(218 days)
HRSpheres Narrow-Size Embolic Microspheres are intended to be used for the embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids.
HRSpheres Narrow-Size Embolic Microspheres are compressible hydrogel microspheres with a regular shape, smooth surface, and calibrated size, which are formed as a result of chemical modification on polyvinyl alcohol (PVA) materials. HRSpheres Narrow-Size Embolic Microspheres consist of a macromer derived from PVA, and are hydrophilic, non-resorbable, and are available in a variety of diameters ranging from 70 - 1,200 um. The preservation solution is 0.9% sodium chloride solution. The water content of a fully polymerized microsphere is 91% ~ 94%. Microspheres are compressible to enable smooth delivery through the indicated delivery catheter. The HRSpheres are available in dyed (blue) and clear (undyed with natural color). Blue-dyed microspheres aid in the visualization of the microspheres in the delivery syringe. HRSpheres Narrow-Size Embolic Microspheres are packaged in sterile sealed glass vials for single use only and available with 1 mL, 2 mL, or 3 mL microspheres volumes per vial.
HRSpheres Narrow-Size Embolic Microspheres can be delivered to a targeted area through typical microcatheters in the 1.7 – 4 Fr range. By blocking the blood supply to the target area, the tumor or malformation is starved of nutrients and shrinks in size. At the time of use. HRSpheres Narrow-Size Embolic Microspheres are mixed with a nonionic contrast agent to form a suspension solution and aid in visualization during a procedure.
The user is asking for information regarding acceptance criteria and a study to prove a device meets those criteria, specifically for the HRSpheres Narrow-Size Embolic Microspheres.
Based on the provided text, this document is a 510(k) Pre-Market Notification for a medical device seeking substantial equivalence to a predicate device, not a study describing a new device and its performance against acceptance criteria as might be seen for an AI/ML medical device. Therefore, a direct response to some of the requested points (like MRMC study, ground truth for training data, number of experts for test set ground truth) is not applicable or cannot be extracted.
However, I can extract the non-clinical performance evaluations and their results, which serve as acceptance criteria for the device's physical and biological properties.
Here's a breakdown of the requested information based on the provided text:
1. A table of acceptance criteria and the reported device performance
The document lists non-clinical performance evaluations with "Met predefined acceptance criteria" as the result for each. While specific numerical acceptance criteria are not detailed in this summary, the overall outcome indicates compliance.
| Acceptance Criteria (Test Items) | Reported Device Performance (Results) |
|---|---|
| Appearance | Met predefined acceptance criteria |
| Compressibility | Met predefined acceptance criteria |
| Quantity | Met predefined acceptance criteria |
| Size Range | Met predefined acceptance criteria |
| Suspension | Met predefined acceptance criteria |
| Catheter Deliverability | Met predefined acceptance criteria |
| Water Content | Met predefined acceptance criteria |
| pH | Met predefined acceptance criteria |
| Impurities and residual solvents | Met predefined acceptance criteria |
| Sterility | Met predefined acceptance criteria |
| Bacterial endotoxin | Met predefined acceptance criteria |
| Packaging Integrity (after aging) | Met specifications |
| Shelf Life (after accelerated aging) | Met specifications (supports 3 years) |
| Biocompatibility: MTT Cytotoxicity Test | Non-cytotoxic |
| Biocompatibility: ISO Guinea Pig Maximization Sensitization Test | Non-sensitizer |
| Biocompatibility: ISO Intracutaneous Study in Rabbits | Non-irritant |
| Biocompatibility: ISO Acute Systemic Toxicity Study in Mice | No mortality or evidence of systemic toxicity |
| Biocompatibility: ASTM Hemolysis Study | Non-hemolytic |
| Biocompatibility: ASTM Partial Thromboplastin Time | Non-activator |
| Biocompatibility: SC5b-9 Complement Activation Assay | Potential activators, but test article lower than control and statistically different |
| Biocompatibility: USP Rabbit Pyrogen Study, Material Mediated | Non-pyrogenic |
| Biocompatibility: Genotoxicity Mouse Lymphoma Assay | Non-mutagenic |
| Biocompatibility: Bacterial Reverse Mutation Study | Non-mutagenic |
| Biocompatibility: ISO Systemic Toxicity Study in Rats Following Subcutaneous Implantation, 13 Weeks | No evidence of systemic toxicity, minimal to no microscopic reaction |
| Biocompatibility: ISO Muscle Implantation Study in Rabbits, 4 Weeks | Not significant macroscopic reaction, minimal to no microscopic reaction |
| Biocompatibility: ISO Muscle Implantation Study in Rabbits, 13 Weeks | Not significant macroscopic reaction, slight microscopic reaction |
| Biocompatibility: Chronic Systemic Toxicity and Carcinogenicity Evaluation | Low risk based on risk assessment |
2. Sample size used for the test set and the data provenance
- Non-clinical Bench Testing (Test Set): For shelf-life testing, "3 batches of each tested for all device specifications" were used. Specific sample sizes for other in-vitro tests are not explicitly stated, but "Met predefined acceptance criteria" implies sufficient testing was performed.
