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.

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.

AI/ML Overview

The provided text describes the acceptance criteria and a study validating the performance of CalliSpheres Embolic Microspheres and 8Spheres Embolic Microspheres, which are vascular embolization devices.

Here's a breakdown of the requested information:

1. Table of acceptance criteria and the reported device performance

The document primarily focuses on non-clinical performance testing (in-vitro bench testing, packaging, shelf-life, sterilization, chemical characterization, and biocompatibility) and an animal study. The "acceptance criteria" are generally implied to be "met predefined acceptance criteria" or "met specifications" for the bench tests, and comparability to a predicate device for the animal study.

Test Item	Acceptance Criteria (Implied)	Reported Device Performance
In-Vitro Bench Testing
Appearance	Met predefined acceptance criteria (e.g., USP <1> & <790>)	Met predefined acceptance criteria
pH test	Met predefined acceptance criteria (e.g., USP <791>)	Met predefined acceptance criteria
Size range confirmation	Met predefined acceptance criteria (e.g., Method adapted from ISO 13322-1:2014)	Met predefined acceptance criteria
Compressibility Test	Met predefined acceptance criteria (e.g., retained shape/no breakage after 30% compression for 10s)	Met predefined acceptance criteria
Catheter deliverability test	Met predefined acceptance criteria (e.g., no clogging, no breakage/shape change)	Met predefined acceptance criteria
Water content test	Met predefined acceptance criteria (e.g., USP <731>)	Met predefined acceptance criteria
Impurities & Residual Solvents Test	Met predefined acceptance criteria (e.g., USP <1086>, <467>, <621>, <857>)	Met predefined acceptance criteria
Suspension	Met predefined acceptance criteria (e.g., time to achieve <10 min, time maintaining >4 mins)	Met predefined acceptance criteria
Sterility Test	Met predefined acceptance criteria (e.g., USP <71>)	Met predefined acceptance criteria
Bacterial Endotoxins	Met predefined acceptance criteria (e.g., USP <85>, not more than 0.5 EU/mL)	Met predefined acceptance criteria
Packaging & Shelf Life
Packaging Integrity	Maintain integrity as per ASTM F1980-16 for 2 years shelf life	All samples met specifications, supported 2-year shelf life
Shelf Life	Maintain specifications for 2 years	All samples met specifications after accelerated aging equivalent to 2 years
Sterilization
Sterility Assurance Level (SAL)	10^-6 (per ANSI/AAMI/ISO 17665-1:2006(R)2013)	Achieved 10^-6 SAL
Chemical Characterization
Risk of Chronic Toxicity & Carcinogenicity	Low risk (based on margins of safety from exhaustive extraction)	Determined to have low risk
Biocompatibility
Cytotoxicity	No evidence of cell lysis or toxicity (grade < 2)	Met requirements (grade < 2)
Intracutaneous Study	Met requirements for irritation	Met requirements
Maximization Sensitization Study	No delayed dermal contact sensitization	Not considered a sensitizer
Systemic Toxicity	No mortality or evidence of systemic toxicity	Met requirements
Hemolysis	Non-hemolytic (hemolytic index for direct contact < 2%)	Hemolytic index 0.6%, non-hemolytic
Partial Thromboplastin Time	Not statistically different from negative reference material	Met requirements
SC5b-9 Complement Activation Assay	Not considered a potential activator	Not considered a potential activator
USP Rabbit Pyrogen Study	Total rise of rabbit temperatures within acceptable USP requirements, absence of pyrogens	Met requirements for absence of pyrogens
Genotoxicity: Bacterial Reverse Mutation	Non-mutagenic	Non-mutagenic for tested strains
Genotoxicity: Mouse Lymphoma Assay	Not mutagenic (no >2-fold increase in mean mutant frequency)	Not mutagenic
ISO Muscle Implantation Study	Macroscopic reaction not significant compared to negative control; microscopic reaction minimal to slight	Macroscopic reaction not significant; microscopic reaction slight
Systemic Toxicity (13 weeks)	No changes in hematology/clinical chemistry related to implantation; no evidence of systemic response; local tissue response comparable to control	No systemic toxicity; minimal to no reaction in tissue
Chronic Systemic Toxicity & Carcinogenicity (Biological Risk Assessment)	Not considered to have chronic systemic toxicity and carcinogenicity risk	Not considered to have chronic systemic toxicity and carcinogenicity risk
Animal Performance Testing
Recanalization/Durability of Occlusion	Comparable to predicate device (Embosphere)	Complete embolization effectively achieved
Local/Systemic Foreign Body Reactions	Mild and comparable to predicate device	Mild and comparable
Embolization Effectiveness	Comparable to predicate device	Complete embolization effectively achieved
Ease of Delivery	Easily delivered to target vessels, comparable to predicate	Easily delivered to target vessels
Rupture/Puncture of Blood Vessels	No rupture or perforation	No vascular rupture or perforation
Non-target Embolization/Device Migration	Comparable to predicate device	Comparable non-target embolization
Clinicopathological Examination	No significant difference in adverse reactions compared to predicate	No significant difference

