Cumulus Remover is an enzyme solution containing recombinant human hyaluronidase that digests hyaluronic acid that binds the cumulus and corona cells surrounding oocytes together. This function of hyaluronidase can be used for denuding cumulus and coronal cells from oocytes prior to performing Intracytoplasmic Sperm Injection (ICSI) fertilization procedures. Cumulus Remover is provided in a polypropylene vial (package size 0.5 mL), and five vials are packaged together in a box. This product is aseptically processed and has a shelf-life of six months when stored at 2-8°C. Cumulus Remover is tested for pH, osmolality, endotoxin, sterility, embryotoxicity, and hyaluronidase activity before lot release.

AI/ML Overview

The provided text describes the "Cumulus Remover," a hyaluronidase solution used for removing cumulus complex and corona radiata from oocytes in preparation for ICSI. Here's a breakdown of the acceptance criteria and the study details:

1. Table of Acceptance Criteria and Reported Device Performance

Test	Acceptance Criteria	Reported Device Performance
pH	7.2-7.6	7.2-7.6 (specified as falling within this range)
Osmolality	270-295 mOsm	270-295 mOsm (specified as falling within this range)
Sterility	No microbial growth (per USP <71>)	No microbial growth
Endotoxin	<0.25 EU/ml (per USP <85>)	<0.25 EU/ml
Mouse Embryo Assay (MEA)	≥80% of embryos expand to blastocyst stage by 96h	Met (implied by statement "in comparison with the control group" and overall conclusion of substantial equivalence)
Hyaluronidase Activity	70-90 units/ml (per Japanese Pharmacopoeia, JP17)	70-90 units/ml (average 80 units/ml)
Shelf-life	All above specifications met at time zero and 6 months	Met (implied by statement that testing was conducted)

2. Sample Size Used for the Test Set and Data Provenance

pH, Osmolality, Sterility, Endotoxin, Hyaluronidase activity: The sample sizes for these tests are not explicitly stated in terms of number of batches or individual samples. However, the tests are conducted as part of lot release, suggesting a representative sample from each manufactured lot.
Mouse Embryo Assay (MEA): The sample size for embryos used in the MEA is not specified.
Data Provenance: The document does not explicitly state the country of origin for the data or whether it was retrospective or prospective. Given that the manufacturer is Kitazato Corporation in Japan, it's likely the studies were conducted there. The studies appear to be prospective, laboratory-based tests conducted on the manufactured product.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

This type of information is generally not applicable to the non-clinical performance tests described for this device (pH, sterility, MEA, etc.). These are objective, laboratory-measured parameters, not subject to expert interpretation for ground truth establishment.

4. Adjudication Method for the Test Set

Not applicable. The tests are objective laboratory measurements, not assessments requiring adjudication.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done

No, a Multi Reader Multi Case (MRMC) comparative effectiveness study was not performed. This type of study is typically relevant for interpretative diagnostic devices where human reader performance is a key metric.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Yes, the studies described are standalone performance evaluations of the device itself (the Cumulus Remover solution) in controlled laboratory settings, independent of human interaction within a clinical workflow.

7. The Type of Ground Truth Used

The "ground truth" for each specific test is defined by established scientific and regulatory standards:

pH: Measured directly against a standard scale.
Osmolality: Measured directly against a standard scale.
Sterility: Absence of microbial growth, determined by standard microbiological culture methods.
Endotoxin: Concentration of endotoxins, determined by standard LIMULUS Amebocyte Lysate (LAL) assay.
Mouse Embryo Assay (MEA): The ability of mouse embryos to develop to the expanded blastocyst stage, which is a biological outcome observed and assessed without subjective expert consensus regarding "ground truth" per se, but rather against a predefined biological benchmark.
Hyaluronidase Activity: Measured directly against a standard activity unit, per Japanese Pharmacopoeia, JP17.

8. The Sample Size for the Training Set

Not applicable. This device is a chemical solution assessed through laboratory performance tests, not an AI/ML algorithm that requires a training set of data.

9. How the Ground Truth for the Training Set Was Established

Not applicable, as there is no training set for this device.

Summary

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October 23, 2018

Kitazato Corporation % Audrey Swearingen Manager. Regulatory Affairs Emergo Global Consulting, LLC 2500 Bee Cave Road Building 1, Suite 300 Austin, TX 78746

Re: K182002

Trade/Device Name: Cumulus Remover Regulation Number: 21 CFR 884.6180 Regulation Name: Reproductive media and supplements Regulatory Class: Class II Product Code: MQL Dated: July 25, 2018 Received: July 26, 2018

Dear Audrey Swearingen:

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. Although this letter refers to your product as a device, please be avare that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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.

