This Form Is Used for the IVDD 98/79/EC

Medical Devices Application Review Form Substantial and Non-substantial Changes

This form is used for the IVDD 98/79/EC: Substantial Change Non-substantial Change

NSAI Use ONLY NSAI File Ref. 304. /

Please submit an unsigned version of this Application in Word as well as a signed copy - either scanned/secured (pdf) copy. All application forms and supporting data to be forwarded in soft copies via NSAI upload facility at http://www.nsaiinc.com/index.php? option=com_wrapper&view=wrapper&Itemid=129 or on a CD or memory stick to NSAI

Europe N. America

NSAI NSAI Inc. 1 Swift Square, 402 Amherst Street Northwood, Nashua Santry, NH 03063 Dublin 9 USA Ireland

Phone : (01) 807 3929 Phone : (603) 882 4412 Fax : (01) 807 3996 Fax : (603) 882 1985 [email protected] [email protected]

NOTE : Only completed Applications will be reviewed.

DECLARATION(s) BY APPLICANT Note: this page to be completed by all applicants

GRF-25-25 Rev 2.1 Page 1 of 23 In signing this form, the manufacturer is verifying that the requirements of the Directive will be applied in full when the change has been implemented.

Signed on behalf of the Manufacturer: Date:

Name (please print): Position / Title: Contact person (if different to Manufacturer): Phone: Email:

------Section 1 - Manufacturer and Product Details

Manufacturer’s Instructions Please complete all the relevant sections below (excluding the NSAI Review sections). If the data is in supporting documentation, please ensure that there is a clear reference to the exact location of this information.

Note the “Manufacturer” as defined by the Directive(s) is “the natural or legal person with responsibility for the design, manufacture, packaging and labelling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party.”

Please also supply QMS certificates for any sites listed below NOT registered with NSAI.

Please complete Table 1, highlighting any changes as necessary Table 1 (Legal) Manufacturer’s Name (Legal) Manufacturer’s Address Design Site(s): Manufacturing Site(s): (i.e. sites of actual manufacture) Assembly Site(s) if applic.: Sterilisation Site(s) if applic.: Scope of Site(s): (i.e. as shown on the QMS cert) Name and address of EU Authorised Representative (if applicable) Product/Product Family Name: (Ensure product family name is in compliance with NB/MED/2.5.1/REC4) & NBOG’S Best Practice Guide 2006-2 GMDN Reference Number: See www.gmdnagency.com/ IVD Type List A List B Self-Test Conformity Route: Annex Date of this application (i.e. date of Declaration of Applicant) Supply Declaration of Conformity (Please reference location within technical file) Description of the proposed change (compared to the approved design/product range/quality system. Reason for the changes / modifications ( Please give detailed descriptions on the change from existing registered models, if necessary) Please outline if this change arises from a vigilance issue

GRF-25-25 Rev 2.1 Page 3 of 23 NSAI Review Check the QMS registration of the various sites listed and that the Declaration of Conformity for this family is present and adequate

Check the data supplied against data previously submitted to NSAI – in cases of amendments, review all data fully.

Ensure that the product family name is in line with GMDN nomenclature.

Check the description of the proposed change; ensure the manufacturer’s description is clear, precise and confirms the extent of the proposed change. Consider the modifications or changes compared to the approved design/product range of the approved quality system, and the validity of the reasons for the change.

Reviewer & date: Queries? No Yes Number(s) Section 1 – Manufacturer and Product Details (CONTINUED)

Manufacturer’s Instructions In cases where the proposed change involves change to the members of a product family or their description, please complete Table 2 with the relevant information relating to only the affected catalogue numbers; otherwise mark as N/A

Please list all kit components (if applicable)

Table 2 Product / Product Family Name:

Intended Use:

Model/Catalogue Description Schedule* Number

*Schedule of Regulations (Irish Statutory Instrument) corresponds to Annex of Directive used for Conformity Assessment

NSAI Review The proposed change involves amending the model numbers in the family or their description: No Yes

Ensure that all kit components are listed (if applicable)

Reviewer & date: Queries? No Yes Number(s)

GRF-25-25 Rev 2.1 Page 5 of 23 Section 2 – Extent of changes to the Technical File

