Predicate Devices

Reference Devices

AI/ML (Artificial Intelligence / Machine Learning)

No
The 510(k) summary describes a physical medical device (embolic microspheres) and its intended use and performance characteristics. There is no mention of software, algorithms, or any components that would typically incorporate AI or ML. The mention of "Image analysis methods" is for particle size analysis, which is a standard measurement technique and does not imply AI/ML.

Therapeutic

Yes
The device is described as "hydrogel microspheres" intended for "embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids" by "blocking the blood supply to the target area." This directly indicates a treatment for medical conditions, classifying it as a therapeutic device.

Diagnostic

No

This device is an embolic agent used for treatment (embolization) of AVMs and tumors, not for diagnosing conditions.

SaMD (Software as a Medical Device)

No

The device description clearly states that the device is composed of physical microspheres made from modified polyvinyl alcohol (PVA) materials, intended for embolization procedures. It is a physical medical device, not software.

IVD (In Vitro Diagnostic)

No, this device is not an IVD (In Vitro Diagnostic).

Here's why:

IVD Definition: In Vitro Diagnostic devices are used to examine specimens taken from the human body (like blood, urine, tissue) to provide information about a person's health. This testing is done outside of the body.
Device Function: Callispheres and 8Spheres Embolic Microspheres are implantable medical devices used for embolization. They are delivered into the body to block blood vessels.
Intended Use: The intended use clearly states they are for "embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids." This is a therapeutic procedure performed within the body.
Device Description: The description details the physical properties of the microspheres and how they are delivered and function within the vascular system.
Input Imaging Modality: DSA angiography is an imaging technique used to visualize blood vessels in vivo, not a method for analyzing in vitro samples.
Anatomical Site: The anatomical sites mentioned are within the body.

While the document mentions "image processing" for particle size analysis, this is a quality control step for the manufacturing of the device itself, not a diagnostic test performed on a patient sample.

Therefore, based on the provided information, Callispheres and 8Spheres Embolic Microspheres are therapeutic medical devices, not In Vitro Diagnostic devices.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres are intended to be used for the embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids.

Product codes (comma separated list FDA assigned to the subject device)

KRD, NAJ

Device Description

CalliSpheres and 8Spheres 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. CalliSpheres and 8Spheres Embolic Microspheres consist of a macromer derived from polyvinyl alcohol (PVA), and are hydrophilic, non-resorbable, and are available in a range of sizes. The preservation solution is 0.9% sodium chloride solution. The water content of fully polymerized microsphere is 91% ~ 94%. Microspheres can tolerate compression of 30%. CalliSpheres Embolic Microspheres are dyed blue to aid in the visualization of the microspheres in the delivery syringe. 8Spheres Embolic Microspheres are undyed and with natural color. CalliSpheres and 8Spheres Embolic Microspheres are supplied sterile and packaged in sealed glass vials.

CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres are intended to be used for the embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids. By blocking the blood supply to the target area, the tumor or malformation is starved of nutrients and shrinks in size.

CalliSpheres and 8Spheres Embolic Microspheres can be delivered through typical microcatheters in the 1.7- 4 Fr range. At the time of use, CalliSpheres and 8Spheres Embolic Microspheres are mixed with a nonionic contrast agent to form a suspension solution. CalliSpheres and 8Spheres Embolic Microspheres are intended for single use and are supplied sterile and non-pyrogenic. The device configurations of CalliSpheres and 8Spheres Embolic Microsphere are described in Table 1 and Table 2 below. Product codes beginning with "B" represent CalliSpheres, while product codes beginning with "U" represent 8Spheres. Among the various size ranges of CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres, the size ranges that can be used for uterine fibroid embolization are 500-700µm, 700-900µm and 900-1200μm.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Arteriovenous malformations (AVMs), hypervascular tumors, including uterine fibroids.

