Technical File Section 10

1.0 Scope In accordance with the standard ISO 14971:2007 "Medical Devices-Application of Risk Management to medical devices" as well as the Risk Management processes, this document gathers the risk management information for the product detailed in table 1: Product Coolinside Classification Active Medical Device of IIb Class. Table 1: Device Information 2.0 Background 2.1 The Coolinside product is a medical device designed for resection of liver tumors. The concept is based on the release of radiofrequency currents to the tissue which induces the coagulation of the tissue. The device is provided with a blade which permits the section of the coagulated tissue in a single maneuver without the need of another device. 2.2 The Apeiron Coolinside Device is manufactured by Gema Medical and Arrotek Medical. Gema Medical is responsible for the manufacturing and assembly of the device and Arrotek Medical are responsible for the packaging, sterilisation and supply of the finished product to Apeirion as per Work Instruction 700090-99. 2.3 The Design Risk Assessment has been prepared by Arrotek Medical and two Process Risk Assessments have been prepared, one by Gema Medical and one by Arrotek Medical.

3.0

Method 3.1 The method by which Arrotek have prepared the risk assessment is detailed in SOP 006 and ISO 14971:2007. The method used by Arrotek is Failure Mode and Effect analysis as per section 3.0 of 14971:2007 3.2 Gema Medical has also carried out a risk assessment using the FMEA process as per as per Annex 1: Risk Management Plan.

4.0

Risk Evaluation 4.1 Arrotek Medical has carried out the risk evaluation process as per SOP 006. If the risk level is defined as low it is considered as acceptable and no further action is required. If the risk level is defined as medium it will be reduced further and risk controls will be implemented but if this is not possible the risk can be considered as low as achievable and therefore acceptable. It the risk level is defined as high the risk is unacceptable and risk reduction must be implemented.

4.2 Gema Medical has carried out the risk evaluation process as per Annex 1: Risk Management Plan. If the risk level is defined as negligible it is considered as acceptable and no further action is required. If the risk level is defined as tolerable it will be reduced further and risk controls will be implemented by indirect means. If the risk level is defined as undesirable it will be reduced further and risk controls will be implemented by direct means. If the risk level is defined as Intolerable the risk is unacceptable and risk reduction must be implemented by reducing probability and / or severity of the hazard.

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5.0 Definition of Risk and Risk Acceptability 5.1 Detailed below is the process by which Arrotek Medical have defined risk acceptability Severity Scale Clinical Death due to product failure Serious injury-surgical intervention required Serious injury-interventional bail out Injury no surgical treatment required Poor performance / noticed by physician Cosmetic fault Severity Scale Commercial Loss of certification Full product recall and design change required Product recall and manufacturing method change Product recall to correct batch Minor detail to impact on user confidence No commercial impact Rating 6 5 4 3 2 1

Table 2: Details Scale for Severity Occurrence Certain occurrence Very high occurrence High occurrence Possible occurrence Small occurrence Remote Percent Greater than 35% 15-35% 5-15% 1-5% 0.2-1% 0.01-0.2% Table 3: Details Scale for Probability 6 S 5 E 4 V 3 E 2 R 1 T 0 Y Med Med Low Low Low Low 1 High Med Med Med Low Low 2 High High Med Med Low Low 3 High High High Med Low Low 4 High High High High Med Low 5 High High High High Med Med 6 Rating 6 5 4 3 2 1

OCCURRANCE Table 4: Graphical Depiction of Risk Level Rating System

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5.2 Detailed below is the process by which Gema Medical have defined risk acceptability Severity Catastrophic Critical Marginal Negligible Qualitative definition Possibility of death or severe injury Possibility of severe injury or irreversible damage. Possibility of minor injury or reversible damage. Possibility of producing any discomfort without risk of injury. Table 5: Details Scale for Severity Probability Frequent Probable Occasional Remote Improbable Qualitative definition Very high occurrence High occurrence Possible occurrence Small occurrence Remote

Table 6: Details Scale for Probability Probability Frequent Intolerable Intolerable Intolerable Undesirable Probable Intolerable Intolerable Undesirable Tolerable Occasional Intolerable Undesirable Tolerable Tolerable Remote Intolerable Tolerable Tolerable Negligible Improbable Tolerable Tolerable Negligible Negligible

Risk Catastrophic Severity Critical Marginal Negligible

Table 7: Graphical Depiction of Risk Level Rating System

6.0

Details of risk Reduction In order to mitigate the risks observed in the Design & Process Failure Mode and Effect analysis the actions detailed in table 8, 9 & 10 have been implemented. The complete DFMEA & PFMEA,s are referenced in section 10 appendices.

