least 5 years post-implantation; and (2) patient/partner assessments
of the mechanical function of the implant (such as ease of inflation,
quality of the erection, ability of the device to operate and function
reliably, etc.) during this follow-up period (which may be influenced by
the manual dexterity of the patient and/or partner).
Documentation of the effect of the penile inflatable implant upon the
fertility of the male shall include: (1) an assessment of the conception
rate among those implant recipients who are interested in future fertility;
and (2) comparison of this rate to either the conception rate of this
patient cohort prior to receiving the implant, or the rate of conception in
an appropriate control population.
Any PMA for the penile inflatable implant should separately analyze
the degree of device safety and efficacy by the following variables: (1)
etiology and duration of erectile dysfunction; (2) anatomical abnormalities
of the genitalia; (3) the number and type of treatments (if any) attempted
to restore potency prior to device implantation; (4) device usage (initial
implantation versus revision); (5) frequency of device usage post-
implantation; (6) degree of manual dexterity; (7) investigational site; (8)
surgeon experience and technique; (9) incision site; and (10) degree of
sexual therapy provided to the subject postoperatively.
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; (2) whether or not the explanted device was
replaced with a new device; and (3) either the manufacturer, type, and
model of the new device (if another penile implant was implanted), or the
type of treatment (if any) that the patient received for his impotence (if
revision surgery was not performed). Additionally, the effect of the
presence of these implants upon future medical diagnoses/treatments to the
lower pelvic region in recipients of penile inflatable implants must be
analyzed. Furthermore, any accessories that are sold with the penile
inflatable implant (such as corporal dilators, suturing tools, etc.) must
be shown to have been effectively used in implant procedures without
adverse effects. Lastly, each clinical investigation should validate the
physician and patient instructions for use (labeling) that were utilized.
For the polyurethane elastomer covered implants, the following
information needs to be presented: (1) the kinetics of the end products
generated from the degradation of the polyurethane elastomer (in vivo); (2)
the frequency and incidence of infection and complication of retrieval of
the implant by surgeons using both polyurethane and non-polyurethane
covered implants 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 elastomer penile
inflatable implants.
Any epidemiological studies that are submitted 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 is not
available to make a reasonable and fair judgement. Therefore, the agency
will require long-term postapproval follow-up for any penile inflatable
implant 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
reproductive/teratogenic effects of the device as well as the later effects
on offspring.
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 penile
inflatable implant in the treatment of erectile dysfunction in the male.
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, 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 penile inflatable implants.
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 patients who have failed prior less invasive therapies
and/or to patients with specific etiologies of impotence 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 pre-implant 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
penile inflatable implant (e.g., handling instructions, resterilization
instructions) for device implantation; (3) instructions for implantation,
including surgical approach, sizing, fluid adjustment (including what
filling solutions may be used and how they must be prepared), device
handling, and intraoperative test procedures to ensure implant
functionality and proper placement; (4) and instructions for follow-up,
including whether patient antibiotic prophylaxis is recommended during the
post-implant period and during any subsequent dental or other surgical
procedures, how to determine when patients are ready to attempt intercourse
and begin periodic activation, and how to evaluate proper functionality and
placement, and how often. The directions should instruct caregivers to
specifically question patients prior to surgery for any history of allergic
reaction to any of the device materials or filling agents. 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 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) and sexual partner. Technical terms should be kept
to a minimum and should be defined if they must be used. Patient
information labeling should not exceed the seventh grade reading
comprehension level.
The patient labeling should provide the patient 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. The patient should be advised that penile length and/or width
reductions may occur, and that any latent erectile capability will be
impaired by implantation of a penile inflatable implant. (3) Alternatives
available to the use of the device, including less invasive treatments,
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 use the device
must be provided to the patient. This information should include the
expected length of recovery from surgery and when to resume intercourse
following implantation, whether and how often the device should be
periodically inflated (if applicable), warnings against certain actions
(e.g., repeated flexing) that could damage 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 should
not be considered a "lifetime" implant must be emphasized. Where possible,
provide information on the approximate number of revisions necessary in the
average patient, and indicate the average longevity of each implant so
patients are fully aware that additional surgery for device modification,
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
surgery to allow each patient sufficient time to review and discuss this
information with his physician(s) and sexual partner.
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.
5. References (Risks and Benefits Associated with Penile
Implants)
1. Carson, C.C., "Infections in Genitourinary Prostheses," Urologic
Clinics of North America, 16(1): 139-147, 1989.
2. Fishman, I.J., "Complicated Implantations of Inflatable Penile
Prostheses," Urologic Clinics of North America, 14(1): 217-239, 1987.
3. Kabalin, J.N., and R. Kessler, "Infectious Complications of Penile
Prosthesis Surgery," The Journal of Urology, 139(5): 953-955, 1988.
4. Merrill, D.C., "Clinical Experience with the Mentor Inflatable
Penile Prosthesis in 301 Patients," The Journal of Urology, 140(6): 1424-
1427, 1988.
5. Merrill, D.C., "Mentor Inflatable Penile Prostheses," Urologic
Clinics of North America, 16(1): 51-66, 1989.