Indicated Patient Age Range

Not Found

Intended User / Care Setting

Not Found

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Non-clinical Performance Testing (In-Vitro Bench Testing):
The device was subjected to various in-vitro bench tests including:

Appearance (Met predefined acceptance criteria)
pH test (Met predefined acceptance criteria)
Size range confirmation (Met predefined acceptance criteria)
Compressibility Test (Met predefined acceptance criteria)
Catheter deliverability test (Met predefined acceptance criteria)
Water content test (Met predefined acceptance criteria)
Impurities and Residual Solvents Test (Met predefined acceptance criteria)
Suspension (Met predefined acceptance criteria)
Sterility Test (Met predefined acceptance criteria)
Bacterial Endotoxins Test (Met predefined acceptance criteria)
Results: All tested samples met predefined acceptance criteria, indicating that device performance met design requirements and is acceptable for intended use.

Packaging Integrity and Shelf Life:
Accelerated aging tests were conducted for 2 years of shelf life on 3 batches of each device specification. Accelerated aging tests for package integrity were also carried out on packaging materials.
Results: All samples met specifications after accelerated aging, supporting a 2-year shelf life.

Sterilization and Shelf Life:
Sterilized by moist heat sterilization (121°C, 30 min) with a sterility assurance level (SAL) of 10-6. Tested for bacterial endotoxins (

Regulation Number and Section

§ 870.3300 Vascular embolization device.

(a)
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.(b)
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).

Summary

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Image /page/0/Picture/0 description: The image contains the logos of the U.S. Department of Health & Human Services and the U.S. Food & Drug Administration (FDA). The Department of Health & Human Services logo is on the left, featuring a stylized symbol. To the right is the FDA logo, with the letters 'FDA' in a blue square, followed by the words 'U.S. FOOD & DRUG' and 'ADMINISTRATION' in blue text.

September 17, 2018

Suzhou Hengrui Callisyn Biomedical Co., Ltd. Xiao Chen Regulatory Affairs Manager Building 9, No. 8 Jinfeng Road, New District Suzhou. Jiangsu Province 215163 China

Re: K173871

Trade/Device Name: CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres Regulation Number: 21 CFR§ 870.3300 Regulation Name: Vascular Embolization Device Regulatory Class: II Product Code: KRD, NAJ Dated: August 13, 2018 Received: August 15, 2018

Dear Xiao Chen:

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.

1

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.html; 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 http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.

For comprehensive regulatory information about mediation-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,

Sharon M. Andrews -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

2

Indications for Use

510(k) Number (if known) K173871

Device Name

CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres

Indications for Use (Describe)

Callispheres Embolic Microspheres and 8Spheres 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)
-------------------------------------------------	--

X Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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3

510(k) Summary

CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres

(per 21 CFR 807.92)

1 Submitter

Suzhou Hengrui Callisyn Biomedical Co., Ltd

Building 9, No. 8 Jinfeng Road, Science & Technology Tower,

New District, Suzhou,

Jiangsu Province,

P.R. China

Phone: +86-512-68050607

Fax: +86-512-66806133

Contact Person: Xiao Chen

Phone: +86-512-68050607

Fax: +86-512-66806133

Email: chenxiao@hrmedical.com.cn

Date Prepared: September 11, 2018

2 Proposed Device

Name of Device: CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres

Common or Usual Name: Polyvinyl Alcohol Embolic Microspheres

Classification Name: Vascular Embolization Device (21 CFR 870.3300)

Classification: Class II

Panel: Cardiovascular

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Product Code: KRD (device, embolization, arterial). NAJ (agents, embolic, for treatment of uterine fibroids)

3 Predicate Device

Device Name: Bead Block™ 510(k) number: K150876 Manufacturer: Biocompatibles UK Ltd. Regulation Number: 21CFR 870.3300 Product code: KRD (device, embolization, arterial),

NAJ (agents, embolic, for treatment of uterine fibroids)

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

4 Device Description

CalliSpheres and 8Spheres 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. CalliSpheres and 8Spheres Embolic Microspheres consist of a macromer derived from polyvinyl alcohol (PVA), and are hydrophilic, non-resorbable, and are available in a range of sizes. The preservation solution is 0.9% sodium chloride solution. The water content of fully polymerized microsphere is 91% ~ 94%. Microspheres can tolerate compression of 30%. CalliSpheres Embolic Microspheres are dyed blue to aid in the visualization of the microspheres in the delivery syringe. 8Spheres Embolic Microspheres are undyed and with natural color. CalliSpheres and 8Spheres Embolic Microspheres are supplied sterile and packaged in sealed glass vials.

CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres are intended to be used for the embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids. By blocking the blood supply to the target area, the tumor or malformation is starved of nutrients and shrinks in size.

CalliSpheres and 8Spheres Embolic Microspheres can be delivered through typical microcatheters in the 1.7- 4 Fr range. At the time of use, CalliSpheres and 8Spheres Embolic Microspheres are mixed with a nonionic contrast agent to form a suspension solution. CalliSpheres and 8Spheres Embolic Microspheres are intended for single use and are supplied sterile and non-pyrogenic. The device configurations of

5

CalliSpheres and 8Spheres Embolic Microsphere are described in Table 1 and Table 2 below. Product codes beginning with "B" represent CalliSpheres, while product codes beginning with "U" represent 8Spheres. Among the various size ranges of CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres, the size ranges that can be used for uterine fibroid embolization are 500-700µm, 700-900µm and 900-1200μm.

| Product
Code | Calibrated
Size (µm) | Quantity |-----------------|-- | | Tumors/
Arteriovenous
Malformations | Uterine Fibroid |
| B107S103 | 100-300 sodium chloride | Yes | B107S305 | 300-500 sodium chloride | Yes | B107S507 | 500-700 sodium chloride | Yes | B107S709 | 700-900 sodium chloride | Yes | B107S912 sodium chloride | Yes | B207S103 | 100-300 sodium chloride | Yes | B207S305 | 300-500 sodium chloride | Yes | B207S507 | 500-700 sodium chloride | Yes | B207S709 | 700-900 sodium chloride | Yes | B207S912 sodium chloride | Yes | Indication | |
-----------------------|------------------------------------------------|------------------------------------------------------------|-----------------|
| | Hypervascular
| 1ml microspheres : 7ml 0.9%
| No |
| 1ml microspheres : 7ml 0.9%
| No |
| 1ml microspheres : 7ml 0.9%
| Yes |
| 1ml microspheres : 7ml 0.9%
| Yes |
| 900-1200 | 1ml microspheres : 7ml 0.9%
| Yes |
| 2ml microspheres : 7ml 0.9%
| No |
| 2ml microspheres : 7ml 0.9%
| No |
| 2ml microspheres : 7ml 0.9%
| Yes |
| 2ml microspheres : 7ml 0.9%
| Yes |
| 900-1200 | 2ml microspheres : 7ml 0.9%
| Yes |

Table 1: Device configurations of CalliSpheres Embolic Microspheres

Table 2: Product configurations of 8Spheres Embolic Microspheres

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| | Calibrated
Size (um) | | Indication | |
|-----------------|-------------------------|------------------------------------------------|------------------------------------------------------------|-----------------|
| Product
Code | | Quantity | Hypervascular
Tumors/
Arteriovenous
Malformations | Uterine Fibroid |
| U107S103 | 100-300 | 1ml microspheres : 7ml
0.9% sodium chloride | Yes | No |
| U107S305 | 300-500 | 1ml microspheres : 7ml
0.9% sodium chloride | Yes | No |
| U107S507 | 500-700 | 1ml microspheres : 7ml
0.9% sodium chloride | Yes | Yes |
| U107S709 | 700-900 | 1ml microspheres : 7ml
0.9% sodium chloride | Yes | Yes |
| U107S912 | 900-1200 | 1ml microspheres : 7ml
0.9% sodium chloride | Yes | Yes |
| U207S103 | 100-300 | 2ml microspheres : 7ml
0.9% sodium chloride | Yes | No |
| U207S305 | 300-500 | 2ml microspheres : 7ml
0.9% sodium chloride | Yes | No |
| U207S507 | 500-700 | 2ml microspheres : 7ml
0.9% sodium chloride | Yes | Yes |
| U207S709 | 700-900 | 2ml microspheres : 7ml
0.9% sodium chloride | Yes | Yes |
| U207S912 | 900-1200 | 2ml microspheres : 7ml
0.9% sodium chloride | Yes | Yes |

5 Indications for Use

CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres are intended to be used for the embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids.

