Applicant - NSAI - The National Standards Authority of Ireland Web viewCompleted application form (Word format, .doc or .docx) Application (min. Signed Declaration page(s)) scanned

Medical Devices – Re-Certification Review Form

Applicant InformationPlease tick all that apply:

Re-Certification Review Fast Track (expedited) if submitted <90 days from cert expiry

P/O number:

Directive(s) that apply : NSAI File Number MDD (93/42/EEC) 252. / AIMD (90/385/EEC) 253. / TSE (2012/722/EU) Human Blood (2000/70/EC)

If OBLs apply to this product, please state the relevant product families below: / ; / ; /

DECLARATION(s) BY APPLICANTIn signing this form, the manufacturer is verifying that the requirements of the Directive have been applied in full during the re-certification process.

Signed on behalf of the Manufacturer:

Date:

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

GRF-25-30 Rev. 3.2 Page 1 of 28

INSTRUCTIONS

1. Please complete all relevant sections of the form (excluding the NSAI Review sections).

2. Please enter as much information onto the form as possible - avoid entering “see Technical File/Design Dossier”. If the data is in supporting documentation, please ensure that there is a clear reference to the exact location of this information.

3. Please submit an unsigned version of this Application in Word as well as a signed copy - either scanned/secured (pdf) copy.

4. All application forms and supporting data to be forwarded in soft copy via one of the following (Hard copies not required)a. NSAI upload facility : see http://www.nsaiinc.com/b.CD or Memory stick to the appropriate address

Europe N. AmericaNSAI1 Swift Square,Northwood,Santry, Dublin 9IrelandPhone : (01) 807 3929Fax : (01) 807 [email protected]

NSAI Inc.402 Amherst StreetNashuaNH 03063USAPhone : (603) 882 4412Fax : (603) 882 [email protected]

5. Supporting documents should be in SEARCHABLE format

6. Applications and supporting documentation must be in English

7. Please send a representative sample of the device(s). This is particularly important for new/novel devices. Any video of procedures/simulated use would also be helpful, if available.

GRF-25-30 Rev. 3.2 Page 2 of 28

APPLICANTS’ SUBMISSION CHECKLIST Completed application form (Word format, .doc or .docx) Application (min. Signed Declaration page(s)) scanned Sample of device(s) QMS certificates for any sites in Table 1 NOT registered with NSAI Type Examination Certificate if required Declaration of Conformity Labelling & IFU Essential Requirements Checklist Performance/Complaint Analysis Risk Management documentation Sterilisation Validation(s) – if sterile/intended to be sterilised Stability data – if necessary Biocompatibility data – if necessary Electrical Safety Testing data – if necessary Software/firmware lifecycle documents – if necessary Bench Testing data – if necessary Clinical investigation(s) report(s) and supporting documents per MEDDEV 2.7.1. Clinical Evaluation Report(s) per MEDDEV 2.7.1 NSAI Equivalence table RF-25-28 if using equivalent route NSAI Post Market Surveillance (PMS) and Post Market Clinical Follow Up (PMCF)

RF-25-27

Note – NSAI do not accept “For Information Only Data” (FIO); all attributes tested shall have clinically relevant specifications

For Transfers Copy of existing Notified Body Certificate(s)

(If not already supplied) Transition Plan Contact details for existing Notified Body

(NSAI will not contact the existing Notified Body prior to agreement with the Manufacturer)

For Own Brand Labeller (OBL) Copy of the OEM (maker’s) CE Certificate and last assessment reports from their Notified Body

Copy of the OEM’s Declaration of Conformity Traceability between OEM cert & devices covered in this application Copy of the contract between OBL & OEM outlining responsibilities Index for Technical documentation/Design dossier (version/date), listing supporting documents

Copy of the OEM’s Instructions for Use/Labelling

For Tissue of Animal Origin falling under TSE Directive 2012/722/EUPlease complete Appendix A

For Human Blood DerivativesPlease complete Appendix B

For Medicinal Substances.Please complete Appendix C

GRF-25-30 Rev. 3.2 Page 3 of 28

Table of ContentsApplicant Information....................................................................................1

INSTRUCTIONS...........................................................................................2APPLICANTS’ SUBMISSION CHECKLIST.......................................................3

