K Number

Device Name

Manufacturer

ALCRESTA, INC.

Date Cleared

2015-11-20

(322 days)

Product Code

PLQ

Regulation Number

876.5985

Type

Direct

Panel

Gastroenterology/Urology

Reference & Predicate Devices

N/A

Predicate For

N/A

Intended Use

RELIZORB™ is indicated for use in adults to hydrolyze fats in enteral formula.

Device Description

The RELIZORB™ device is a point-of-care accessory designed to fit in series with currently used enteral feeding circuits. During the submission process, the device was also known as the Enteral Feeding In-Line Cartridge (EFIC). Therefore, the subject device may be referred to as EFIC in some figures within this document. RELIZORB™ is designed to hydrolyze (break down) fats present in enteral formulas from triglycerides into fatty acids and monoglycerides to allow for their absorption and utilization by the body. This breakdown of fats by the RELIZORB™ is intended to mimic the function of the enzyme lipase in patients who do not excrete sufficient levels of pancreatic lipase. The subject device is shown below in Figure 1. The RELIZORB™ is comprised of a cylindrical, hollow port and a single outlet port connection.

RELIZORB™ is packed with polymeric beads that have lipase enzyme immobilized on the surface. This lipase enzyme is Generally Regarded as Safe (GRAS). The chemical action of the lipase enzyme is shown in Figure 2, where triglyceride molecules are broken into constituent monoglycerides and fatty acids. The food contacting substance (FCS) of (b) (4) beads manufactured using the RELIZORBTM are (b) (4). The lipase enzyme is chemically bound to the FCS and is intended to remain within the cartridge.

RELIZORB™ is an intermediary between an enteral feeding source (infusion pump) and an implanted feeding tube, as shown in Figure 3. The distal end of compatible infusion pump administration sets (Figure 3A) should have a stepped connector (Christmas tree). This connector plugs into the proximal end of the RELIZORB™ device (Figure 3B). The distal end of the RELIZORB™ (Figure 3C) connects to the enteral funnel of an extension set (Figure 3D). This extension set connects to an enteral feeding tube on the patient, such as a nasogastric or gastrostomy tube.

AI/ML Overview

Here's a breakdown of the acceptance criteria and the studies performed for the RELIZORB™ device:

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document primarily focuses on non-clinical and animal studies. There is no information provided about human-in-the-loop performance, multi-reader multi-case studies, or traditional algorithm-only performance metrics like sensitivity, specificity, etc., as this is a medical device (enzyme-packed cartridge) performing a chemical function, not an AI/imaging device.

Biocompatibility Testing

Test	Purpose	Acceptance Criteria	Reported Device Performance
Cytotoxicity – MEM Elution Test	Assess biological activity of mouse fibroblast cells after exposure to extracts.	Non-cytotoxic	Non-cytotoxic
Irritation – Intracutaneous reactivity	Determine if extracts produce an irritation reaction when injected intracutaneously.	Non-irritating	Non-irritating
Sensitization – Guinea Pig Maximization	Determine potential for sensitization of extracts.	Non-sensitizing	Non-sensitizing
Acute systemic toxicity	Determine potential for acute systemic toxicity of extracts by injection into mice.	Not systemically toxic	Not systemically toxic
Genotoxicity – In Vitro Gene Mutations	Determine potential mutagenic activity of extracts by measuring reversion rates in bacteria.	Non-mutagenic	Non-mutagenic
Genotoxicity – In Vitro Mouse Lymphoma	Determine if extracts induce forward mutations at the thymidine kinase locus.	Non-mutagenic	Non-mutagenic
Genotoxicity – In Vivo Mouse Micronucleus	Determine potential for extracts to induce micronuclei formation in immature polychromatic erythrocytes in the bone marrow of mice.	Non-mutagenic	Non-mutagenic

Performance Testing - Bench

Test	Purpose	Acceptance Criteria	Reported Device Performance
Torque strength	Determine torque necessary to separate small bore connectors from the cartridge body.	Torque at separation higher than 3 times the estimated clinical force.	RELIZORB™ met the acceptance criteria.
Tensile strength	Determine force required to separate small bore connectors from the cartridge using a linear tensile force.	Linear tensile strength shall be greater than [b)(4) psi] (value obscured in document).	RELIZORB™ met the established acceptance criteria.
Air leakage test	Establish that material bonds would not fail or leak when challenged with pressurized air.	Material bonds shall not leak when challenged with [b)(4) psi] compressed air.	RELIZORB™ did not leak and met the acceptance criteria.
Filter integrity	Ensure FCS/enzyme beads are retained within the cartridge, by subjecting device to maximum pump flow rate in forward and reverse flow.	Should not allow for beads to pass the filter and leave the cartridge.	Allowed 5 particles in 3 forward flow repetitions and 1 particle in reverse flow. Only 1 particle had a diameter of [b)(4) - size obscured]. Justified as contamination and clinically acceptable due to small number and biocompatibility.
Fat hydrolysis	Determine amount of free fatty acids (FFA) produced by enzymatic hydrolysis using a simulated enteral circuit.	Produce [b)(4) FFA] per serving.	Breaks down ≈90% of fats in most enteral formulas. (Detailed results added to labeling).
Unconjugated lipase analysis	Evaluate potential leaching of lipase enzyme from beads.	No formal acceptance criteria. Measured lipase concentration using a [b)(4) assay].	Observed [b)(4) %] leaching by BCA assay and [b)(4) %] by absorbance. Deemed safe due to biocompatibility and GRAS status of lipase.
Assessment of impact to other nutrients	Ensure device does not adversely affect other nutrients (vitamins, minerals) in enteral formula under simulated use.	No formal acceptance criteria. Conducted nutritional analysis of vitamins and minerals.	No meaningful difference for any vitamins or minerals after exposure to RELIZORB™.
Flow rate	Ensure device does not restrict the flow of formula using an enteral feeding pump.	Presence of RELIZORB™ should not affect the flow rate of formula.	No statistical differences between flow rate with or without RELIZORB™.
Liquid leakage test	Inspect material joints for leaks during priming or flow rate testing after simulated feeding.	Should not leak under normal and worst-case conditions.	No leaking observed using two formulas and two different enteral feeding pumps.
Pump alarm verification	Verify that the flow error alarm works both before and after RELIZORB™ by kinking the tubing during flow rate testing.	Shall not cause pump alarm failure.	Verified that the flow alarm sounds if tubing becomes occluded before or after RELIZORB™.