Manufacturer’s Instructions The manufacturer must assess the extent of changes to the Technical File this proposed change will bring- using the guidance below:

This is a Quality System Product Range Design Dossier IVD Type significant change to the :

In the case of design or product range changes, briefly state the outcome of the review against a) The essential requirements b) The safety and efficacy of the device as demonstrated by the risk analysis. c) The clinical safety/performance of the device

In the case of design dossier amendments: a) briefly describe the design dossier amendment here or in an attachment b) briefly state or attach the design or project plan c) attach all relevant verification and validation test data and/or summary reports d) include any update to the solutions to the essential requirements and risk analysis I, as manufacturer, deem that the following sections of the Technical File are affected by the proposed change: Table 3 – Impact of Change SECTION YES NO AGREED BY REVIEWER REVIEWER DATE Te Intended Use of the Device ch Correct IVD type & Appropriate ni Conformity Assessment Annex ca Labelling & IFU l Solutions to Essential R Requirements eq Compliance to Harmonised ui Standards re Performance/complaint m Analysis en Risk Analysis ts Sterilisation Stability – Device Pr Stability – Packaging e- Biocompatibility Cli Medical Electrical Equipment ni ca Medical Electrical System l Design Verification & Validation

Clinical/Performance Evaluation Design Dossier (Annex II Section 6 Self Test or Annex IV Section 4 (List A only)) Other areas: please specify

NOTE - If Section is deemed to be not affected by the proposed change please add N/A to the particular sections on the form, i.e. within sections 3 through 15 below - If section is applicable please complete each section (2 through 15 below) in full and supply supporting documentation as required. NSAI Review

Review the manufacturer’s list above and assess its validity against the proposed change(s); from this review, the extent of NSAI’s review will be determined

GRF-25-25 Rev 2.1 Page 7 of 23 Section 3 - Intended Use of the Device

Manufacturer’s Instructions Please enter a full description of the intended use of the device, which supports the product classification:

NSAI Review Ensure that the intended use of the device is clearly stated does it confirm the type of IVD indicated by the Manufacturer.

Section 4 - Correct IVD Type and Appropriate Annex

Manufacturer’s Instructions Please advise the type of IVD in this product family – Annex II List A, Annex II List B, IVD for Self Test

Please enter the rationale for the type of IVD

NSAI Review Refer to Annex II and Article 9 of the IVDD 98/79/EC – confirm type of IVD

Is the conformity assessment route selected in Table 1 suitable for the IVD type?

Reviewer & date: Queries? No Yes Number(s) Section 5 - Labelling and IFU

Manufacturer’s Instructions Please provide a sample of the (draft) labelling & IFU in English, and indicate below the location of these items in the File/Submission.

Confirm that the language requirements of the countries where the device is to be placed on the market have been fulfilled

Confirm compliance with EN 980 - 2003, 2008. If not, please advise rationale :

NSAI Review Ensure that the labelling and the IFU comply with the requirements of: Annex I ER 8 Yes - No

Are symbols used in compliance with EN 980 – version 2003 2008. If not, is rationale provided & acceptable and if applicable:

EN 61010-2-101:2002 Yes - No N/A EN 61326-2-6:2006 Yes - No N/A EN 375:2001 Yes - No N/A EN 376:2002 Yes - No N/A EN 591:2001 Yes - No N/A EN 592:2002 Yes - No N/A EN 13532:2002 Yes - No N/A EN 15197:2003 Yes - No N/A

When an issue is identified with the sample labelling, ensure the corrective actions are applied to all labelling operations

GRF-25-25 Rev 2.1 Page 9 of 23 Section 6 - Solutions to Essential Requirements

Manufacturer’s Instructions Please indicate how relevant Essential Requirements (Annex I) of the Directive are met with specific reference to the design elements associated with this application and demonstrate how the design outputs meet the design inputs through design verification and validation

NSAI Review Ensure that the solutions to the Essential Requirements are completed and reference the location of the supporting documentation. Reference should also be made to the Harmonised Standards used. Ensure the manufacturer adequately demonstrates that the design outputs meet the design inputs through design verification and validation activities

Section 7 - Compliance with Harmonised Standards

Manufacturer’s Instructions Please list the relevant Harmonised Standards and identify where compliance is demonstrated: If standards other than Harmonised Standards are used or where Harmonised Standards are not available, please rationalise their use. see http://ec.europa.eu/enterprise/newapproach/standardization/harmstds/reflist/invimedd.html

Note - The 3 standards below are shown as indication only- please include all other relevant Harmonised Standards from the applicable website(s) above.

