HRSpheres Narrow-Size Embolic Microspheres

K210562 · Suzhou Hengrui Hongyuan Medical Co., Ltd. · KRD · Oct 1, 2021 · Cardiovascular

Device Facts

• Record ID: K210562
• Device Name: HRSpheres Narrow-Size Embolic Microspheres
• Applicant: Suzhou Hengrui Hongyuan Medical Co., Ltd.
• Product Code: KRD · Cardiovascular
• Decision Date: Oct 1, 2021
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 870.3300
• Device Class: Class 2
• Attributes: Therapeutic

Intended Use

HRSpheres Narrow-Size Embolic Microspheres are intended to be used for the embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids.

Device Story

HRSpheres are compressible, non-resorbable hydrogel microspheres derived from polyvinyl alcohol (PVA). They are supplied in 0.9% sodium chloride solution within sterile glass vials. During clinical procedures, the microspheres are mixed with non-ionic contrast media to form a suspension, then delivered via microcatheter (1.7–4 Fr) under fluoroscopic guidance. By blocking blood supply to target hypervascular tumors or AVMs, the device induces nutrient deprivation, causing the target tissue to shrink. The device is intended for use by physicians in clinical settings. Blue-dyed variants aid visualization in the delivery syringe. The device provides a mechanical embolization effect; it does not incorporate active electronic components or software algorithms.

Clinical Evidence

No human clinical data provided. Safety and effectiveness supported by in-vitro bench testing (compressibility, size, deliverability, sterility, endotoxins) and a prospective animal study. Animal study used 15 female swine (7 test, 8 control) for partial renal artery embolization. Endpoints included recanalization, foreign body reaction, deliverability, and vessel integrity at 3, 8, and 29 days. Results showed no significant differences between HRSpheres and predicate (K173871).

Technological Characteristics

Hydrogel microspheres composed of PVA, N-acryloylaminoacetaldehyde dimethyl acetal, and 2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt. Sizes: 70-1,200µm. Compressibility: 50% by diameter. Sterilization: Moist heat (121°C, 30 min) per ANSI/AAMI/ISO 17665-1. Packaging: Borosilicate glass vials. Shelf life: 3 years per ASTM F1980-16. Non-resorbable. Standalone mechanical device.

Indications for Use

Indicated for embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids, in patients requiring vascular embolization.

Regulatory Classification

Identification

A vascular embolization device is an intravascular implant intended to control hemorrhaging due to aneurysms, certain types of tumors (e.g., nephroma, hepatoma, uterine fibroids), and arteriovenous malformations. This does not include cyanoacrylates and other embolic agents, which act by polymerization or precipitation. Embolization devices used in neurovascular applications are also not included in this classification, see § 882.5950 of this chapter.

Special Controls

*Classification.* Class II (special controls.) The special control for this device is the FDA guidance document entitled “Class II Special Controls Guidance Document: Vascular and Neurovascular Embolization Devices.” For availability of this guidance document, see § 870.1(e).

Predicate Devices

• CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres (K173871)

Submission Summary (Full Text)

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October 1, 2021

Suzhou Hengrui Hongyuan Medical Co., Ltd. Qianqian Zhang Regulatory Affairs Engineer Building B9 Unit 201, No. 218 Xinghu Road, SIP Suzhou, Jiangsu 215123 China

Re: K210562

> Trade/Device Name: HRSpheres Narrow-Size Embolic Microspheres Regulation Number: 21 CFR§ 870.3300 Regulation Name: Vascular embolization device Regulatory Class: II Product Code: KRD, NAJ Dated: September 8, 2021 Received: September 16, 2021

Dear Qianqian Zhang:

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 aware 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.

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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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 801and Part 809); 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/combination-products/guidance-regulatoryinformation/postmarketing-safety-reporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) 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 (Sections 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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). 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 (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email ([e-mail]) or phone [phone] or 301-796-7100).