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Hazard

Risk Level Pre Mitigation Med Med Med High Medium Med Med Med Med Med Med Med Med Medium Medium Medium High Med Med

Risk Reduction

Risk Level Post Mitigation Med Med Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Med Low

The device is used after is use by date The Device is used more than once Blade may break/detach in use Blade is not sufficiently sharp Blade made of an incorrect material The blade corrodes/rusts Liquid leaks from system Liquid leaks from system Tip of the device kinks/bends/breaks off The flow rate of the tube is insufficient for effective temperature control of the tip The flow rate of the tube is insufficient for effective temperature control of the tip The flow rate of the tube is insufficient for effective temperature control of the tip The tube detaches/fails in use Heat shrink moves/ slides on the device/Melts Heat shrink delaminated from the device Handle sides detach from each other Handle restricts the flow of fluid in the device Tubes restrict the flow of fluid Tubes restrict the flow of fluid

IFU to include instruction for a correct use and the labeling states the date of expiration IFU and label to be verified Validate manufacturing Process Validate manufacturing Process Verify design in clinical trial Corrosion test in DVT (EN 1618:1997) Leak test in DVT (EN 1618:1997) Leak test in DVT (EN 1618:1997) Apeiron to carry out compression test on the tip Flow test in DVT (EN 1618:1997) Flow test in DVT (EN 1618:1997) Flow test in DVT (EN 1618:1997) Clinical Trial Materials selected are to be Gamma compatible Verify in manufacturing process Validate manufacturing Process Flow test in DVT (EN 1618:1997) Flow test in DVT (EN 1618:1997) Flow test in DVT (EN 1618:1997)

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Tubes disconnect from attachments Tube restricts fluid flow Insulation damaged Wire unable to transfer correct energy/load Wire breaks free inside case Spike/lure detaches from the system Product is contaminated/dirty Sterile barrier broken Aspects of the device damaged Device may not work correctly with the RF Generator User does not know how to use the product properly, does not observe the necessary precautions, and does not perform the necessary pre-checks or the conditions for the intended use are not met. Electric shock, burns, fire Med Med Medium Medium Low Medium Med Med High Medium Med Tensile test in DVT Apeiron to carry out flow test with pump Clinical Trial Clinical Trial Electrical wire attachment to be verified during the manufacturing process Tensile Test in DVT Cleaning process during manufacture to be verified Transportation test in DVT Transportation test in DVT Clinical Trial Design of the device according to EN 60601-1, EN 60601-2-10, EN 60601-1-4, and Safety Assays performed at Laboratory SGS TECNOS, Routine electrical safety assays. Design of equipment according to EN 60601-1, laboratory assays at SGS TECNOS, EMC problems are minimized by the manufacturer of the generator, which has the CE mark their product and has passed the relevant controls. Low Low Low Low Low Med Low Med Med Med Med

High

Low

Excessive susceptibility to external EM emissions User does not know how to use the product properly, does not observe the necessary precautions, and does not perform the necessary pre-checks or the conditions for the intended use are not met. Device may not be sterile at the point of use Device may not be sterile at the point of use Device may react with the surrounding tissue and cause a negative reaction Device may not be sterile at the point of use

High High IFU to include instruction for treatment location

Low Med

Med Med Med High

Device is to be tested post simulated aging testing Procedure for the manufacture of the packaging to be validated Materials to be assessed from a medical use perspective Validate Sterilization Process