6. Walters, F.P., D.E. Neal, Jr., A.B. Rege, W.J. George, M.J. Ricci,
and W.J.G. Hellstrom, "Cavernous Tissue Antibiotic Levels in Penile
Prosthesis Surgery," The Journal of Urology, 147(5): 1282-1284, 1992.
7. Wilson, S.K., G.E. Wahman, and J.L. Lange, "Eleven Years of
Experience with the Inflatable Penile Prosthesis," The Journal of Urology,
139(5): 951-952, 1988.
8. Parulkar, B.G., and D.M. Barrett, "Combined Implantation of
Artificial Sphincter and Penile Prostheses," The Journal of Urology,
142(3): 732-735, 1989.
9. McClellan, D.S., and B.K. Masih, "Gangrene of the Penis as a
Complication of Penile Prosthesis," The Journal of Urology, 133(5): 862-
863, 1985.
10. Thomas, C.L. (ed.), "Taber'sR Cyclopedic Medical Dictionary,"
15th Edition, F.A. Davis Company, Philadelphia, pp. 569, 591 and 1052,
1985.
11. Carson, C.C., "Genitourinary Prostheses," in S.D. Graham, Jr.
(ed.), Urologic Oncology, New York, Raven Press, pp. 459-470, 1986.
12. Dupont, M.C., and H.I. Hochman, "Erosion of an Inflatable Penile
Prosthesis Reservoir into the Bladder, Presenting as Bladder Calculi," The
Journal of Urology, 139(2): 367-368, 1988.
13. Fein, R.L., "Clinical Evaluation of Inflatable Penile Prosthesis
with Combined Pump-Reservoir," Urology, 32(4): 311-314, 1988.
14. Gasser, T.C., E.H. Larsen and R.G. Bruskewitz, "Penile Prosthesis
Reimplantation," The Journal of Urology, 137(1): 46-47, 1987.
15. Godiwalla, S.Y., J. Beres, and S.C. Jacobs, "Erosion of an
Inflatable Penile Prosthesis Reservoir into an Ileal Conduit," The Journal
of Urology, 137(2): 297-298, 1987.
16. Mulcahy, J.J., "A Technique of Maintaining Penile Prosthesis
Position to Prevent Proximal Migration," The Journal of Urology, 137(2):
294-296, 1987.
17. Brooks, M.B., "42 Months of Experience with the Mentor Inflatable
Penile Prosthesis," The Journal of Urology, 139(1): 48-49, 1988.
18. Fein, R.L., "Cylinder Problems with AMS 700 Inflatable Penile
Prosthesis," Urology, 31(4): 305-307, 1988.
19. Fein, R.L., "The G. F. S. Mark II Inflatable Penile Prosthesis,"
The Journal of Urology, 147(1): 66-68, 1992.
20. Kabalin, J.N., and R. Kessler, "Penile Prosthesis Surgery:
Review of Ten-Year Experience and Examination of Reoperations," Urology,
33(1): 17-19, 1989.
21. Moul, J.W., and D.G. McLeod, "Negative Pressure Devices in the
Explanted Penile Prosthesis Population," The Journal of Urology, 142(3):
729-731, 1989.
22. Furlow, W.L., and B. Goldwasser, "Salvage of the Eroded
Inflatable Penile Prosthesis: A New Concept," The Journal of Urology,
138(2): 312-314, 1987.
23. Steidle, C.P., and J.J. Mulcahy, "Erosion of Penile Prostheses:
A Complication of Urethral Catheterization," The Journal of Urology,
142(3): 736-739, 1989.
24. Furlow, W.L., and R.C. Motley, "The Inflatable Penile Prosthesis:
Clinical Experience with a New Controlled Expansion Cylinder," The Journal
of Urology, 139(5): 945-946, 1988.
25. Knoll, L.D., W.L. Furlow, and R.C. Motley, "Clinical Experience
Implanting an Inflatable Penile Prosthesis with Controlled-Expansion
Cylinder," Urology, 36(6): 502-504, 1990.
26. Weese, D.L., and P.E. Zimmern, "Corporeal Perforation or
Undersized Prosthesis? The Role of Corpus Cavernosum Endoscopy," The
Journal of Urology, 144(3): 714-716, 1990.
27. Sender, M.B., M.A. Koyle, and J. Rajfer, "Complications of
Scrotal Surgery," in R.B. Smith and R.M. Ehrlich (eds.), Complications of
Urologic Surgery: Prevention and Management, Philadelphia, Harcourt Brace
Jovanovich, Inc., pp. 528-529, 1990.
28. Barrett, D.M., D.C. O'Sullivan, A.A. Malizia, H.M. Reiman, and
P.C. Abell-Aleff, "Particle Shedding and Migration from Silicone
Genitourinary Prosthetic Devices," The Journal of Urology, 146(2): 319-322,
1991.
29. Bertram, R.A., C.C. Carson, III, and L.F. Altaffer, "Sever Penile
Curvature after Implantation of an Inflatable Penile Prosthesis," The
Journal of Urology, 139(4): 743-745, 1988.
30. Fitch, III, W.P., and T. Roddy, "Erosion of Inflatable Penile
Prosthesis Reservoir into Bladder," The Journal of Urology, 136(5): 1080,
1986.
31. Montague, D.K., "Penile Prostheses: An Overview," Urologic
Clinics of North America, 16(1): 7-12, 1989.
