(192 days)
The Cryotop® Vitrification Kit is indicated for use in the preparation, and storage of promuclear (PN) zygotes through day 3 cleavage stage embryos and blastocyst stage embryos.
The Cryotop® Thawing Kit is indicated for use in the preparation and thawing of vitrified pronuclear (PN) zygotes through day 3 cleavage stage embryos and blastocyst stage embryos.
The Cryotop® Vitrification and Thawing Kits are composed of a set of five media to vitrify and warm pronuclear (PN) through blastocyst stage embryos for Assisted Reproductive Technologies (ART) procedures.
The Cryotop® Vitrification Kit includes two media components, Equilibration Solution (ES) and Vitrification Solution (VS), containing the cryoprotectants ethylene glycol and dimethyl sulfoxide. During the vitrification process, embryos are first exposed to ES and then in VS. Using this methodology, the permeating cryoprotectants can replace water in the PN through blastocyst stage embryos prior to vitrification and storage in liquid nitrogen. The Cryotop® Vitrification Kit comes pre-packaged with one 1.5 ml vial of ES, two 1.5 ml vials of VS, 4 Cryotop devices (Cryotop SC, or Cryotop US), and two Repro Plates.
The Cryotop® Thawing Kit is composed of three media used stepwise for thawing and removing cryoprotectants from vitrified PN through blastocyst stage embryos. The Cryotop® Thawing Kit is composed of TS (Thawing Solution), DS (Dilution Solution) and WS (Wash Solution). The Cryotop Thawing Kit comes pre-packaged with two 4.0 ml vials of thawing solution, one 4.0 ml vial of dilution solution, one 4.0 ml vial of washing solution, one Repro Plate, and two 35 mm dishes.
All of the media in the Cryotop® Vitrification Kit and Cryotop® Thawing Kit contain Gentamicin. The media in these kits undergo aseptic filtration, while storage devices are sterilized by radiation.
This document describes the Kitazato BioPharma Co., Ltd. Cryotop® Vitrification Kit and Cryotop® Thawing Kit, which are reproductive media and supplements used for the cryopreservation and thawing of pronuclear (PN) zygotes through day 3 cleavage stage embryos and blastocyst stage embryos.
Here's an analysis of the provided information regarding acceptance criteria and the study:
1. Table of Acceptance Criteria and Reported Device Performance
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Non-Clinical Performance Criteria | |
| Cleanliness and appearance: Free of turbidity and sedimentation | Passes |
| pH Testing: Average pH reading is from 7.2 – 7.6 | Passes (Average pH reading is from 7.2 – 7.6) |
| Endotoxin Testing: Endotoxin values conform to the value <0.25 EU/mL | Passes (<0.25 EU/mL) |
| Osmolality Testing: Pass specification for each solution | Passes specification for each solution |
| Sterility Testing: No microbial growth from sterility testing | Passes |
| Mouse Embryo Assay: ≥80% of 1-cell control embryos develop at 96 hours | ≥80% blastocyst at 96 hours (one-cell MEA) |
| Package Integrity Testing | Passes |
| Clinical Performance Criteria (Effectiveness Indicators from Literature) | |
| Clinical pregnancies (from Literature 1) | 42% from total transfer number |
| Live births (from Literature 1) | 30% from total transfer number |
| Clinical pregnancies (from Literature 2) | 59% from number of cycles |
| Ongoing pregnancies (from Literature 2) | 48% from number of cycles |
| Clinical pregnancies (from Literature 3) | 49% from number of cycles |
| Ongoing pregnancies (from Literature 3) | 46% from number of cycles |
| Embryo survival rates | Consistent with normal ART procedures |
2. Sample Size Used for the Test Set and the Data Provenance
The document does not explicitly state the sample sizes used for the non-clinical performance tests (e.g., number of vials for pH testing, number of mouse embryos for MEA).
For the clinical performance data, the provenance is clearly stated as retrospective data from published scientific literature. The countries of origin for the data are not explicitly stated, but the authors' affiliations in the cited literature might provide this information (e.g., "Minimal ovarian stimulation combind with elective single embryo transfer policy: age-specific results of a large, single-center, Japanese cohort" suggests Japanese data for Literature 1).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts
For the non-clinical performance data, the "ground truth" is established by the specifications themselves, which are standard laboratory parameters. The testing would have been performed by qualified laboratory personnel following validated protocols. However, the exact number and qualifications of these experts are not explicitly mentioned in this summary.