Table 4 – Applicable Harmonised Standards List – Sample Harmonised Standard Compliant – YES/NO EN ISO 13485:2003 YES EN ISO 14971: 2007 YES EN 980:2008 YES

Table 4 – Applicable Harmonised Standards List Harmonised Standard Compliant – YES/NO NSAI Review Verify compliance and check the current Harmonised Standards list to ensure all relevant Harmonised Standards have been included in the Essential Requirements Checklist. Review any justification if a Harmonised Standard is NOT used.

Section 8 - Performance / Complaint Analysis

Manufacturer’s Instructions If the change(s) relate to vigilance issue(s), please provide the Vigilance Report for the vigilance issues that triggered the change(s) and any relevant trending data.

For List A devices ONLY, please also include any information about changes to the pathogen and markers of infections to be tested which is likely to affect the performance of the device concerned.

NSAI Review Review complaints vs. units placed on the market and the nature of the reportable incidents/associated corrective actions and complaint trends. Review QC / Production trends

GRF-25-25 Rev 2.1 Page 11 of 23 Section 9 - Risk Analysis and Risk Management

Manufacturer’s Instructions 1. Please provide a Risk Analysis/ Risk Management report/document/file, including a signed and dated conclusion regarding residual/remaining risks. The analysis and conclusion shall include clear reference to the proposed change(s)

2. Please confirm that the risk analysis has been carried out in compliance with EN ISO 14971:2007

Note – EN ISO 14971:2000 will be superseded by EN ISO 14971:2007 on March 31st 2010

3. If applicable, please indicate which of the multi-functional team provided the clinical input – i.e. risks associated with the clinical use of the device.

4. If applicable please clearly outline how the risks are transposed into the IFU, e.g. numerically between the Risk analysis and the IFU.

NOTES – Additional information may be required for devices containing tissue of animal origin,or human blood derivatives – If applicable please ensure to include relevant risk analysis for ME Equipment, ME Systems & ME Software

NSAI Review Ensure that the Risk Analysis/Management includes the proposed change and complies with EN ISO 14971:2007 completed by a cross-functional team, and that a signed and dated conclusion is made as to whether the remaining risks associated with the proposed change are acceptable, having regard to the intended application of the device.

Check that contra-indications in the IFU originate in the risk analysis and that mitigating actions have been incorporated in the IFU if applicable. Also check that the clinical risks (actual risks involved in the use, application of the treatment or deployment of the device) have been identified by a suitably qualified person, if applicable.

Challenge the robustness of the risk analysis and the on-going risk management with respect to any assumptions made and the decision taken.

Determine whether or not the solutions adopted by the manufacturer conform to the safety principles, taking account of the generally accepted state of the art. Verify that the characteristics and performance are not affected during transport and storage and the device lifetime.

Has Annex H (Guidance on risk management for in vitro diagnostic medical devices) been considered?

Reviewer & date: Queries? No Yes Number(s) Section 10 - Sterilisation

Manufacturer’s Instructions Is the product provided sterile, or intended to be sterilised prior to use? No Yes

If “Yes” - Please provide the necessary sterilisation validation protocol & report –

If the changes are not subjected to a sterilisation validation, please provide adequate justification for inclusion of the changes in the current validated cycle -

Please populate the following table with the necessary information:

TABLE 4 – STERILIZATION INFORMATION SUMMARY Device Sub-family Catalogue Sterilizatio Sterilizatio Protocol / Site Responsible Number n Method n Location Report No. for Release

NSAI Review Review the sterilisation validation/revalidation protocol and report(s) to ensure compliance with EN ISO 11135-1:2007 (EtO), EN ISO 11137-1:2006, EN ISO 11137-2:2007 (Irradiation), EN ISO 13824:2004 (Aseptic Processing) or EN ISO 17665-1:2006 (Moist Heat) as appropriate.