32. Kaufman, J.J., A. Linder, and S. Raz, "Complications of Penile
Prosthesis Surgery for Impotence," The Journal of Urology, 128(6): 1192-
1194, 1982.
33. Fallen, M.J., and R.W. Lewis, "Experience with a Two-Piece
Inflatable Penile Prosthesis," Abstract, The Journal of Urology, 143(4):
409A, 1990.
34. McLaren, R.H., and R.W. Lewis, "Analysis of Reoperation in the
Patient with Inflatable Penile Prosthesis," Abstract, The Journal of
Urology, 143(4): 408A, 1990.
35. Montague, D.K., "Experience with Semirigid Rod and Inflatable
Penile Prostheses," The Journal of Urology, 129(5): 967-968, 1983.
36. Joseph, D.B., R.C. Bruskewitz, and R.C. Benson, "Long-Term
Evaluation of the Inflatable Penile Prosthesis," The Journal of Urology,
131(4): 670-673, 1984.
37. Malloy, T.R., A.J. Wein, and V.L. Carpiniello, "Reliability of
AMS M700 Inflatable Penile Prosthesis," Urology, 28(5): 385-387, 1986.
38. Merrill, D.C., "Clinical Experience with Mentor Inflatable Penile
Prosthesis in 206 Patients," Urology, 28(3): 185-189, 1986.
39. Stanisic, T.H., and J.C. Dean, "The Flexi-Flate and Flexi-Flate
II Penile Prostheses," Urologic Clinics of North America, 16(1): 39-49,
1989.
40. Fallon, B., and W.L. Gerber, "New Complication of Inflatable
Penile Prosthesis," Urology, 18(4): 405, 1981.
41. Goulding, F.J., "Fracture of Hydroflex Penile Implant," Urology,
30(5): 490-491, 1987.
42. Furlow, W.L., B. Goldwasser, and J.C. Gundian, "Implantation of
Model AMS 700 Penile Prosthesis: Long-Term Results," The Journal of
Urology, 139(4): 741-742, 1988.
43. Mulcahy, J.J., "The Hydroflex Penile Prosthesis," Urologic
Clinics of North America, 16(1): 33-38, 1989.
44. Mulcahy, J.J., "The Hydroflex Self-Contained Inflatable Penile
Prosthesis: Experience with 100 Patients," The Journal of Urology, 140(6):
1422-1423, 1988.
45. Gregory, J.G., and M.H. Purcell, "Scott's Inflatable Penile
Prosthesis: Evaluation of Mechanical Survival in the Series 700 Model,"
The Journal of Urology, 137(4): 676-677, 1987.
46. Beaser, R.S., C. Van der Hoek, A.M. Jacobson, T.M. Flood, and
R.E. Desautels, "Experience with Penile Prostheses in the Treatment of
Impotence in Diabetic Men," Journal of the American Medical Association,
248(8): 943-948, 1982.
47. Diokno, A.C., "Asymmetric Inflation of the Penile Cylinders:
Etiology and Management," The Journal of Urology, 129(6): 1127-1130, 1983.
48. Earle, C.M., G.R. Watters, A.G.S. Tulloch, Z.S. Wisniewski, D.J.
Lord, and E.J. Keogh, "Complications Associated with Penile Implants Used
to Treat Impotence," Australia and New Zealand Journal of Surgery, 59: 959-
962, 1989.
49. Casey, W.C., "Tubing Kinks in Inflatable Penile Prosthesis: A
Cause and Prevention," Urology, 20(5): 542, 1982.
50. Engel, R.M.E., and R.L. Fein, "Mentor GFS Inflatable Prostheses,"
Urology, 35(5): 405-406, 1990.
51. Malloy, T.R., V.L. Carpiniello, and A.J. Wein, "Mechanical
Stability AMS M700 CX Inflatable Penile Prosthesis Cylinders," Abstract,
The Journal of Urology, 139(4): 329A, 1988.
52. Stanisic, T.H., J.C. Dean, J.M. Donovan, and L.E. Beutler,
"Clinical Experience with a Self-Contained Inflatable Penile Implant: The
Flexi-Flate," The Journal of Urology, 139(5): 947-950, 1988.
53. McLaren, R.H., and D.M. Barrett, "Patient and Partner
Satisfaction with the AMS 700 Penile Prosthesis," The Journal of Urology,
147(1): 62-65, 1992.
54. Whalen, R.K., and D.C. Merrill, "Patient Satisfaction with Mentor
Inflatable Penile Prosthesis," Urology, 37(6): 531-539, 1991.
55. Boyd, S.D., and W. M. Schiff, "Inflatable Penile Prostheses in
Patients Undergoing Cystoprostatectomy with Urethrectomy," The Journal of
Urology, 141(1): 60-62, 1989.
56. Merrill, D.C., "Clinical Experience with Scott Inflatable Penile
Prosthesis in 150 Patients," Urology, 22(4): 371-375, 1983.
57. Fallon, B., S. Rosenberg, and D.A. Culp, "Long-Term Follow-up in
Patients with an Inflatable Penile Prosthesis," The Journal of Urology,
132(2): 270-271, 1984.
58. Medical Device Reporting (MDR) and Product Problem Reporting
(PPR), Device Experience Network (DEN), FDA.
