"Medi-Cult Sperm Freeze Medium" is composed from a modified Tyrodes Solution that has been Hepes buffered. The cryoprotective is Glycerol (15% v/v) and its cryoprotective properties have been enhanced by the addition of Assisted Reproduction Technique Supplement (ARTS) and human serum albumin.

AI/ML Overview

The provided text describes the "Medi-Cult Sperm Freeze Medium" and its performance compared to a predicate device, TEST-Yolk buffer (TYB). Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state quantitative acceptance criteria in a formal table with pass/fail values. Instead, it aims to demonstrate that its performance is not significantly different or is superior to the predicate device, TEST-Yolk buffer (TYB).

Performance Metric	Predicate Device (TYB) Performance (Mean ± SE)	Medi-Cult SFM Performance (Mean ± SE)	Comparison/Acceptance Status
Sperm Survival Study (University of Rochester)
Motility (%)	19.1 (1.0)	20.6 (2.4)	No significant difference reported
Viability (%)	49.6 (1.7)	40.7 (4.2)	No significant difference reported
Normal Cells (%)	49.3 (5.5)	53.8 (5.1)	No significant difference reported
VSL (straight line velocity)	29.7 (1.6)	31.5 (1.5)	No significant difference reported
Hemi-Zona Assay (HZA) (The Jones Institute)
HZA Binding	103.9 ± 6.0	149.0 ± 10.4*	Significantly higher in SFM (p < 0.0001)
Motility	N/A (compared indirectly)	N/A (compared indirectly)	No differences found (compared to TYB)
Velocity (VSL, VCL)	N/A (compared indirectly)	N/A (compared indirectly)	No differences found (compared to TYB)
Beat Amplitude (ALH)	N/A (compared indirectly)	N/A (compared indirectly)	No differences found (compared to TYB)
Frequency (BCF)	N/A (compared indirectly)	N/A (compared indirectly)	No differences found (compared to TYB)
Linearity (LIN)	N/A (compared indirectly)	N/A (compared indirectly)	No differences found (compared to TYB)
Hyperactivation (HA)	N/A (compared indirectly)	N/A (compared indirectly)	No differences found (compared to TYB)

Note: The acceptance criteria are implicitly that the device performs at least as well as, or better than, the predicate device in relevant sperm viability and functional assays.

2. Sample Sizes used for the Test Set and Data Provenance:

The document provides summary statistics (means and standard errors), but the exact sample sizes (number of patients or sperm samples) used in either study are not explicitly stated.

Data Provenance:
- Sperm Survival Study: Rochester Regional Cryobank and Andrology Laboratory, University of Rochester Medical Center, Rochester, NY, USA. (Prospective, comparing the two media on fresh semen samples).
- Hemi-Zona Assay: The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, USA. (Prospective, comparing the ability of sperm frozen in the two media to bind to isolated zona pellucidae).

3. Number of Experts used to establish the Ground Truth for the Test Set and their Qualifications:

Sperm Survival Study: The study was conducted at a "Cryobank and Andrology Laboratory." The assessment of motility, viability, and normal cells would typically involve trained technicians or scientists using established methodologies (e.g., CASA for motility, manual counts for viability/morphology). The document does not specify the number or qualifications of these "experts," but it implies standard laboratory practice.
Hemi-Zona Assay: Dr. Mary Mahoney at The Jones Institute for Reproductive Medicine. Dr. Mahoney is identified as the evaluator, implying an expert in reproductive medicine or embryology. Her specific qualifications (e.g., number of years of experience, specific certifications) are not detailed.

4. Adjudication Method for the Test Set:

Not applicable. This is a scientific study comparing two products, not a diagnostic device where adjudication of interpretations against a ground truth is typically required. The results are quantitative measurements.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done and its effect size:

No, an MRMC comparative effectiveness study was not conducted. This type of study is relevant for diagnostic devices where human readers interpret medical images or data, and an AI system might assist them. The product here is a cryopreservation medium, and the studies involve direct measurement of sperm parameters and function, not reader interpretation.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done:

Not applicable. The product is a cryopreservation medium, not an algorithm or AI device. The studies directly measure the biological impact of the medium on sperm.