Sincerely,

Jason R. Roberts, Ph.D. Assistant Director DHT3B: Division of Reproductive. Gynecology and Urology Devices OHT3: Office of GastroRenal, ObGyn, General Hospital and Urology Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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## Indications for Use

510(k) Number (if known) K210562

Device Name

HRSpheres Narrow-Size Embolic Microspheres

Indications for Use (Describe)

HRSpheres Narrow-Size Embolic Microspheres are intended to be used for the embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids.

| 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

HRSpheres Narrow-Size Embolic Microspheres (per 21 CFR 807.92)

## 1. Submitter

| Submitter Name: | Suzhou Hengrui Hongyuan Medical Co., Ltd |
|-----------------|----------------------------------------------------------------------------------|
| Address: | Building B9 Unit 201, No. 218 Xinghu Road, SIP, Suzhou,<br>Jiangsu, China 215123 |
| Phone: | [phone] |
| Contact Person: | Qianqian Zhang |
| Email: | [e-mail] |

September 30, 2021

# 2. Subject Device

Date Prepared:

| Device Name: | HRSpheres Narrow-Size Embolic Microspheres |
|-----------------------|-----------------------------------------------------------------------------------------------------------------|
| Common or Usual Name: | Polyvinyl Alcohol Embolic Microspheres |
| Classification Name: | Vascular Embolization Device (21 CFR 870.3300) |
| Regulatory Class: | Class II |
| Product Code: | KRD (device, vascular, for promoting embolization),<br>NAJ (agents, embolic, for treatment of uterine fibroids) |

## 3. Predicate Device

| Device Name: | CalliSpheres Embolic Microspheres, 8Spheres |
|--------------------|---------------------------------------------|
| | Embolic Microspheres |
| 510(k) number: | K173871 |
| Manufacturer: | Suzhou Hengrui Callisyn Biomedical Co., Ltd |
| Regulation Number: | 21 CFR 870.3300 |
| Product Code: | KRD, NAJ |

The predicate device has not been subject to any design-related recall.

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## 4. Device Description

HRSpheres Narrow-Size Embolic Microspheres are compressible hydrogel microspheres with a regular shape, smooth surface, and calibrated size, which are formed as a result of chemical modification on polyvinyl alcohol (PVA) materials. HRSpheres Narrow-Size Embolic Microspheres consist of a macromer derived from PVA, and are hydrophilic, non-resorbable, and are available in a variety of diameters ranging from 70 - 1,200 um. The preservation solution is 0.9% sodium chloride solution. The water content of a fully polymerized microsphere is 91% ~ 94%. Microspheres are compressible to enable smooth delivery through the indicated delivery catheter. The HRSpheres are available in dyed (blue) and clear (undyed with natural color). Blue-dyed microspheres aid in the visualization of the microspheres in the delivery syringe. HRSpheres Narrow-Size Embolic Microspheres are packaged in sterile sealed glass vials for single use only and available with 1 mL, 2 mL, or 3 mL microspheres volumes per vial.

HRSpheres Narrow-Size Embolic Microspheres can be delivered to a targeted area through typical microcatheters in the 1.7 – 4 Fr range. By blocking the blood supply to the target area, the tumor or malformation is starved of nutrients and shrinks in size. At the time of use. HRSpheres Narrow-Size Embolic Microspheres are mixed with a nonionic contrast agent to form a suspension solution and aid in visualization during a procedure. The device configurations are described in Table 1. Product codes beginning with "B" represent microspheres with blue dye (Reactive Blue #4) and codes beginning with "C" represent undyed microspheres. Among the various size ranges of HRSpheres Narrow-Size Embolic Microspheres, the sizes that can be used for uterine fibroid embolization are 500 um, 700um, 900 um, 1200 um.