- Animal Study (Test Set):
- Sample Size: A total of 15 female domestic swine.
- Test Article Group (HRSpheres): 7 pigs
- Control Article Group (CalliSpheres): 8 pigs
- Data Provenance: The study was performed on healthy swine models, indicating prospective animal study data. The country of origin for the animal study is not specified, but the applicant company is in China.
- Sample Size: A total of 15 female domestic swine.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
- Not applicable for this type of device. This is a physical embolic microsphere device, not an AI/ML diagnostic device requiring expert interpretation of images for ground truth. The "ground truth" for this device's performance is established by direct measurement (e.g., size, pH), chemical analysis, and biological responses in animal models and in-vitro tests.
4. Adjudication method for the test set
- Not applicable for this type of device. Adjudication is relevant for subjective expert interpretation, which is not the primary method of evaluation for this physical device. Performance was measured objectively.
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 device is an embolic microsphere, not an AI/ML software for image analysis or diagnosis. Therefore, an MRMC study is irrelevant.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
- Not applicable. This is a physical medical device, not an algorithm.
7. The type of ground truth used
For the non-clinical performance testing and animal study:
- Physical/Chemical Properties: Measured values against predefined specifications (e.g., pH, size range, water content).
- Biological Endpoints: Direct observation of biological responses in in-vitro assays and animal models (e.g., cytotoxicity, hemolytic activity, pyrogenicity, tissue reactions, systemic toxicity).
- Animal Study Outcomes: Comparison of physiological, imaging, and pathological changes between the test and control groups over time points (3, 8, and 29 days post-embolization). This includes:
- Recanalization of vessels/durability of occlusion
- Local and systemic foreign body reactions
- Ease of delivery
- Rupture or puncture of blood vessels
- Non-target embolization/device migration
- Clinicopathological examination results (hematology, blood coagulation, serum biochemistry).
8. The sample size for the training set
- Not applicable for this submission. This document describes the non-clinical and animal testing for a physical medical device for 510(k) clearance, not the development or validation of an AI/ML model that would require a distinct training set. The data presented are for product verification and validation.
9. How the ground truth for the training set was established
- Not applicable for this submission. (See point 8).
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Image /page/0/Picture/0 description: The image contains the logos of the Department of Health & Human Services and the Food and Drug Administration (FDA). The Department of Health & Human Services logo is on the left, and the FDA logo is on the right. The FDA logo includes the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text.
October 1, 2021
Suzhou Hengrui Hongyuan Medical Co., Ltd. Qianqian Zhang Regulatory Affairs Engineer Building B9 Unit 201, No. 218 Xinghu Road, SIP Suzhou, Jiangsu 215123 China
Re: K210562
Trade/Device Name: HRSpheres Narrow-Size Embolic Microspheres Regulation Number: 21 CFR§ 870.3300 Regulation Name: Vascular embolization device Regulatory Class: II Product Code: KRD, NAJ Dated: September 8, 2021 Received: September 16, 2021
Dear Qianqian Zhang:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies.