7. The Type of Ground Truth Used:

Sperm Survival Study: The "ground truth" is the measured biological parameters of sperm (motility, viability, morphology, velocity) determined using established laboratory methods. This is equivalent to laboratory assay results. The fresh semen served as a baseline control, and the comparison was between the two freezing media.
Hemi-Zona Assay: The "ground truth" is the measured ability of sperm to bind to isolated zona pellucidae, which is a functional assessment critical for fertilization. This is also laboratory assay results or functional outcome data in a controlled invitro setting.

8. The Sample Size for the Training Set:

Not applicable. This is a cryopreservation medium, not a machine learning algorithm that requires a "training set." The product's formulation is based on "data published in peer reviewed international journals by internationally recognised scientists in the field," which acts as a form of scientific basis or "prior knowledge" rather than a computational training set.

9. How the Ground Truth for the Training Set was Established:

Not applicable, as there is no "training set" in the context of an AI/ML device. The ground truth for the scientific basis of the formulation would be derived from decades of reproductive biology research and established scientific methodologies for assessing media components and sperm cryopreservation success.

Summary

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510(k) Summary Summary of Safety and Effectiveness Information FEB 2 8 2000 Supporting a Substantially Equivalent Determination (K991333)

The product

"Medi-Cult Sperm Freeze Medium" Cat.No. 1067 -

Indications for use:

"Medi-Cult Sperm Freeze Medium" is intended for the cryopreservation of human spermatozoa and tissue from testicular biopsies.

The product formulation:

Modified Tyrodes with HEPES buffer containing sucrose, glucose and sodium lactate Assisted Reproduction Technique Supplement, (ARTS) Glycerol Human Serum Albumin (HSA) Penicillin Streptomycin

The product testing control contents:

Bioburden, production-test
-Integrity filter testing, production-test
Sterility, QC-test .
pH, QC-test
Endotoxin, QC-test ・
-Sperm Survival, QC-test

The culture media from Medi-Cult have been used by many European IVF-units since the end of the 1980's. (Produced and distributed by GEA-Biotech 1987 to 1989 and by Medi-Cult a/s from 1989). The Medi-Cult media were at that time introduced as a replacement for in-house prepared culture media.

The Medi-Cult products for cryopreservation is in general formulated according to data published in peer reviewed international iournals by internationally recognised scientists in the field.

Medi-Cult has recently introduced a medium for the crypreservation of human spermatozooa. Medi-Cult Sperm Freezing Medium (SFM) is composed from a modified Tyrodes Solution that has been Hepes buffered. The cryoprotective is Glycerol (15% v/v) and its crypprotective properties have been enhanced by the addition of Assisted Reproduction Technique Supplement (ARTS) and human serum albumin.

The product contains small amounts of potentially hazardous Human Serum Albumin, which has been obtained from a U.S licensed source (U.S license No.140). It origins from larger pools of screened healthy donors, tested negative for HBbsAg, Anti-HCV, anti HIV-1/2. Levels of ALT (GPT) in the plasma are determined and donations are rejected if the values found are above the upper limit of the specifications. Donors of the source material have been screened for CJD.

At the Rochester Regional Cryobank and Andrology Laboratory, University of Rochester Medical center, Rochester, NY, the Medi-Cult Sperm Freezing medium have been compared with TEST-Yolk buffer (TYB, Irvine Scientific, Irvine CA). The following results were obtained:

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	Motility %	Viability %	Normal cells %	VSL*
Fresh semen	61.1(3.6)		50.0 (6.1)	43.1 (3.1)
SFM**	20.6(2.4)	40.7(4.2)	53.8(5.1)	31.5(1.5)
TYB ***	19.1 (1.0)	49.6(1.7)	49.3(5.5)	29.7(1.6)

*VSL: straight line velocity

**SFM: Sperm Freezing Medium from Medi-Cult

***TYB: TEST-Yolk buffer from Irvine Scientific

No differences between sperm frozen with SFM or with TYB were found in this study.