| | | | | Indication | |
|-----------------|-------------------------|--------------------|-------------------------------------------------------------------------------------------|-------------------------------------------------------------|--------------------|
| Product<br>Code | Calibrated<br>size (µm) | Size Range<br>(µm) | Quantity | Hypervascular<br>Tumors /<br>Arteriovenous<br>Malformations | Uterine<br>Fibroid |
| B107S007 | 70 | 70-100 | 1 mL microspheres: 7 mL<br>0.9% sodium chloride solution | Yes | No |
| B207S007 | | | 2 mL microspheres: 7 mL<br>0.9% sodium chloride solution | | |
| B306S007 | | | 3 mL microspheres: 6 mL<br>0.9% sodium chloride solution | | |
| B107S010 | 100 | 75-125 | 1 mL microspheres: 7 mL<br>0.9% sodium chloride solution | Yes | No |
| Product<br>Code | Calibrated<br>size (µm) | Size Range<br>(µm) | Quantity | Indication | |
| | | | | Hypervascular<br>Tumors /<br>Arteriovenous<br>Malformations | Uterine<br>Fibroid |
| B207S010 | | | 0.9% sodium chloride solution<br>2 mL microspheres: 7 mL | | |
| B306S007 | | | 0.9% sodium chloride solution<br>3 mL microspheres: 6 mL | | |
| B107S025 | | | 0.9% sodium chloride solution<br>1 mL microspheres: 7 mL | | |
| B207S025 | 250 | 200-300 | 0.9% sodium chloride solution<br>2 mL microspheres: 7 mL | Yes | No |
| B306S025 | | | 0.9% sodium chloride solution<br>3 mL microspheres: 6 mL | | |
| B107S040 | | | 0.9% sodium chloride solution<br>1 mL microspheres: 7 mL | | |
| B207S040 | 400 | 350-450 | 0.9% sodium chloride solution<br>2 mL microspheres: 7 mL | Yes | No |
| B306S040 | | | 0.9% sodium chloride solution<br>3 mL microspheres: 6 mL | | |
| B107S050 | | | 0.9% sodium chloride solution<br>1 mL microspheres: 7 mL | | |
| B207S050 | 500 | 480-580 | 0.9% sodium chloride solution<br>2 mL microspheres: 7 mL | Yes | Yes |
| B306S050 | | | 0.9% sodium chloride solution<br>3 mL microspheres: 6 mL | | |
| B107S070 | | | 0.9% sodium chloride solution<br>1 mL microspheres: 7 mL | | |
| B207S070 | 700 | 650-750 | 0.9% sodium chloride solution<br>2 mL microspheres: 7 mL | Yes | Yes |
| B306S070 | | | 0.9% sodium chloride solution<br>3 mL microspheres: 6 mL | | |
| B107S090 | | | 0.9% sodium chloride solution<br>1 mL microspheres: 7 mL | | |
| B207S090 | 900 | 825-975 | 0.9% sodium chloride solution<br>2 mL microspheres: 7 mL | Yes | Yes |
| B306S090 | | | 0.9% sodium chloride solution<br>3 mL microspheres: 6 mL | | |
| B107S120 | 1,200 | 1,000-<br>1,200 | 0.9% sodium chloride solution<br>1 mL microspheres: 7 mL | Yes | Yes |