If applicable, for new model numbers, ensure that they are included in the current validated cycle.

Ensure the responsibility for release of sterile product is clearly stated.

GRF-25-25 Rev 2.1 Page 13 of 23 Section 11 – Stability Testing

Manufacturer’s Instructions Please define the shelf life/expiry date which is stated for the product / model / catalogue number(s)- Years

Device Stability For the proposed change(s), please supply the necessary device stability data (protocols & reports for accelerated aging testing, accelerated durability testing, etc) to substantiate the above shelf-life(s).

Confirm start date of real time studies:

Packaging Stability For the proposed change(s), please supply the necessary data (Protocols & Reports) to substantiate the stability of the product packaging, and hence the product sterility, at the proposed shelf-life(s):

NOTE – additional information may be required for devices containing human blood derivatives

NSAI Review Review the stability data, including mechanical/device stability, accelerated durability, packaging and sterilisation stability, where appropriate. Ensure compliance to relevant Harmonised Standards, if appropriate; e.g. EN 13640:2002 – Stability testing of in vitro diagnostic reagents EN ISO 11607-1/- 2:2006 (packaging stability)

Real time or accelerated data is acceptable; however, real time testing must be planned & should be conducted concurrently with accelerated aging.

For new model numbers ensure that the substantive data has been supplied

For extension of Shelf life, ensure that the real time data is planned.

Reviewer & date: Queries? No Yes Number(s) Section 12 – Biocompatibility

Manufacturer’s Instructions Confirm that the devices contact the patient’s body directly or indirectly? Yes

If “Yes”, please provide biocompatibility data:

Has biocompatibility testing been performed on the actual devices in question to demonstrate compliance with EN ISO 19003-1:2003? No Yes

If “No”, in accordance with EN ISO 10993-1:2003 clause 6, please document that the material has a demonstrable history of use in a specified role that is equivalent to that of the device in question.

Please document the knowledge/experience of the individual responsible for this decision.

NSAI Review Review the device biocompatibility, to ensure the device is biocompatible of its intended use. Review the data against the tests suggested by EN ISO 10993-1:2003.

If no testing has been completed, ensure that the history of use has been adequately documented & is appropriate for the product family.

Has an informed decision been made & documented by knowledgeable/experienced individuals weighing the advantages/disadvantages of the choices made?

Confirm that the biocompatibility data supplied substantiates the proposed change(s)

GRF-25-25 Rev 2.1 Page 15 of 23 Section 13 – Medical Electrical Equipment & Systems

Definitions: ME Equipment – electrical equipment having an applied part or transferring energy to or form the PATIENT or detecting such energy transfer to or from the patient and which is: provided with not more than one connection to a particular supply mains; and intended by its manufacturer to be used: a. in the diagnosis, treatment, or monitoring of a patient; or b. for compensation or alleviation of disease, injury or disability

ME System – combination, as specified by its manufacturer, of items of equipment, at least one of which is ME Equipment to be inter-connected by functional connection or by us of a multiple socket-outlet

Manufacturer’s Instructions Is the Medicall Device Product (i) ME Equipment Yes No (ii) ME System Yes No

Have the applicable requirements of EN 61010-2-101:2002, including the mandatory risk assessment to EN 14971 been applied for the proposed change(s) Yes No

What is the expected Service Life of the ME Equipment/ME System: Years

What is the Essential Performance of the ME Equipment/ME System:

Does the ME Equipment/ME System incorporate Software Yes No

Do the proposed changes affect the ME Equipment/ME System Software Yes No

If “Yes” – Have the requirements of EN 62304:2006, including the mandatory Risk Assessment to EN14971, been applied to the Software Development for the proposed change(s) Yes No

Please clarify if any additional Standards apply:e.g. EN 61326-2-6:2006 Yes No

In respect of the ME Equipment/ME System, please provide each of the following as applicable: Test Report to EN 61010-2-101:2002 The associated Risk Management File The EN62304 Software Development Process and Validation Report, as well as the software Risk Assessment Any additional test reports e.g. EN 61326-2-6:2006 (EMC)

Also provide details of Labelling and Marking, as well as “Accompanying Documents”.