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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. 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 of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions 531-542 of the Act); 21 CFR 1000-1050.

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 comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely.

Michael T. Bailey -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) K182002

Device Name Cumulus Remover

Indications for Use (Describe)

Cumulus Remover is for the removal of the cumulus complex and corona radiata surrounding the oocyte in preparation for ICSI.

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 Cumulus Remover K182002

1. Submission Sponsor

Kitazato Corporation 81 Fuji Shizuoka 416-0907 JAPAN Phone number: +(81) 545-66-2202 Contact: Mr. 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: Audrey Swearingen, RAC Title: Director, Regulatory Affairs

3. Date Prepared

October 23, 2018

4. Device Identification

Trade name:	Cumulus Remover
Common name:	Hyaluronidase Solution
Regulation name:	Reproductive Media and Supplements
Regulation number:	21 CFR 884.6180
Product code:	MQL (Media, Reproductive)
Regulatory class:	II

5. Predicate Device

ICSI Cumulase (K081639) manufactured by MediCult a/s. This predicate device is now branded by Origio a/s and has not been subject to any design related recalls.

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6. Device Description

7. Indication for Use

Cumulus Remover is for the removal of the cumulus complex and corona radiata surrounding the oocyte in preparation for ICSI.

Device	K182002 (subject device)	K081639 (predicate device)
Indications for Use	Cumulus Remover is for the removal ofthe cumulus complex and corona radiatasurrounding the oocyte in preparationfor ICSI.	ICSI Cumulase is for the removal ofcumulus complex and corona radiatasurrounding the oocyte in preparationfor ICSI.
pH	7.2-7.6	Information is not available
Osmolality	270-295 mOsm	Information is not available
Hyaluronidase activity	70-90 units/ml (average 80 units/ml)	40-120 units/ml (average 80 units/ml)
Formulation	Physiological salts	Physiological salts
	Energy substance	Energy substance
	Buffering substance (HEPES)	Buffering substance (HEPES)
	Recombinant human hyaluronidase	Recombinant human hyaluronidase
	Human albumin	Human albumin
	Gentamicin
	Dextran

8. Substantial Equivalence Discussion

The subject and predicate devices have the same indications for use/intended use; however, there are differences in technological characteristics. Although the subject and predicate devices possess different ranges of hyaluronidase activity, the activity range of the subject device falls within the activity range of the predicate and both devices have the same average hyaluronidase activity (80 units/ml). Regarding formulation, the subject and predicate devices have the same or comparable salts, energy substance, and buffering agents. The subject device is different from the predicate device in that it contains gentamicin and dextran. These differences in formulation do not raise different questions of safety and effectiveness. In addition, the pH and osmolality values for the predicate device are not known; however, differences in pH and osmolality are common in assisted reproduction media products and do not raise different questions of safety and effectiveness. Also, the subject device pH and osmolality ranges are comparable to other assisted reproduction media products.

9. Summary of Non-Clinical Performance Testing

The following studies have been performed to support substantial equivalence to the predicate devices:

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pH testing per USP <791> See table above .
Osmolality per USP <785> See table above .
Aseptic Processing Validation per ISO 13408-1:2015 and ISO 13408-2:2003 .
Sterility testing per USP <71> No microbial growth .
. Endotoxin testing per USP <85> - <0.25 EU/ml
Mouse embryo assay (MEA) .

One-cell mouse embryos were exposed to subject devices and cultured at 37°C in an atmosphere containing 5% CO2. The percent of embryos developed to the expanded blastocyst stage within 96 hours were assessed in comparison with the control group. The acceptance specification is that ≥80% of embryos expand to the blastocyst stage by 96h.

. Hyaluronidase activity - 70-90 units/ml (per Japanese Pharmacopoeia, JP17)
Shelf-life testing was conducted to ensure that the following product specifications are met at time . zero and end of shelf-life (six months).
- - pH
- - Osmolality
- - 1-cell MEA
- - Endotoxin
- - Sterility
- - Hyaluronidase activity

10. Conclusion

The subject and predicate devices have the same intended use and comparable technological characteristics. The differences in technological characteristics between the subject and predicate devices do not raise different questions of safety and effectiveness. The performance data demonstrate that the subject device is substantially equivalent to the predicate device.

Regulation Number and Section

§ 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.