For the clinical performance data, the "ground truth" is based on the outcomes reported in the published clinical studies (pregnancies, live births, survival rates). These outcomes were determined by the clinical teams involved in those studies. The document does not specify the number of experts (e.g., embryologists, reproductive endocrinologists) involved in each specific study or their qualifications, but it is implied that these are qualified professionals in the field of Assisted Reproductive Technologies (ART).
4. Adjudication Method for the Test Set
This information is not provided for either the non-clinical or clinical data. For non-clinical tests, results are typically determined by objective measurements against established specifications. For the clinical studies cited, the adjudication methods for clinical endpoints would be described within the individual publications, but are not summarized here.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted or reported here. This type of study is typically used for diagnostic devices involving human interpretation against an AI algorithm. The Cryotop® Vitrification and Thawing Kit is a laboratory media kit, not a diagnostic device with an AI component.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
This question is not applicable as the device is a laboratory media kit and does not involve an algorithm or AI component.
7. Type of Ground Truth Used
- Non-Clinical Data: The ground truth for non-clinical performance is based on established laboratory specifications and quantitative measurements (e.g., pH values, endotoxin levels, mouse embryo development).
- Clinical Data: The ground truth for clinical performance (pregnancy rates, live birth rates, embryo survival) is based on clinical outcomes data reported in peer-reviewed scientific literature.
8. Sample Size for the Training Set
This question is not applicable as the device is a laboratory media kit and does not involve an AI algorithm that requires a training set. The performance data is derived from specific tests and clinical use, not from an AI model.
9. How the Ground Truth for the Training Set Was Established
This question is not applicable for the same reason as above; there is no training set for this type of device.
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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
October 7, 2016
KITAZATO BioPharma Co., Ltd. % Richard Vincins, CBA, CQA, RAC (US,EU) Vice President, QA/RA Emergo Global Consulting, LLC 816 Congress Avenue, Suite 1400 Austin, TX 78701
Re: K160864
Trade/Device Name: Cryotop® Vitrification Kit and Cryotop® Thawing Kit Regulation Number: 21 CFR§ 884.6180 Regulation Name: Reproductive Media and Supplements Regulatory Class: II Product Code: MOL. MOK Dated: September 2, 2016 Received: September 7, 2016
Dear Richard Vincins:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies.
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Page 2 - Richard Vincins, CBA, CQA, RAC (US,EU)
You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely vours.
Joyce M. Whang -S
for
Benjamin R. Fisher, Ph.D. Director Division of Reproductive, Gastro-Renal, and Urological Devices Office of Device Evaluation Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K160864
Device Name
Cryotop® Vitrification Kit and Cryotop® Thawing Kit
Indications for Use (Describe)
The Cryotop® Vitrification Kit is indicated for use in the preparation, and storage of promuclear (PN) zygotes through day 3 cleavage stage embryos and blastocyst stage embryos.
The Cryotop® Thawing Kit is indicated for use in the preparation and thawing of vitrified pronuclear (PN) zygotes through day 3 cleavage stage embryos and blastocyst stage embryos.
Type of Use (Select one or both, as applicable)
| Prescription Use (Part 21 CFR 801 Subpart D) | ☑ |
|---|---|
| Over-The-Counter Use (21 CFR 801 Subpart C) | ☐ |
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510(k) Summary
Cryotop Vitrification and Thawing Kit
K160864
1. Submission Sponsor
KITAZATO BioPharma Co., Ltd.
81 Nakajima, Fuji-city
Shizuoka 416-0907
JAPAN
Phone number: +(81) 546-66-2202
Contact: Futoshi Inoue
Title: President
2. Submission Correspondent
Emergo Global Consulting, LLC
2500 Bee Cave Road
Building 1, Suite 300
Austin, TX 78746
Office Phone: (512) 327.9997
Contact: Richard A. Vincins, Vice President, QA/RA
Email: project.management@emergogroup.com
3. Date Prepared
6 October 2016
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4. Device Identification
| Trade/Proprietary Name: | Cryotop® Vitrification KitCryotop® Thawing Kit |
|---|---|
| Common/Usual Name: | Vitrification Cryopreservation Media |
| Classification Name: | Reproductive Media and Supplements |
| Regulation Number: | 884.6180 |
| Product Code: | MQL, Media, ReproductiveMQK, Labware, Assisted Reproduction |
| Device Class: | Class II |
| Classification Panel: | Obstetrics/Gynecology |
5. Legally Marketed Predicate Device(s)
K093273, Vit Kit® - Vitrification Freeze Kit/ Vitrification Thaw Kit, Irvine Scientific Sales Co., Inc.