Shelf Life Testing (6 months)

Test	Purpose/Acceptance Criteria (identical to bench tests)	Reported Device Performance
Fat hydrolysis	Demonstrate equivalent fat hydrolysis after aging.	No meaningful difference between baseline and aged product
Tensile strength	Not compromised after aging.	Not compromised
Filter integrity	Not compromised after aging.	Not compromised
Flow rate	Not compromised after aging.	Not compromised
Package integrity	Demonstrate package integrity (visual inspection, peel strength, bubble leak test).	Clean barrier not compromised after simulated shipping.

Animal Studies (Effectiveness - primarily based on increased fat absorption)

Study	Acceptance Criteria	Reported Device Performance
Chronic Porcine Study 1	Enhanced absorption of LCPUFAs, reflected by reduced total and PUFA fecal fats, and increase in %CFA (Coefficient of Fat Absorption), and increased AA and DHA in plasma/tissues. No adverse clinical effects.	Increased LCPUFA absorption, reduced total stool fat, fecal AA, and DHA. 20-30% improvement in %CFA (e.g., CV lipase 86.6±4.3% vs. control 67±5.8%, p=0.002; RO lipase 87.1±3.5% vs. control 67±5.8%, p=0.003). No adverse clinical effects or pathologic macroscopic findings.
Chronic Porcine Study 2	Safety and effectiveness of continuous feeding (RO lipase enzyme in beads) over 6 weeks. Reduced fecal fats, improved AA/DHA levels, normalized blood lipid profile, improved consumption of LCPUFA, and improved Vitamins A and E absorption. No safety signals on histopathology.	38% and 53% reduction in omega-3 and omega-6 fecal LCPUFA. 66% and 50% respective reduction in fecal AA and DHA. Normalized blood lipid profile, improved LCPUFA consumption, and improved Vitamins A and E absorption. No safety signals related to treatment in blinded GLP histopathology (observed issues related to EPI status, not treatment).
12 Day Efficacy Study	Increased fat absorption, measured as %CFA, and reduced stool weight. No adverse events. Validation of simulated use of RELIZORB™.	Statistically significant decrease in stool weight (p=0.014). Statistically significant increase in %CFA (approx. 60% for PepAF+EFIC vs. 42% for PepAF, p=0.036). No adverse events.
24 Hour Pharmacodynamics	Statistically significant improvement in fat absorption in the treatment arm (prototype device) as evidenced by increased plasma omega-3 fat (DHA and EPA) concentrations.	Statistically significant (p <0.05) increase in plasma omega-3 fats (DHA and EPA) when using RELIZORB™ compared to non-prehydrolyzed formula.

2. Sample Size Used for the Test Set and Data Provenance

Biocompatibility, Mechanical, Filter Integrity, Leakage, Flow Rate, Pump Alarm, Unconjugated Lipase, Nutrient Impact Bench Tests: Sample sizes are not explicitly stated for individual bench tests, but the results indicate testing was performed (e.g., "several lots" for lipase analysis, repetitions for filter integrity).
Fat Hydrolysis Bench Test: Sample size not explicitly stated for the benchmark, but shelf-life fat hydrolysis included 4 time points.
Shelf Life Testing: Includes testing at t=0, 1 month, 3 months, and 6 months.
Animal Studies:
- Chronic Porcine Study 1: n=3 pigs per arm (Control, CV Lipase, RO Lipase).
- Chronic Porcine Study 2: Number of pigs not explicitly stated, but refers to "(b)(4) control pigs" and "O (b)(4) pigs treated with the RO enzyme."
- 12 Day Efficacy study (Study 3): Comparing "(8) (4) control" and "(8) treatment pigs" (number obscured).
- 24 Hour Pharmacodynamics Study (Study 4): n=11 pigs.
Data Provenance: All non-clinical/bench tests and animal studies were conducted by the sponsor. The animal studies used porcine (pig) models. There is no information regarding the country of origin of the data provided explicitly, but it's presented in an FDA submission, implying it meets U.S. regulatory standards. All studies are prospective as they were conducted by the sponsor for the submission.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications

This section is not applicable in the traditional sense for this device. The "ground truth" for the device's performance, such as fat hydrolysis, mechanical strength, or biocompatibility, is established through direct measurements, chemical assays, and observation against defined physical and chemical criteria, not human expert consensus.