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You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatoryinformation/postmarketing-safety-reporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Jason R. Roberts, Ph.D. Assistant Director DHT3B: Division of Reproductive. Gynecology and Urology Devices OHT3: Office of GastroRenal, ObGyn, General Hospital and Urology Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K210562
Device Name
HRSpheres Narrow-Size Embolic Microspheres
Indications for Use (Describe)
HRSpheres Narrow-Size Embolic Microspheres are intended to be used for the embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids.
| Type of Use (Select one or both, as applicable) | |
|---|---|
|× Prescription Use (Part 21 CFR 801 Subpart D)
| | Over-The-Counter Use (21 CFR 801 Subpart C)
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510(k) Summary
HRSpheres Narrow-Size Embolic Microspheres (per 21 CFR 807.92)
1. Submitter
| Submitter Name: | Suzhou Hengrui Hongyuan Medical Co., Ltd |
|---|---|
| Address: | Building B9 Unit 201, No. 218 Xinghu Road, SIP, Suzhou,Jiangsu, China 215123 |
| Phone: | +86-512-6835-6665 |
| Contact Person: | Qianqian Zhang |
| Email: | zhangqianqian@hrmedical.com.cn |
September 30, 2021
2. Subject Device
Date Prepared:
| Device Name: | HRSpheres Narrow-Size Embolic Microspheres |
|---|---|
| Common or Usual Name: | Polyvinyl Alcohol Embolic Microspheres |
| Classification Name: | Vascular Embolization Device (21 CFR 870.3300) |
| Regulatory Class: | Class II |
| Product Code: | KRD (device, vascular, for promoting embolization),NAJ (agents, embolic, for treatment of uterine fibroids) |
3. Predicate Device
| Device Name: | CalliSpheres Embolic Microspheres, 8Spheres |
|---|---|
| Embolic Microspheres | |
| 510(k) number: | K173871 |
| Manufacturer: | Suzhou Hengrui Callisyn Biomedical Co., Ltd |
| Regulation Number: | 21 CFR 870.3300 |
| Product Code: | KRD, NAJ |
The predicate device has not been subject to any design-related recall.
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4. Device Description
HRSpheres Narrow-Size Embolic Microspheres are compressible hydrogel microspheres with a regular shape, smooth surface, and calibrated size, which are formed as a result of chemical modification on polyvinyl alcohol (PVA) materials. HRSpheres Narrow-Size Embolic Microspheres consist of a macromer derived from PVA, and are hydrophilic, non-resorbable, and are available in a variety of diameters ranging from 70 - 1,200 um. The preservation solution is 0.9% sodium chloride solution. The water content of a fully polymerized microsphere is 91% ~ 94%. Microspheres are compressible to enable smooth delivery through the indicated delivery catheter. The HRSpheres are available in dyed (blue) and clear (undyed with natural color). Blue-dyed microspheres aid in the visualization of the microspheres in the delivery syringe. HRSpheres Narrow-Size Embolic Microspheres are packaged in sterile sealed glass vials for single use only and available with 1 mL, 2 mL, or 3 mL microspheres volumes per vial.
HRSpheres Narrow-Size Embolic Microspheres can be delivered to a targeted area through typical microcatheters in the 1.7 – 4 Fr range. By blocking the blood supply to the target area, the tumor or malformation is starved of nutrients and shrinks in size. At the time of use. HRSpheres Narrow-Size Embolic Microspheres are mixed with a nonionic contrast agent to form a suspension solution and aid in visualization during a procedure. The device configurations are described in Table 1. Product codes beginning with "B" represent microspheres with blue dye (Reactive Blue #4) and codes beginning with "C" represent undyed microspheres. Among the various size ranges of HRSpheres Narrow-Size Embolic Microspheres, the sizes that can be used for uterine fibroid embolization are 500 um, 700um, 900 um, 1200 um.