59. Witherington, R., "Mechanical Devices for the Treatment of
Erectile Dysfunction," American Family Physician, 43(5): 1611-1620, 1991.
60. Klabalin, J.N., and R. Kessler, "Experience with the Hydroflex
Penile Prosthesis," The Journal of Urology, 141(1): 58-59, 1989.
61. Ball, Jr., T.P., "Surgical Repair of Penile 'SST' Deformity,"
Urology, 15: 603-604, 1980.
62. Engel, R.M.E., J.K. Smolev, and R. Hackler, "Mentor Inflatable
Penile Prosthesis," Urology, 29(5): 498-500, 1987.
63. Knoll, L.D., W.L. Furlow, and R.C. Benson, Jr., "Management of
Peyronie Disease by Implantation of Inflatable Penile Prosthesis," Urology,
36(5): 406-409, 1990.
64. Walther, P.J., R.T. Andriani, M.I. Maggio, and C.C. Carson, III,
"Fournier's Gangrene: A Complication of Penile Prosthetic Implantation in
a Renal Transplant Patient," The Journal of Urology, 137(2): 299-300, 1987.
65. Tiefer, L., S. Moss, and A. Melman, "Follow-up of Patients and
Partners Experiencing Penile Prosthesis Malfunction and Corrective
Surgery," Journal of Sex and Marital Therapy, 17(2): 113-128, 1991.
66. Schover, L.R., "Sex Therapy for the Penile Prosthesis Recipient,"
Urologic Clinics of North America, 16(1): 91-98, 1989.
67. Nelson, R.P., "Male Sexual Dysfunction: Evaluation and
Treatment," Southern Medical Journal, 80(1): 69-74, 1987.
68. Bischoff, F., and G. Bryson, "Carcinogenesis Through Solid State
Surfaces," Progress in Experimental Tumor Research, 5: 85-133, 1964.
69. Hueper, W.C., "Cancer Induction by Polyurethane and Polysilicone
Plastics," Journal of the National Cancer Institute, 33: 1005-1027, 1964.
70. Hueper, W.C., "Carcinogenic Studies on Water-Soluble and
Insoluble Macromolecules," Archives of Pathology and Laboratory Medicine,
67: 589-617, 1959.
71. Maekawa, A., T. Ogiu, H. Onodera, K. Furuta, C. Matsuoka, Y.
Ohno, H. Tanigawa, G.S. Salmo, M. Matsuyama, and Y. Hayashi, "Malignant
Fibrous Histiocytomas Induced in Rats by Polymers," Cancer Research and
Clinical Oncology, 108: 364-365, 1984.
72. Pedley, R.B., G. Meachim, and D.F. Williams, "Tumor Induction by
Implant Materials," in "Fundamental Aspects of Biocompatibility," vol. 2,
D.F. Williams (ed.), CRC Critical Reviews in Biocompatibility, CRC Press,
Boca Raton, FL., pp. 165-202, 1981.
73. Benjamin, E., A. Ahmed, A.T.F. Rashid, and D.H. Wright, "Silicone
Lymphadenopathy: A Report of Two Cases, One with Concomitant Malignant
Lymphoma," Diagnostic Histopathology, 5: 133-141, 1982.
74. Digby, J.M., and A.L. Wells, "Malignant Lymphoma with Intranodal
Refractile Particles After Insertion of a Silicone Prostheses," Lancet, 2:
580, 1981.
75. Morgenstern, L., S.H. Gleischman, S.L. Michel, J.E. Rosenberg, I.
Knight, and D. Goodman, "Relation of Free Silicone to Human Breast
Carcinoma," Archives of Surgery, 120: 573-577, 1985.
76. Zafiracopoulos, P., and A. Rouskas, "Breast Cancer at Site of
Implantation of Pacemaker Generator," letter to the editor, Lancet, p.
1114, June 1, 1974.
77. Le Vier, R.R., and M.E. Jankowiak, "Effects of Oral 2,6-cis-
Diphenylhexamethylcyclotetrasiloxane on the Reproductive System of the Male
Rat," Toxicology and Applied Pharmacology, 21: 80-88, 1972.
78. Bates, H., R. Filler, and C. Kimmel, "Developmental Toxicity
Study of Polydimethylsiloxane Injection in the Rat," Teratology, 31:50A,
1985.
79. Haley, T.J., "Biocompatibility of Monomers," in Systemic Aspects
of Biocompatibility, vol. 2, pp. 59-90, Williams, D.F. (ed.), CRC Series in
Biocompatibility, Boca Raton, FL., 1981.
80. Kennedy, G.L., M.L. Keplinger, and J.C. Calandra, "Reproductive,
Teratologic and Mutagenic Studies with Some Polydimethylsiloxanes," Journal
of Toxicology and Environmental Health, 1: 909-920, 1976.
81. Varga, J., H.R. Schumacher, and S.A. Jimenez, "Systemic Sclerosis
after Augmentation Mammoplasty with Silicone Implants," Annals of Internal
Medicine, 111: 337-383, 1989.
82. Picha, G.J., and J.A. Goldstein, "Analysis of the Soft-Tissue
Response to Components Used in the Manufacture of Breast Implants: Rat
Animal Model," Plastic and Reconstructive Surgery, 87: 490-500, 1991.