For the animal studies:

Chronic Porcine Study 2: A blinded GLP histopathology examination was conducted, and the pathologist's findings were peer-reviewed. Specific qualifications (e.g., years of experience) for the pathologist and peer-reviewers are not provided.

4. Adjudication Method for the Test Set

Adjudication methods (like 2+1, 3+1) are typically used in clinical trials involving human observation or interpretation (e.g., radiology reads). This is not relevant for the bench tests or the animal studies described, which involve objective measurements or histological evaluations. The histopathology was "blinded" to treatment group.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done

No. MRMC studies are primarily for evaluating diagnostic imaging devices or other tools where human readers interpret results. This is an enzyme-packed cartridge, so such a study is not applicable.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Yes, the vast majority of the studies presented in the document are "standalone" performance evaluations of the device itself (the enzyme-packed cartridge) without human interpretation as part of its primary function. The device's "performance" is its ability to hydrolyze fat or maintain mechanical integrity, which is measured directly.

7. The Type of Ground Truth Used

Bench and Shelf-Life Tests: Objective, quantitative measurements from chemical assays (e.g., FFA production, lipase concentration), physical tests (e.g., torque, tensile strength, flow rate), and direct observation against defined criteria (e.g., leakage, particle escape).
Animal Studies (Effectiveness):
- Physiological measurements: Fecal fat analysis (total, PUFA, AA, DHA), Coefficient of Fat Absorption (%CFA), plasma AA/DHA levels, blood lipid profiles, Vitamin A/E absorption, stool weight. These act as objective indicators of fat digestion and absorption.
- Histopathology: Microscopic examination of tissues.
Animal Studies (Safety): Observation for adverse clinical effects, macroscopic pathological findings, blinded GLP histopathology.

8. The Sample Size for the Training Set

The concept of a "training set" is relevant for machine learning algorithms. This document describes a physical medical device. Therefore, there is no "training set" in the context of an AI algorithm. The development and optimization of the RELIZORB™ device itself would have involved iterative design and testing, but not in the format of a machine learning training set.

9. How the Ground Truth for the Training Set Was Established

As noted above, there is no training set for this type of device. The specifications and performance targets for the device were established through scientific understanding of fat hydrolysis, engineering principles, and regulatory requirements.

Summary

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DE NOVO CLASSIFICATION REQUEST FOR RELIZORB™

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Enzyme Packed Cartridge: The enzyme packed cartridge is an ex vivo prescription device that is used in enzymatic hydrolysis of macronutrients into their essential nutrient forms at the time of delivery. The device consists of an outer casing containing an inert polymer with a covalently bound enzyme through which nutritional formula is directed. The device fits in line with enteral feeding systems.

NEW REGULATION NUMBER: 21 CFR 876.5985

CLASSIFICATION: II

PRODUCT CODE: PLQ

BACKGROUND

DEVICE NAME: RELIZORBTM

SUBMISSION NUMBER: DEN150001

DATE OF DE NOVO: DECEMBER 17, 2014

CONTACT:

ALCRESTA, INC. One Newton Executive Park SUITE 202 NEWTON, MA 02462

INDICATIONS FOR USE

RELIZORB™ is indicated for use in adults to hydrolyze fats in enteral formula.

LIMITATIONS

The sale, distribution, and use of the device are restricted to prescription use in accordance with 21 CFR §801.109.

RELIZORB™ is for use with enteral feeding only. The "Feed Only" lettering on the RELIZORB™ purple outlet is there to identify that the RELIZORB™ cartridge is intended for connection to enteral feeding lines only.

Medications should not be administered through the RELIZORB™ cartridge. Do

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not add medications to the enteral feed line in between the pump and RELIZORB™ (before RELIZORB™). The passage of medications through RELIZORB™ may adversely affect the medications or the ability of RELIZORB™ to hydrolyze fats.

Do not re-use RELIZORB™. RELIZORB™ is a single-use product. Re-use may result in contamination of the product. If re-used, RELIZORB™ may not effectively hydrolyze fats.

Enteral formulas containing insoluble fiber should NOT be used. Insoluble fiber may clog the RELIZORB™ cartridge.

The use of RELIZORB™ along with porcine pancreatic enzyme replacement therapy (PERT) has not been investigated. The appropriate dose and administration of PERT should be evaluated on an individual basis. Patients should continue to follow physician's guidance and PERT product labeling when used in conjunction with RELIZORB™.

The use of RELIZORB™ has not been studied in patients with exocrine pancreatic insufficiency (0) (4) RELIZORB™ has not been evaluated in pediatric populations.

PLEASE REFER TO THE LABELING FOR A MORE COMPLETE LIST OF WARNINGS, PRECAUTIONS, AND CONTRAINDICATIONS.

DEVICE DESCRIPTION

The RELIZORB™ device is a point-of-care accessory designed to fit in series with currently used enteral feeding circuits. During the submission process, the device was also known as the Enteral Feeding In-Line Cartridge (EFIC). Therefore, the subject device may be referred to as EFIC in some figures within this document. RELIZORB™ is designed to hydrolyze (break down) fats present in enteral formulas from triglycerides into fatty acids and monoglycerides to allow for their absorption and utilization by the body. This breakdown of fats by the RELIZORB™ is intended to mimic the function of the enzyme lipase in patients who do not excrete sufficient levels of pancreatic lipase. The subject device is shown below in Figure 1. The RELIZORB™ is comprised of a cvlindrical. hollow port and a single outlet port connection.