| Indication | |||||
|---|---|---|---|---|---|
| ProductCode | Calibratedsize (µm) | Size Range(µm) | Quantity | HypervascularTumors /ArteriovenousMalformations | UterineFibroid |
| B107S007 | 70 | 70-100 | 1 mL microspheres: 7 mL0.9% sodium chloride solution | Yes | No |
| B207S007 | 2 mL microspheres: 7 mL0.9% sodium chloride solution | ||||
| B306S007 | 3 mL microspheres: 6 mL0.9% sodium chloride solution | ||||
| B107S010 | 100 | 75-125 | 1 mL microspheres: 7 mL0.9% sodium chloride solution | Yes | No |
| ProductCode | Calibratedsize (µm) | Size Range(µm) | Quantity | Indication | |
| HypervascularTumors /ArteriovenousMalformations | UterineFibroid | ||||
| B207S010 | 0.9% sodium chloride solution2 mL microspheres: 7 mL | ||||
| B306S007 | 0.9% sodium chloride solution3 mL microspheres: 6 mL | ||||
| B107S025 | 0.9% sodium chloride solution1 mL microspheres: 7 mL | ||||
| B207S025 | 250 | 200-300 | 0.9% sodium chloride solution2 mL microspheres: 7 mL | Yes | No |
| B306S025 | 0.9% sodium chloride solution3 mL microspheres: 6 mL | ||||
| B107S040 | 0.9% sodium chloride solution1 mL microspheres: 7 mL | ||||
| B207S040 | 400 | 350-450 | 0.9% sodium chloride solution2 mL microspheres: 7 mL | Yes | No |
| B306S040 | 0.9% sodium chloride solution3 mL microspheres: 6 mL | ||||
| B107S050 | 0.9% sodium chloride solution1 mL microspheres: 7 mL | ||||
| B207S050 | 500 | 480-580 | 0.9% sodium chloride solution2 mL microspheres: 7 mL | Yes | Yes |
| B306S050 | 0.9% sodium chloride solution3 mL microspheres: 6 mL | ||||
| B107S070 | 0.9% sodium chloride solution1 mL microspheres: 7 mL | ||||
| B207S070 | 700 | 650-750 | 0.9% sodium chloride solution2 mL microspheres: 7 mL | Yes | Yes |
| B306S070 | 0.9% sodium chloride solution3 mL microspheres: 6 mL | ||||
| B107S090 | 0.9% sodium chloride solution1 mL microspheres: 7 mL | ||||
| B207S090 | 900 | 825-975 | 0.9% sodium chloride solution2 mL microspheres: 7 mL | Yes | Yes |
| B306S090 | 0.9% sodium chloride solution3 mL microspheres: 6 mL | ||||
| B107S120 | 1,200 | 1,000-1,200 | 0.9% sodium chloride solution1 mL microspheres: 7 mL | Yes | Yes |
| B207S120 | 2 mL microspheres: 7 mL | ||||
| ProductCode | Calibratedsize (µm) | Size Range(μm) | Quantity | Indication | |
| HypervascularTumors /ArteriovenousMalformations | UterineFibroid | ||||
| B306S120 | 0.9% sodium chloride solution3 mL microspheres: 6 mL0.9% sodium chloride solution | ||||
| C107S007 | 1 mL microspheres: 7 mL0.9% sodium chloride solution | ||||
| C207S007 | 70 | 70-100 | 2 mL microspheres: 7 mL0.9% sodium chloride solution | Yes | No |
| C306S010 | 3 mL microspheres: 6 mL0.9% sodium chloride solution | ||||
| C107S010 | 1 mL microspheres: 7 mL0.9% sodium chloride solution | ||||
| C207S010 | 100 | 75-125 | 2 mL microspheres: 7 mL0.9% sodium chloride solution | Yes | No |
| C306S010 | 3 mL microspheres: 6 mL0.9% sodium chloride solution | ||||
| C107S025 | 1 mL microspheres: 7 mL0.9% sodium chloride solution | ||||
| C207S025 | 250 | 200-300 | 2 mL microspheres: 7 mL0.9% sodium chloride solution | Yes | No |
| C306S025 | 3 mL microspheres: 6 mL0.9% sodium chloride solution | ||||
| C107S040 | 1 mL microspheres: 7 mL0.9% sodium chloride solution | ||||
| C207S040 | 400 | 350-450 | 2 mL microspheres: 7 mL0.9% sodium chloride solution | Yes | No |
| C306S040 | 3 mL microspheres: 6 mL0.9% sodium chloride solution | ||||
| C107S050 | 1 mL microspheres: 7 mL0.9% sodium chloride solution | ||||
| C207S050 | 500 | 480-580 | 2 mL microspheres: 7 mL0.9% sodium chloride solution | Yes | Yes |
| C306S050 | 3 mL microspheres: 6 mL0.9% sodium chloride solution | ||||