83. Baker, J.L. et al., "Positive Identification of Silicone in Human
Mammary Capsular Tissue," Plastic and Reconstructive Surgery, 69: 56, 1982.
84. Barker, D.E., M.I. Retsky, and S. Schultz, "Bleeding of Silicone
from Bag-gel Breast Implants, and Its Clinical Relation to Fibrous Capsule
Reaction," Plastic and Reconstructive Surgery, 61: 836-841, 1978.
85. Brody, G.S., "Fact and Fiction About Breast Implant 'Bleed',"
Plastic and Reconstructive Surgery, 60: 615, 1977.
86. Gayou, R., and R. Rudolph, "Capsular Contraction Around Silicone
Mammary Prostheses," Annals of Plastic Surgery, 2(1): 62-71, 1979.
87. Gibbons, D.F., et al., "Wear and Degradation of Retrieved
Ultrahigh Molecular Weight Polyethylene and Other Polymeric Implants," in
B.C. Syrett and A. Acharya (eds.), "Corrosion and Degradation of Implant
Materials," American Society for Testing and Materials (ASTM), Kansas City,
MO, Philadelphia ASTM, pp. 20-40, 1979.
88. Hausner, R.J., et al., "Migration of Silicone Gel to Auxiliary
Lymph Nodes After Prosthetic Mammoplasty," Archives of Pathology Laboratory
Medicine, 195: 371-372, 1981.
89. Jenny, H., and J. Smahel, "Clinicopathologic Correlations in
Pseudocapsule Formation After Breast Augmentation," Aesthetic Plastic
Surgery, 5: 63-68, 1981.
90. Mandel, M.A., and D.F. Gibbons, "The Presence of Silicone in
Breast Capsules," Aesthetic Plastic Surgery, 3: 219-225, 1979.
91. Smahel, J., "Foreign Material in the Capsules Around Breast
Prostheses and the Cellular Reaction To It," British Journal of Plastic
Surgery, 32: 35-42, 1979.
92. Wickham, M.G., et al., "Silicon Identification in Prosthesis-
Associated Fibrous Capsules," Science, 199: 437-439, 1978.
93. "Bioassay of 2,4-Diaminotoulene for Possible Carcinogenicity,"
Bethesda, Maryland: National Institutes of Health, U.S. Department of
Health, Education and Welfare, Publication 79-1718, 1979.
94. "Carcinogenesis Studies of 4,4'-Methylenedianiline
Dihydrochloride (CAS No. 13552-44-8) in F334/N Rats and B6C3F1 Mice
(Drinking Water Studies)," National Toxicology Program, Technical Report
No. 248, 1983.
95. Kessler, R., "Complications of Inflatable Penile Prostheses,"
Urology, 18(5): 470-472, 1981.
96. Flanagan, M.J., E.B. Krisch, and W.L. Gerber, "Complication of a
Penile Prosthesis Reservoir: Venous Compression Masquerading as a Deep
Venous Thrombosis," The Journal of Urology, 146(3): 847-848, 1991.
97. Nelson, R.P., and J.C. Gregory, "Gonococcal Infections of Penile
Prostheses," Urology, 31(5): 391-394, 1988.
98. Scott, F.B., "Outpatient Implantation of Penile Prostheses Under
Local Anesthesia," Urologic Clinics of North America, 14(1): 177-185, 1987.
99. Lief, H.I., "Sex and the Physician," Sexual Problems in Medical
Practice, American Medical Association, pp. 3-8, 1981.
100. Masters, W.H., and V.E. Johnson, "Secondary Impotence," Human
Sexual Inadequacy, Boston, Little, Brown and Company, pp. 157-192, 1970.
101. Pedersen, B., L. Tiefer, M. Ruiz, and A. Melman, "Evaluation of
Patients and Partners 1 to 4 Years After Penile Prosthesis Surgery," The
Journal of Urology, 139(5): 956-958, 1988.
102. Tiefer, L., B. Pedersen, and A. Melman, "Psychosocial Follow-up
of Penile Prosthesis Implant Patients and Partners," Journal of Sex and
Marital Therapy, 14(3): 184-201, 1988.
103. Domanskis, E., and J. Owsley, "Histological Investigations of
the Etiology of Capsular Contraction Following Augmentation Mammoplasty,"
Plastic and Reconstructive Surgery, 58: 689-693, 1976.
104. Vargas, A., "Shedding of Silicone Particles from Inflated Breast
Implants," letter to the editor, Plastic and Reconstructive Surgery, 64:
252-253, 1979.
Appendix I
Extraction Guidelines for Polymers
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 a device component will very likely be
controlled by diffusion processes in the polymer itself unless there is
partitioning in the external phase, in most cases, 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 device
components, 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 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.
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 polymers that may used,
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, Pharmaaceutical
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
GENERAL REFERENCES
Wheeler, D.A., "Determination of Antioxidants in Polymeric Materials",
Talanta, 15, 1315-1334, (1968).
Majors, R.E., "High Speed Liquid Chromatography of Antioxidants and
Plasticizers Using Solid Core Supports", J. Chromatogr. Sci., 8, 338-345,
(1970).
Schroeder, E., "The Development of Methods for Examining Stabilizers in
Polymers and their Conversion Products", Pure Appl. Chem., 36, 233-251,
(1973).