The predicate device has not been subject to a design-related recall.
6. Device Description
The Cryotop® Vitrification and Thawing Kits are composed of a set of five media to vitrify and warm pronuclear (PN) through blastocyst stage embryos for Assisted Reproductive Technologies (ART) procedures.
The Cryotop® Vitrification Kit includes two media components, Equilibration Solution (ES) and Vitrification Solution (VS), containing the cryoprotectants ethylene glycol and dimethyl sulfoxide. During the vitrification process, embryos are first exposed to ES and then in VS. Using this methodology, the permeating cryoprotectants can replace water in the PN through blastocyst stage embryos prior to vitrification and storage in liquid nitrogen. The Cryotop® Vitrification Kit comes pre-packaged with one 1.5 ml vial of ES, two 1.5 ml vials of VS, 4 Cryotop devices (Cryotop SC, or Cryotop US), and two Repro Plates.
The Cryotop® Thawing Kit is composed of three media used stepwise for thawing and removing cryoprotectants from vitrified PN through blastocyst stage embryos. The Cryotop® Thawing Kit is composed of TS (Thawing Solution), DS (Dilution Solution) and WS (Wash Solution). The Cryotop Thawing Kit comes pre-packaged with two 4.0 ml vials of thawing solution, one 4.0 ml vial of dilution solution, one 4.0 ml vial of washing solution, one Repro Plate, and two 35 mm dishes.
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All of the media in the Cryotop® Vitrification Kit and Cryotop® Thawing Kit contain Gentamicin. The media in these kits undergo aseptic filtration, while storage devices are sterilized by radiation. The specifications for the Cryotop Vitrification and Thawing Kits are listed in Table 1 below.
7. Indication for Use Statement
The Cryotop® Vitrification Kit is indicated for use in the preparation, vitrification and storage of pronuclear (PN) zygotes through day 3 cleavage stage embryos and blastocyst stage embryos.
The Cryotop® Thawing Kit is indicated for use in the preparation and thawing of vitrified pronuclear (PN) zygotes through day 3 cleavage stage embryos and blastocyst stage embryos.
8. Substantial Equivalence Discussion
The following table compares the Cryotop® Vitrification and Thawing Kits to the predicate device with respect to indications for use, principles of operation, technological characteristics, materials, and performance testing. The comparison of the devices provides more detailed information regarding the basis for the determination of substantial equivalence. Based on the information below, the proposed and predicate device have comparable intended uses, and differences in technology noted do not raise different questions of safety or effectiveness as compared to the predicate.
| Manufacturer | Kitazato BioPharma Co,Ltd. | Irvine Scientific SalesCo., Inc. | SignificantDifferences |
|---|---|---|---|
| Trade Name | Cryotop® Vitrificationand Thawing Kits | Vit Kit® - VitrificationFreeze Kit andVitrification Thaw Kit | |
| 510(k) Number | K160864 | K093273 | N/A |
| Product Code | MQL, MQK | MQL | Similar |
| Regulation Number | 884.6180 | 884.6180 | Same |
| Regulation Name | Reproductive Media andSupplements | Reproductive Media andSupplements | Same |
| Indications for Use | The Cryotop®Vitrification Kit —Vitrification is indicatedfor use in thepreparation, vitrificationand storage ofpronuclear (PN) zygotesthrough day 3 cleavagestage embryos and | Vit Kit® - Freeze,Vitrification Freeze Kit forEmbryos (PN throughBlastocyst Stage) isintended for use in thevitrification of pronuclear(PN) zygotes through day3 cleavage stage embryosand blastocyst stage | Similar indications –same intended use |
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| Manufacturer | Kitazato BioPharma Co,Ltd. | Irvine Scientific SalesCo., Inc. | SignificantDifferences |
|---|---|---|---|
| Trade Name | Cryotop® Vitrificationand Thawing Kits | Vit Kit® - VitrificationFreeze Kit andVitrification Thaw Kit | |