| B207S120 | | | 2 mL microspheres: 7 mL | | |
| Product<br>Code | Calibrated<br>size (µm) | Size Range<br>(μm) | Quantity | Indication | |
| | | | | Hypervascular<br>Tumors /<br>Arteriovenous<br>Malformations | Uterine<br>Fibroid |
| B306S120 | | | 0.9% sodium chloride solution<br>3 mL microspheres: 6 mL<br>0.9% sodium chloride solution | | |
| C107S007 | | | 1 mL microspheres: 7 mL<br>0.9% sodium chloride solution | | |
| C207S007 | 70 | 70-100 | 2 mL microspheres: 7 mL<br>0.9% sodium chloride solution | Yes | No |
| C306S010 | | | 3 mL microspheres: 6 mL<br>0.9% sodium chloride solution | | |
| C107S010 | | | 1 mL microspheres: 7 mL<br>0.9% sodium chloride solution | | |
| C207S010 | 100 | 75-125 | 2 mL microspheres: 7 mL<br>0.9% sodium chloride solution | Yes | No |
| C306S010 | | | 3 mL microspheres: 6 mL<br>0.9% sodium chloride solution | | |
| C107S025 | | | 1 mL microspheres: 7 mL<br>0.9% sodium chloride solution | | |
| C207S025 | 250 | 200-300 | 2 mL microspheres: 7 mL<br>0.9% sodium chloride solution | Yes | No |
| C306S025 | | | 3 mL microspheres: 6 mL<br>0.9% sodium chloride solution | | |
| C107S040 | | | 1 mL microspheres: 7 mL<br>0.9% sodium chloride solution | | |
| C207S040 | 400 | 350-450 | 2 mL microspheres: 7 mL<br>0.9% sodium chloride solution | Yes | No |
| C306S040 | | | 3 mL microspheres: 6 mL<br>0.9% sodium chloride solution | | |
| C107S050 | | | 1 mL microspheres: 7 mL<br>0.9% sodium chloride solution | | |
| C207S050 | 500 | 480-580 | 2 mL microspheres: 7 mL<br>0.9% sodium chloride solution | Yes | Yes |
| C306S050 | | | 3 mL microspheres: 6 mL<br>0.9% sodium chloride solution | | |
| C107S070 | | | 1 mL microspheres: 7 mL<br>0.9% sodium chloride solution | | |
| Product<br>Code | Calibrated<br>size (µm) | Size Range<br>(µm) | Quantity | Indication | |
| | | | | Hypervascular<br>Tumors /<br>Arteriovenous<br>Malformations | Uterine<br>Fibroid |
| C107S090 | | | 0.9% sodium chloride solution<br>1 mL microspheres: 7 mL<br>0.9% sodium chloride solution | | |
| C207S090 | 900 | 825-975 | 2 mL microspheres: 7 mL<br>0.9% sodium chloride solution | Yes | Yes |
| C306S090 | | | 3 mL microspheres: 6 mL<br>0.9% sodium chloride solution | | |
| C107S120 | | | 1 mL microspheres: 7 mL<br>0.9% sodium chloride solution | | |
| C207S120 | 1,200 | 1,000-<br>1,200 | 2 mL microspheres: 7 mL<br>0.9% sodium chloride solution | Yes | Yes |
| C306S120 | | | 3 mL microspheres: 6 mL<br>0.9% sodium chloride solution | | |