2. Sample sized used for the test set and the data provenance

In-vitro Bench Testing: The specific sample sizes for each bench test are not explicitly provided, but it's stated that for Packaging Integrity and Shelf Life, "3 batches of each tested for all device specifications."
Animal Performance Testing:
- Sample Size: 24 swine (12 for CalliSpheres Embolic Microspheres, 12 for Embosphere microspheres).
- Data Provenance: The study was an "animal study... intended to simulate the clinical application... A pig model was chosen." This indicates prospective animal data, conducted to support the device's substantial equivalence. The country of origin for the study is not explicitly stated in the provided text.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

This document describes a pre-market notification (510(k)) for a medical device (embolic microspheres). It does not describe a study involving human experts establishing ground truth for AI model testing. The ground truth for the non-clinical tests is based on established laboratory standards, and for the animal study, it's based on clinical observations, histopathological results, and standard measurements.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

Not applicable, as this is not a human expert-based ground truth adjudication for an AI device.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This document is for a medical device (embolic microspheres), not an AI-assisted diagnostic or triaging tool.

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

Not applicable. This document is for a medical device, not a software algorithm.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

In-vitro Bench Testing: Ground truth is based on established international and national standards (e.g., USP, ISO, ASTM guidelines) and predefined acceptance criteria for physical, chemical, and biological properties.
Animal Performance Testing: Ground truth was established through:
- Direct observation and measurement: Ease of delivery, presence of rupture/perforation, non-target embolization.
- Clinical tests: Blood routine, coagulation function, renal function, liver function.
- Imaging: DSA angiography.
- Pathology/Histopathology: Evaluation of local and systemic foreign body reactions, and assessment of embolization effectiveness after necropsy.

8. The sample size for the training set

Not applicable. This document describes the validation of a physical medical device (embolic microspheres), not an AI model requiring a training data set.

9. How the ground truth for the training set was established

Not applicable, as there is no training set for an AI model.

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.

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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 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

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Indications for Use

510(k) Number (if known) K173871

Device Name

CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres

Indications for Use (Describe)

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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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

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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.

ProductCode	CalibratedSize (µm)	Quantity	Indication
			HypervascularTumors/ArteriovenousMalformations	Uterine Fibroid
B107S103	100-300	1ml microspheres : 7ml 0.9%sodium chloride	Yes	No
B107S305	300-500	1ml microspheres : 7ml 0.9%sodium chloride	Yes	No
B107S507	500-700	1ml microspheres : 7ml 0.9%sodium chloride	Yes	Yes
B107S709	700-900	1ml microspheres : 7ml 0.9%sodium chloride	Yes	Yes
B107S912	900-1200	1ml microspheres : 7ml 0.9%sodium chloride	Yes	Yes
B207S103	100-300	2ml microspheres : 7ml 0.9%sodium chloride	Yes	No
B207S305	300-500	2ml microspheres : 7ml 0.9%sodium chloride	Yes	No
B207S507	500-700	2ml microspheres : 7ml 0.9%sodium chloride	Yes	Yes
B207S709	700-900	2ml microspheres : 7ml 0.9%sodium chloride	Yes	Yes
B207S912	900-1200	2ml microspheres : 7ml 0.9%sodium chloride	Yes	Yes