Section 1 – Manufacturer and Product Details..............................................5Section 2 – Intended Use of the Device.........................................................7Section 3 – Summary of all changes.............................................................8Section 4 – Product Stability and On-Going Testing......................................9Section 5 - Harmonised Standards..............................................................10Section 6 – Performance / Complaint Analysis............................................12Section 7 – Risk Management.....................................................................14Section 8 – Sterilisation...............................................................................15Section 9 – Clinical Performance (Human)..................................................16Section 10 – Additional Information............................................................18Section 11 - NSAI Queries...........................................................................19

11.1 QUERIES, Responses and Dispositions.............................................1911.2 Query Status Table 8:......................................................................22

Section 12 - Conclusion of Assessment.......................................................23Approval...................................................................................................23

Section 13 - Medical Devices Supplemental Review Form..........................24APPENDIX A................................................................................................2APPENDIX B................................................................................................5APPENDIX C..............................................................................................14

GRF-25-30 Rev. 3.2 Page 4 of 28

Section 1 – Manufacturer and Product Details

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.

Table 1 – Manufacturers Information & Summary Product data(Legal) Manufacturer’s Name (Legal) Manufacturer’s Address Design Site(s): Manufacturing Site(s):(i.e. sites of actual manufacture)

Assembly Site(s) if applicable: Sterilisation Site(s) if applicable: 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:(In compliance with NB/MED/2.5.1/REC4 & NBOG’S Best Practice Guide 2006-2)

GMDN Reference Number: See www.gmdnagency.com

Declaration of Conformity included - Location within submission : MDD ONLY :Class III IIb IIa Is Im Rule(s)RationaleConformity Assessment

Annex II V (+VII) V + III VIFull QA Prodn QA + Type Testing Product QA

AIMD ONLY :Conformity Assessment

Annex 2 Annex 3 + 5Full QA Prodn QA + Type Testing

ALL DEVICES :Original Clinical Strategy-- Clinical data from:

Clinical Investigation Literature (Equivalence) Combination

Date of this application (i.e. date of Declaration of Applicant)

GRF-25-30 Rev. 3.2 Page 5 of 28

http://www.gmdnagency.com/

Please complete the Table below, providing a full and up-to-date list of the current model numbers and descriptions related to this Application.If the Declaration of Conformity is being used (instead of completing Table 2), please make sure that the WORD version is supplied.

Table 2 – Product Family InformationSub-Family Model/Catalogue

NumberDescription Class

NSAI REVIEW NSAI registration(s) -

If Annex II is “Design” included in scope Yes No NSAI Certificate(s) valid Scope of registration(s) still adequate to cover the product family Client QMS Certificates are valid and scope of registration(s) remains adequate for product family under review Product family name in line with GMDN & remains valid DoC reviewed - lists model numbers

Agree with Classification - Yes No Appropriate Conformity Assessment route

Type Testing Certificate required – No Yes – if so Supplied, Valid Has any information above changed during the current product certification cycle (if so, review & confirm that substantial change notification was previously received and reviewed by NSAI – see Section 3)

NSAI REVIEWTechnical Reviewer: Date: COMMENTS:

Clinical Reviewer (if applicable): Date: COMMENTS:

Additional Reviewer (if applicable): Date: COMMENTS:

QUERIES No Yes Number(s):

GRF-25-30 Rev. 3.2 Page 6 of 28

Section 2 – Intended Use of the Device

1. Please enter a full description of the intended use of the device, which supports the product classification: Please provide copies of all levels of current product labels (device, packaging, carton) and Instructions for Use (IFU’s)

2.Has Intended Use/indications for use/patient population been revised or amended during the current product certification cycle?

Yes NoIf “Yes” please provide submission amendment number – 252.XXX.YY

For class III and Class IIb implantables ONLY,Please outline the “Indications for use” (i.e. specific patient population intended for this device/family).

Full list of contraindications:

3.Have contraindications or warnings been amended during the current product certification cycle? (see Section 3) Yes No

4.Ensure traceability between the Risk Management File, the CER and Labelling is evident Yes No

NSAI REVIEWIntended Use clearly stated

Yes NoDo the “intended use” and “contraindication” statements above match information found in product labeling and Instructions for Use?

Yes NoLegal Manufacturer and EU Representative information included on labeling?

Yes No Does that information match Table 1 above.

Yes NoAre correct symbols utilized?

Yes No N/A



GRF-25-30 Rev. 3.2 Page 7 of 28


QUERIES No Yes Number(s):

GRF-25-30 Rev. 3.2 Page 8 of 28

Section 3 – Summary of all changes

1. Is the product family AIMD/MDD Class III Yes No

2. MANUFACTURER - Please provide a complete listing of all Substantial Changes made during the current product certification cycle.