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Image /page/2/Picture/0 description: The image shows a filtration device with labels pointing to different parts. The labels indicate the inlet, filters, immobilized lipase, and outlet. The device is cylindrical in shape and appears to be made of plastic, with a white filter material visible inside.

Figure 1. Photograph of the RELIZORB™ device.

RELIZORB™ is packed with polymeric beads that have lipase enzyme immobilized on the surface. This lipase enzyme is Generally Regarded as Safe (GRAS) . The chemical action of the lipase enzyme is shown in Figure 2, where triglyceride molecules are broken into constituent monoglycerides and fatty acids. The food contacting substance (FCS) of (b) beads manufactured using the RELIZORBTM are (b) (4) . The lipase enzyme is process. The FCS was an effective notification chemically bound to the FCS and is intended to remain within the cartridge.

Image /page/2/Figure/3 description: This image shows the chemical reaction of a triglyceride being broken down by lipase. On the left side of the image, a triglyceride is shown with a glycerol backbone and three fatty acids attached. The lipase enzyme breaks down the triglyceride into a monoglyceride and two fatty acids, which are shown on the right side of the image.

Figure 2. The lipase enzyme breaks down triglycerides into monoglycerides and fatty acids.

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Image /page/3/Figure/0 description: The image shows a final setup of a medical device with labels A, B, C, and D. The device includes a pump on the left side and a connection to the patient on the right side, labeled as 'Downstream'. A Y-connector extension set is present, and a note indicates that medications or other solutions may be added at point D.

Figure 3. Illustration showing a proposed enteral feeding circuit with RELIZORB™!

SUMMARY OF NON-CLINICAL/BENCH STUDIES

Non-clinical/bench studies conducted on the RELIZORB™ to demonstrate a reasonable assurance of safety and effectiveness of the device are summarized in the sections below.

BIOCOMPATIBILITY/MATERIALS

The RELIZORBTM cartridge is constructed using a	(b) (4) housing,	(b) (4)
inlet connector,	(b) (4) outlet connector, and	(b) (4) filters. The
food contacting materials are the acrylic copolymer beads, lipase enzyme, and
(b) (4) stabilizer.

All materials within the RELIZORB™ have indirect contact with the patient's gastrointestinal tract. The RELIZORB™ is categorized as a permanent (>30 days) contact device that is externally communicating. The following biocompatibility testing was conducted on the final RELIZORB™ device in Table 1.

Test	Purpose	Results
Cytotoxicity – MEM ElutionTest (ISO 10993-5: 2009(b) (4)	To assess the biological activity of L-929 mouse fibroblast cells after exposure to extracts prepared from the final RELIZORB™ device.	Non-cytotoxic
Irritation – Intracutaneousreactivity (ISO 10993-10:2010)	To determine if extracts from the final RELIZORB™ device produce an irritation reaction when injected intracutaneously in the rabbit model.	Non-irritating
Sensitization – Guinea PigMaximization Test (ISO10993-10: 2010)	To determine the potential for sensitization of extracts prepared from the final RELIZORB™ device using the guinea pig animal model.	Non-sensitizing
Acute systemic toxicity (ISO10993-11: 2010)	To determine the potential for acute systemic toxicity of extracts prepared from the final RELIZORB™ device by injections into mice.	Not systemically toxic
Genotoxicity – In Vitro GeneMutations in Bacteria (AmesAssay, ISO 10993-3: 2003(b) (4)	To determine the potential mutagenic activity of extracts prepared from the final RELIZORB™ device by measuring reversion rates in bacteria.	Non-mutagenic
Genotoxicity – In VitroMouse Lymphoma (ISO10993-3: 2003 (b) (4)	To determine if extracts prepared from the final RELIZORB™ device induce forward mutations at the thymidine kinase locus	Non-mutagenic

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Test	Purpose	Results
Genotoxicity – In VivoMouse Micronucleus Assay(ISO 10993-3:2003 (b) (4) )	To determine the potential for extracts prepared from thefinal RELIZORBTM device induce micronucleiformation in immature polychromatic erythrocytes in thebone marrow of mice.	Non-mutagenic

Table 1. RELIZORB™ Biocompatibility Testing.

The sponsor justified that for non-polar extractions, sesame oil would be degraded by the lipase enzyme. Because the sponsor did leachability testing on the lipase enzyme from the beads, the sponsor used a surrogate bead for non-polar extractions. This approach was deemed acceptable by FDA.

PERFORMANCE TESTING - BENCH

The sponsor conducted bench tests to demonstrate mechanical integrity, package integrity, enzyme activity, and that RELIZORB™ can be integrated into existing enteral feeding circuits. Table 2 summarizes each of the bench tests.