Table 1: Device configurations of CalliSpheres Embolic Microspheres

Table 2: Product configurations of 8Spheres Embolic Microspheres

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	CalibratedSize (um)		Indication
ProductCode		Quantity	HypervascularTumors/ArteriovenousMalformations	Uterine Fibroid
U107S103	100-300	1ml microspheres : 7ml0.9% sodium chloride	Yes	No
U107S305	300-500	1ml microspheres : 7ml0.9% sodium chloride	Yes	No
U107S507	500-700	1ml microspheres : 7ml0.9% sodium chloride	Yes	Yes
U107S709	700-900	1ml microspheres : 7ml0.9% sodium chloride	Yes	Yes
U107S912	900-1200	1ml microspheres : 7ml0.9% sodium chloride	Yes	Yes
U207S103	100-300	2ml microspheres : 7ml0.9% sodium chloride	Yes	No
U207S305	300-500	2ml microspheres : 7ml0.9% sodium chloride	Yes	No
U207S507	500-700	2ml microspheres : 7ml0.9% sodium chloride	Yes	Yes
U207S709	700-900	2ml microspheres : 7ml0.9% sodium chloride	Yes	Yes
U207S912	900-1200	2ml microspheres : 7ml0.9% sodium chloride	Yes	Yes

5 Indications for Use

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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 and8Spheres Embolic Microspheres areintended to be used for the embolization ofarteriovenous malformations (AVMs) andhypervascular tumors, including uterinefibroids.	Bead Block microspheres areintended to be used for theembolization of hypervasculartumors, including uterine fibroidsand arteriovenous malformations(AVMs).	Identical: Indications for use ofthe proposed device is identicalto that of Bead Block(K150876).
Materials	Polyvinyl alcohol (PVA), N-acryloylaminoacetaldehyde dimethylacetal (NAAADA), 2-acrylamido-2-methyl-1-propanesulfonic acid sodiumsalt, 0.9% Sodium Chloride Solution,Reactive Blue Dye #4 (only forCalliSpheres Embolic Microspheres)	Polyvinyl alcohol (PVA), N-acryloylaminoacetaldehydedimethyl acetal (NAAADA), 2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt,buffered Saline, Reactive BlueDye #4	Identical
PolymerizationMethod	Suspension polymerization	Suspension polymerization	Identical
Resorption	Non-resorbable	Non-resorbable	Identical