7

Comparison of Technological Characteristics with the Predicate Device 6

The subject devices and predicate device have identical / similar technological characteristics as shown in Table 3.

Items	Proposed Device	Predicate Device	Discussion of Differences
Device Name	CalliSpheres Embolic Microspheres &
8Spheres Embolic Microspheres	Bead Block TM	N/A
510(k) Number	K173871	K150876	N/A
Product Code	KRD, NAJ	KRD, NAJ	Identical
Intended Use /
Indications For Use	CalliSpheres Embolic Microspheres and
8Spheres Embolic Microspheres are
intended to be used for the embolization of
arteriovenous malformations (AVMs) and
hypervascular tumors, including uterine
fibroids.	Bead Block microspheres are
intended to be used for the
embolization of hypervascular
tumors, including uterine fibroids
and arteriovenous malformations
(AVMs).	Identical: Indications for use of
the proposed device is identical
to that of Bead Block
(K150876).
Materials	Polyvinyl alcohol (PVA), N-
acryloylaminoacetaldehyde dimethyl
acetal (NAAADA), 2-acrylamido-2-
methyl-1-propanesulfonic acid sodium
salt, 0.9% Sodium Chloride Solution,
Reactive Blue Dye #4 (only for
CalliSpheres Embolic Microspheres)	Polyvinyl alcohol (PVA), N-
acryloylaminoacetaldehyde
dimethyl acetal (NAAADA), 2-
acrylamido-2-methyl-1-
propanesulfonic acid sodium salt,
buffered Saline, Reactive Blue
Dye #4	Identical
Polymerization
Method	Suspension polymerization	Suspension polymerization	Identical
Resorption	Non-resorbable	Non-resorbable	Identical

Appearance	Hydrogel microspheres with regular shape,
smooth surface and calibrated size,
CalliSpheres: Blue dyed
8Spheres: Undyed	Hydrogel microspheres with
regular shape, smooth surface and
calibrated size,
Bead Block: Blue dyed	CalliSpheres are identical in
appearance to Bead Block,
8Spheres are undyed. 8Spheres
are identical to CalliSpheres
except for the color.
The lack of dye in 8spheres
does not raise different
questions of safety and
effectiveness from the
predicate.
Size Range
(um)	100-300
300-500
500-700
700-900
900-1200	100-300
300-500
500-700
700-900
900-1200	Identical
Sizes indicated for
UAE
(um)	500-700
700-900
900-1200	700-900
900-1200	Different. CalliSpheres and
8Spheres of 500-700um are
indicated for UAE.
The
difference in size does not raise
different questions of safety and
effectiveness.
Water content of
microspheres	91% ~ 94%	Approximately 90-95%	Similar. Water content range of
proposed device is narrower
than that of predicate device.
The slight difference of water
content does not raise different
questions of safety and
effectiveness.
Storage media	0.9% sodium chloride solution	Phosphate buffered saline (PBS)	Similar. Both 0.9% sodium
chloride solution and phosphate
buffered saline (PBS) can be
used for injection.
Quantity of
Microspheres	1mL, 2mL	1mL, 2mL	Identical
Quantity of Storage
Media	Both CalliSpheres and 8Spheres have the
following two quantities:

1ml microspheres in 7ml 0.9%
sodium chloride solution to form a
total volume of 8mL
2)
2ml microspheres in 7ml 0.9%
sodium chloride solution to form a
total volume of 9mL. | Bead Block Compressible
Microspheres have the following
two quantities:
1)
1 mL microspheres in 6ml
PBS to form a total volume
of 7mL
2)
2 mL microspheres in 5ml
PBS to form a total volume
of 7mL. | Similar, the slight difference of
saline quantity does not raise
different questions of safety and
effectiveness. |
| Packaging | Both CalliSpheres and 8Spheres are sealed
in borosilicate glass vial. | Bead Block is sealed in
polycarbonate syringe | Similar. Packaging has been
verified by packaging
compatibility testing and does
not raise different questions of
safety and effectiveness. |
| Compressibility | 30% by diameter | Approximately 30% by diameter | Identical |
| Suspension | The time taken to achieve suspension is
less than 10 min, and the time maintaining
suspension is longer than 4 mins. | The time taken to achieve
suspension is less than 4 min, and
the time maintaining suspension is
longer than 4.5 mins. | Similar. The slight difference of
time does not raise different
questions of safety and
effectiveness. |
| Delivery Method | Delivered to target position by micro-
catheter under DSA. | Delivered to target position by
micro-catheter under DSA. | Identical |
| Compatible
Delivery Catheter | 1.7-4Fr | 1.5-5Fr | Similar. The specification for
CalliSpheres and 8Spheres lies
within the range of the
predicate. The slight difference
does not raise different
questions of safety and
effectiveness. |
| Radiopacity
Method | Mixed with non-ionic contrast agent prior
to injection | Mixed with non-ionic contrast
agent prior to injection | Identical |
| Method of Supply | Sterile and single use | Sterile and single use | Identical |
| Shelf Life | Two years | Two years | Identical |
| Sterilization | Moist heat and non-pyrogenic | Moist heat and non-pyrogenic | Identical |

Table 3: Performance Characteristics Comparison Table of CalliSpheres & 8Spheres Embolic Microspheres verses Predicate Devices

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9

10

Overall, the differences in technological characteristics between the subject and predicate 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 issued on 29 December 2004 and was evaluated accordingly. The safety and effectiveness of CalliSpheres and 8Spheres have been evaluated by non-clinical testing including:

7.1 In-Vitro Bench Testing

The test items, methods and method references of CalliSpheres and 8Spheres Embolic Microspheres are as follows:

No.	Test items	Test methods and basis	Result
1	Appearance	USP 39 NF34 (2016) Injections
and Implanted Drug Products
(Parenterals) -Product Quality Tests and
Visible Particulates In Injections	Met predefined acceptance
criteria
2	pH test	USP39 NF34 (2016) - pH	Met predefined acceptance
criteria
3	Size range
confirmation	Method adapted from ISO 13322-1:2014
Particle size analysis - Image analysis
methods – Part 1: Static image analysis
methods. The particle sizes of
Callispheres and 8spheres Embolic
Microspheres were measured and
confirmed by optical microscope, digital
camera and corresponding particle size
measurement software which have been
calibrated and validated.	Met predefined acceptance
criteria
4	Compressibility
Test	A texture analyzer was used to test the
compressibility of microspheres;
microspheres were compressed of 30%
by diameter and maintained for 10s.
After the compression the microspheres	Met predefined acceptance
criteria
		were inspected by microscope for
maintenance of shape and breakage.
5	Catheter
deliverability test	Particles were delivered through 1.7Fr -
4.0Fr microcatheters to evaluate the
potential for clogging and breakage of
spheres. The size of the microcatheter
was selected based on the size of the
microspheres. In order to simulate the
tortuosity of the catheters used in
clinical practice, the microcatheters were
inserted into a model simulated to
human hepatic artery to conduct the
catheter deliverability test. Clogging was
assessed during the test, and
microspheres were inspected
microscopically following delivery for
signs of breakage or changes in shape.	Met predefined acceptance
criteria
6	Water content test	USP 39 NF34 (2016) - Loss on
Drying	Met predefined
acceptance
criteria
7	Impurities and
Residual Solvents
Test	USP39 NF34 (2016) -
Impurities in Drug Substances and Drug
Products, Residual Solvents,
Chromatography,
Ultraviolet -Visible Spectroscopy	Met predefined acceptance
criteria
8	Suspension	A suspension study of all variants of
CalliSpheres and 8Spheres Embolic
Microspheres was conducted with three
commercially-available nonionic
contrast agents based upon the following
study:
Lewis AL et. al. Comparative in vitro
evaluation of microspherical
embolization agents. J Mater Sci Mater
Med. 2006 Dec: 17(12):1193-204.	Met predefined acceptance
criteria
9	Sterility Test	USP 39 -NF34 (2016) Sterility
Tests	Met predefined acceptance
criteria
10	Bacterial	USP39 -NF34 (2016) -	Met predefined acceptance

11

12

Samples of CalliSpheres and 8Spheres Embolic Microspheres passed the performance tests listed above, indicating that device performance met the design requirements and is acceptable for the intended use.

