[Federal Register: September 10, 1998 (Volume 63, Number 175)]
[Rules and Regulations]
[Page 48428-48437]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr10se98-9]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

 21 CFR Part 884

[Docket No. 97N-0335]


Obstetric and Gynecologic Devices; Reclassification and
Classification of Medical Devices Used for In Vitro Fertilization and
Related Assisted Reproduction Procedures

AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that it
is reclassifying instrumentation intended for use in in vitro
fertilization (IVF) and related assisted reproduction technology (ART)
procedures, including but not limited to gamete intrafallopian transfer
(GIFT), embryo transfer (ET), and intracytoplasmic sperm injection
(ICSI), from class III (premarket approval) to class II (special
controls). FDA is also reclassifying assisted reproduction microscopes
and microscope accessories from class III to class I. This
reclassification is on the Secretary of the Department of Health and
Human Services' (the Secretary's) own initiative based on new
information. Accordingly, the order is being codified in the Code of
Federal Regulations. Upon the effective date, this Federal Register
document may be cited in the absence of an existing predicate device
which would be used to support substantial equivalence. Elsewhere in
this issue of the Federal Register, FDA is announcing the

[[Page 48429]]

availability of a draft guidance entitled ``Devices Used for In Vitro
Fertilization and Related Assisted Reproduction Procedures: Submission
Guidance for a 510(k).''

EFFECTIVE DATE: The regulation is effective October 13, 1998.
FOR FURTHER INFORMATION CONTACT: Elisa D. Harvey, Center for Devices
and Radiological Health (HFZ-470), Food and Drug Administration, 9200
Corporate Blvd., Rockville, MD 20850, 301-594-1180.

SUPPLEMENTARY INFORMATION:

 I. Background--Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 301
et seq.), as amended by the Medical Device Amendments of 1976 (the 1976
amendments) (Pub. L. 94-295), the Safe Medical Devices Act of 1990 (the
SMDA) (Pub. L. 101-629), and the Food and Drug Administration
Modernization Act of 1997 (FDAMA) (Pub. L. 105-115), established a
comprehensive system for the regulation of medical devices intended for
human use. Section 513 of the act (21 U.S.C. 360c) established three
categories (classes) of devices, depending on the regulatory controls
needed to provide reasonable assurance of their safety and
effectiveness. The three categories of devices are class I (general
controls), class II (special controls), and class III (premarket
approval).
    Under section 513 of the act, devices that were in commercial
distribution before May 28, 1976 (the date of enactment of the 1976
amendments), generally referred to as preamendments devices, are
classified after FDA has: (1) Received a recommendation from a device
classification panel (an FDA advisory committee); (2) published the
panel's recommendation for comment, along with a proposed regulation
classifying the device; and (3) published a final regulation
classifying the device. FDA has classified most preamendments devices
under these procedures.
    Devices that were not in commercial distribution prior to May 28,
1976, generally referred to as postamendments devices, are classified
automatically by statute (section 513(f) of the act) (21 U.S.C.
360c(f)) into class III without any FDA rulemaking process. Those
devices remain in class III and require premarket approval, unless and
until: (1) The device is reclassified into class I or II; (2) FDA
issues an order classifying the device into class I or II in accordance
with new section 513(f)(2) of the act, as amended by FDAMA; or (3) FDA
issues an order finding the device to be substantially equivalent,
under section 513(i) of the act, to a predicate device that does not
require premarket approval. The agency determines whether new devices
are substantially equivalent to previously offered devices by means of
premarket notification procedures in section 510(k) of the act (21
U.S.C. 360(k)) and part 807 (21 CFR part 807) of the regulations.
    A preamendments device that has been classified into class III may
be marketed, by means of premarket notification procedures, without
submission of a premarket approval application (PMA) until FDA issues a
final regulation under section 515(b) of the act (21 U.S.C. 360e(b))
requiring premarket approval.
    Reclassification of classified postamendments devices is governed
by section 513(f)(3) of the act, formerly section 513(f)(2) of the act.
This section provides that FDA may initiate the reclassification of a
device classified into class III under section 513(f)(1) of the act, or
the manufacturer or importer of a device may petition the Secretary for
the issuance of an order classifying the device in class I or class II.
FDA's regulations in Sec. 860.134 (21 CFR 860.134) set forth the
procedures for the filing and review of a petition for reclassification
of such class III devices. In order to change the classification of the
device, it is necessary that the proposed new class have sufficient
regulatory controls to provide reasonable assurance of the safety and
effectiveness of the device for its intended use.
     FDAMA added a new section 513(f)(2) to the act, which addresses
classification of postamendments devices. New section 513(f)(2) of the
act provides that, upon receipt of a ``not substantially equivalent''
determination, a 510(k) applicant can request FDA to classify a
postamendments device into class I or class II. Within 60 days from the
date of such a written request, FDA must classify the device by written
order. If FDA classifies the device into class I or II, the applicant
has then received clearance to market the device and it can be used as
a predicate device for other 510(k)'s. It is expected that this process
will be used for low risk devices. This process does not apply to
devices that have been classified by regulation into class III--i.e.,
preamendments class III devices, or class III devices for which a PMA
is appropriate.
    Under section 513(f)(3)(B)(i) of the act, formerly section
513(f)(2)(B)(i) of the act, the Secretary may, for good cause shown,
refer a proposed reclassification to a device classification panel. The
Panel shall make a recommendation to the Secretary respecting approval
or denial of the proposed reclassification. Any such recommendation
shall contain: (1) A summary of the reasons for the recommendation, (2)
a summary of the data upon which the recommendation is based, and (3)
an identification of the risks to health (if any) presented by the
device with respect to which the proposed reclassification was
initiated.
    Section 510(l) of the act (21 U.S.C. 360(l)) provides that a class
I device is exempt from the premarket notification requirements under
section 510(k) of the act, unless the device is intended for a use
which is of substantial importance in preventing impairment of human
health or it presents a potential unreasonable risk of illness or
injury. Hereafter, these are referred to as ``reserved criteria.''
    Such an exemption permits manufacturers to introduce into
commercial distribution generic type of class I devices without first
submitting a premarket notification to FDA. If FDA has concerns about
certain types of changes to a particular class I device, the agency may
grant a limited exemption from premarket notification for that generic
type of device.