Appearance	Hydrogel microspheres with regular shape,smooth surface and calibrated size,CalliSpheres: Blue dyed8Spheres: Undyed	Hydrogel microspheres withregular shape, smooth surface andcalibrated size,Bead Block: Blue dyed	CalliSpheres are identical inappearance to Bead Block,8Spheres are undyed. 8Spheresare identical to CalliSpheresexcept for the color.The lack of dye in 8spheresdoes not raise differentquestions of safety andeffectiveness from thepredicate.
Size Range(um)	100-300300-500500-700700-900900-1200	100-300300-500500-700700-900900-1200	Identical
Sizes indicated forUAE(um)	500-700700-900900-1200	700-900900-1200	Different. CalliSpheres and8Spheres of 500-700um areindicated for UAE.Thedifference in size does not raisedifferent questions of safety andeffectiveness.
Water content ofmicrospheres	91% ~ 94%	Approximately 90-95%	Similar. Water content range ofproposed device is narrowerthan that of predicate device.The slight difference of watercontent does not raise differentquestions of safety andeffectiveness.
Storage media	0.9% sodium chloride solution	Phosphate buffered saline (PBS)	Similar. Both 0.9% sodiumchloride solution and phosphatebuffered saline (PBS) can beused for injection.
Quantity ofMicrospheres	1mL, 2mL	1mL, 2mL	Identical
Quantity of StorageMedia	Both CalliSpheres and 8Spheres have thefollowing two quantities:1)1ml microspheres in 7ml 0.9%sodium chloride solution to form atotal volume of 8mL2)2ml microspheres in 7ml 0.9%sodium chloride solution to form atotal volume of 9mL.	Bead Block CompressibleMicrospheres have the followingtwo quantities:1)1 mL microspheres in 6mlPBS to form a total volumeof 7mL2)2 mL microspheres in 5mlPBS to form a total volumeof 7mL.	Similar, the slight difference ofsaline quantity does not raisedifferent questions of safety andeffectiveness.
Packaging	Both CalliSpheres and 8Spheres are sealedin borosilicate glass vial.	Bead Block is sealed inpolycarbonate syringe	Similar. Packaging has beenverified by packagingcompatibility testing and doesnot raise different questions ofsafety and effectiveness.
Compressibility	30% by diameter	Approximately 30% by diameter	Identical
Suspension	The time taken to achieve suspension isless than 10 min, and the time maintainingsuspension is longer than 4 mins.	The time taken to achievesuspension is less than 4 min, andthe time maintaining suspension islonger than 4.5 mins.	Similar. The slight difference oftime does not raise differentquestions of safety andeffectiveness.
Delivery Method	Delivered to target position by micro-catheter under DSA.	Delivered to target position bymicro-catheter under DSA.	Identical
CompatibleDelivery Catheter	1.7-4Fr	1.5-5Fr	Similar. The specification forCalliSpheres and 8Spheres lieswithin the range of thepredicate. The slight differencedoes not raise differentquestions of safety andeffectiveness.
RadiopacityMethod	Mixed with non-ionic contrast agent priorto injection	Mixed with non-ionic contrastagent 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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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) <1> Injectionsand Implanted Drug Products(Parenterals) -Product Quality Tests and<790> Visible Particulates In Injections	Met predefined acceptancecriteria
2	pH test	USP39 NF34 (2016) - <791> pH	Met predefined acceptancecriteria
3	Size rangeconfirmation	Method adapted from ISO 13322-1:2014Particle size analysis - Image analysismethods – Part 1: Static image analysismethods. The particle sizes ofCallispheres and 8spheres EmbolicMicrospheres were measured andconfirmed by optical microscope, digitalcamera and corresponding particle sizemeasurement software which have beencalibrated and validated.	Met predefined acceptancecriteria
4	CompressibilityTest	A texture analyzer was used to test thecompressibility of microspheres;microspheres were compressed of 30%by diameter and maintained for 10s.After the compression the microspheres	Met predefined acceptancecriteria
		were inspected by microscope formaintenance of shape and breakage.
5	Catheterdeliverability test	Particles were delivered through 1.7Fr -4.0Fr microcatheters to evaluate thepotential for clogging and breakage ofspheres. The size of the microcatheterwas selected based on the size of themicrospheres. In order to simulate thetortuosity of the catheters used inclinical practice, the microcatheters wereinserted into a model simulated tohuman hepatic artery to conduct thecatheter deliverability test. Clogging wasassessed during the test, andmicrospheres were inspectedmicroscopically following delivery forsigns of breakage or changes in shape.	Met predefined acceptancecriteria
6	Water content test	USP 39 NF34 (2016) - <731> Loss onDrying	Met predefinedacceptancecriteria
7	Impurities andResidual SolventsTest	USP39 NF34 (2016) - <1086>Impurities in Drug Substances and DrugProducts, <467> Residual Solvents,<621> Chromatography, <857>Ultraviolet -Visible Spectroscopy	Met predefined acceptancecriteria
8	Suspension	A suspension study of all variants ofCalliSpheres and 8Spheres EmbolicMicrospheres was conducted with threecommercially-available nonioniccontrast agents based upon the followingstudy:Lewis AL et. al. Comparative in vitroevaluation of microsphericalembolization agents. J Mater Sci MaterMed. 2006 Dec: 17(12):1193-204.	Met predefined acceptancecriteria
9	Sterility Test	USP 39 -NF34 (2016) <71> SterilityTests	Met predefined acceptancecriteria
10	Bacterial	USP39 -NF34 (2016) - <85>	Met predefined acceptance

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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 <85> 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

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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.