Test	Purpose	Acceptance Criteria	Results
Torque strength	To determine the torquenecessary to separate thesmall bore connectors fromthe cartridge body at boththe distal and proximal endsof RELIZORB™	The sponsor estimated theclinical force thatRELIZORB™ mayencounter and built in athree-fold safety factor.The sponsor defined apassing result as a torqueat separation higher (b) (4)	RELIZORB™ met the acceptancecriteria for this test.
Tensile strength	To determine the forcerequired to separate thedevice small boreconnectors from thecartridge using a lineartensile force.	RELIZORB™ shall havea linear tensile(b) (4)break.	RELIZORB™ met the establishedacceptance criteria.
Air leakage test	To establish that theRELIZORB™'s materialbonds would not fail or leakwhen challenged withpressurized air.	RELIZORB™ materialbonds shall not leak whenchallenged with (b) (4)compressed air.	RELIZORB™ did not leak whenpressurized with air. The devicemet the acceptance criteria.
Filter integrity	To ensure that theFCS/enzyme beads areretained within thecartridge. The sponsorconnected RELIZORB™ toan enteral feeding circuitand subjected the device tothe maximum pump flowrate for five minutes. Thesponsor conducted this testin both a forward and	RELIZORB™ should notallow for beads (b) (4)to pass the filter and leavethe cartridge.	RELIZORB™ allowed for fiveparticles to leave the cartridge inthree repetitions in the forwardflow direction. RELIZORB™allowed one particle to exit thecartridge in the reverse flowdirection. Out of these sixparticles, only one had a diameter(b) (4)The sponsor investigated the
Test	Purpose	Acceptance Criteria	Results
	reverse flow orientationThe sponsor collected anypotential escaped particlesduring this test using a (b)(4)filter.		source of this particle usingspectroscopy and concluded that itwas a contamination from theirtesting laboratory. The Agencyreviewed the sponsor's data andagrees with their justification.
			Because the sponsor did observesome particles exiting thecartridge, FDA considered clinicalor toxicological adverse eventsresulting from escaped particles. Aclinical assessment determined thatso few escaped beads would likelypass in a patient's stool.Additionally, the sponsorsubmitted acceptablebiocompatibility data and the FCS-enzyme complex are acceptablefor use in foods. Based on theseassessments, this is an acceptableresult.
Fat hydrolysis	Using a simulated enteralcircuit, this test is todetermine the amount offree fatty acids (FFA) thatRELIZORB™ produces byenzymatic hydrolysis. Thesponsor used acommercially availablecolorimetric assay todetermine the amount offree fatty acids produced byRELIZORB™ aftersimulated use.	RELIZORB™ shouldproduce (b)(4)FFA perserving.	The sponsor submitted benchtesting data demonstrating thatRELIZORB™ breaks down ≈90%of fats in most enteral formulas.The sponsor added these results totheir labeling. This is anacceptable result.
Unconjugatedlipase analysis	The sponsor evaluated thepotential leaching of thelipase enzyme from thebeads. The sponsorextracted the beads for (b)(4)at roomtemperature.	There were no formalacceptance criteria forthis test. The sponsormeasured the lipaseconcentration using a	Using several lots, the sponsorobserved (b)(4) leaching by theBCA assay and (b)(4) leaching byabsorbance. Based on thebiocompatibility testing and theGRAS status of lipase, there are nosafety concerns with this smallamount of enzyme released.
Assessment ofimpact to othernutrients	Using simulated useconditions, the sponsorflowed enteral formulathrough their device. Thesponsor analyzed	There were no formalacceptance criteria forthis bench test. Thesponsor conducted anutritional analysis of	After exposure to RELIZORBTM,there was no meaningfuldifference for any vitamins orminerals. This is an acceptableresult.
Test	Purpose	Acceptance Criteria	Results
	nutritional componentssuch as vitamins andminerals to ensure thatRELIZORB™ does notadversely affect othernutrients in enteral formula.	vitamins and minerals.
Flow rate	The sponsor conducted thistest to ensure thatRELIZORB™ does notrestrict the flow of formulausing an enteral feedingpump.	The presence ofRELIZORB™ in anenteral feeding circuitshould not affect the flowrate of formula.	There were no statisticaldifferences between the flow ratewith or without RELIZORB™ inthe enteral feeding line. This resultis acceptable.
Liquid leakagetest	After simulated feeding, thesponsor inspected materialjoints to determine if thedevice leaked duringpriming or flow rate testing.	RELIZORB™ should notleak under normal andworst-case conditions.	The sponsor used two formulasand two different enteral feedingpumps. In all cases, the sponsordid not observe any leaking fromany material joints.
Pump alarmverification	After performing flow ratetesting, the sponsor kinkedthe tubing while the pumpwas in run mode to verifythat the flow error alarmworks both before and afterRELIZORB™.	RELIZORB™ shall notcause pump alarm failure.	The sponsor verified that the flowalarm sounds if the tubingbecomes occluded before or afterthe RELIZORB™. This is anacceptable result.

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Table 2. RELIZORB™ Bench Testing.

In accordance with the recommendations outlined in the guidance document "Safety Considerations to Mitigate the Risks of Miscomnections with Small-bore Connectors Intended for Enteral Applications," mechanical misconnection testing was conducted and a warning is included in the labeling to reduce the risk of misconnection.

SHELF LIFE/STERILITY

RELIZORB™ is provided non-sterile in a foil package. RELIZORBTM is a single use only device that is disposed of after each use. The identified shelf life for RELIZORBTM is six months.

In support of the six-month shelf life, the sponsor completed several tests using real-time aged devices after simulated shipping. The shelf life tests have identical acceptance criteria to those identified in the Performance Testing - Bench section.