 II. Regulatory History of the Device

    FDA consulted with the Obstetrics and Gynecology Devices Panel (the
Panel). During an open public meeting on October 23, 1995, the Panel
indicated its concurrence, given the history of safe and effective use
of these devices, with FDA's intention to reclassify instrumentation
intended for use in IVF and ART procedures.
    Based on this input from the Panel, FDA published a proposed
reclassification rule in the Federal Register of September 4, 1997 (62
FR 46686), proposing that the generic type of device, instrumentation
intended for use in IVF and related ART procedures, should be
reclassified from class III to class II, and that assisted reproduction
microscopes and microscope accessories should be reclassified from
class III to class I.
    FDA received 10 comments from manufacturers of devices used in
assisted reproduction procedures in response to the proposed rule. A
summary of the comments and FDA's response is discussed in section III
of this document. The comments primarily addressed issues relating to
clarification of the proposed rule, and suggestions for the special
controls required for the various categories of assisted reproduction
devices. It should be noted

[[Page 48430]]

that while clinical studies have been identified as a special control
for the class II devices, FDA only intends to require clinical studies
on a case-by-case basis where, based on the design or function of the
device, the performance in its intended use can only be validated with
clinical data.

 III. Summary and Analysis of Comments and FDA's Response

 A. General Comments

    1. One comment stated that it would be helpful to state in the
reclassification final rule that the final rule itself can be used to
support substantial equivalence, obviating the need to cite existing
predicate devices.
    FDA agrees with this comment, and has included such a statement in
the summary section of the final rule. The draft guidance document
entitled ``Devices Used for In Vitro Fertilization and Related Assisted
Reproduction Procedures: Submission Guidance for a 510(k),'' which is
the subject of a notice of availability published elsewhere in this
issue of the Federal Register, also provides discussion of the
documentation necessary to establish substantial equivalence.
    2. One comment stated that the proposed date for guidance document
issuance should be provided in the final rule.
    FDA agrees with this comment. A notice of availability of the draft
guidance document, entitled ``Devices Used for In Vitro Fertilization
and Related Assisted Reproduction Procedures: Submission Guidance for a
510(k),'' is published elsewhere in this issue of the Federal Register,
and is available through the Dockets Management Branch (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852.
    3. One comment stated that although the proposed rule is clearly
intended to cover devices used in GIFT procedures, the preamble to the
proposed rule refers only to IVF/ET, without specifically referring to
GIFT. The comment requested that FDA clarify in the final rule that it
reclassifies medical devices used in GIFT, as well as IVF, ICSI, ET,
and other ART procedures. The comment also provided recommended
language specifying the inclusion of devices used for GIFT for the
definitions of assisted reproduction needles and assisted reproduction
catheters.
    FDA agrees with this comment. Medical devices used during GIFT and
other well-established ART procedures are included in the category of
assisted reproduction catheters. The final rule has been appropriately
revised to include them. In addition, the proposed language for the
definitions of assisted reproduction needles and assisted reproduction
catheters has been incorporated.
    4. One comment pointed out the potential applicability of FDA's
guidance entitled ``Convenience Kits Interim Regulatory Guidance,'' May
20, 1997, to GIFT sets or kits, and recommended that this guidance be
updated to include GIFT sets as a type of device covered by this
policy.
    FDA disagrees with this comment. Devices used for GIFT procedures
do not meet the criteria identified under ``Components.'' That is, they
are not: (1) Legally marketed preamendments devices, (2) exempt from
premarket notification, or (3) found to be substantially equivalent
through the premarket notification process. Nevertheless, FDA
anticipates that these types of kits may become eligible for
consideration in time, and is willing to consider the inclusion of GIFT
sets for this new regulatory approach once a sufficient 510(k) data
base for these devices is obtained.
    5. One comment questioned the inclusion of micropipette fabrication
instruments as a category in this reclassification. The comment noted
that it was not clear why the machines (micropipette fabrication
instrument micropipette ``puller'') used to manufacture a regulated end
product (the micropipette) should also be subject to such regulation.
The comment stated that if such a device were included in this
reclassification, it would mean that micropipettes would not be
available commercially unless they have been processed with FDA
approved instrumentation and that any IVF/ART laboratory making its own
micropipettes would not be able to make those without an FDA approved
instrument. The comment was concerned that this might mean that IVF/ART
procedures would be stopped because there is currently no FDA approved
instrument for manufacturing the micropipettes.
    FDA disagrees with this comment. Only the end product device that
is specifically promoted and marketed to the medical community with a
claim relating to an intended use for IVF/ART will be subject to a
premarket notification submission (510(k)). This applies to the
micropipette itself, as well as the micropipette fabrication
instrumentation. If the micropipette itself is the device marketed for
that intended use, a 510(k) would be necessary, but the instrumentation
to manufacture that micropipette would not require a 510(k). However,
if the micropipette fabrication instrumentation itself is the device
marketed for the specific intended use of IVF/ART, then a 510(k) for
that device would be necessary. If neither the micropipette itself nor
the micropipette fabrication instrumentation have a specific claim for
use during IVF/ART, then no 510(k) is required. Thus, it is incorrect
to state that this reclassification would result in a lack of
commercially available micropipettes because they have not been
processed with FDA approved instrumentation or that any IVF laboratory
making its own micropipettes would not be able to make those without an
FDA approved instrument. This classification regulation neither
addresses individual IVF/ART laboratory decisions about what
instruments are necessary, nor does it prohibit any individual
laboratory from making its own micropipettes. However, when those
devices (whether they are the micropipettes or the micropipette
fabrication instrumentation) are marketed and promoted for the specific
intended use of IVF/ART by the manufacturer (including a laboratory
that markets the devices to others), those products become subject to
section 510(k) of the act requirements.
     6. One comment stated that laser microtools are also used to
denude human gametes or embryos and that these devices should be
classified in class II and added to pipettes and other devices under
the category of assisted reproduction microtools.
    FDA disagrees with this comment. The intent of this
reclassification is to reclassify those devices associated with IVF/ART
procedures which have a long and well-established history of safe use.
Laser microtools used to manipulate and treat human gametes or embryos
are relatively new. The Panel which recommended reclassification of
devices used in IVF/ART did not identify laser microtools as having a
sufficiently established history of reasonably safe and effective use
to justify their classification in class II. Therefore, the agency
believes that it is not appropriate to include laser microtools in this
reclassification. As a result, laser microtools remain in class III.
    7. One comment stated that there was ambiguity with respect to the
classification of assisted reproduction microscopes and microscope
accessories. The comment stated that fluorescence microscopes should
not be classified as class I and exempt, but rather, class II because
of the potential for damage to human gametes and embryos.
    FDA agrees with this comment. The intent of this reclassification
is to