Med Med Low Med

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Use of non-compatible products with others. Discard the product without the precautions of its danger as biological waste Use of a product damaged or scratched in contact with patient User does not know how to use the product properly, does not observe the necessary precautions, and does not perform the necessary pre-checks or the conditions for the intended use are not met. User does not know how to use the product properly, does not observe the necessary precautions, and does not perform the necessary pre-checks or the conditions for the intended use are not met. Med Med Med Med IFU to include instruction for treatment The IFU to state biological disposal according to standard rules in user's location. IFU to include instruction for treatment Development and implementation of a checklist (checklist) of all product labeling requirements under Directive 93/42/EEC and UNE EN 980. Development and implementation of a checklist (checklist) of all product labeling requirements under Directive 93/42/EEC and UNE EN 980. User does not know how to use the product properly, does not observe the necessary precautions, and does not perform the necessary pre-checks or the conditions for the intended use areconnection with other accessories. D.14 Design trials in not met. Inspection of critical dimensions in routine Use of a product possibly degraded / expired. User does not know how to use the product properly, does not observe the necessary precautions, and does not perform the necessary pre-checks or the conditions for the intended use are not met. User does not know how to use the product properly, does not observe the necessary precautions, and does not perform the necessary pre-checks or the conditions for the intended use are not met. User does not know how to use the product properly, does not observe the necessary precautions, and does not perform the necessary pre-checks or the conditions for the intended use are not met. The user does not know what accessories are appropriate M ed High Include indication to verify that the equipment is working properly before applying to the patient in Instructions for use Development and implementation of a checklist of all product labeling requirements under Directive 93/42/EEC and UNE EN 980. Development and implementation of a checklist of all product labeling requirements under Directive 93/42/EEC and UNE EN 980. Development and implementation of a checklist of all product labeling requirements under Directive 93/42/EEC and EN EN 980. Warning on the use by qualified and properly trained personnel Design trials of connection with other accessories. Inspection of critical dimensions in routine Low Med Med Med Low Low

Med

Low

The user does not know what accessories are appropriate

Med

Low

Med

Med

Med

Med

Med

Low

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Device is unusable Equipment malfunction. Burns. Treatment not performed. Equipment malfunction. Burns. Treatment not performed. Not clearly indicated to the user what to do if malfunction is observed Med High Med Med Routine inspection in the manufacturing process Design trials of connection with other accessories. Design trials of connection with other accessories. Development and implementation of a checklist of all product labeling requirements under Directive 93/42/EEC and EN EN 980. Warning on the use by qualified and properly trained personnel Shelf life testing in DVT Confirmation of shelf life by accelerated aging tests. Continuous confirmation of the shelf life by continuous checking of routine production samples maintained in stock for this purpose. Product design according to EN 60601-1. Laboratory Tests by SGS TECNOS Packaging materials conforming to UNE EN 868ff; Notice "Do not use if individual package is not intact." Peel-pack package with materials conforming to the UNE EN 868ff. Symbol "Do not reuse" UNE EN 980. Implantation of a Quality Management System ISO 13485. Internal Audits and QMS review by Senior management. Use of ECO (change orders) - Communication to Notified Body in case of significant changes. Use of ECO (change orders) - Notify Health Authorities in case of significant changes Implantation of a Quality Management System ISO 13485. -D.21 Internal Audits and QMS review by Senior management. Use of ECO (change orders) - Communication to Notified Body in case of significant changes. Use of ECO (change orders) - Notify Health Authorities in case of significant changes Implantation of a Quality Management System ISO 13485. Internal Audits and QMS review by Senior management. - Data Analysis (NC repetitive NCs, ...) Implantation of a Quality Management System ISO 13485. Evaluation of suppliers and subcontractors Low Low Low Low

The device will not function correctly near it's "use by" date A potentially degraded product comes in contact with the patient.

High High

Low Low

Use of a product whose packaging is damaged or corrupted. Use of a product whose packaging is damaged or corrupted. Use of a product whose packaging is damaged or corrupted. Not approved product re-processing. -Non validated processes

High High Med High

Low Low Low Low

In adverted repeated nonconformities. - Incidents or potential incidents undetected. -Loss of traceability

High

Low

Inspection not statistically significant. -Use of instruments not calibrated or inappropriate Not approved product re-processing. -Non validated processes. Materials out of specifications.

High

Low

High

Low

Table 8: Details the DFMEA risk levels pre and post mitigation

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Potential hazard Units out of Spec Units Dirty Incorrect Label APEIRON 001 Incorrect tray used Blade Cover has separated Device not Sterile Device not Sterile Device not Sterile Device labelled Incorrectly Incorrect Quantity packed Damaged during transport No Instructions for Use Incorrect IFU Inserted Incorrect Quantity packed Damaged during transport Device Not Sterile Damaged during transport

Current Process Control Incoming Inspection SOP 002 Incoming Inspection SOP 003 Incoming Inspection SOP 004 WI & Training as per SOP 004 Material Spec WI & Training as per SOP 004 Settings in WI Material Spec WI & Training as per SOP 004 WI & Training as per SOP 004 WI & Training as per SOP 004 WI and Material Specs WI & Training as per SOP 004 Material Spec WI & Training as per SOP 004 WI and Material Specs WI & Training as per SOP 004 WI & Training as per SOP 004