| C107S070 | 1 mL microspheres: 7 mL0.9% sodium chloride solution | ||||
| ProductCode | Calibratedsize (µm) | Size Range(µm) | Quantity | Indication | |
| HypervascularTumors /ArteriovenousMalformations | UterineFibroid | ||||
| C107S090 | 0.9% sodium chloride solution1 mL microspheres: 7 mL0.9% sodium chloride solution | ||||
| C207S090 | 900 | 825-975 | 2 mL microspheres: 7 mL0.9% sodium chloride solution | Yes | Yes |
| C306S090 | 3 mL microspheres: 6 mL0.9% sodium chloride solution | ||||
| C107S120 | 1 mL microspheres: 7 mL0.9% sodium chloride solution | ||||
| C207S120 | 1,200 | 1,000-1,200 | 2 mL microspheres: 7 mL0.9% sodium chloride solution | Yes | Yes |
| C306S120 | 3 mL microspheres: 6 mL0.9% sodium chloride solution |
Table 1: Device configurations of HRSpheres Embolic Microspheres
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3 mL microspheres: 6 mL
2 mL microspheres: 7 mL
0.9% sodium chloride solution
Yes
Yes
700
C207S070
C306S070
650-750
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5. Indications for Use
HRSpheres Narrow-Size Embolic Microspheres are intended to be used for the embolization of arteriovenous malformations (AVMs) and hypervascular tumors, including uterine fibroids.
6. Comparison of Technological Characteristics with the Predicate Device
A comparison of the technological characteristics of HRSpheres and the CalliSpheres and 8Spheres embolic beads is summarized in Table 2 below:
| Performance Characteristics Comparison Table | |||
|---|---|---|---|
| DeviceCharacteristic | Subject Device:HRSpheres Narrow-SizeEmbolic Microspheres | Predicate Device:CalliSpheres and8Spheres EmbolicMicrospheres | Comment |
| 510(k) Number | K210562 | K173871 | N/A |
| Classification | II | II | Same |
| Product Code | KRD, NAJ | KRD, NAJ | Same |
| Performance Characteristics Comparison Table | |||
| DeviceCharacteristic | Subject Device:HRSpheres Narrow-SizeEmbolic Microspheres | Predicate Device:CalliSpheres and8Spheres EmbolicMicrospheres | Comment |
| Regulation | 21 CFR 870.3300 | 21 CFR 870.3300 | Same |
| Indication forUse | HRSpheres Narrow-SizeEmbolic Microspheres areintended to be used for theembolization ofarteriovenousmalformations (AVMs)and hypervascular tumors,including uterine fibroids. | CalliSpheres EmbolicMicrospheres and8Spheres EmbolicMicrospheres are intendedto be used for theembolization ofarteriovenousmalformations (AVMs)and hypervascular tumors,including uterine fibroids. | Same |
| PolymerizationMethod | Suspensionpolymerization | Suspensionpolymerization | Same |
| Resorption | Non-resorbable | Non-resorbable | Same |
| Materials | Polyvinyl alcohol (PVA),N-acryloylaminoacetaldehyde dimethyl acetal, 2-acrylamido-2-methyl-1-propanesulfonic acidsodium salt, 0.9% sodiumchloride solution, ReactiveBlue Dye #4 (only forblue type microspheres) | Polyvinyl alcohol (PVA),N-acryloylaminoacetaldehyde dimethyl acetal(NAAADA), 2-acrylamido-2-methyl-1-propanesulfonic acidsodium salt, 0.9% sodiumchloride solution, ReactiveBlue Dye #4 (only forCalliSpheres) | Different. The differencesin material do not raisedifferent questions ofsafety and effectiveness. |
| Storage media | 0.9% sodium chloridesolution | 0.9% sodium chloridesolution | Same |
| MicrosphereDiameter | Size range: 70-1,200μmLabeled size range:70-100 μm75-125 μm200-300 μm350-450 μm480-580 μm650-750 μm825-975 μm1,000-1,200 μm | Size range: 100-1,200μmLabeled size range:100-300μm300-500μm500-700μm700-900μm900-1,200μm | Different. The subjectdevice contains a smallersize range specificationthan the predicate device.The difference in sizeranges does not raisedifferent questions ofsafety and effectiveness. |