Binding of the spermatozoa to the zona pellucida (ZP) is a necessary step in fertilisation both in vivo and in vitro (IVF). Freezing/thawing might have a detrimental effect on the receptors on the surface of sperm cells and thus impair binding to the zona pellucida. Dr Mary Mahonev at The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, USA, have evaluated the ability of frozen/thawed spermatozoa to bind to isolated zona pellucidae using the "hemi-zona assay". Sperm frozen and thawed in Medi-Cult Sperm Freezing medium and in TEST-Yolk buffer form Irvine Scientific was compared.

Table 1. Hemi-zona assay (HZA) after freezing/thawing in Sperm Freezing Medium from Medi-Cult (SFM) or TEST-Yolk buffer from Irvine Scientific (Test-Yolk)

HZA binding in TEST-Yolk	HZA Binding in SFM	HZA-SFM/HZA-TEST-yolk %
Mean ± SE	Mean ± SE	Mean ± SE
103.9 ± 6.0	149.0 ± 10.4*	152.3 ± 10.2

*Significantly higher than in Test-Yolk buffer p< 0.0001

Dr. Mahoney also compared other parameters such as motility, velocity (+VSL and VCL) beat amplitude (ALH) and frequency (BCF), linearity (LIN) and hyperactivation (HA) and found no differences between sperm frozen in SFM or in TEST-Yolk buffer.

There have been no registered complaints on the product and there is no evidence in the last 1.5 year that the product has been the cause of any serious adverse events in connection with its intended use.

Thus based on the Federal Register Notice (Final Rule, Vol. 63, No. 175, page 48429, September 10, 1998), "Obstetric and Gynecologic Devices; Reclassification and Classification of Medical Devices Used for In-Vitro Fertilization and Related Reproduction Procedures" effective on October 13, 1998 and the supportive clinical data we feel that the safety and effectiveness of the product for its intended use is shown in the present submission.

Prepared and Submitted by:

Rice Wickey-Lermaid for feruary 18, 2018
Ronald G. Leonardi, Ph. D.
Date

President R & R Registrations P.O. Box 262069 San Diego CA 92196 858-586-0751

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Public Health Service

Rockville MD 20850

Food and Drug Administration 9200 Corporate Boulevard

Image /page/2/Picture/2 description: The image shows the logo for the Department of Health & Human Services - USA. The logo is circular and contains the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. In the center of the circle is an abstract image of an eagle.

FEB 28 2000

Medi-Cult A/S c/o Ronald G. Leonardi, Ph.D. President R & R Registrations P.O. Box 262069 San Diego, CA 92196

Re: K991333

Medi-Cult Sperm Freeze Medium Dated: December 14, 1999 Received: December 15, 1999 Regulatory Class: II 21 CFR 884.6180/Procode: 85 MQL

Dear Dr. Leonardi:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we 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). 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.

If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Requiations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for vour device and thus. permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diacnostic devices), please contact the Office of Compliance at (301) 594-4591. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsma/dsmamain.html".

Sincerely yours,

Daniel G. Schultz, M.D.

Captain, USPHS Acting Director, Division of Reproductive, Abdominal, and Radiological Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure(s)

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K991333 510(k) Number (if known):

Device Name: MEDI-CULT SPERM FREEZING MEDIUM (SFM)

Indications for Use:

For the cryopreservation of human spermatozoa and tissue from testicular biopsies.

(PLEASE DO NO WRITE BELOW THIS LINE – CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use
(Per 21 CFR 801.109)
OR
Over-The-Counter Use __

(Optional Format 1-2-96)

(Division Sign-Off)
Division of Reproductive, Abdominal, ENT,
and Radiological Devices
510(k) Number K991333

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.