Who is the manufacturer of CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres?

Suzhou Hengrui Callisyn Biomedical Co., Ltd. filed the 510(k) submission for CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres (K173871).

What is the FDA product code for CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres?

NAJ. It is classified under 21 CFR 870.3300 as a Class 2 device in the Cardiovascular panel.

What is the regulatory pathway for CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres?

510(k) clearance (submission type: Traditional).

Who can help prepare an FDA 510(k) submission like CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres?

Innolitics — a medical-device software consultancy — provides regulatory and engineering support for FDA 510(k) submissions. See https://innolitics.com/services/510ks/ or contact https://innolitics.com/contact.

CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres

K173871 · Suzhou Hengrui Callisyn Biomedical Co., Ltd. · NAJ · Sep 17, 2018 · Cardiovascular

Device Facts

Record ID	K173871
Device Name	CalliSpheres Embolic Microspheres, 8Spheres Embolic Microspheres
Applicant	Suzhou Hengrui Callisyn Biomedical Co., Ltd.
Product Code	NAJ · Cardiovascular
Decision Date	Sep 17, 2018
Decision	SESE
Submission Type	Traditional
Regulation	21 CFR 870.3300
Device Class	Class 2
Attributes	Therapeutic

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.

Device Story

Compressible hydrogel microspheres; PVA-based; non-resorbable; regular shape; smooth surface. Input: mixed with non-ionic contrast agent at time of use. Operation: delivered via microcatheter (1.7-4 Fr) under DSA guidance to target vasculature; blocks blood supply to tumor/malformation to induce shrinkage. Output: mechanical occlusion of target vessels. Used in clinical interventional radiology settings by physicians. Benefits: minimally invasive treatment for hypervascular tumors and AVMs.

Clinical Evidence

No human clinical data. Evidence includes extensive in-vitro bench testing (size, compressibility, deliverability, suspension, sterility, chemical characterization) and a comparative animal study (swine model, n=24) against Embosphere (K021397). Animal study evaluated recanalization, foreign body reaction, embolization effectiveness, and delivery ease at 2, 7, and 28 days; results showed comparable safety and effectiveness to the predicate.

Technological Characteristics

Hydrogel microspheres composed of PVA, NAAADA, and 2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt. 91-94% water content. 30% compressibility. Sizes 100-1200µm. Sterile, single-use, moist heat sterilized (121°C, 30 min). Packaged in borosilicate glass vials with 0.9% NaCl. Non-resorbable.

Indications for Use

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

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

Bead Block (K150876)

Reference Devices

Embosphere Microspheres (K021397)

Submission Summary (Full Text)

{0}------------------------------------------------ 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) ### CONTINUE ON A SEPARATE PAGE IF NEEDED. This section applies only to requirements of the Paperwork Reduction Act of 1995. ### *DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.* The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to: > Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov "An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number." {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 {4}------------------------------------------------ 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 | Indication | | |-----------------|-------------------------|------------------------------------------------|------------------------------------------------------------|-----------------| | | | | Hypervascular Tumors/ Arteriovenous Malformations | 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 {6}------------------------------------------------ | | 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: 1) 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 {8}------------------------------------------------ {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) <1> Injections and Implanted Drug Products (Parenterals) -Product Quality Tests and <790> Visible Particulates In Injections | Met predefined acceptance criteria | | 2 | pH test | USP39 NF34 (2016) - <791> 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) - <731> Loss on Drying | Met predefined acceptance criteria | | 7 | Impurities and Residual Solvents Test | USP39 NF34 (2016) - <1086> Impurities in Drug Substances and Drug Products, <467> Residual Solvents, <621> Chromatography, <857> 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) <71> Sterility Tests | Met predefined acceptance criteria | | 10 | Bacterial | USP39 -NF34 (2016) - <85> | 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 <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 {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 <151>, 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. | | {14}------------------------------------------------ {15}------------------------------------------------ {16}------------------------------------------------ #### 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…

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