| blastocyst stageembryos.The Cryotop® ThawingKit – Thawing isindicated for use in thepreparation andthawing of vitrifiedpronuclear (PN) zygotesthrough day 3 cleavagestage embryos andblastocyst stageembryos. | embryos.Vit Kit® - Thaw,Vitrification Thaw Kit forEmbryos (PN throughBlastocyst Stage) isintended for use in thethawing of pronuclear(PN) zygotes through day3 cleavage stage embryosand blastocyst stageembryos. | ||
| Components of Kit | Vitrification MediaThawing MediaCryotop35 mm dishRepro Plate | Freeze KitVitrification Thaw Kit | Different. During astandard procedure,users would obtainthese componentsseparately tocomplete theprocedure. Theseaccessories have beenincluded in this kit as aconvenience tocomplete theprocedure. Inclusionof these componentsdoes not represent adifferent question ofsafety andeffectiveness. |
| Embryo Stage | PN through Blastocyst | PN through Blastocyst | Same |
| Principal ofOperation | Provides users with theability to cryopreservesupernumerary embryoscreated during the invitro fertilization | Provides users with theability to cryopreservesupernumerary embryoscreated during the invitro fertilization | Same |
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| Manufacturer | Kitazato BioPharma Co,Ltd. | Irvine Scientific SalesCo., Inc. | SignificantDifferences |
|---|---|---|---|
| Trade Name | Cryotop® Vitrificationand Thawing Kits | Vit Kit® - VitrificationFreeze Kit andVitrification Thaw Kit | |
| procedure and then tore-warm them for use ata future point in time | procedure and then tore-warm them for use ata future point in time | ||
| VitrificationFormulation | Medium 199 (HEPESbuffered Medium) | Medium 199 (HEPESbuffered Medium) | Similar; the subjectdevice utilizestrehalose instead ofsucrose and HPCinstead of DSS in theformulation.However, differencesin these componentsdo not raise differentquestions of safetyand effectiveness(e.g., material safety,embryotoxicity, post-thaw survival, etc.). |
| Ethylene glycol | Ethylene glycol | ||
| DMSO | DMSO | ||
| Trehalose | Sucrose | ||
| Hydroxypropyl Cellulose(HPC) | Dextran SerumSupplement (DSS) | ||
| Gentamicin | Gentamicin | ||
| Vitrification Steps | 2 Step | 2 Step | Same |
| Vitrification MediaComponent | Equilibration Solution(ES) 1.5mL x 1 Vial | Equilibration Solution(ES) 1.0mL x 1 Vial | Similar |
| Vitrification Solution(VS) 1.5mL x 2 Vials | Vitrification Solution (VS)1.0mL x 2 Vials | ||
| ThawingFormulation | Medium 199 (HEPESbuffered Medium) | Medium 199 (HEPESbuffered Medium) | Similar; the subjectdevice utilizestrehalose instead ofsucrose and HPCinstead of DSS in theformulation.However, differencesin these componentsdo not raise differentquestions of safetyand effectiveness |
| Hydroxypropyl Cellulose(HPC) (v/v) | Dextran SerumSupplement (DSS) (v/v) | ||
| Gentamicin | Gentamicin | ||
| Trehalose | Sucrose |
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| Manufacturer | Kitazato BioPharma Co,Ltd. | Irvine Scientific SalesCo., Inc. | SignificantDifferences |
|---|---|---|---|
| Trade Name | Cryotop® Vitrificationand Thawing Kits | Vit Kit® - VitrificationFreeze Kit andVitrification Thaw Kit | |
| (e.g., material safety,embryotoxicity, post-thaw survival, etc.). | |||
| Thawing Steps | 3 Step | 3 Step | Same |
| Thawing MediaComponent | Thawing Solution (TS)4.0mL x 2 Vials | Thawing Solution (TS)1.0mL x 4 Vials | Similar |
| Diluent Solution (DS)4.0mL x 1 Vial | Diluent Solution (DS)1.0mL x 1 Vial | ||
| Washing Solution (WS)4.0mL x 1 Vial | Washing Solution (WS)2.0mL x 1 Vial | ||
| Carton Packaging | Each solution iscontained in plasticvials. Vials are packed ina card board outer boxwith partition. | Each solution iscontained in plastic vials.Vials are packed in a cardboard outer box withpartition. | Same |
| CryopreservationStorage Device UsedWith | Kitazato BioPharma,Cryotop®CL - K112695Cryotop®SC - K140072Cryotop®US - K153027 | None are provided withthe kit | Different. During astandard procedure,users would obtaincleared storagedevices separately tocomplete theprocedure. Storagedevices have beenincluded in this kit as aconvenience tocomplete theprocedure. Inclusionof storage devicesdoes not represent adifferent question ofsafety andeffectiveness. |
| Sterile | Solutions sterilized usingaseptic processing | Solutions sterilized usingaseptic processing | Same |