| Performance Characteristics Comparison Table | |||
| DeviceCharacteristic | Subject Device:HRSpheres Narrow-SizeEmbolic Microspheres | Predicate Device:CalliSpheres and8Spheres EmbolicMicrospheres | Comment |
| Quantity ofMicrospheres(and storagemedia) | 1 mL (in 7 mL saline), 2mL (in 7 mL saline) or 3mL (in 6 mL saline) | 1 mL (in 7 mL saline) or 2mL (in 7 mL saline) | Different. The differencein microsphere volumesdoes not raise differentquestions of safety andeffectiveness. |
| Packaging | Sealed in borosilicateglass vial | Sealed in borosilicateglass vial | Same |
| Compressibility | 50% by diameter | 30% by diameter | Different. The subjectdevice is able to tolerate agreater compressibilitythan the predicate device.The difference incompressibility tolerancedoes not raise differentquestions of safety andeffectiveness. |
| RadiopacityMethod | Mixed with non-ioniccontrast media prior toinjection | Mixed with non-ioniccontrast media prior toinjection | Same |
| DeliveryMethod | Via catheter underfluoroscopic visualization | Via catheter underfluoroscopic visualization | Same |
| Method ofSupply | Sterile and single use | Sterile and single use | Same |
| Shelf Life | Three years | Two years | Different. The increasedshelf life does raisedifferent questions ofsafety and effectiveness. |
| Sterilization | Moist heat and non-pyrogenic | Moist heat and non-pyrogenic | Same |
Table 2: Technological Characteristic Comparison Table
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Overall, the differences in technological characteristics between the subject and predicate device do not raise different questions of safety and effectiveness.
7. Summary of Non-clinical Performance Testing
The device is subject to Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: Vascular and Neurovascular Embolization Devices
{10}------------------------------------------------
issued on December 29, 2004. The safety and effectiveness of HRSpheres Narrow-Size Embolic Microspheres have been evaluated by non-clinical performance testing including:
In-Vitro Bench Testing 7.1
The test items, methods, and method references of HRSpheres Narrow-Size Embolic Microspheres are as follows:
| Test Items | Test Methods | Results |
|---|---|---|
| Appearance | USP 39 - <1> Injections and Implanted DrugProducts (Parenterals) -Product Quality Testsand <790> Visible Particulates In Injections | Met predefined acceptance criteria |
| Compressibility | Internal Methods | Met predefined acceptance criteria |
| Quantity | USP <1151> Pharmaceutical | Met predefined acceptance criteria |
| Size Range | Internal Methods | Met predefined acceptance criteria |
| Suspension | In House Methods | Met predefined acceptance criteria |
| CatheterDeliverability | In House Methods | Met predefined acceptance criteria |
| Water Content | USP 39 NF34 (2016) - <731> Loss ondrying | Met predefined acceptance criteria |
| pH | USP 39 NF 34 (2016) - <791> pH | Met predefined acceptance criteria |
| Impurities andresidual solvents | USP39 NF34 - <1086> Impurities in DrugSubstances and Drug Products | Met predefined acceptance criteria |
| Sterility | USP <71> Sterility Tests | Met predefined acceptance criteria |
| Bacterialendotoxin | USP<85> Bacterial Endotoxins | Met predefined acceptance criteria |
Table 3: Device Non-Clinical Performance Evaluations
7.2 Packaging Integrity and Shelf Life
HRSpheres Narrow-Size Embolic Microspheres are supplied sterile and packaged in borosilicate glass vials.