[[Page 48431]]

reclassify those devices associated with IVF/ART procedures which have
a long and well-established history of safe use. The use of
fluorescence microscopy for the purpose of preimplantation diagnosis is
relatively new. The Panel which recommended reclassification of devices
used in IVF/ART did not identify fluorescence microscopes as having a
sufficiently established history of reasonably safe and effective use
to justify their classification in class I. Therefore, although the
proposed rule did refer to fluorescence microscopy, the agency has
concluded that is not appropriate to include fluorescence microscopy in
this reclassification. Thus, fluorescence microscopy is retained in
class III. The category of assisted reproduction microscopes and
microscope accessories is intended to specifically refer to
conventional optical microscopes and accessories which are used for the
most common and routine IVF/ART procedures.
    8. One comment stated that stylets (a tube or rod which can be
inserted into a catheter or cannula to give it form and assist in its
passage) are commonly used in IVF/ART procedures, but are not
explicitly included in the reclassification.
    FDA agrees with this comment and has amended the final rule to
include stylets, which are a common component of devices used in IVF/
ART procedures, in the category of assisted reproduction catheters.
    9. One comment stated that the proposed definition of assisted
reproduction microtools should be revised to read:
    Assisted reproduction microtools are pipettes or other devices
used in the laboratory to denude, micromanipulate, hold or transfer
human gametes, or embryos for assisted hatching, ICSI, embryo
biopsy, or other similar procedures used specifically for assisted
reproduction methods, including preimplantation diagnosis.
    FDA disagrees with this comment. Although devices used in
preimplantation diagnosis procedures such as embryo biopsy were
inadvertently included in the proposed rule, the agency does not
believe this type of device should be included in this reclassification
because the use of such preimplantation diagnosis procedures is
relatively new. The intent of this reclassification is to reclassify
those devices associated with IVF/ART procedures that have a long and
well-established history of safe use, as stated in the response to
comment numbers 6 and 7. The use of preimplantation diagnosis
procedures such as embryo biopsy is relatively new. The Panel which
recommended reclassification of devices used in IVF/ART did not
identify devices associated with preimplantation diagnosis procedures
as having a sufficiently established history of reasonably safe and
effective use to justify their reclassification. The category of
assisted reproduction microtools refers only to those devices that are
used for the most common and routine IVF/ART procedures.
    10. One comment recommended that catheters, accessories, and
reproductive media and supplements warrant regulation as class II
products, but that all other specified products intended for use during
IVF/ART procedures should be considered class I products.
    FDA disagrees with this comment, which did not offer any
explanation for the position expressed. The agency believes that
assisted reproduction needles, assisted reproduction microtools,
assisted reproduction micropipette fabrication instruments, assisted
reproduction micromanipulators and microinjectors, assisted
reproduction labware, and assisted reproduction water and water
purification systems also warrant regulation as class II medical
devices. FDA has concluded that the special controls identified for
these categories of devices are necessary at this time to ensure the
safe and effective use of these devices. However, the agency does not
rule out the possibility that these devices may be considered for
further downclassification at some later date after a sufficient 510(k)
data base has been obtained.
    11. One comment stated that the College of American Pathologists
(CAP) and the Society for Assisted Reproductive Technology (SART)
references may be considered voluntary standards, but that the SART
references are published patient registries, not recognized standards
with which to comply or adhere.
     FDA agrees with this comment. FDA recognizes that the SART
reference is a patient registry and data base, and that it does not
contain specific guidelines or recommendations for techniques of
employing IVF/ART procedures. Nevertheless, the agency wishes to
acknowledge this organization and encourage laboratories to consult
this reference for its significant guidance to IVF/ART laboratories in
obtaining data on the safety and effectiveness of these procedures.
    12. One comment stated that validation of clinical performance is
not warranted if there are no new types of safety and effectiveness
questions raised.
    FDA disagrees with this comment. Even if no new types of safety and
effectiveness questions are raised regarding a device, clinical data
may still be required in some cases to adequately assess the
performance of a device based on its unique design or function, as is
outlined in FDA's guidance document ``510(k) Substantial Equivalence
Decision-Making Process (Detailed)'' that is available from the
Division of Small Manufacturers Assistance (HFZ-220), FDA, 1350 Piccard
Dr., Rockville, MD 20850, or on the World Wide Web at ``http://
www.fda.gov/cdrh/k863.html''. Further information on the need for
clinical data is provided in the draft guidance document on IVF decives
that is being announced elsewhere in this issue of the Federal
Register.
    13. One comment stated that water purification systems have
demonstrated a long history of safe and effective use in IVF/ART
applications, and that placing them into class II with special controls
would provide no additional benefit to end-users. The comment
recommended that these devices be classified into class I and exempted
from premarket notification and good manufacturing practice (GMP)
requirements.
    FDA disagrees with this comment. Water purification systems with
specific claims for other applications (e.g., kidney dialysis) are also
placed in class II and are subject to special controls. The quality of
water that directly contacts human gametes or embryos in IVF/ART
procedures is similar to that for dialysis. If a manufacturer of a
water purification system wishes to market and promote that system with
specific claim(s) for its use in IVF/ART procedures, then that device
will require a 510(k). However, if a manufacturer of a water
purification system wishes to market and promote that system for
general purposes only, then no 510(k) is needed, and the device is not
affected by this reclassification.
    14. Two comments suggested using the USP ``water for injection''
requirement as the special control for the quality of water used in
reconstitution of IVF media, rather than requiring type I reagent grade
water. The rationale was that water meeting the latter requirement may
still be corrosive to metals, causing possible exposure of metal ions
to human gametes or embryos as a result of its use in final rinsing of
packaging materials in a pharmaceutical washing machine. Water produced
in conformance with the USP water for injection requirement has
properties sufficient and appropriate for its intended use. The second
comment's rationale was that their validated system producing USP