Table 1: Device configurations of HRSpheres Embolic Microspheres

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3 mL microspheres: 6 mL

2 mL microspheres: 7 mL

0.9% sodium chloride solution

Yes

Yes

700

C207S070

C306S070

650-750

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## 5. Indications for Use

HRSpheres Narrow-Size Embolic Microspheres are intended to be used for the embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids.

## 6. Comparison of Technological Characteristics with the Predicate Device

A comparison of the technological characteristics of HRSpheres and the CalliSpheres and 8Spheres embolic beads is summarized in Table 2 below:

| Performance Characteristics Comparison Table | | | |
|-------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Device<br>Characteristic | Subject Device:<br>HRSpheres Narrow-Size<br>Embolic Microspheres | Predicate Device:<br>CalliSpheres and<br>8Spheres Embolic<br>Microspheres | Comment |
| 510(k) Number | K210562 | K173871 | N/A |
| Classification | II | II | Same |
| Product Code | KRD, NAJ | KRD, NAJ | Same |
| Performance Characteristics Comparison Table | | | |
| Device<br>Characteristic | Subject Device:<br>HRSpheres Narrow-Size<br>Embolic Microspheres | Predicate Device:<br>CalliSpheres and<br>8Spheres Embolic<br>Microspheres | Comment |
| Regulation | 21 CFR 870.3300 | 21 CFR 870.3300 | Same |
| Indication for<br>Use | HRSpheres Narrow-Size<br>Embolic Microspheres are<br>intended to be used for the<br>embolization of<br>arteriovenous<br>malformations (AVMs)<br>and hypervascular tumors,<br>including uterine fibroids. | CalliSpheres Embolic<br>Microspheres and<br>8Spheres Embolic<br>Microspheres are intended<br>to be used for the<br>embolization of<br>arteriovenous<br>malformations (AVMs)<br>and hypervascular tumors,<br>including uterine fibroids. | Same |
| Polymerization<br>Method | Suspension<br>polymerization | Suspension<br>polymerization | Same |
| Resorption | Non-resorbable | Non-resorbable | Same |
| Materials | Polyvinyl alcohol (PVA),<br>N-<br>acryloylaminoacetaldehyd<br>e dimethyl acetal, 2-<br>acrylamido-2-methyl-1-<br>propanesulfonic acid<br>sodium salt, 0.9% sodium<br>chloride solution, Reactive<br>Blue Dye #4 (only for<br>blue type microspheres) | Polyvinyl alcohol (PVA),<br>N-<br>acryloylaminoacetaldehyd<br>e dimethyl acetal<br>(NAAADA), 2-<br>acrylamido-2-methyl-1-<br>propanesulfonic acid<br>sodium salt, 0.9% sodium<br>chloride solution, Reactive<br>Blue Dye #4 (only for<br>CalliSpheres) | Different. The differences<br>in material do not raise<br>different questions of<br>safety and effectiveness. |
| Storage media | 0.9% sodium chloride<br>solution | 0.9% sodium chloride<br>solution | Same |
| Microsphere<br>Diameter | Size range: 70-1,200μm<br>Labeled size range:<br>70-100 μm<br>75-125 μm<br>200-300 μm<br>350-450 μm<br>480-580 μm<br>650-750 μm<br>825-975 μm<br>1,000-1,200 μm | Size range: 100-1,200μm<br>Labeled size range:<br>100-300μm<br>300-500μm<br>500-700μm<br>700-900μm<br>900-1,200μm | Different. The subject<br>device contains a smaller<br>size range specification<br>than the predicate device.<br>The difference in size<br>ranges does not raise<br>different questions of<br>safety and effectiveness. |
| Performance Characteristics Comparison Table | | | |
| Device<br>Characteristic | Subject Device:<br>HRSpheres Narrow-Size<br>Embolic Microspheres | Predicate Device:<br>CalliSpheres and<br>8Spheres Embolic<br>Microspheres | Comment |
| Quantity of<br>Microspheres<br>(and storage<br>media) | 1 mL (in 7 mL saline), 2<br>mL (in 7 mL saline) or 3<br>mL (in 6 mL saline) | 1 mL (in 7 mL saline) or 2<br>mL (in 7 mL saline) | Different. The difference<br>in microsphere volumes<br>does not raise different<br>questions of safety and<br>effectiveness. |
| Packaging | Sealed in borosilicate<br>glass vial | Sealed in borosilicate<br>glass vial | Same |
| Compressibility | 50% by diameter | 30% by diameter | Different. The subject<br>device is able to tolerate a<br>greater compressibility<br>than the predicate device.<br>The difference in<br>compressibility tolerance<br>does not raise different<br>questions of safety and<br>effectiveness. |
| Radiopacity<br>Method | Mixed with non-ionic<br>contrast media prior to<br>injection | Mixed with non-ionic<br>contrast media prior to<br>injection | Same |
| Delivery<br>Method | Via catheter under<br>fluoroscopic visualization | Via catheter under<br>fluoroscopic visualization | Same |
| Method of<br>Supply | Sterile and single use | Sterile and single use | Same |
| Shelf Life | Three years | Two years | Different. The increased<br>shelf life does raise<br>different questions of<br>safety and effectiveness. |
| Sterilization | Moist heat and non-<br>pyrogenic | Moist heat and non-<br>pyrogenic | Same |

Table 2: Technological Characteristic Comparison Table

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Overall, the differences in technological characteristics between the subject and predicate device do not raise different questions of safety and effectiveness.

## 7. Summary of Non-clinical Performance Testing

The device is subject to Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: Vascular and Neurovascular Embolization Devices

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issued on December 29, 2004. The safety and effectiveness of HRSpheres Narrow-Size Embolic Microspheres have been evaluated by non-clinical performance testing including:

#### In-Vitro Bench Testing 7.1

The test items, methods, and method references of HRSpheres Narrow-Size Embolic Microspheres are as follows:

| Test Items | Test Methods | Results |
|-------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|
| Appearance | USP 39 - <1> Injections and Implanted Drug<br>Products (Parenterals) -Product Quality Tests<br>and <790> Visible Particulates In Injections | Met predefined acceptance criteria |
| Compressibility | Internal Methods | Met predefined acceptance criteria |
| Quantity | USP <1151> Pharmaceutical | Met predefined acceptance criteria |
| Size Range | Internal Methods | Met predefined acceptance criteria |
| Suspension | In House Methods | Met predefined acceptance criteria |
| Catheter<br>Deliverability | In House Methods | Met predefined acceptance criteria |
| Water Content | USP 39 NF34 (2016) - <731> Loss on<br>drying | Met predefined acceptance criteria |
| pH | USP 39 NF 34 (2016) - <791> pH | Met predefined acceptance criteria |
| Impurities and<br>residual solvents | USP39 NF34 - <1086> Impurities in Drug<br>Substances and Drug Products | Met predefined acceptance criteria |
| Sterility | USP <71> Sterility Tests | Met predefined acceptance criteria |
| Bacterial<br>endotoxin | USP<85> Bacterial Endotoxins | Met predefined acceptance criteria |

Table 3: Device Non-Clinical Performance Evaluations

## 7.2 Packaging Integrity and Shelf Life

HRSpheres Narrow-Size Embolic Microspheres are supplied sterile and packaged in borosilicate glass vials.

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According to ASTM F1980-16, accelerated aging tests equivalent to 3 years of shelf life were carried out on HRSpheres Narrow-Size Embolic Microspheres, with 3 batches of each tested for all device specifications. Accelerated aging tests for package integrity were also carried out on the packaging materials including the bottles, rubber closures, and aluminum plastic covers.

The results of the performance tests after accelerated aging demonstrated all samples met specifications. Therefore, the results support a 3 year shelf life of HRSpheres Narrow-Size Embolic Microspheres.

#### 7.3 Sterilization and Shelf Life

HRSpheres Narrow-Size Embolic Microspheres are labeled as "Sterile" and "nonpyrogenic." HRSpheres Narrow-Size Embolic Microspheres are sterilized by moist heat sterilization with validated parameters (121 ℃, 30 min) after sealing the vials. Sterilization validation was completed to a sterility assurance level (SAL) of 10° using the Overkill Approach per ANSI/AAMI/ISO 17665-1:2006(R)2013.

HRSpheres Narrow-Size Embolic Microspheres were tested for bacterial endotoxins per USP <85> Bacterial Endotoxins Test to a level of not more than 0.5 EU/mL in accordance with the requirements of FDA guidance document: Guidance for Industry: Pyrogen Endotoxins Testing: Questions and Answers, issued June 2012.

## 7.4 Chemical Characterization

Chemical characterization testing was conducted on HRSpheres Narrow-Size Embolic Microspheres. The testing consisted of exhaustive extraction of the microspheres in purified water, ethanol, and hexane. Extracts were analyzed per FTIR, GC-MS and UPLC-MS. Water extract was also analyzed by ICP-MS. A risk analysis using a worst-case risk assessment approach was conducted based upon the findings of the exhaustive extraction. Using this approach, it was determined that the margins of safety (MOS) for potential chemical exposures indicated a low risk of chronic toxicity and carcinogenicity.

## 7.5 Biocompatibility Evaluation

Biocompatibility testing was conducted in accordance with the 2020 FDA guidance document Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process." The following biocompatibility tests listed in Table 3 were completed, and the results demonstrate the subject device is biocompatible:

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| Biological Endpoint | Test Method | Results |
|--------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| MTT Cytotoxicity Test | ISO 10993-5:2009 | Non-cytotoxic |
| ISO Guinea Pig Maximization<br>Sensitization Test | ISO 10993-10:2010 | Non-sensitizer |
| ISO Intracutaneous Study in<br>Rabbits | ISO 10993-10:2010 | Non-irritant |
| ISO Acute Systemic Toxicity<br>Study in Mice | ISO 10993-11:2017 | No mortality or evidence of systemic<br>toxicity |
| ASTM Hemolysis Study | ISO 10993-4:2017<br>ASTM F756:2017 | Non-hemolytic |
| ASTM Partial Thromboplastin<br>Time | ASTM F2382:2018 | Non-activator |
| SC5b-9 Complement<br>Activation Assay | ISO 10993-4:2017 | Both the test article and the sponsor<br>provided control were considered to be<br>potential activators of the complement<br>system.<br>The test article was compared<br>statistically to the control and the test<br>article was lower than the control and<br>was statistically different. |
| USP Rabbit Pyrogen Study,<br>Material Mediated | ISO 10993-11:2017 | Non-pyrogenic |
| Genotoxicity Mouse<br>Lymphoma Assay | ISO 10993-3:2014 | Non-mutagenic |
| Bacterial Reverse Mutation<br>Study | ISO 10993-3:2014 | Non-mutagenic |
| ISO Systemic Toxicity Study<br>in Rats Following<br>Subcutaneous Implantation,<br>13 Weeks | ISO 10993-6:2016<br>ISO 10993-11:2017 | There was no evidence of systemic<br>toxicity from the test article following<br>subcutaneous implantation in the rat.<br>Microscopically, the test article was<br>classified as causing minimal to no<br>reaction. |
| Biological Endpoint | Test Method | Results |
| ISO Muscle Implantation<br>Study in Rabbits, 4 Weeks | ISO 10993-6:2016 | The macroscopic reaction was not<br>significant as compared to the negative<br>control article.<br><br>Microscopically, the test article caused<br>a minimal to no reaction as compared<br>to the negative control article. |
| ISO Muscle Implantation<br>Study in Rabbits, 13 Weeks | ISO 10993-6:2016 | The macroscopic reaction was not<br>significant as compared to the negative<br>control article.<br><br>Microscopically, the test article caused<br>a slight reaction as compared to the<br>negative control article. |
| Chronic Systemic Toxicity<br>and Carcinogenicity<br>Evaluation | ISO 10993-1:2018<br>ISO 14971:2019<br>2020 FDA Biocompatibility<br>Guidance | A biological risk assessment was used<br>to support chronic systemic toxicity<br>and carcinogenicity endpoints. The<br>risk assessment was based on chemical<br>characterization results and supported<br>by information on the HRSpheres<br>materials of construction, gathered<br>toxicological data on these materials,<br>and biological data on the HRSpheres. |

## Table 4: Device Biological Endpoints

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## 8. Animal Study Testing

An animal study was performed on the healthy swine models to evaluate the safety and effectiveness of the HRSpheres Narrow-Size Embolic Microspheres. A total of 15 female domestic swine were selected for evaluation. The animal study was intended to simulate the clinical application of the embolization microspheres by interventional procedure for partial renal artery embolization. Seven pigs were selected for embolization with the test article (75 - 125 um), and the other 8 pigs were selected for embolization with the control article (CalliSpheres Polyvinyl Alcohol Embolization Microspheres; K173871) (100 - 300 um). Several preoperative and postoperative observation time points were selected, including 3, 8 and 29 days after embolization.

At each observation time point, the changes of hematology, blood coagulation and serum biochemistry, as well as the imaging changes and pathological changes of kidney were detected, and the performance differences of test article and control were compared. The safety and effectiveness of HRSpheres Narrow-size embolic

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microspheres were comprehensively evaluated. These evaluations included the following:

- 1) Comparison of recanalization of the vessels/durability of occlusion of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
- 2) Comparison of local and systemic foreign body reactions of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
- 3) Comparison of the ease of delivery of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
- 4) Comparison of the rupture or puncture of the blood vessels of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
- 5) Comparison of the non-target embolization/device migration of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
- 6) Comparison of local and systemic foreign body reactions of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.

Animal evaluation indexes of HRSpheres Narrow-Size Embolic Microspheres on day 3, 8, and 29 were comparable to those from the control group. Tissue reactions of both test and control groups were found to be mild and comparable. Preoperative and postoperative clinicopathological examination results demonstrated that there was no significant difference between test group and control group with respect to adverse reactions. The results demonstrate that the subject device is as safe and effective as the cleared CalliSphere Embolic Microspheres (K173871).

## 9. Conclusion

As described above, the subject device has the same intended use as the predicate device. The differences in technological characteristics between the subject device and the predicate device do not raise different questions of safety and effectiveness. To evaluate the impact of the technological differences, performance testing was conducted as described above. The results of the testing demonstrate that the subject device, HRSpheres, is as safe and effective as the predicate device. Therefore, HRSpheres are substantially equivalent to the predicate.