NSAI Review Review relevant reports and risk management file to ensure compliance has been demonstrated to the harmonized standard EN 61010-2-101:2002 & any other necessary standards for the proposed change(s).

Reviewer & date: Queries? No Yes Number(s) Section 14 – Design Dossier : Design Verification & Validation (Annex III Section 6 : devices for self-testing or Annex IV Section 4 : Annex II List A devices ONLY)

Manufacturer’s Instructions For the proposed change(s): Please submit the necessary design verification activities, i.e. data to demonstrate that output meet inputs. Demonstrate that the laboratory results obtained and the conclusions made are applicable to the design specifications and performances claimed.

The design validation data to include where appropriate a critical analysis of relevant scientific literature in relation to the medical device being designed and developed, historical evidence that similar designs and or materials are clinically safe and a clinical investigation or trial to demonstrate that the product is capable of meeting the requirements for its intended use.

Devices for self-testing : design verification & validation data to - Ensure that the device is easy to use by the intended lay user at all stages of the procedure & - Reduce as far as possible, the risk of user error in the handling of the device and in the interpretation of the results.

Annex II List A devices : design verification & validation data to include - the determination of the characteristics of the basic materials, characteristics and limitation of the performance of the devices, - results of the design calculations & of the inspections carried out, etc. - if the device is to be combined with other device(s) in order to operate as intended, proof that it conforms to Essential Requirements when combined.

NSAI Review Self Test Devices - - Does the application enable the design of the device to be understood? - Can NSAI assess that conformity with the design-related requirements of the Directive? - Has handling suitability has been adequately addressed?

Annex II List A Devices – - Can NSAI assess whether the device conforms to section 3.2(c) of Annex IV?

GRF-25-25 Rev 2.1 Page 17 of 23 Section 15 – Clinical Evaluation

Manufacturer’s Instructions Please indicate if a performance evaluation has been completed to substantiate the safe use and effectiveness of the device design, including the proposed change(s) of this submission? No Yes

If “No” please justify -

NOTE – This data should arise from studies in a clinical or other appropriate environment or result from relevant biographical references

NSAI Clinical Review Evaluation is in accordance with: CTS for List A devices and EN 13612:2002 (Performance evaluation of IVD MDs) for all other devices.

Has adequate performance evaluation data been supplied showing the performances claimed by the Manufacturer & supported by a reference measurement system (when available) for the proposed change(s)?

Review details of the post market clinical follow-up.

Evidence of the competence and relevancy of the clinical evaluator of clinical data is requested.

NSAI Clinical Assessment: (Chronology of review)

Conclusion :

Signature: Date : Additional Information

Manufacturer’s Instructions Please use this section to document any additional information not already covered:

NSAI Review Review (if applicable).

GRF-25-25 Rev 2.1 Page 19 of 23 NSAI Queries

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GRF-25-25 Rev 2.1 Page 21 of 23 Company Query #13 -

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Query Disposition Date Conclusion of Assessment

NOTIFIED BODY STATEMENT Conclusion:

File Manager: Date : IVD Expert Review by: Date : Biomechanical Review by: Date : Electrical Review by: Date : Clinical Review by: Date : Other Expert Opinion by: Date : Outcome of Competent Authority Review (where applicable)

(Remarks: By signing this report, the reviewer confirms that he / she has no conflict of interest with the above named company (e.g. training, consultancy, financial, personal or political) that would affect the integrity of the technical review process and hence the review results.)

Approval

FOR SUBSTANTIAL CHANGES ONLY – PRESENTED TO THE TECHNICAL REVIEW COMMITTEE ON:

Outcome of Meeting : Follow Up required :

Approval demonstrated by signed Approval Amendment Record.

Competent Authority Notified of Notified Body Decision (Devices incorporating Medicinal Substances/Human Blood Derivatives only)

The decision of the NSAI to grant approval / not to grant approval of the file has been communicated to the Competent Authority:

Personnel in C.A. Notified of decision: Date of Notification: Notification performed by: If the NSAI decided to grant approval of the file despite the receipt of a negative opinion from the Competent Authority please enter the justification for this decision:

GRF-25-25 Rev 2.1 Page 23 of 23