Table 3: List of Changes (AIMD/Class III only)Product(s) affected

Description of change NSAI file #

3. Have there been any changes to the technical documentation within the technical file over the certification period? Yes No

If “Yes” please provide these records and list the titles below:

*Note technical documentation=documentation used to support compliance to the Essential Requirements.

NSAI REVIEWTechnical Reviewer Date: COMMENTS:

Additional Reviewer (if applicable) Date: COMMENTS:

QUERIES No Yes Number(s)

GRF-25-30 Rev. 3.2 Page 9 of 28

Section 4 – Product Stability and On-Going Testing

1.Does the product have a shelf life Yes No

NSAI REVIEWAgreed that this section is not required Yes No Reviewer: Date: Comments:

2.Please specify the current shelf-life of your product:

3.Please list/identify the reports which substantiate the stated shelf-life:

4.Has the product shelf life / expiry date changed during the current product certification cycle? Yes NoIf “Yes”, please detail the change(s):

5. If applicable, please provide an update on any real time aging activities currently underway, or completed during the current product certification cycle: N/A

NSAI REVIEWAll Devices:

Does stated shelf life above match previously approved submission or amendment? Update on real time for packaging; if supplied review report Update on real time for device; if supplied review report





GRF-25-30 Rev. 3.2 Page 10 of 28

GRF-25-30 Rev. 3.2 Page 11 of 28

Section 5 - Harmonised Standards

1. In the cases where there have been changes or updates to the technical content/requirement of the standard, please:(a) List any updated Harmonized Standards in Table 4 below and(b) Provide evidence of compliance to the new standard, addressing how

the revised standard has been considered and implemented.

For MDD seehttp://ec.europa.eu/enterprise/policies/european-standards/documents/harmonised-standards-legislation/list-references/medical-devices/index_en.htm

For AIMD seehttp://ec.europa.eu/enterprise/policies/european-standards/documents/harmonised-standards-legislation/list-references/implantable-medical-devices/index_en.htm

Harmonized Standard Year Compliance

Yes/No

Evidence of Compliance

EN ISO 10993-1 2009 Yes Report # x, pg x, para. XEN ISO 14971 2012 Yes Report # x, pg x, para. XIEC 60601-1, 3rd Edition 2006 Yes Report #

Table 4: Compliance with updated Harmonized Standards onlyHarmonized Standard Year Complianc

eYes/No

Evidence of Compliance (e.g.

Delta or new report)

NSAI REVIEWIs this an active device? Yes No

Has the company provided evidence of compliance with IEC 60601, 3rd Edition? OR-Has the company identified, and complies with a particular standard for this device?

For other devices Evidence of compliance provided as appropriate

NSAI REVIEWTechnical Reviewer: Date: COMMENTS:GRF-25-30 Rev. 3.2 Page 12 of 28




GRF-25-30 Rev. 3.2 Page 13 of 28

Section 6 – Performance / Complaint Analysis

MANUFACTURER: Please provide a summary analysis of product complaints and Vigilance Reportable Incidents as outlined below

A. COMPLAINTS:1. Is the device commercialized Yes No

If “No” please explain -

2. Time period of the complaint data being provided – Last 3yrs – Lifetime of the device (Please define- )

3. SummaryTotal no. units placed on the market*Total no. of complaintsTotal no. of reportable events (worldwide)

*including devices used on patients as part of a preference study, trial, etc.

4. Please provide an analysis of complaint data over the stated period of time, in either graphic or table form, summarizing types of complaints, (e.g. performance related, clinical user related, labeling issue, off-label use, product misuse, complaint justified / non-justified) with quantity and % total sales.

5. Are there currently any regulatory actions, or pending regulatory actions against this device (e.g. recalls, withdrawals, field safety notices, consent decrees, refusals to approve) Yes NoIf “Yes” please describe -

6. Please provide details of any OEM/OBL performance issues:

B. VIGILANCE REPORTS:

7. Summary supplied of all Vigilance Report(s) submitted to EU Competent Authorities during the current product certification cycle – (see table 5) Yes

8. Has this product been the subject of product recalls or Incident Reports in other Regulatory geographies outside EU? Yes No

If “yes”, please summarize and provide details – see table 5

9. Has NSAI received all the Vigilance Report(s) Yes No

GRF-25-30 Rev. 3.2 Page 14 of 28

If “Yes” please provide the relevant Unique Identifier number(s) - If “No” please:

(a) Justify (b) If applicable, please submit a copy of the Vigilance Report(s)

submitted to EU Competent Authorities along with the completed NSAI Vigilance Form located at [http://www.nsaiinc.com/services/MedicalDevice -“Vigilance Reporting”] to [email protected]

C. CORRECTIVE ACTIONS:

10.In the table below, please provide a summary of corrective actions implemented as a result of vigilance or complaint trends.