[[Page 48432]]

water for injection has routinely produced water which passes the mouse
embryo assay test. Additionally, this same requirement should suffice
for water used to wash and rinse labware.
    FDA agrees with these comments. Because the USP water for injection
requirement delineates testing requirements for producing water that is
safe for parenteral use, it should also suffice for production of water
with potential for exposure to human gametes and embryos. Therefore,
FDA agrees with the comment, and the USP water for injection
requirement will be used as a special control for: (1) Water
specifically intended for reconstitution of reproductive media, (2)
water specifically intended for washing and rinsing of labware to be
used in IVF/ART procedures, and (3) purification systems specifically
intended for production of water to be used for IVF/ART procedures.
    15. One comment stated that regulating water quality specific to
these products is not warranted because: (1) These devices are
sterilized and pyrogen tested, and (2) typical use consists of flushing
any lumens with media or sterile water prior to use. The comment stated
that water quality is a user issue that should be addressed by Clinical
Laboratory Improvement Amendments of 1988 (CLIA) or accrediting bodies.
    FDA disagrees with this comment. As previously stated, the
rationale for requiring water quality testing (USP water for injection
testing) is that the quality of water used to reconstitute media and
supplements, as well as to wash and rinse labware, is critically
important to the success of ART procedures. As was also previously
stated, water purification systems with specific claims for other
applications (e.g., kidney dialysis) are also placed in class II and
are subject to special controls. The quality of water needed for IVF/
ART procedures in which human gametes or embryos are directly contacted
is similar to that for dialysis. If a manufacturer of a water
purification system wishes to market and promote that system with
specific claim(s) for its use in IVF/ART procedures, then that device
will require a 510(k). However, if a manufacturer of a water
purification system wishes to market and promote that system for
general purposes only, then no 510(k) is needed, and the device is not
affected by this reclassification.
    16. One comment stated that IVF media are products as critical as
parenterals and should therefore be manufactured according to aseptic
GMP conditions.
    FDA agrees with this comment. Sections 820.70(c) and 820.75 of the
quality system regulation, pertaining to environmental control and
process validation, respectively, address this concern. These sections
describe requirements for adequate control of environmental conditions
to assure no adverse effect of the environment on product quality, and
measures which shall be used to validate and document the manufacturing
processes to assure the quality of the product. A further explanation
of these portions of the quality system regulation may be found in the
Association for the Advancement of Medical Instrumentation (AAMI)
Guidelines entitled ``The Quality System Compendium: GMP Requirements
and Industry Practice'' (Ref. 1).
    17. One comment stated that because the purity of chemicals used
for IVF media is critical, that FDA should require these chemicals to
be of pharmacopoeial grade, with additional requirements regarding
cytotoxicity, endotoxin, and sterility.
    FDA disagrees with this comment. While FDA agrees that the quality
of the components of IVF media is critical, FDA believes that it is not
necessary to require that all chemicals be of pharmacopoeial grade,
since not all desired components may be available in that grade.
Additionally, there exist other special controls, including mouse
embryo assay information, endotoxin testing and sterilization
validation, which are sufficient to assure the safety of the product.
    18. One comment recommended that human-derived or animal-derived
macromolecules (such as serum albumin or hyaluronic acid) not be
allowed in IVF media, and proposed the requirement that macromolecules
be manufactured instead by recombinant methods. The rationale for this
was: (1) The potential for transmission of pathogens such as
Creutzfeld-Jacob Disease (CJD) or bovine spongiform encephalopathy
(BSE) to the human gamete or embryo that may be difficult to detect;
and (2) the potential for transmission of foreign deoxyribonucleic acid
(DNA) into the human oocyte during ICSI. The comment also indicated
that a European standard, now in preparation, would be appropriate to
consider as a special control if FDA does allow use of biological
macromolecules.
    FDA disagrees with this comment. While FDA recognizes the
previously mentioned risks, the agency believes that a requirement for
the use of only recombinant macromolecules in the manufacture of IVF
media is not feasible at this time due to the limited availability of
these macromolecules. FDA does not currently recognize any European
standard regarding the use of biological macromolecules in IVF media.
However, with the controls in place for donor screening and testing, it
should be appropriate to use human derived macromolecules with the
proper notification and consent. In addition, there currently exist
special controls for the use of animal-derived macromolecules in IVF
media.
    19. One comment suggested a requirement that IVF media shall be
tested by the manufacturer according to the special controls listed,
and that a certificate with test results be issued for each approved
batch.
    FDA agrees with this comment. The end-user will benefit if labeling
for IVF media includes information which indicates test results for
each approved batch, even if some labs opt to do further testing to
supplement what is done by the manufacturer. This will also provide
quality assurance to the general public without being unduly burdensome
to the manufacturer.
    20. One comment recommended that an acceptance criterion for
endotoxin levels be set for ready-to-use IVF media.
    FDA disagrees with this comment. Because there is no ``gold
standard'' in the medical community for what the lower limit of
acceptability of endotoxin levels is for IVF and assisted reproduction
procedures, it is not possible to identify an appropriate threshold.
Rather, it is important that the manufacturer perform an established
USP endotoxin test, such as the limulus mebocyte lysate (LAL) or rabbit
pyrogen assay, on any device potentially contacting human gametes or
embryos, and identify this information in the labeling.
    21. One comment stated that the category of reproductive media
should also include: (1) Acid solutions (prepared from liquid or
powder), which are commonly utilized to denude human gametes or
embryos, (2) rinsing solutions used after acid treatment, and (3)
separation media used to separate and concentrate sperm.
    FDA agrees with this comment. Because these products come into
direct physical contact with gametes or embryos, they will also be
listed in the category of reproductive media.
    22. One comment recommended that FDA require that the mouse embryo
assay (MEA) test be mandatory rather than voluntary, and that the two-
cell MEA be used, with an acceptance criterion of greater than 80
percent hatching.
    FDA disagrees with this comment. FDA recognizes that the MEA is
currently the most appropriate test for

[[Page 48433]]