Fat hydrolysis
· Tensile strength
· Filter integrity
· Flow rate
· Package integrity
- o Visual inspection

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o Peel strength (ASTM F88)

o Bubble leak test (ASTM F2096)

The sponsor reported fat hydrolysis conversions that were in agreement with their baseline data:

	TwoCal HN	Peptamen
t=0	51%	85%
t=1 month	44%	89%
t=3 months	49%	84%
t=6 months	47%	92%

Table 3. Fat hydrolysis results (% conversion of fats).

Because there was no meaningful difference between the baseline and aged product, the Agency determined that the fat hydrolysis results were acceptable. The tensile strength, filter integrity, and flow rate were not compromised after aging. After simulated shipping, the clean barrier for the RELIZORB™ was not compromised. The six-month shelf life is acceptable.

PERFORMANCE TESTING - ANIMAL

The sponsor completed four animal tests using exocrine pancreatic insufficient (0) ( (b) (4) pig models.

The four animal studies are summarized below.

1. Chronic Porcine Study

Protocol

The purpose of this study was to determine if the absorption of long-chain polyunsaturated fatty acids (LCPUFAs) is enhanced when formulas were prehydrolyzed with soluble microbial lipase.

Image /page/7/Picture/12 description: The image is mostly obscured by a gray block. The visible text says "hydrolyzed with soluble microbial lipase."

The pigs were monitored for a reduction of total and PUFA fecal fats, and change in coefficient of fat absorption (% CFA). The pigs were also monitored for an increase in arachidonic acid (AA) and docosahexaenoic acid (DHA) in plasma and tissues such as the liver, retina, heart, and fat. This result is consistent with increased absorption of LCPUFAs. After the study endpoint, the sponsor performed necropsy of study animals to harvest specified tissues, such as the liver, retina. heart, fat, red blood cells, hippocampus, cerebellum, and brain cortex.

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Results

There were no adverse clinical effects or pathologic macroscopic findings in the gut or liver after seven days of administration. Both the RO and CV pre-hydrolyzed formulas increased the absorption of LCPUFA as reflected by reduced total stool fat, fecal AA, and DHA. The sponsor included a summary showing the %CFA for the control and treated groups. The sponsor's data supports their conclusion that the enriched diets enhanced fat absorption with an improvement in %CFA of 20-30% in comparison to controls.

WEEK	CFA% (MEAN ± SD)
	CONTROL	CV LIPASE	RO LIPASE
CONTROL	66.5±7.8	51.7±14.3	76.9±1.9
TREATMENT	67±5.8	86.6±4.3*	87.1±3.5*
P value		0.002	0.003

Shown is a mean (± SD) CFA values during Control and Treatment weeks for Control RO organe. Difference was consider sinnificant tocol 05 for company on helpers of and RO groups during treatment week, n=3/arm

Image /page/8/Figure/4 description: The image shows the title of a table. The title is "Table 4. Mean of 24 hour %CFA during 3 consecutive days (Study 1)". The table will likely contain data related to the mean percentage of CFA over a 24-hour period for three consecutive days.

2. Chronic Porcine Study

Protocol

The sponsor tested the safety and effectiveness of continuous feeding of the RO lipase enzyme in the b)(4) porcine model over six weeks. The sponsor used the same lipase bound beads that are packed into the final device in this study.

During the study, the sponsor measured total and PUFA fecal fats, %CFA, and AA and DHA levels in both plasma and tissue. At study termination, the sponsor completed a gross postmortem examination of tissue and a blinded GLP histopathology examination.

Results

The sponsor reported food intake and body weight of all pigs. The formula intake The spensor reported root make and body wergit of were its (b) (4) control pigs grew 2-4 kg per week. The sponsor observed a 38% and 53% reduction in omega-3 and omega-6 fecal LCPUFA in (0) pigs treated with the RO enzyme. Similarly, the sponsor reported a 66% and 50% respective reduction in fecal AA and DHA levels for (b)(0) pigs treated with RO enzyme. These data suggest that the inability for (0) (4) pigs to absorb fat was reversed by feeding with pre-hydrolyzed formula treated with the lipase enzyme. Additionally, the pigs fed a pre-hydrolyzed diet had a more normalized blood lipid profile, improved consumption of LCPUFA. and improved Vitamins A and E absorption.

The sponsor harvested the cranial alimentary. GI tract, and the liver to send the samples for a blinded, GLP histopathology examination. The sponsor included analyses on the tongue, esophagus, stomach, small intestines, large intestines, liver,

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and liver fat. The pathologist found no safety signals relative to the consumption of the lipase enzyme. The pathologist had the following observations:

Increased periportal fat in the liver (all study animals). .
Inflammatory lesions in the liver, stomach, and tongue of (b)(4) ● animals, but not healthy control animals.
. An increase in distribution and severity of inflammatory lesions in EPI animals compared to healthy control animals.

The sponsor's findings seemed related to the pigs' 1010 status and not the 10/4/ treatment group. Some of the findings showed milder and less frequent issues in the treatment (4) animals in comparison to (1) controls. The observations noted in the (b)(4) treatment group were not related to the treatment itself and were of low incidence. The histopathological examination followed GLP regulations and was complete. Because the pathologist's findings were also peer reviewed, this study supported the accuracy of the sponsor's conclusions.

3. 12 Day Efficacy study with Gastrostomy Tube Feeding

Protocol

The sponsor conducted a simulated use study of RELIZORB™. The sponsor did nightly gastrostomy tube feeding over 12 days in the 014) porcine model.