Pacco, J., Mukherji, A.K., "Determination of Polychlorinated Biphenyls in a
Polymer Matrix by Gel Permeation Chromatography using micro-Styragel*
Columns", J. Chromatogr., 144, 113-117, (1977).
Crompton, T.R. Chemical Analysis of Additives in Plastics; International
Series in Analytical Chemistry, Pergamon Press: New York, 1977; Vol. 46.
Majors, R.E., Johnson, E.L., "High-Performance Exclusion Chromatography of
Low-Molecular-Weight Additives", J. Chromatogr., 167, 17-30, (1978).
Thompson, R.M., Howard, C.C., Crowley, J.P. DeRoos, F.L., Leininger, R.I.,
"Literature Review: Polymeric Material Leachables and their Biological
Effects and Toxicology"; final report to Food and Drug Administration,
Center for Devices and Radiological Health (formerly Bureau of Medical
Devices) on Contract Number 233-77-5038; Battelle - Columbus Laboratories:
Columbus, OH, 1979.
Walter, R.B., Johnson, J.F., "Analysis of Antioxidants in Polymers by
Liquid Chromatography", J. Polym. Sci.: Macromol. Rev., 15, 29-53, (1980).
Shepherd, M.J., Gilbert, J., "Analysis of Additives in Plastics by High-
Performance Size-Exclusion Chromatography", J. Chromatogr., 218, 703-713,
(1981).
Squirrell, D.C.M., "Analysis of Additives and Process Residues in Plastics
Materials", Analyst, 106, 1042-1056, (1981).
Low Molecular Weight Leachables from Medical Grade Polymers; U.S.
Department of Commerce, National Institute of Science and Technology
(formerly National Bureau of Standards). National Technical Information
Service (NTIS), Springfield, VA, 1982; NBSIR 81-2436.
Krause, A., Lange, A., Erzin, M. Plastics Analysis Guide: Chemical and
Instrumental Methods; Hanser: New York, 1983.
Crompton, T.R. The Analysis of Plastics; Pergamon Series in Analytical
Chemistry, Pergamon Press: New York, 1984; Vol. 8.
Vargo, J.D., Olson, K.L., "Characterization of Additives in Plastics by
Liquid Chromatography-Mass Spectrometry", J. Chromatogr., 353, 215-224,
(1986).
Gibbons, J.J., "An Evaluation of Plasticizers by Fourier Transform Infrared
Spectroscopy", American Laboratory, November, 78-85, 1987.
Middleditch, B.S., Zlatkis, A., "Artifacts in Chromatography: An Overview",
J. Chromatogr. Sci., 25, 547-551, (1987).
Hopkins, J.L., Cohen, K.A., Hatch, F.W., Pitner, T.P., Stevenson, J.M.,
Hess, F.K., "Pharmaceuticals: Tracking Down an Unidentified Trace Level
Constituent", Anal. Chem., 59(11), 784-790, (1987).
McGorrin, R.J., Pofahl, T.R., Croasmun, W.R., "Identification of the Musty
Component From an Off-Odor Packaging Film", Anal. Chem., 59(18), 1109-1112,
(1987).
Del Rios, J.K., "Polymer Characterization Using the Photodiode Array
Detector", American Laboratory, January, 1988.
Multidimensional Chromatography; Cortes, H.J., Ed.; Chromatographic Science
Series 50; Dekker, New York, 1990.
The Analytical Chemistry of Silicones, Smith, A. Lee, Ed.; Chemical
Analysis: A Series of Monographs on Analytical Chemistry and Its
Applications 112; Wiley-Interscience, New York, 1991.
Braybrook, J.H., Mackay, G.A., "Supercritical Fluid Extraction of Polymer
Additives for Use in Biocompatibility Testing", Polym. Int., 27, 157-164
(1992).
Erickson, M.D., Analytical Chemistry of PCBs;Lewis:Boca Raton,1992.
POLYOLEFINS
Spell, R.L., Eddy, R.D., "Determination of Additives in Polyethylene by
Absorption Spectroscopy", Anal. Chem., 32(13), 1811-1814, (1960).
Crompton, T.R., "Identification of Additives in Polyolefins and
Polystyrenes", Eur. Polym. J., 4, 473-496, (1968).
Howard, J.M., "Gel Permeation Chromatography and Polymer Additive Systems",
J. Chromatogr., 55, 15-24, (1971).
Couper, J., Pokorny, S., Protivova, J., Holcik, J., Karvas, M., Pospisil,
J., "Antioxidants and Stabilizers. XXXIII. Analysis of Stabilizers of
Isotactic Polypropylene: Application of Gel Permeation Chromatography", J.
Chromatogr., 65, 279-286, (1972).
Wims, A.M., Swarin, S., "Determination of Antioxidants in Polypropylene by
Liquid Chromatography", J. Appl. Polym. Sci., 19, 1243-1256, (1975).
Lichenthaler, R.G., Ranfelt, F., "Determination of Antioxidants and their
Transformation Products in Polyethylene by High-Performance Liquid
Chromatography", J. Chromatogr., 149, 553-560, (1978).
Schabron, J.F., Fenska, L.E., "Determination of BHT, Irganox 1076, and
Irganox 1010 Antioxidant Additives in Polyethylene by High Performance
Liquid Chromatography", Anal. Chem., 52, 1411-1415, (1980).