7.2 Packaging Integrity and Shelf Life

CalliSpheres and 8Spheres Embolic Microspheres are supplied as sterile devices and packaged in sealed borosilicate glass vials.

According to ASTM F1980-16, accelerated aging tests equivalent to 2 years of shelf life were carried out on Callispheres and 8Spheres 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 of Callispheres and 8Spheres microspheres after accelerated aging demonstrated all samples met specifications. Therefore, the results support a 2 year shelf life of Callispheres and 8Spheres Embolic Microspheres.

7.3 Sterilization and Shelf Life

CalliSpheres and 8Spheres Embolic Microspheres are labeled as "Sterile" and " non pyrogenic." CalliSpheres & 8Spheres Embolic Microspheres are sterilized by moist heat sterilization with validated parameters (121°C, 30 min) after sealing the vials. Sterilization validation was completed to a sterility assurance level (SAL) of 10 6 using the Overkill Approach per ANSI/AAMI/ISO 17665-1:2006(R)2013.

Callispheres and 8Spheres were tested for bacterial endotoxins per USP Bacterial Endotoxins Test to a level of not more than 0.5EU/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 the CalliSpheres and 8Spheres Embolic microspheres and the saline preservation solution. The testing consisted of exhaustive extraction of the CalliSpheres and 8Spheres Embolic microspheres in purified water, ethanol, and hexane and analyzing the extracts using FTIR, ICP/MS, GC/MS, GC/MS headspace, and UPLC/MS. A risk analysis using a worst case risk Page 10 of 16

13

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

Tests for biocompatibility were conducted in accordance with ISO 10993-1 and ASTM standards.

The conducted biocompatibility testing is shown in the following table, and the subject devices were demonstrated to be biocompatible.