embryotoxicity; however, there is no consensus in the medical community
on whether the one-cell or the two-cell MEA is most appropriate. Both
have their advantages and disadvantages, and these may be weighed
differently by each end-user of a product. Therefore, it would be
inappropriate for FDA to mandate one test over the other. In addition,
FDA believes it would be inappropriate to mandate that the MEA be
conducted, because it recognizes that some end-users will perform their
own testing on the product to assure its safety, regardless of whether
the manufacturer performs these tests. Requiring that the MEA be
conducted would add an unnecessary burden and cost to the manufacturer.
The final regulation requires each manufacturer to provide clear and
prominent information both on the label and in the labeling to the user
about whether and how the MEA was performed, and the results. FDA
believes that this requirement to clearly label the product and provide
information to the end-user in this regard will be adequate to assure
appropriate testing and use of the product.
    23. One comment stated that certain materials (substances which
denature protein, chelate cations, bind endotoxin, or alter endotoxin's
hydrophobic state) may interfere with the LAL assay used to measure
endotoxin, and proposed that this reclassification state that USP
methods such as the rabbit pyrogen assay may also be submitted for
endotoxin testing.
    FDA agrees with this comment. Manufacturers may perform either the
LAL assay or the rabbit pyrogen assay in accordance with established
USP test methods for determination of endotoxin levels, and must
clearly identify on the label what endotoxin test was performed, as
well as the results of the testing in the labeling.
    24. One comment requested that the ``hybritest,'' a bioassay based
on the culture of mouse hybridoma cells, be allowed as an alternative
to the MEA test for embryotoxicity. The comment pointed out the
limitations of the MEA test and provided documentation to support the
use of the Hybritest as an alternative to the MEA.
    FDA disagrees with this comment. Although FDA recognizes that there
are limitations to both the one-cell and the two-cell MEA test, it is
currently the most widely recognized and accepted method for
determining potential embryotoxicity. Although the hybritest has
potential for becoming more widely accepted in the medical community as
a valid alternative to the MEA, it has not yet established sufficient
history, acceptance, and validity to be acceptable as an alternative to
the MEA. FDA will periodically review new information and consult with
the medical community to determine if the hybritest should be included
as an alternative to the MEA test.
    25. One comment stated that if MEA testing is not required by the
agency for assisted reproduction devices, then language stating that
MEA testing was not performed is not warranted.
    FDA disagrees with this comment. As previously stated, FDA believes
it would be inappropriate to mandate that the MEA be conducted, because
it recognizes that some end-users will perform their own testing on the
product to assure its safety, regardless of whether the manufacturer
performs these tests. Nevertheless, it is still essential for each
manufacturer to provide information both on the label and in the
labeling to the user about whether the MEA was performed. FDA believes
that this requirement to clearly label the product is essential to
assure that the end-user (in the laboratory) has sufficient information
to determine if any further testing of the product is necessary.
    26. One comment stated that the language regarding MEA testing in
the special controls section of the proposed rule should be revised
from, ``Whether a one-cell or two-cell MEA is used, the bioassay should
duplicate, as closely as possible, the procedures used for human IVF,
including acquisition, maintenance, culture, transfer (relocation) and
cryopreservation of embryos'' to, ``Whether a one-cell or two-cell MEA
is used, the bioassay should represent, as closely as possible, the
corresponding procedures for which the device is used for human IVF,
such as acquisition, maintenance, culture, transfer (relocation) or
cryopreservation of embryos.''
    FDA agrees with this comment. FDA is including such advice in the
guidance document, for which a notice of availability is being
published elsewhere in this issue of the Federal Register.
    27. One comment stated that for assisted reproduction accessories
that do not contact gametes, embryos or patients, the cited special
controls of MEA testing, device sterilization validation, and/or water
quality testing have no impact on mitigating risks of gamete or embryo
damage.
    FDA agrees with this comment. It is true that the particular
special controls of MEA testing, device sterilization validation, and
water quality testing are not applicable to certain assisted
reproduction accessories, such as syringe pumps, incubators and
cryopreservation instrumentation, which do not directly contact the
human gamete, embryo, or patient. Nevertheless, the other identified
special controls for design specifications, labeling and voluntary
standards are applicable and can mitigate the potential risks to the
human gamete or embryo associated with use of assisted reproduction
accessories.
    28. One comment stated that the risk of hematuria would not be
mitigated by the use of design specifications, and that hematuria is
primarily associated with the procedure/technique.
    FDA disagrees with this comment. The agency recognizes that a risk
such as hematuria is primarily associated with the procedure/technique.
However, FDA believes that design specifications can help to ensure the
safe and appropriate use of the product and thereby reduce the
possibility of inadvertent needle puncture of the bladder.
    29. One comment stated that the risk of puncture would not be
mitigated by the use of design specifications, and that puncture is
primarily associated with the procedure/technique.
    FDA disagrees with this comment. The agency recognizes that a risk
such as puncture is primarily associated with the procedure/technique.
However, FDA believes that design specifications can help to ensure the
safe and appropriate use of the product and thereby reduce the
possibility of inadvertent needle puncture of other unintended
abdominal or pelvic structures.
    30. One comment stated that the risk of infection would not be
mitigated by the use of MEA testing, and that instead, use of embryo-
compatible materials should be advocated.
    FDA agrees with this comment. The agency recognizes that a risk
such as infection would not be mitigated by the use of MEA testing.
However, the agency believes that the other identified special controls
of endotoxin testing, device sterilization validation, water quality
testing, design specifications, and labeling requirements will mitigate
this risk and thereby help to ensure the safe and appropriate use of
the product.
    31. One comment stated that the potential complications of ectopic
pregnancy, multiple gestation, or chromosomal congenital abnormalities
are not device specific, and that, therefore, the statement that: ``The
assisted reproduction devices most likely to present this risk are
assisted reproduction needles, assisted reproduction catheters, * * *
'' (62 FR 46689) should be deleted. The comment also stated that these
risks would not be

[[Page 48434]]