11.Please summarize all global Vigilance issues that fulfill the European Reporting requirements in the following/similar format:

Table 5 Vigilance Summary Table:Unique ID

No:Competent Authority

Details of Investigation

Root Cause

CAPA Raised - Y/N & Details

Status

Note: Please supply this table as an attachment to the submission

NSAI REVIEW Suitable rationale if device not commercialized at 3yr renewal Complaint data & possible trends reviewed Vigilance reports & possible trends reviewed Performance issues worldwide considered & reviewed


Clinical Reviewer (if applicable) Date: COMMENTS:


GRF-25-30 Rev. 3.2 Page 15 of 28

mailto:[email protected]

http://www.nsaiinc.com/services/MedicalDevice


GRF-25-30 Rev. 3.2 Page 16 of 28

Section 7 – Risk Management

MANUFACTURER: Please provide the current Risk Management Plan/ Report and most recent version of Risk Analysis, which shall include a signed and dated conclusion regarding residual/remaining risks

Have the severity and/or occurrence ratings changed over the three year period?

Yes No

If ‘Yes’ please give details of the modifications in question:

NSAI REVIEWCompliance with ISO 14971 – version: Residual/remaining risks continue to be acceptable, based upon type of device, special circumstances (e.g. drug/device, animal tissue, human blood), and intended application of the deviceOn-going Risk Management Plan suitableSolutions adopted by Manufacturer conform to safety principles, taking account of the generally accepted state of the art


Clinical Reviewer (if applicable) Date: Clinical risks (actual risks involved in the use, application of the

treatment or deployment of the device) identified by suitably qualified person

Evidence of linkages between RMF, CER and Labelling observedCOMMENTS:



GRF-25-30 Rev. 3.2 Page 17 of 28

Section 8 – Sterilisation

1. Is the product provided Sterile? Yes No

NSAI REVIEWAgreed that this section is not required Yes No Reviewer: Date: Comments:

MANUFACTURER: Please provide the latest Sterilization Revalidation protocol(s) & report(s)

For Irradiation, please supply the last year’s Dose Audits.

Table 6: Sterilisation Information SummaryDevice sub-family

Cat. Number

Sterilization Method

Sterilization Location

Protocol/ Report No.

Site resp for Release

Include lines & cycles

2. If EtO is utilized for Sterilization, please categorize the device according to the duration of contact below, and provide data in support of the most recently completed residual testing:

A – Limited Exposure B – Prolonged Exposure C – Permanent Contact

NSAI REVIEWCompliance with relevant harmonized standard for sterilization - If harmonized standard for sterilization is not followed, identify the industry standard used for cycle determination & validations (e.g. AAMI, TIR) EtO Residuals compliant with EN ISO 10993-7 – version Validation / Revalidation schedules defined, documented and maintained

Validation Report reviewed & results support a validated sterilization cycle.

NSAI REVIEWGRF-25-30 Rev. 3.2 Page 18 of 28

Technical Reviewer Date: COMMENTS:



GRF-25-30 Rev. 3.2 Page 19 of 28

Section 9 – Clinical Performance (Human)MANUFACTURER: Please provide a documented procedure / plan addressing Post Market Clinical Follow-up in accordance with MEDDEV 2.12/2

Please provide an updated Clinical Evaluation Report to support the on-going safety and performance of the device as per MEDDEV 2.7.1.

1. Does the CER comply with MEDDEV 2.7.1, and include the collection and analysis of post market clinical data per MEDDEV 2.12/2?

Yes NoIf “No” please explain -

2. Does the CER address the relative risks of predicate devices Yes No

If “No” please explain -

3. Please identify the individual(s) who performed the clinical evaluation - Has a suitably qualified individual been involved in the review of data and the determination of clinical safety and performance?

Yes NoIs their CV included? Yes NoIf “No” please explain -

4. For this device:a. Are any further clinical investigations planned

Yes Nob. Are any clinical investigations on-going

Yes Noc. Have any additional clinical investigations been completed

during the current product certification cycle? Yes No

If “Yes” please provide additional information and status (per MEDDEV 2.7.1)

- investigation report signed and dated- investigation protocol- CA(s) letter of no objection or other regulatory bodies

approval of protocol- Ethics Committee approval letter(s)

NSAI REVIEW

NSAI REVIEW Summary - CERYes No Comments

or Queries1 Signed and dated clinical evaluation

provided?