Haney, M.A., W.A. Dark, "A Reversed-Phase High Pressure Liquid
Chromatographic Method for Analysis of Additives in Polyolefins", J.
Chromatogr. Sci., 18, 655-659, (1980).
Lehotay, J., Danecek, J., Lisa, O., Lesko, J., Brandsteterova, E.,
"Analytical Study of the Additives System in Polyethylene", J. Appl. Polym.
Sci., 25, 1943-1950, (1980).
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 Polymers by High Performance
Liquid Chromatography", Angew. Makromol. Chem., 113, 219-225, (1983).
Choudhary, V., Varshney, S., Varma, I.K., "Degradation of Polypropylene:
Effect of Stabilizers", Angew. Makromol. Chem., 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 Supercritical Fluid
Chromatography/Fourier Transform Infrared Microspectrometry", Anal. Chem.,
60, 427-433, (1988).
"Deformulating Polypropylene by HPLC", Polymer Notes, Waters Chromatography
Division, 2(2), 1988.
Neilson, R. C., "Extraction and Quantitation of Polyolefin Additives", J.
Liquid. Chromatogr., 14 (3), 503-519, (1991).
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 Chromatography
Measurements on PVC Resins and Plasticisers", Br. Polym. J., 1, 138-141,
(1969).
Howard, J.M., "Gel Permeation Chromatography and Polymer Additive 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. Acta, 21-27, (1983).
Preussler, V., Slais, K., Hanus, J., "The Use of Micro-HPLC with 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 Tetraethylene
Glycol Dimethacrylate by High Pressure Liquid Chromatography", Anal. Chem.,
49(3), 363-364, (1977).
Brauer, G.M., Termini, D.J., Dickson, G., "Analysis of the Ingredients and
Determination of the Residual Components of Acrylic Bone Cements", J.
Biomed. Mater. Res., 11, 577-607, (1977).
Schoenfeld, C.M., Conard, G.J., "Monomer Release from Methacrylate Bone
Cements During Simulated in vivo Polymerization", J. Biomed. Mater. Res.,
13, 135-147, (1979).
Brynda, E., Stol, M., Chytry, V., Cifkova, I., "The Removal of Residuals
and Oligomers from Poly(2-hydroxyethylmethacrylate)", J. Biomed. Mater.
Res., 19, 1169-1179, (1985).
Huribut, J.A., Cummins, J.D., "Analysis of 2-Hydroxyethyl Methacrylate in
Soft Contact Lenses by High Performance Liquid Chromatography with UV
Detection", LC GC, 8(6), 478-479, (1990).
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 Polyurethane
Prepolymers by High-Performance Liquid Chromatography", J. Chromatogr.,
123, 468-473, (1976).
Guthrie, J.L. and McKinney, R.W., "Determination of 2,4- and 2,6-
Diaminotoluene in Flexible Urethane Foams", Anal. Chem., 49(12), 1676-1680,
(1977).
Bagon, D.A., Hardy, H.L., "Determination of Free Monomeric Toluene
Diisocyanate (TDI) and 4,4'-diisocyanatodiphenylmethane (MDI) in TDI and
MDI Prepolymers, Respectively, by High-Performance Liquid Chromatography",
J. Chromatogr., 152, 560-564, (1978).
Unger, P.D., Friedman, M.A., "High-Performance Liquid Chromatography of
2,6- and 2,4-Diaminotoluene, and its Application to the Determination of
2,4-Diaminotoluene in Urine and Plasma", J. Chromatogr., 174, 379-384,
(1979).
Snyder, R.C., Breder, C.V., "High-Performance Liquid Chromatographic
Determination of 2,4- and 2,6-Toluenediamine in Aqueous Extracts", J.
Chromatogr., 236, 429-440, (1982).
Lattimer, R.P., Welch, K.R., "Direct Analysis of Polymer Chemical Mixtures
by Field Desorption Mass Spectroscopy", Rubber Chem. Technol., 53, 151-159,
(19**).
Hepburn, C., Polyurethane Elastomers, Applied Sci. Publ.: New York, 1982,
Chapter 11.
Owen, D.R., Zone, R., Armer, T., Kilpatrick, C., "Analytical Methods for
the Determination of Biologically Derived Absorbed Species in Biomedical
Elastomers", In Biomaterials: Interfacial Phenomena and Applications;
Cooper, S.L., Peppas, N.A., Eds.; Advances in Chemistry 199; American
Chemical Society: Washington, DC, 1982; pp 395-411.
Guise, G.B., Smith, G.C., "Liquid Chromatography of Some Polurethane
Polyols", J. Chromatogr., 247, 369-373, (1982).
Kuo, C., Provder, T., Kah, A.F., "Application of HPGPC and HPLC to
Characterise Oligomers and Small Molecules used in Enviromentally
Acceptable Coatings Systems", Paint & Resin, 53(2), 26-33, (1983).
Ernes, D.A., Hanshumaker, D.T., "Determination of Extractable Methylene
(aniline) in Polyurethane Films by Liquid Chromatography", Anal. Chem., 55,
408-409, (1983).