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According to ASTM F1980-16, accelerated aging tests equivalent to 3 years of shelf life were carried out on HRSpheres Narrow-Size Embolic Microspheres, with 3 batches of each tested for all device specifications. Accelerated aging tests for package integrity were also carried out on the packaging materials including the bottles, rubber closures, and aluminum plastic covers.
The results of the performance tests after accelerated aging demonstrated all samples met specifications. Therefore, the results support a 3 year shelf life of HRSpheres Narrow-Size Embolic Microspheres.
7.3 Sterilization and Shelf Life
HRSpheres Narrow-Size Embolic Microspheres are labeled as "Sterile" and "nonpyrogenic." HRSpheres Narrow-Size Embolic Microspheres are sterilized by moist heat sterilization with validated parameters (121 ℃, 30 min) after sealing the vials. Sterilization validation was completed to a sterility assurance level (SAL) of 10° using the Overkill Approach per ANSI/AAMI/ISO 17665-1:2006(R)2013.
HRSpheres Narrow-Size Embolic Microspheres were tested for bacterial endotoxins per USP <85> Bacterial Endotoxins Test to a level of not more than 0.5 EU/mL in accordance with the requirements of FDA guidance document: Guidance for Industry: Pyrogen Endotoxins Testing: Questions and Answers, issued June 2012.
7.4 Chemical Characterization
Chemical characterization testing was conducted on HRSpheres Narrow-Size Embolic Microspheres. The testing consisted of exhaustive extraction of the microspheres in purified water, ethanol, and hexane. Extracts were analyzed per FTIR, GC-MS and UPLC-MS. Water extract was also analyzed by ICP-MS. A risk analysis using a worst-case risk assessment approach was conducted based upon the findings of the exhaustive extraction. Using this approach, it was determined that the margins of safety (MOS) for potential chemical exposures indicated a low risk of chronic toxicity and carcinogenicity.
7.5 Biocompatibility Evaluation
Biocompatibility testing was conducted in accordance with the 2020 FDA guidance document Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process." The following biocompatibility tests listed in Table 3 were completed, and the results demonstrate the subject device is biocompatible:
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| Biological Endpoint | Test Method | Results |
|---|---|---|
| MTT Cytotoxicity Test | ISO 10993-5:2009 | Non-cytotoxic |
| ISO Guinea Pig MaximizationSensitization Test | ISO 10993-10:2010 | Non-sensitizer |
| ISO Intracutaneous Study inRabbits | ISO 10993-10:2010 | Non-irritant |
| ISO Acute Systemic ToxicityStudy in Mice | ISO 10993-11:2017 | No mortality or evidence of systemictoxicity |
| ASTM Hemolysis Study | ISO 10993-4:2017ASTM F756:2017 | Non-hemolytic |
| ASTM Partial ThromboplastinTime | ASTM F2382:2018 | Non-activator |
| SC5b-9 ComplementActivation Assay | ISO 10993-4:2017 | Both the test article and the sponsorprovided control were considered to bepotential activators of the complementsystem.The test article was comparedstatistically to the control and the testarticle was lower than the control andwas statistically different. |
| USP Rabbit Pyrogen Study,Material Mediated | ISO 10993-11:2017 | Non-pyrogenic |
| Genotoxicity MouseLymphoma Assay | ISO 10993-3:2014 | Non-mutagenic |
| Bacterial Reverse MutationStudy | ISO 10993-3:2014 | Non-mutagenic |
| ISO Systemic Toxicity Studyin Rats FollowingSubcutaneous Implantation,13 Weeks | ISO 10993-6:2016ISO 10993-11:2017 | There was no evidence of systemictoxicity from the test article followingsubcutaneous implantation in the rat.Microscopically, the test article wasclassified as causing minimal to noreaction. |
| Biological Endpoint | Test Method | Results |
| ISO Muscle ImplantationStudy in Rabbits, 4 Weeks | ISO 10993-6:2016 | The macroscopic reaction was notsignificant as compared to the negativecontrol article.Microscopically, the test article causeda minimal to no reaction as comparedto the negative control article. |