During the last three days of the study, the sponsor collected two 24 hour stool and urine samples. On the last day after overnight fasting, the sponsor collected blood samples for protein and fat profiles, as well as DHA and eicosapentaenoic acid (EPA) measurements.

Results

The sponsor did not report any adverse events during this study. While the food intake between (8) (4) control and [8] treatment pigs was similar, the sponsor reported a statistically significant decrease in the stool weight for the treatment group (p=0.014). The sponsor reported a statistically significant increase in %CFA, as shown in Figure 4.

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Image /page/10/Figure/0 description: This bar graph compares the %CFA of PepAF and PepAF+EFIC. PepAF has a %CFA of approximately 42, while PepAF+EFIC has a %CFA of approximately 60. The error bars for PepAF+EFIC are larger than the error bars for PepAF. The y-axis ranges from 0 to 100.

Figure 4. Improved fat absorption expressed as %CFA for EFIC/RELIZORBIM (p=0.036, Study 3).

4. 24 Hour Pharmacodynamics Study

Protocol

The sponsor conducted a 24 hour, randomized, cross-over study in 11 pigs to assess the pharmacodynamics of gastrostomy tube feeding using a prototype of the RELIZORBTM device through a gastrostomy tube. While the sponsor used a device prototype for the treatment arm, this prototype was nearly identical in form and function to the finished device.

The sponsor collected baseline samples and at several time points after tube feeding began.

Results

Due to the short study duration, food consumption and body weight were not endpoints. The sponsor reported a statistically significant improvement in fat absorption in the treatment arm in comparison to the control. The plasma omega-3 fat (DHA and EPA) concentrations over 24 hours are shown in Figure 5. The sponsor reported a statistically significant (p <0.05) increase in plasma omega-3 fats when using RELIZORB™ in comparison to formula that was not prehydrolyzed with RELIZORB™

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Image /page/11/Figure/0 description: The image contains two line graphs comparing the levels of DHA and EPA in different conditions over time. The left graph shows DHA levels (ng/mL) over 24 hours for three conditions: RELIZORB, No-RELIZORB, and HEALTHY. The right graph shows EPA levels (ng/mL) over the same 24-hour period for the same three conditions. Both graphs show that the RELIZORB and HEALTHY conditions have a higher peak in DHA and EPA levels around the 7-hour mark compared to the No-RELIZORB condition.

Figure 5. Plasma DHA and EPA concentration over 24h period after single administration of hydrolyzed formula (500 mL) using RELIZORB™ in a porcine model of exocrine pancreatic insufficiency(b) (4)

The sponsor completed a proof of concept (Study 1), safety (Study 2), and a simulated use study (Study 3) using the same enzyme as the finished device. These studies demonstrated safety using the enzyme and simulated use conditions. The sponsor demonstrated improvements in fat absorption and Vitamins D and E absorption in these studies. The sponsor also observed increased concentrations of LCPUFAs in several organs after the studies were completed. The Agency expects these results would also be seen in humans using pre-hydrolyzed formula due to the nutritional benefits observed from fat hydrolysis in the literature.

HUMAN FACTORS TESTING

The sponsor conducted a human factors summative protocol in the submission. This study evaluated both the clinical care setting with trained operators and the home care setting with lay users. The sponsor conducted a subjective assessment on the performance of the critical tasks. The sponsor noted clinician errors after they neglected to change the device after one feeding session versus institutional policies that change feeding sets after 24 hours. This resulted in an update to the directions for use with a precaution that the device is for single use only. Based on the low risk of injury to the patient, the Agency determined that the sponsor's human factors activities are adequate.

LABELING

The sponsor provided labeling that includes the physician's instructions for use, patient guide, and package labels for the RELIZORBTM

The labeling is acceptable and meets the requirements of 21 CFR 8801.109 for prescription devices. The patient guide also follows the principles identified in the FDA Guidance Document Medical Device Patient Labeling.

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RISKS TO HEALTH

The table below identifies the risks to health that may be associated with use of Enzyme Packed Cartridges and the measures necessary to mitigate these risks.

Identified Risk	Mitigation Measure
Adverse tissue reaction	Biocompatibility testing Non-clinical testing In vivo testing Labeling
Mechanical failure Deprivation of care Device clogging Filter becomes dislodged and releases beads into enteral formula	Non-clinical testing Shelf life testing Labeling
Reduced enzymatic effect	Non-clinical testing In vivo testing Shelf life testing Labeling
Use error	Human factors testing Labeling
Infection	Shelf life testing Labeling

SPECIAL CONTROLS:

In combination with the general controls of the FD&C Act, the Enzyme Packed Cartridge is subject to the following special controls:

1. The patient contacting components of the device must be demonstrated to be biocompatible.
1. In vivo testing must be performed and must demonstrate that the device causes neither an adverse tissue response nor adverse performance.
1. Non-clinical testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be demonstrated:
- (A). Mechanical testing to demonstrate that the device can withstand clinical forces.
- Flow rate and leakage testing to demonstrate that the device does not impede the (B). flow of enteral formula.
- Demonstration of enzymatic effect on intended macronutrient. (C).
- The amount of enzyme that exits the cartridge must be characterized. (D).
- Validation that the device does not adversely impact the nutritional composition (E). of enteral formula.