mitigated by the use of design specifications.
    FDA disagrees with this comment. The agency does agree that the
potential complications of multiple gestation or chromosomal congenital
abnormalities are not device specific, and that assisted reproduction
needles do not contribute to the risk of these potential complications.
Nevertheless, assisted reproduction catheters may pose a risk of
increasing the rate of ectopic pregnancies following embryo transfer,
either by: (1) Allowing for an increased volume of transfer fluid, or
(2) being designed in such a way as to promote inadvertent location of
the catheter tip in or near the fallopian tube ostium (two postulated
mechanisms for the occurrence of ectopic pregnancy in IVF/ART
patients). These risks would be mitigated not only by design
specifications, but also by labeling and appropriate instructions for
use which caution against these possibilities. Therefore, the agency
has modified the statement accordingly.
    32. One comment questioned whether it was appropriate to require
instructions for use for disposable labware. The comment stated that
generalized instructions would not be useful to the user because of the
diversity of techniques, and that as laboratories become regulated by
other organizations such as SART, CAP, and the Health Care Finance
Administration (HCFA) under CLIA, they are generating their own written
procedures to meet their own specific needs.
    FDA agrees with this comment. Because of the variability in
techniques from user to user, it is not feasible or helpful to provide
specific instruction for use on devices such as labware. Guidance from
the appropriate regulatory entities (CAP, SART, HCFA) should be
followed wherever applicable, and the manufacturer should provide a
general statement in the labeling to users to use the labware as
appropriate for the particular technique they are employing. FDA will
review the labeling to ascertain that any instructions are appropriate
given the indication for use identified on the labeling.
    33. One comment recommended that the statement ``labeling * * *
will ensure that devices are used properly, that the user is adequately
informed, that the intended use of the device is clearly understood,
and that claims by the manufacturer do not exceed the intended use of
the device,'' be revised to indicate that labeling ``promotes'' or
``supports reasonable assurance of'' the items listed.
    FDA disagrees with this comment. The meaning intended to be
conveyed by the word ``ensure'' is that the labeling should be
carefully and clearly written so as to provide the user with the
information necessary to use the device as intended. The agency does
not believe that the recommended revisions would adequately convey this
intent.
    34. One comment stated that labeling requirements need to be
clarified, and that boilerplate language should be suggested to provide
useful information.
    FDA disagrees with this comment. Because of the large number of
devices identified in the several categories of assisted reproduction
devices intended for this reclassification, as well as variability in
techniques from user to user, it is not feasible to provide specific
boilerplate language for labeling in this final rule. Guidance from the
appropriate regulatory entities (CAP, SART, and HCFA) should be
followed wherever applicable, and the manufacturer should provide a
general statement in the labeling to the user to use the device as
appropriate for the particular technique they are employing. As stated
previously, FDA will review labeling to ascertain that any instructions
are appropriate given the indication for use identified on the
labeling. In addition, FDA will work with manufacturers to develop
appropriate labeling and may revise the guidance document for these
devices once an appropriate 510(k) data base has been obtained.
    35. Two comments expressed a concern with respect to the
requirement that all devices coming into contact with embryos and
gametes must demonstrate a sterility assurance level (SAL) of
10<SUP>-6</SUP>. Both comments stated that while a SAL of
10<SUP>-6</SUP> may be reasonable for a terminally sterilized product,
most liquid media used for the processing or culture of embryos and
gametes are not compatible with existing technologies for terminal
sterilization, and therefore must be aseptically filled. The comments
proposed that a SAL of 10<SUP>-3</SUP> be stipulated for aseptically
filled products.
    FDA agrees with this comment. A SAL of 10<SUP>-3</SUP> is
recommended for reproductive media used for the processing or culture
of embryos and gametes. Products which are processed in this way must
clearly identify the SAL, and that they were ``aseptically processed''
or ``membrane filtered'' both on the label and in the labeling.
    36. One comment stated that the identification for assisted
reproduction needles should be revised from ``Assisted reproduction
needles are devices used to obtain gametes, * * *'' to ``Assisted
reproduction needles are devices used to obtain gametes from the body *
* *''.
    FDA agrees with this comment and has revised this identification
accordingly.
    After reviewing the data presented before the Panel and considering
the Panel's recommendation, as well as the comments received on the
proposed reclassification, FDA, based on the information set forth, is
reclassifying instrumentation intended for use in IVF and related ART
procedures, and substantially equivalent devices of this generic type,
from class III to class II, and assisted reproduction microscopes and
microscope accessories, and substantially equivalent devices of this
generic type, from class III to class I.
     FDAMA added a new section 510(l) to the act. New section 510(l) of
the act provides that a class I device is exempt from the premarket
notification requirements under section 510(k) of the act, unless the
device is intended for a use which is of substantial importance in
preventing impairment of human health or it presents a potential
unreasonable risk of illness or injury. Hereafter, these are referred
to as ``reserved criteria.'' FDA has considered assisted reproduction
microscopes and microscope accessories in accordance with the reserved
criteria and determined that the device does not require premarket
notification. Such an exemption permits manufacturers to introduce into
commercial distribution generic types of devices without first
submitting a premarket notification to FDA.
    Accordingly, as required by Sec. 860.134(b)(6) and (b)(7) of the
regulations, FDA is reclassifying instrumentation intended for use in
IVF and related ART procedures, and substantially equivalent devices of
this generic type, from class III to class II, and assisted
reproduction microscopes and microscope accessories, and substantially
equivalent devices of this generic type, from class III to class I. In
addition, FDA is codifying the reclassification of the device by adding
21 CFR part 884 subpart G which consists of Secs. 884.6100, 884.6200,
884.6300, 884.6400, 884.6500, 884.6600, 884.6700, 884.6800, 884.6900,
and 884.7000.

 B. Special Controls

    The following special controls have been identified for assisted
reproduction devices classified into class II:

[[Page 48435]]

1. Mouse Embryo Assay Information
    The manufacturer should provide information to the user on whether
an MEA was performed for toxicity and functionality testing of assisted
reproduction needles, catheters, microtools, water or water
purification systems, reproductive media, labware or other devices
coming into contact with gametes and/or embryos. The rationale for
requiring information on this test as a special control for class II
assisted reproduction devices is that the MEA is a good surrogate
indicator of potential toxicity of materials used in assisted
reproduction devices to gametes and/or embryos. Both one-cell and two-
cell assays are used. FDA will not dictate to the manufacturer which
MEA should be used during the manufacture of a particular product, or
even that any MEA is performed. Rather, if the mouse embryo assay is
conducted, the manufacturer should provide clear information to the
user about how the assay was performed and the assay results, both on
the label and in the labeling. The bioassay should duplicate, as
closely as possible, the procedures used for human IVF, including the
acquisition, maintenance, culture, transfer (relocation) and
cryopreservation of embryos. If no MEA is used, then this information
must also be clearly provided to the user.
2. Endotoxin Testing
    The rationale for requiring endotoxin testing as a special control
for class II assisted reproduction devices is that it will provide a
mechanism for ensuring that devices coming into contact with gametes,
embryos, and/or the patient have been tested for levels of endotoxin
released from gram-negative bacteria, which is the major pyrogen of
concern. Of primary concern, endotoxin can be harmful to embryos and
thus potentially affect development of the embryo, implantation and
pregnancy rates. An established USP endotoxin assay (LAL or rabbit
pyrogenicity) must be performed on any device, including needles,
catheters, microtools, labware, water or water purification systems and
media coming into contact with gametes, embryos, and/or the patient.
3. Sterilization Validation
    The rationale for requiring sterilization validation as a special
control for class II assisted reproduction devices is that it will
provide a mechanism for ensuring that devices, including needles,
catheters, microtools, labware, water or water purification systems,
and media coming into contact with gametes and/or embryos are sterile
to a SAL of 10<SUP>-6</SUP>. The SAL for media should be
10<SUP>-3</SUP> or better. Established sterilization validation testing
must be performed on all devices according to AAMI guidelines. The
label should clearly identify the method of sterilization (for media,
whether they were aseptically processed or membrane filtered) and SAL.
4. Water Quality
    The rationale for requiring this test as a special control for
class II assisted reproduction devices is that water quality is
critically important to successful assisted reproductive technology
procedures. The quality of water that directly contacts human gametes
or embryos in IVF/ART procedures is similar to that for dialysis. Water
used to reconstitute reproductive media and to wash and rinse labware,
whether generated in-house using purification systems or obtained in
bottled form from vendors, should be in conformance with USP water for
injection requirements. As stated previously, general purpose water
purification systems without a specific assisted reproduction claim
will not be affected by this proposed rule.
5. Design Specifications
    Particular design specifications may be identified for each type of
device which assure minimally acceptable standards. The rationale for
including design specifications as a special control for all class II
assisted reproduction devices is that it will help to reduce the
incidence of adverse events such as bleeding, pain or perforation which
could be due to suboptimal device design. For example, assisted
reproduction needles may be specified to be 16 to 18 gauge, 22 to 23
centimeters long, 45 to 60 degree beveled stainless steel, and sterile
to assure safe and adequate access to ovarian follicles.
6. Labeling Requirements
    Specific labeling which identifies the intended use, indication for
use, contraindications, precautions, warnings, instructions for use and
other information will be required. The rationale for including
labeling as a special control for all class II assisted reproduction
devices is that it will ensure that devices are used properly, that the
user is adequately informed, that the intended use of the device is
clearly understood, and that claims by the manufacturer do not exceed
the intended use of the device. The label and labeling should also
include information on the mouse embryo assay (see section III.B.1 of
this document), the method of sterilization (for media, whether they
were aseptically processed or membrane filtered) and SAL (see section
III.B.3 of this document), and endotoxin levels (see section III.B.2 of
this document).
7. Biocompatibility Testing
    Aside from concerns with gamete- or embryotoxicity, devices which
are patient-contacting should demonstrate that the materials of which
they are comprised are biocompatible with their intended use using
conventional biocompatibility testing. Tests performed should conform
to those recommended by international standard ISO-10993, ``Biological
Evaluation of Medical Devices, Part 1: Evaluation and Testing.''
8. Clinical Testing
    Certain device designs may not conform to conventional
configurations used in assisted reproduction today, e.g., a specially-
configured embryo transfer catheter. Although the device designs
envisioned for this special control do not raise new types of safety
and effectiveness questions, clinical data may still be required in
some cases to adequately assess the performance of a device for its
intended use. As stated previously, FDA does not intend to routinely
require clinical testing; instead, clinical testing will be required on
a case-by-case basis, where, based on the design or function of the
device, the performance in its intended use can only be validated with
clinical data.