BiocompatibilityEvaluation	Summary
Cytotoxicity Study Usingthe ISO Elution Method	The test article, CalliSpheres Embolic Microspheres, was evaluatedfor potential cytotoxic effects using an in vitro mammalian cellculture test. This study was conducted following the guidelines ofISO 10993-5, Biological evaluation of medical devices - Part 5:Tests for in vitro cytotoxicity. The test article extract showed noevidence of causing cell lysis or toxicity. The test article extractmet the requirements of the test since the grade was less than agrade 2 (mild reactivity).
ISO Intracutaneous Studyin Rabbits	The test article, CalliSpheres Embolic Microspheres, was evaluatedfor the potential to cause irritation following intracutaneousinjection in rabbits. This study was conducted based on ISO10993-10, Biological evaluation of medical devices - Part 10: Testsfor irritation and skin sensitization. The test article met therequirements of the test.
ISO MaximizationSensitization Study	The test article, CalliSpheres Embolic Microspheres, was evaluatedfor the potential to cause delayed dermal contact sensitization in aguinea pig maximization test. This study was conducted based onthe requirements of ISO 10993-10, Biological evaluation ofmedical devices - Part 10: Tests for irritation and skin sensitization.The test article extracts showed no evidence of causing delayeddermal contact sensitization in the guinea pig. The test article wasnot considered a sensitizer in the guinea pig maximization test.
ISO Systemic ToxicityStudy	The test article, CalliSpheres Embolic Microspheres, was evaluatedfor acute systemic toxicity in mice. This study was conductedbased on ISO 10993-11, Biological evaluation of medical devices -Part 11: Tests for systemic toxicity. There was no mortality orevidence of systemic toxicity from the extracts injected into mice.Each test article extract met the requirements of the study.
Modified ASTMHemolysis Study	The test article, CalliSpheres Embolic Microspheres, was evaluatedfor the potential to cause hemolysis. This study was conductedbased on ASTM F756, Standard Practice for Assessment ofHemolytic Properties of Materials and ISO 10993-4, Biologicalevaluation of medical devices - Part 4: Selection of tests torinteractions with blood. The hemolytic index tor the test article indirect contact with blood was 0.6% and the direct contact was non-hemolytic.
ASTM PartialThromboplastin Time	The test article, CalliSpheres Embolic Microspheres, was evaluatedto determine the potential to cause an effect on the coagulationcascade via the intrinsic coagulation pathway. The study wasconducted in accordance to ASTM F2382: Standard Test Methodfor Assessment of Circulating Blood-Contacting Medical DeviceMaterials on Partial Thromboplastin Time (PTT). The test articleaverage clotting time was lower and was not statistically differentthan the negative reference material. The test article met therequirements of the test.
SC5b-9 ComplementActivation Assay	The test article, CalliSpheres Embolic Microspheres, and sponsorprovided control (SPC), Embospheres, were evaluated for thepotential to activate the complement system. This study wasconducted based on ISO 10993-4, Biological evaluation of medicaldevices - Part 4: Selection of tests for interactions with blood. Thetest article, SPC, and comparative control were incubated in normalhuman serum (NHS) and SC5b-9 was measured in the exposedserum using an enzyme immunoassay. The test article was notconsidered to be a potential activator of the complement system.
USP Rabbit PyrogenStudy	The test article, CalliSpheres Embolic Microspheres, was evaluatedfor material mediated pyrogenicity in rabbits. The test wasconducted based on USP, General Chapter <151>, Pyrogen Test.The procedure is recommended in ISO 10993-11, Biologicalevaluation of medical devices - Part 11: Tests for systemic toxicity.The total rise of rabbit temperatures during the 3 hour observationperiod was within acceptable USP requirements. The test articlemet the requirements for the absence of pyrogens.
Genotoxicity: BacterialReverse Mutation Study	The test article, CalliSpheres Embolic Microspheres and 8SpheresEmbolic Microspheres, were evaluated for the potential to causemutagenic changes at the histidine locus of the Salmonellatyphimurium tester strains TA98, TA100, TA1535. And TA1537 orat the tryptophan locus of the Escherichia coli tester strainWP2wv/v4. The study was conducted in the presence and absenceof S9 metabolic activation based on ISO 10993-3, Biologicalevaluation 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: MouseLymphoma 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 ImplantationStudy in Rabbits, 4Weeks	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 ToxicityStudy in Rats FollowingSubcutaneous andMuscle Implantation, 13Weeks	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.

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).