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(F). Validation that the device does not impede flow alarms on enteral feeding pumps.
1. Human factors testing must be performed to characterize use error risks.
1. Performance data must support shelf life by demonstrating package integrity and device functionality over the identified shelf life.
1. Labeling must include the following:
- (A). A detailed summary of in vivo testing pertinent to use of the device, including device-related adverse events.
- (B). A detailed summary of compatible formulas that is supported by non-clinical testing, including the expected enzymatic conversion as a percentage.
- (C). Detailed instructions on how to place the device into an enteral feeding circuit.
- A warning regarding the possibility for misconnections. (D).
- (E). Expiration date or shelf life.
1. Patient labeling must be provided and must include:
- (A). Relevant warnings, precautions, adverse effects, and complications.
- A description of the device and how it operates. (B).
- Instructions on how to correctly use the device. (C).
- The benefits and risks associated with the use of the device. (D).

BENEFIT/RISK DETERMINATION

The observed risks of the device are based on the animal studies described above. The sponsor did not include any clinical data. The sponsor presented safety data from four different porcine studies. The sponsor did not observe any adverse events in their animal studies. Since the sponsor's small bore connector is based on a legacy design, there is a risk for misconnection with devices from other healthcare applications.

The observed probable benefits of the device are also based on nonclinical laboratory and animal study data as described above. The sponsor demonstrated in laboratory testing that the device was able to hydrolyze >90% of fat in most enteral formulas. The four preclinical animal studies appeared to provide benefit to pigs displaying clinical signs of exocrine pancreatic insufficiency (b) (4) when fed a diet pre-hydrolyzed by the lipase enzyme manually or through the RELIZORB™ device. In their animal studies, the sponsor demonstrated that treating (9) (4) pigs using RELIZORB™ led to increases in total fat absorption, improved update of omega-3 fatty acids in plasma, and improved Vitamin D and E levels. FDA expects these benefits would also be seen using pre-hydrolyzed formula due to the nutritional benefits observed from fat hydrolysis in the literature.

Additional factors to be considered in determining probable risks and benefits for the RELIZORB™ include:

The cumulative data from the animal studies were robust. Thev were designed logically, . systematically, and built on each other. The first two studies did not use the device. The

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pigs in the first study were fed soluble lipase enzyme, while the second study used the beads bound with lipase in a mesh bag. The final two studies used a device prototype that was functionally equivalent to the final device.

. Study 2 had a safety endpoint and the histopathology was conducted at a GLP pathology lab under blinded conditions. Study results were peer-reviewed prior to release of final study report.
Study 4 was a randomized, blinded, cross-over study.
Patients can have abdominal cramps, steatorrhea (loose, greasy, foul-smelling . voluminous stools), and malnutrition with weight loss. The condition is currently treated with oral administration of pancreatic enzyme replacement therapy tablets (PERTs).
. Human factors testing and clear labeling help mitigate risks.
The device is beneficial because no enteral formulas currently contain pre-hydrolyzed fat. ●

In conclusion, given the available information above, the data support that the probable benefits for the RELIZORB™ device to hydrolyze fats in enteral formula outweigh the probable risks. The device provides probable benefits and the risks can be mitigated by the use of general and the identified special controls.

CONCLUSION

The De Novo request for the RELIZORB™ is granted and the device is classified under the following:

Product Code: PLQ Device Type: Enzyme Packed Cartridge Class: II Regulation: 21 CFR 876.5985

Regulation Number and Section

§ 876.5985 Enzyme packed cartridge.

(a)
Identification. An enzyme packed cartridge is anex vivo prescription device that is used in enzymatic hydrolysis of macronutrients into their essential nutrient forms at the time of delivery. The device consists of an outer casing containing an inert polymer with a covalently bound enzyme through which nutritional formula is directed. The device fits in line with enteral feeding systems.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The patient contacting components of the device must be demonstrated to be biocompatible.
(2)
In vivo testing must be performed and must demonstrate that the device causes neither an adverse tissue response nor adverse performance.(3) Non-clinical testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be demonstrated:
(i) Mechanical testing to demonstrate that the device can withstand clinical forces;
(ii) Flow rate and leakage testing to demonstrate that the device does not impede the flow of enteral formula;
(iii) Demonstration of enzymatic effect on intended macronutrient;
(iv) The amount of enzyme that exits the cartridge must be characterized;
(v) Validation that the device does not adversely impact the nutritional composition of enteral formula; and
(vi) Validation that the device does not impede flow alarms on enteral feeding pumps.
(4) Human factors testing must be performed to characterize use error risks.
(5) Performance data must support shelf life by demonstrating package integrity and device functionality over the identified shelf life.
(6) Labeling must include the following:
(i) A detailed summary of
in vivo testing pertinent to use of the device, including device-related adverse events;(ii) A detailed summary of compatible formulas that is supported by non-clinical testing, including the expected enzymatic conversion as a percentage;
(iii) Detailed instructions on how to place the device into an enteral feeding circuit;
(iv) A warning regarding the possibility for misconnections; and
(v) Expiration date or shelf life.
(7) Patient labeling must be provided and must include:
(i) Relevant warnings, precautions, adverse effects, and complications;
(ii) A description of the device and how it operates;
(iii) Instructions on how to correctly use the device; and
(iv) The benefits and risks associated with the use of the device.