| Biocompatibility

Evaluation	Summary
Cytotoxicity Study Using
the ISO Elution Method	The test article, CalliSpheres Embolic Microspheres, was evaluated
for potential cytotoxic effects using an in vitro mammalian cell
culture test. This study was conducted following the guidelines of
ISO 10993-5, Biological evaluation of medical devices - Part 5:
Tests for in vitro cytotoxicity. The test article extract showed no
evidence of causing cell lysis or toxicity. The test article extract
met the requirements of the test since the grade was less than a
grade 2 (mild reactivity).
ISO Intracutaneous Study
in Rabbits	The test article, CalliSpheres Embolic Microspheres, was evaluated
for the potential to cause irritation following intracutaneous
injection in rabbits. This study was conducted based on ISO
10993-10, Biological evaluation of medical devices - Part 10: Tests
for irritation and skin sensitization. The test article met the
requirements of the test.
ISO Maximization
Sensitization Study	The test article, CalliSpheres Embolic Microspheres, was evaluated
for the potential to cause delayed dermal contact sensitization in a
guinea pig maximization test. This study was conducted based on
the requirements of ISO 10993-10, Biological evaluation of
medical devices - Part 10: Tests for irritation and skin sensitization.
The test article extracts showed no evidence of causing delayed
dermal contact sensitization in the guinea pig. The test article was
not considered a sensitizer in the guinea pig maximization test.
ISO Systemic Toxicity
Study	The test article, CalliSpheres Embolic Microspheres, was evaluated
for acute systemic toxicity in mice. This study was conducted
based on ISO 10993-11, Biological evaluation of medical devices -
Part 11: Tests for systemic toxicity. There was no mortality or
evidence of systemic toxicity from the extracts injected into mice.
Each test article extract met the requirements of the study.
Modified ASTM
Hemolysis Study	The test article, CalliSpheres Embolic Microspheres, was evaluated
for the potential to cause hemolysis. This study was conducted
based on ASTM F756, Standard Practice for Assessment of
Hemolytic Properties of Materials and ISO 10993-4, Biological
evaluation of medical devices - Part 4: Selection of tests tor
interactions with blood. The hemolytic index tor the test article in
direct contact with blood was 0.6% and the direct contact was non-
hemolytic.
ASTM Partial
Thromboplastin Time	The test article, CalliSpheres Embolic Microspheres, was evaluated
to determine the potential to cause an effect on the coagulation
cascade via the intrinsic coagulation pathway. The study was
conducted in accordance to ASTM F2382: Standard Test Method
for Assessment of Circulating Blood-Contacting Medical Device
Materials on Partial Thromboplastin Time (PTT). The test article
average clotting time was lower and was not statistically different
than the negative reference material. The test article met the
requirements of the test.
SC5b-9 Complement
Activation Assay	The test article, CalliSpheres Embolic Microspheres, and sponsor
provided control (SPC), Embospheres, were evaluated for the
potential to activate the complement system. This study was
conducted based on ISO 10993-4, Biological evaluation of medical
devices - Part 4: Selection of tests for interactions with blood. The
test article, SPC, and comparative control were incubated in normal
human serum (NHS) and SC5b-9 was measured in the exposed
serum using an enzyme immunoassay. The test article was not
considered to be a potential activator of the complement system.
USP Rabbit Pyrogen
Study	The test article, CalliSpheres Embolic Microspheres, was evaluated
for material mediated pyrogenicity in rabbits. The test was
conducted based on USP, General Chapter , Pyrogen Test.
The procedure is recommended in ISO 10993-11, Biological
evaluation of medical devices - Part 11: Tests for systemic toxicity.
The total rise of rabbit temperatures during the 3 hour observation
period was within acceptable USP requirements. The test article
met the requirements for the absence of pyrogens.
Genotoxicity: Bacterial
Reverse Mutation Study	The test article, CalliSpheres Embolic Microspheres and 8Spheres
Embolic Microspheres, were evaluated for the potential to cause
mutagenic changes at the histidine locus of the Salmonella
typhimurium tester strains TA98, TA100, TA1535. And TA1537 or
at the tryptophan locus of the Escherichia coli tester strain
WP2wv/v4. The study was conducted in the presence and absence
of S9 metabolic activation based on ISO 10993-3, Biological
evaluation of medical devices - Part 3: Tests for genotoxicity,
carcinogenicity and reproductive toxicity and OECD 471,
Guideline for Testing of Chemicals, Bacterial Reverse Mutation
	Test. The test article was extracted in dimethyl sulfoxide (DMSO) and saline.
The DMSO and saline test article extracts were considered to be nonmutagenic to S. typhimurium tester strains TA98, TA100, TA1535, and TA1537. and to E. coli tester strain WP2uvrA.
Genotoxicity: Mouse
Lymphoma Assay	The test article, CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres, were evaluated for mutagenic potential using the mouse lymphoma forward gene mutation assay. The mouse lymphoma L5178Y/TK+/ cell line, heterozygous at the thymidine kinase (TK) locus, was used for this assay. The test article was extracted in serum-free cell culture medium (RPMIo) and dimethyl sulfoxide (DMSO). The RPMIo and DMSO test article extracts did not cause a 2-fold or greater increase in the mean mutant frequency of the L5178Y/TK+/ cell line either in the presence or absence of metabolic activation. The test article was not mutagenic.
ISO Muscle Implantation
Study in Rabbits, 4
Weeks	The test article, CalliSpheres Embolic Microspheres, was implanted in muscle tissue of the rabbit to evaluate the local tissue response in accordance with ISO 10993-6, Biological evaluation of medical devices - Part 6: Tests for local effects after implantation. Sterile implant test articles were aseptically prepared. Negative control articles were sterilized by steam. The test article and negative control were intramuscularly implanted and animals were euthanized 4 weeks later. Muscle tissues were excised and the implant sites examined macroscopically. A microscopic evaluation of representative implant sites from each animal was conducted to further define any tissue response. The macroscopic reaction was not significant as compared to the negative control article. Microscopically, the test article caused a slight reaction as compared to the negative control article.
ISO Systemic Toxicity
Study in Rats Following
Subcutaneous and
Muscle Implantation, 13
Weeks	The test article, CalliSpheres Embolic Microspheres, was surgically implanted in the gluteal muscle and subcutaneous tissue of the rat to evaluate potential systemic toxicity and local tissue response at the implantation sites. A separate group of animals was similarly implanted with high density polyethylene (HDPE) to serve as the control group. Twenty male and 20 female rats were randomly assigned to either the test or control group (10/sex/group). There were no changes in hematology or clinical chemistry values considered related to implantation with the test article. Microscopic evaluation of collected organs revealed no evidence of a systemic test article related response. Microscopic evaluation of the implantation sites indicated no difference in the local tissue response between the control and test articles. There was no evidence of systemic toxicity from the test article following
	subcutaneous and muscle implantation in the rat. Microscopically,
	the test article was classified as causing a minimal to no reaction
	in both the subcutaneous tissue and the gluteal muscle.
Chronic Systemic	We conducted a biological risk assessment for chronic toxicity and
Toxicity and	carcinogenicity of proposed device based upon chemical
Carcinogenicity	extractable/leachable analysis (described above). The CalliSpheres
Evaluation	and 8Spheres Embolic Microspheres are not considered to have
	chronic systemic toxicity and carcinogenicity risk. To evaluate the
	biological safety of the device, consideration was given to the
	following: type of patient contact; potential hazards of the
	materials of construction, the history of clinical use and testing of
	the materials of construction, biocompatibility and chemical
	characterization testing on the device; and other information
	available in the literature.