C. Summary of Other Changes

    In addition, FDA would like to note the following changes from the
proposed rule which are incorporated into the final rule:
    (1) Although devices used for preimplantation diagnosis procedures
such as embryo biopsy were inadvertently included in the proposed rule,
the agency does not believe this type of device should be included in
this reclassification because the use of such devices for this intended
use is relatively new (see comment 9 of this document).
    (2) Voluntary standards have been omitted as a special control from
the final rule. While several organizations such as the CAP and the
SART have provided significant guidance to IVF/ART laboratories, FDA
recognizes that standards and recommendations from these organizations
do not include specific guidelines for devices (see comment 11 of this
document).
     (3) The special control of water quality testing has been modified
to require conformance with USP water for

[[Page 48436]]

injection requirements (see comment 14 of this document).
     (4) The special control of sterilization validation has been
modified to allow a SAL of 10<SUP>-3</SUP> for reproductive media
rather than 10<SUP>-6</SUP> (see comment 36 of this document).
    (5) The special control of biocompatibility testing for patient-
contacting devices has been added to the appropriate categories of
assisted reproduction devices.
    In light of the general controls and special controls proposed for
these devices, and the known risks and benefits of the devices, there
exists reasonable assurance that these devices are safe and effective
for their intended use.

IV. Environmental Impact

    The agency has determined under 21 CFR 25.34(b) that this
reclassification is of a type that does not individually or
cumulatively have a significant effect on the human environment.
Therefore, neither an environmental assessment nor an environmental
impact statement is required.

 V. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354) as
amended by subtitle D of the Small Business Regulatory Fairness
Enforcement Act of 1996 (Pub. L. 104-121), and the Unfunded Mandates
Reform Act of 1995 (Pub. L. 104-4)). Executive Order 12866 directs
agencies to assess all costs and benefits of available regulatory
alternatives and, when regulation is necessary, to select regulatory
approaches that maximize net benefits (including potential economic,
environmental, public health and safety and other advantages,
distributive impacts, and equity). The agency believes that this final
rule is consistent with the regulatory philosophy and principles
identified in the Executive Order. In addition, the final rule is not a
significant regulatory action as defined by the Executive Order and so
is not subject to review under the Executive Order. The Regulatory
Flexibility Act requires agencies to analyze regulatory options that
would minimize any significant impact of a rule on small entities.
Reclassification of these devices from class III to class II or class I
will relieve all manufacturers of the device of the cost of complying
with the premarket approval requirements in section 515 of the act.
Because reclassification will reduce regulatory costs with respect to
this device, it will impose no significant economic impact on any small
entities, and it may permit small potential competitors to enter the
marketplace by lowering their costs. The agency therefore certifies
that this final rule will not have a significant economic impact on a
substantial number of small entities. In addition, this final rule will
not impose costs of $100 million or more on either the private sector
or State, local, and tribal governments in the aggregate, and therefore
a summary statement or analysis under section 202(a) of the Unfunded
Mandates Reform Act of 1995 is not required.

 VI. Paperwork Reduction Act of 1995

    FDA has determined that this final rule does not contain any
information collection requirements and, therefore, is not subject to
review by the Office of Management and Budget (OMB) under the Paperwork
Reduction Act of 1995.

 VII. References

    The following reference has been placed on display in the Dockets
Management Branch and may be seen by interested persons between 9 a.m.
and 4 p.m., Monday through Friday.
     1. Association for the Advancement of Medical Instrumentation
(AAMI) Guideline, ``The Quality System Compendium: GMP Requirements and
Industry Practice.''

List of Subjects in 21 CFR Part 884

    Medical devices.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
884 is amended as follows:

PART 884--OBSTETRICAL AND GYNECOLOGICAL DEVICES

    1. The authority citation for 21 CFR part 884 continues to read as
follows:

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.

    2. Subpart G, consisting of Secs. 884.6100 through 884.6190, is
added to read as follows:

 Subpart G--Assisted Reproduction Devices

 Sec.
 884.6100  Assisted reproduction needles.
 884.6110  Assisted reproduction catheters.
 884.6120  Assisted reproduction accessories.
 884.6130  Assisted reproduction microtools.
 884.6140  Assisted reproduction micropipette fabrication
instruments.
 884.6150  Assisted reproduction micromanipulators and
microinjectors.
 884.6160  Assisted reproduction labware.
 884.6170  Assisted reproduction water and water purification
systems.
 884.6180  Reproductive media and supplements.
 884.6190  Assisted reproductive microscopes and microscope
accessories.

 Subpart G--Assisted Reproduction Devices

Sec. 884.6100   Assisted reproduction needles.