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| Manufacturer | Kitazato BioPharma Co,Ltd. | Irvine Scientific SalesCo., Inc. | SignificantDifferences |
|---|---|---|---|
| Trade Name | Cryotop® Vitrificationand Thawing Kits | Vit Kit® - VitrificationFreeze Kit andVitrification Thaw Kit | |
| techniques throughfiltration.Vials, vitrificationstorage device, 35 mmdish, and Repro Plateare sterilized viaradiation. | techniques throughfiltration.Vial containers aresterilized via radiation. | ||
| Endotoxin | Passes | Passes | Same |
| Mouse EmbryoAssay | >80% blastocyst at 96hours (one-cell MEA) | >80% blastocyst at 96hours (one-cell MEA) | Same |
| Sterility Testing | Passes | Passes | Same |
| pH Test | 7.20 - 7.60 | Not available | n/a |
| Osmolarity | ES: 2,300 - 2,800VS: 4,900 - 6,000TS: 1,600 - 2,000DS: 830 - 1020WS: 240 - 300 | Not available | n/a |
| Storage | 2 – 8°C | 2 – 8°C | Same |
| Shelf Life | 6 months | 1 year | Different; the subjectdevice has a shortershelf life period. Theshorter shelf-life doesnot raise differentquestions of safety oreffectiveness. |
9. Non-Clinical Performance Data
The Cryotop® Vitrification Kit, Cryotop® Thawing Kit, Repro Plate, and 35 mm dish passed all applicable testing in accordance with internal requirements and applicable standards that are shown below to support substantial equivalence of the subject device:
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- Cleanliness and appearance: Free of turbidity and sedimentation ●
- pH Testing: Average pH reading is from 7.2 – 7.6 passing
- . Endotoxin Testing: Endotoxin values conform to the value <0.25 EU/mL
- . Osmolality Testing: Passes specification for each solution
- Sterility Testing: No microbial growth from sterility testing
- . Mouse Embryo Assay: ≥80% of 1-cell control embryos develop at 96 hours
- . Package integrity testing
10. Clinical Performance Data
The clinical information presented provides published papers that specifically identify the use of the Cryotop® and Vitrification/Thawing media with HPC as the vitrification method used for the cryopreservation of embryos and blastocysts from female subjects. A summary of the results are shown below:
- Literature 1: results of the study shows clinical pregnancies of 42% from total transfer number and live births of 30% from total transfer number1
- . Literature 2: results of the study shows clinical pregnancies of 59% from number of cycles and ongoing pregnancies of 48% from number of cycles2
- . Literature 3: results of the study shows clinical pregnancies of 49% from number of cycles and ongoing pregnancies of 46% from number of cycles3
The birth rates of vitrified embryo/blastocyst transfer as compared to fresh embryo/blastocyst transfer described in the literature are comparable. Each of the studies reported survival rates of embryos that are consistent with normal ART procedures using similar IVF treatments and cryopreservation techniques.
11. Statement of Substantial Equivalence
The results of the performance testing described above demonstrates that the Cryotop® Vitrification Kit and Cryotop® Thawing Kit are as safe and effective as the predicate device and supports a determination of substantial equivalence.
Kato, K. Takehara, Y. Tomoya, S., Kawachiya, S. Okuno, T. Kobayashi, T. Bodri, D. "Minimal ovarian stimulation combind with elective single embryo transfer policy: age-specific results of a large, single-center, Japanese cohort." Reproductive Biology and Endocrinology 2012, 10:35
´ Ku, P. Lee, R.K. Lin, S. Lin, M. Hwu, Y. "Comparison of the clinical outcomes between fresh blastocyst and vitrified-thawed blastocyst transfer." J Assist Reprod Genet 2012. 29:1353-56
3 Inoue, F., Yelian, F.. "Efficiency of a Closed Vitrification System with Oocytes and Blastocysts." Low Temperature Medicine 2014. 40/3:53-59
§ 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). The device, when it is phosphate-buffered saline used for washing, and short-term handling and manipulation of gametes and embryos; culture oil used as an overlay for culture media containing gametes and embryos; and water for assisted reproduction applications, is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 884.9.