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8 Summary of Animal Performance Testing

An animal study was conducted to evaluate the safety and effectiveness of CalliSpheres and 8Spheres Embolic Microsphere. The animal study was intended to simulate the clinical application of the embolization microspheres by interventional procedure for partial renal artery embolization. A pig model was chosen, with Embosphere Microspheres, manufactured by Biosphere Medical, Inc. (K021397) selected as the control group.

Random grouping method was used to assign treatment in the animals. The lower polar second branch artery and subordinated branch artery of 12 swine (female and male) were selected for embolization by CalliSpheres Embolic Microspheres (300-500um), and the other 12 swine (female and male) were selected for embolization with Embosphere microspheres (300-500um) in the lower polar second branch artery and subordinated branch artery. Several preoperative and postoperative observation time points were selected, including 2, 7 and 28 days after embolization. At these time points, the change of blood routine, coagulation function, renal function and liver function were tested, the results of DSA angiography and histopathological results were checked, and the performance differences of CalliSpheres embolic microsphere and Embosphere microspheres were compared. Finally, the safety and effectiveness of CalliSpheres embolic microsphere were comprehensively evaluated.

The assessment items for this animal study are as follows:

(1) Compare the recanalization of the vessels/durability of occlusion of CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres

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(2) Compare the local and systemic foreign body reactions of CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres

(3) Compare the embolization effectiveness of CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres

(4) Compare the ease of delivery of CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres

(5) Compare the rupture or puncture of the blood vessels of CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres

(6) Compare the non-target embolization /device migration of CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres

The monitoring indexes of the animals were normal during preoperative adaptation period and postoperative observation period; there was no difference between the test group and the control group. Embolic agents from both groups were easily delivered to the target vessels, and neither of the two embolic agents showed vascular rupture or perforation during embolization. Both the subject and control devices were shown to achieve complete embolization effectively with the same number of embolic target vessels and amount of embolic materials. In addition, both embolic agents had had comparable non-target embolization. Animal evaluation indexes of CalliSpheres Embolic Microspheres on day 2, day 7 and day 28 after embolization were comparable to those from the Embosphere group. Tissue reactions of both CalliSpheres and Embospheres 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.

Overall, the results of the study demonstrate that CalliSpheres Embolic Microspheres are as safe and effective as the cleared device Embosphere (K021397).

9 Conclusions

As described above, the subject devices have the same intended use as the predicate device. The differences in technological characteristics between the subject devices and the predicate 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 devices, CalliSpheres and 8Spheres Embolic Microspheres, are as safe and effective

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as the predicate device. Therefore, CalliSpheres and 8Spheres Embolic Spheres are substantially equivalent to the predicate.