[Federal Register Volume 63, Number 175 (Thursday, September 10, 1998)]
[Rules and Regulations]
[Pages 48428-48437]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-24242]


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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availability of a draft guidance entitled ``Devices Used for In Vitro 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 
10-6. Both comments stated that while a SAL of 
10-6 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 10-3 be stipulated for aseptically 
filled products.
    FDA agrees with this comment. A SAL of 10-3 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 10-6. The SAL for media should be 
10-3 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 10-3 for reproductive media 
rather than 10-6 (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