Risk Level Pre Mitigation Med Med Low Low Low Med High Low Med Low Low Low Low Low Low Low Low Low

Action taken Supplier Audited Supplier Audited Supplier Audited N/A N/A N/A Pouch Sealing Process Validated N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A

Risk Level Post Mitigation Low Low Low N/A N/A N/A Low N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A

Table 9: Details Arrotek Medicals PFMEA risk levels pre and post mitigation

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Potential hazard Incorrect product supply Dirtiness in non-medical grade products (electrical cable and connector) Dirtiness Deformation and /or broken blade Wrong location of the blade The blade may detach Incorrect length of the shrink tube Incorrect shrinkage, roughness Incorrect length from the insulate tube to the blade Incorrect length from the insulate tube to the blade Wrong connection between the tube and the fitting. Weak connection between tube and fitting. The tube of the fitting falls off. Wrong direction of the cooling system Broken flange Incorrect sealing between the intersection between cooling tubes and the electrical wire. Improper solidification of the resin

Current Process Control Control in the reception of batches in the reception of Control batches Control in the reception of batches Verification of all the units Control in the reception of batches Verification of the units. Sample control in process Verification of the units. Checking the initial position Verification of all the units. Sample control in process Sample control in process Visual verification. Verification of the units. Verification 100% by inspection under magnifying glass. Training staff on the preparation of the resin.

Risk Level Pre Mitigation Tolerable Intolerable Undesirable Tolerable Tolerable Undesirable Tolerable Tolerable Tolerable Tolerable Tolerable Tolerable Tolerable Tolerable Tolerable Tolerable

Action taken Assessment of suppliers Cleaning of the materials. Cleaning of the electrodes Staff training and improvement in packaging. Verification of all the units received. Verification of the 100% of the units received. Staff training. N/A Verification 100% Indirect control risk. Dimensional control. Verification 100%. Bonding validation in a sample size. N/A Reduce the pressure of the flanges or changing the method of subjection. Staff training on the application of composite. Staff training on the preparation of the resin and Verification by those members of the staff.

Risk Level Post Mitigation Tolerable Tolerable Tolerable Negligible Tolerable Tolerable N/A Tolerable Tolerable Tolerable Negligible Tolerable N/A Negligible Negligible Tolerable

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Checking of a correct position inside the tool by two members of the staff. Validation of the 100% of the units. Validation of the system for leaks in 100% of the units N/A N/A N/A Conductivity verification of all the units. Verification of all the units and Test the machine before use.

Incorrect shape or position Leaking on the resin Incorrect connection between fittings and cooling tube Incorrect shrink, generation of pores Incorrect deposition, roughness Falls off the connector No electrical conductivity Generation of burrs

Verification of the units. Visual verification of the units. Sample control in process Verification of the units. Verification of the units. Verification of the units. Sample control in process Control parameters of the ultrasound machine to sealing.

Intolerable Undesirable Tolerable Tolerable Tolerable Tolerable Undesirable Tolerable

Tolerable Tolerable Tolerable N/A N/A N/A Tolerable Tolerable

Table 10: Details Gema Medicals PFMEA risk levels pre and post mitigation

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7.0 Residual risk assessment After the implementation of all measures of control / risk mitigation, each hazard was reassessed were it was concluded that: a) All risks have been established including all warnings and descriptive methods of risk reduction. b) The most significant hazards associated with the manufacture of the product have been addressed and reduced. c) A cumulative effect of various residual risks during production has been considered without finding reasons for taking further measures to reduce risk.

8.0

Post-production information The information post-production of this product will be collected as indicated in Annex 1 Risk Management Plan

9.0

Statement of Completeness Each of the risks have been evaluated correctly through the processes detailed in ISO 14971:2007 and the risk reduction methods are applicable and practical for the reduction of risk in the product. All remaining risks have been assessed and compared to the benefits of the product.

10.0

Appendices Arrotek Medical Documents DFMEA PFMEA APEIR001 Rev A APEIR001Rev A

Gema Medical Documents Annex 1 Risk Management Plan Risk Assessment Initial Report PFMEA ???????????? ???????????? ???????????

11.0

Approval Name Jonathan Mcloughlin Mark Pugh Apeiron Representative Signature Date

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