Ratner, B.D., "ESCA Studies of Extracted Polyurethanes and Polyurethane
Extracts: Biomedical Implications", In Physicochemical Aspects of Polymer
Surfaces, Mittal, K.L., Ed.; Plenum: New York, 1983; pp 969-983.
Mazzu, A.L., Smith, C.P., "Determination of Extractable Methylene Dianiline
in Thermoplastic Polyurethanes by HPLC", J. Biomed. Mater. Res., 18, 961-
968, (1984).
O'Mara, M.M., Ernes, D.A., Hanshumaker, D.T., "Determination of Extractable
Methylenebis(aniline) in Polyurethane Films by Liquid Chromatography", In
Polyurethanes in Biomedical Engineering, H. Planck, G. Egbers, I. Syr ,
Eds.;Elsevier:Amsterdam,1984;pp. 83-92.
Ward, C.J.P., Radzik, D.M., Kissinger, P.T., "Detection of Toxic Compounds
in Polyurethane Food Bags by Liquid Chromatography/Electrochemistry", J.
Liq. Chromatogr., 8(4), 677-690, (1985).
Rosenberg, C., Ainen, H.S., "Detection of Urinary Metabolites in Toluene
Diisocyanate Exposed Rats", J. Chromatogr., 323, 429-433, (1985).
Hirayama, T., Ono, M., Uchiyama, K., Nohara, M., J. Assoc. Off. Anal.
Chem., 68(4), 746-748, (1985).
Vimalasiri, P.A.D.T., Burford, R.P., Haken, J.K., "Chromatographic Analysis
of Elastomeric Polyurethanes", Rubber Chem. Tech., 60, 555-577, (1987).
Richards, J.M., McClennen, W.H., Meuzelaar, H.L.C., Shockcor, J.P.,
Lattimer, R.P., "Determination of the Structure and Composition of
Clinically Important Polyurethanes by Mass Spectrometric Techniques", J.
Appl. Polym. Sci., 34, 1967-1975, (1987).
Noel, D., VanGheluwe, "High-Performance Liquid Chromatography of Industrial
Polyurethane Polyols", J. Chromatogr. Sci., 25, 231-236, (1987).
Marchant, R.E., Zhao, Q., Anderson, J.M., Hiltner, A., "Degradation of a
Poly(ether urethane urea) Elastomer: Infra-red and XPS Studies", Polymer,
28, 2032-2039, (1987).
Grasel, T.G., Lee, D.C., Okkema, A.Z., Slowinski, T.J., Cooper, S.L.,
"Extraction of Polyurethane Block Copolymers: Effects on Bulk and Surface
Properties and Biocompatibility", Biomaterials, 9, 383-392, (1988).
Hull, C.J., Guthrie, J.L., McKinney, R.W., Taylor, D.C., Mabud, Md.A.,
Prescott, S.R., "Determination of Toluenediamines in Polyurethane Foams by
High-Pressure Liquid Chromatography with Electrochemical Detection", J.
Chromatogr., 477, 387-395, (1989).
Richards, J.M., Meuzelaar, H.L.C., Bunger, J.A., "Spectrometric and
Chromatographic Methods for the Analysis of Polymeric Explant 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 of Biomer",
J. Biomed. Mater. Res., 24, 1585-1598, (1990).
Dillon, J.G., Hughes, M.K., "Determination of Cholesterol and Cortisone Absorption in Polyurethane I. Methodology Using Size-exclusion
Chromatography and Dual Detection," J. Chromatogr., 572, 41-49, (1991).
Shintani, H., "Solid-Phase Extraction and High-Performance Liquid
Chromatographic Analysis of a Toxic Compound from g-irradiated
Polyurethane", J. Chromatogr., 600, 93-97, (1992).
RUBBERS
Protivova, J., Posp sil, J., "XLVII. Behavior of Amine Antioxidants and
Antiozonants and Model Compounds in Gel Permeation Chromatography", J.
Chromatogr., 88, 99-107, (1974).
Protivova, J., Posp sil, J., "XLVIII. Analysis of the Components of
Stabilization and Vulcanization Mixtures for Rubbers by Gel Permeation
Chromatography and Thin-Layer Chromatographic Methods", J. Chromatogr., 92,
361-370, (1974).
Weston, R.J., "Volatile Nitrosamine Levels in Rubber Teats and Pacifiers
Available in New Zealand", J. Anal. Toxicol., 9, 95-96, (1985).
Zwickenpflug, W., Richter, E., "Rapid Method for the Detection and
Quantification of N-Nitrosodibutylamine in Rubber Products", 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 Spectroscopic
Determination of Trace Amounts of Silicones in Foods and Biological
Materials", Anal. Chem., 32(7), 858-861, (1960).
Estes, Z.E., Faust, R.M., "A Colorimetric Method for the Determination of
Silicon in Biological Materials", Anal. Biochem., 13, 518-522, (1965).
Neal, P., "Note on the Atomic Absorption Analysis of Dimethylpolysiloxanes
in the Presence of Silicates", J. Assoc. Off. Anal. Chem., 52(4), 875-876,
(1969).
Neal, P., Campbell, A.D., Firestone, D., "Low Temperature Separation of
Trace Amounts of Dimethylpolysiloxanes from Food", J. Am. Oil Chemists
Soc., 46, 561-562, (1969).
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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