| ISO Muscle ImplantationStudy in Rabbits, 13 Weeks | ISO 10993-6:2016 | The macroscopic reaction was notsignificant as compared to the negativecontrol article.Microscopically, the test article causeda slight reaction as compared to thenegative control article. |
| Chronic Systemic Toxicityand CarcinogenicityEvaluation | ISO 10993-1:2018ISO 14971:20192020 FDA BiocompatibilityGuidance | A biological risk assessment was usedto support chronic systemic toxicityand carcinogenicity endpoints. Therisk assessment was based on chemicalcharacterization results and supportedby information on the HRSpheresmaterials of construction, gatheredtoxicological data on these materials,and biological data on the HRSpheres. |
Table 4: Device Biological Endpoints
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8. Animal Study Testing
An animal study was performed on the healthy swine models to evaluate the safety and effectiveness of the HRSpheres Narrow-Size Embolic Microspheres. A total of 15 female domestic swine were selected for evaluation. The animal study was intended to simulate the clinical application of the embolization microspheres by interventional procedure for partial renal artery embolization. Seven pigs were selected for embolization with the test article (75 - 125 um), and the other 8 pigs were selected for embolization with the control article (CalliSpheres Polyvinyl Alcohol Embolization Microspheres; K173871) (100 - 300 um). Several preoperative and postoperative observation time points were selected, including 3, 8 and 29 days after embolization.
At each observation time point, the changes of hematology, blood coagulation and serum biochemistry, as well as the imaging changes and pathological changes of kidney were detected, and the performance differences of test article and control were compared. The safety and effectiveness of HRSpheres Narrow-size embolic
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microspheres were comprehensively evaluated. These evaluations included the following:
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- Comparison of recanalization of the vessels/durability of occlusion of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
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- Comparison of local and systemic foreign body reactions of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
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- Comparison of the ease of delivery of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
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- Comparison of the rupture or puncture of the blood vessels of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
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- Comparison of the non-target embolization/device migration of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
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- Comparison of local and systemic foreign body reactions of HRSpheres Narrow-size embolic microspheres and CalliSpheres Embolic Microspheres.
Animal evaluation indexes of HRSpheres Narrow-Size Embolic Microspheres on day 3, 8, and 29 were comparable to those from the control group. Tissue reactions of both test and control groups were found to be mild and comparable. Preoperative and postoperative clinicopathological examination results demonstrated that there was no significant difference between test group and control group with respect to adverse reactions. The results demonstrate that the subject device is as safe and effective as the cleared CalliSphere Embolic Microspheres (K173871).
9. Conclusion
As described above, the subject device has the same intended use as the predicate device. The differences in technological characteristics between the subject device and the predicate device do not raise different questions of safety and effectiveness. To evaluate the impact of the technological differences, performance testing was conducted as described above. The results of the testing demonstrate that the subject device, HRSpheres, is as safe and effective as the predicate device. Therefore, HRSpheres are substantially equivalent to the predicate.
§ 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).