     (a) Identification. Assisted reproduction needles are devices used
in in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT),
or other assisted reproduction procedures to obtain gametes from the
body or introduce gametes, zygote(s), preembryo(s) and/or embryo(s)
into the body. This generic type of device may include a single or
double lumen needle and component parts, including needle guides, such
as those used with ultrasound.
     (b) Classification. Class II (special controls) (mouse embryo
assay information, endotoxin testing, sterilization validation, design
specifications, labeling requirements, biocompatibility testing, and
clinical testing).

Sec. 884.6110   Assisted reproduction catheters.

     (a) Identification. Assisted reproduction catheters are devices
used in in vitro fertilization (IVF), gamete intrafallopian transfer
(GIFT), or other assisted reproduction procedures to introduce or
remove gametes, zygote(s), preembryo(s), and/or embryo(s) into or from
the body. This generic type of device may include catheters, cannulae,
introducers, dilators, sheaths, stylets, and component parts.
     (b) Classification. Class II (special controls) (mouse embryo
assay information, endotoxin testing, sterilization validation, design
specifications, labeling requirements, biocompatibility testing, and
clinical testing).

Sec. 884.6120   Assisted reproduction accessories.

     (a) Identification. Assisted reproduction accessories are a group
of devices used during assisted reproduction procedures, in conjunction
with assisted reproduction needles and/or assisted reproduction
catheters, to aspirate, incubate, infuse, and/or maintain temperature.
This generic type of device may include:
     (1) Powered aspiration pumps used to provide low flow,
intermittent vacuum for the aspiration of eggs (ova).
     (2) Syringe pumps (powered or manual) used to activate a syringe
to infuse or aspirate small volumes of fluid during assisted
reproduction procedures.
     (3) Collection tube warmers, used to maintain the temperature of
egg (oocyte)

[[Page 48437]]

collection tubes at or near body temperature. A dish/plate/microscope
stage warmer is a device used to maintain the temperature of the egg
(oocyte) during manipulation.
    (4) Embryo incubators, used to store and preserve gametes and/or
embryos at or near body temperature.
    (5) Cryopreservation instrumentation and devices, used to contain,
freeze, and maintain gametes and/or embryos at an appropriate freezing
temperature.
    (b) Classification. Class II (special controls) (design
specifications, labeling requirements, and clinical testing).

Sec. 884.6130   Assisted reproduction microtools.

    (a) Identification. Assisted reproduction microtools are pipettes
or other devices used in the laboratory to denude, micromanipulate,
hold, or transfer human gametes or embryos for assisted hatching,
intracytoplasmic sperm injection (ICSI), or other assisted reproduction
methods.
    (b) Classification. Class II (special controls) (mouse embryo assay
information, endotoxin testing, sterilization validation, design
specifications, labeling requirements, and clinical testing).

Sec. 884.6140   Assisted reproduction micropipette fabrication
instruments.

    (a) Identification. Assisted reproduction micropipette fabrication
devices are instruments intended to pull, bevel, or forge a
micropipette or needle for intracytoplasmic sperm injection (ICSI), in
vitro fertilization (IVF) or other similar assisted reproduction
procedures.
    (b) Classification. Class II (special controls) (design
specifications, labeling requirements, and clinical testing).

Sec. 884.6150   Assisted reproduction micromanipulators and
microinjectors.

    (a) Identification. Assisted reproduction micromanipulators are
devices intended to control the position of an assisted reproduction
microtool. Assisted reproduction microinjectors are any device intended
to control aspiration or expulsion of the contents of an assisted
reproduction microtool.
    (b) Classification. Class II (special controls) (design
specifications, labeling requirements, and clinical testing).

Sec. 884.6160   Assisted reproduction labware.

    (a) Identification. Assisted reproduction labware consists of
laboratory equipment or supplies intended to prepare, store,
manipulate, or transfer human gametes or embryos for in vitro
fertilization (IVF), gamete intrafallopian transfer (GIFT), or other
assisted reproduction procedures. These include syringes, IVF tissue
culture dishes, IVF tissue culture plates, pipette tips, dishes,
plates, and other vessels that come into physical contact with gametes,
embryos or tissue culture media.
    (b) Classification. Class II (special controls) (mouse embryo assay
information, endotoxin testing, sterilization validation, design
specifications, labeling requirements, and clinical testing).

Sec. 884.6170   Assisted reproduction water and water purification
systems.

    (a) Identification. Assisted reproduction water purification
systems are devices specifically intended to generate high quality,
sterile, pyrogen-free water for reconstitution of media used for
aspiration, incubation, transfer or storage of gametes or embryos for
in vitro fertilization (IVF) or other assisted reproduction procedures.
These devices may also be intended as the final rinse for labware or
other assisted reproduction devices that will contact the gametes or
embryos. These devices also include bottled water ready for
reconstitution available from a vendor that is specifically intended
for reconstitution of media used for aspiration, incubation, transfer,
or storage of gametes or embryos for IVF or other assisted reproduction
procedures.
    (b) Classification. Class II (special controls) (mouse embryo assay
information, endotoxin testing, sterilization validation, water quality
testing, design specifications, labeling requirements, biocompatibility
testing, and clinical testing).

Sec. 884.6180   Reproductive media and supplements.

    (a) Identification. Reproductive media and supplement are products
that are used for assisted reproduction procedures. Media include
liquid and powder versions of various substances that come in direct
physical contact with human gametes or embryos (including water, acid
solutions used to treat gametes or embryos, rinsing solutions, sperm
separation media, supplements, or oil used to cover the media) for the
purposes of preparation, maintenance, transfer or storage. Supplements
are specific reagents added to media to enhance specific properties of
the media (e.g., proteins, sera, antibiotics, etc.).
    (b) Classification. Class II (special controls) (mouse embryo assay
information, endotoxin testing, sterilization validation, design
specifications, labeling requirements, biocompatibility testing, and
clinical testing).

Sec. 884.6190   Assisted reproductive microscopes and microscope
accessories.

    (a)  Identification. Assisted reproduction microscopes and
microscope accessories (excluding microscope stage warmers, which are
classified under assisted reproduction accessories) are optical
instruments used to enlarge images of gametes or embryos. Variations of
microscopes and accessories used for these purposes would include phase
contrast microscopes, dissecting microscopes and inverted stage
microscopes. This device is exempt from the premarket notification
procedures in subpart E of part 807 of this chapter subject to the
limitations in Sec. 884.9.
    (b) Classification. Class I.

    Dated: August 25, 1998.
D.B. Burlington,
Director, Center for Devices and Radiological Health.
[FR Doc. 98-24242 Filed 9-9-98; 8:45 am]
BILLING CODE 4160-01-F