GRF-25-30 Rev. 3.2 Page 20 of 28

2 Justification provided if no clinical data is submitted. Is this approach justified in the context of the risk management process, the device body interaction and the claims made for the device?

3 CER compiled in accordance with 93/42/EEC Annex X or 90/385/EEC Annex 7 and MEDDEV 2.7.1 and 2.7.2 as appropriate

4 Has a suitably qualified individual been involved in the review of data and the determination of clinical safety and performance? (CV or Bio)

5 Statement of relationship between the evaluator and the product included.

6 The objectives and scope of the clinical evaluation are outlined. The manufacturer has specified the clinical ER’s to be met (e.g. clinical performance(s), safety, risks and favorable benefit/risk ratio related to intended use, target group(s) and indication(s) to be met).

7 The procedures and steps (sections 5-9 of MEDDEV 2.7.1) are outlined in report.

8 Is data presented from clinical experience of the device in question or equivalent devices (e.g. PMS reports, studies, registries, adverse event databases, FCAs etc)?

9 Has both favorable and unfavorable data been considered?

10

Has the opinion of all experts involved been documented? Has the opinion of the expert(s) been observed? If not please justify.

9 Any literature review reflects current state of the art for technology and medical practice, and the rationale for selection / relevance of published literature provided.

10

Analysis of market experience of same or similar devices included

11

Is there a clinical data analysis & conclusion provided, to address safety & performance of device, compliance with ERs & the risk benefit analysis of device? Are the conclusions of the manufacturer valid?

Clinical Reviewer: Date: GRF-25-30 Rev. 3.2 Page 21 of 28

COMMENTS:

External Reviewer (if applicable): Date: COMMENTS:


Conclusion:

Internal & External Assessors used: No YesIf Yes – Details: Opinion/Comments:

Signature: Date:

GRF-25-30 Rev. 3.2 Page 22 of 28

Section 10 – Additional Information

Please use this section to document any additional information not already covered.

If any of the APPENDICES apply, please complete Table 7.

Table 7 – Applicable AppendicesDirective Description – Devices containing Applicable Appendix2012/722/EU Tissue of Animal Origin No, Yes → A2000/70/EC Human Blood Derivative(s) No, Yes → B2001/83/EC Medicinal Substances No, Yes → C1. Devices containing Tissue of Animal Origin falling under

2012/722/EUEDQM Cert # EDQM Cert expiry Any change in GBR rating No, Yes – if Yes, please comment: Justification for continued use of tissue of animal origin –

2. Devices containing Human Blood Derivatives under 2000/70/ECEDQM Cert # EDQM Cert expiry Justification for continued use of human blood derivative(s) –

3. Devices containing Medicinal Substances under 2001/83/ECStatus of Drug Master File

NSAI REVIEW EDQM cert(s) valid Adequate justification for continued use of tissue of animal origin & human blood derivatives

Any change to GBR Rating – No Yes – impact assessed Status of drug master file Competent Authority review continues to cover the usefulness of the medicinal substance and models covered by the CE certificate.

NSAI REVIEWTable 7 – Agreed the Appendices are not required. Yes No Reviewer Date: COMMENTS:


GRF-25-30 Rev. 3.2 Page 23 of 28

Section 11 - NSAI Queries11.1 QUERIES, Responses and Dispositions.

Company Query #1 – Company Response: Date:

Response Disposition: By: Date: Accepted Yes NoRationale:

If not accepted:FOLLOW-ON QUERY:







Company Query #4 –

Company Response: Date:

GRF-25-30 Rev. 3.2 Page 24 of 28





If not accepted:FOLLOW-ON QUERY: Company Query #6 – Company Response: Date:






Company Query #8 –GRF-25-30 Rev. 3.2 Page 25 of 28

Company Response: Date:


If not accepted:FOLLOW-ON QUERY: Company Query #9 – Company Response: Date:






GRF-25-30 Rev. 3.2 Page 26 of 28

11.2 Query Status Table 8:

QUERY # Disposition By: Date:

GRF-25-30 Rev. 3.2 Page 27 of 28

Section 12 - Conclusion of Assessment

NOTIFIED BODY STATEMENT:Conclusion –

(The following details shall appear on the Approval Letter)

1. Intended use : 2. Indications for use: 3. Shelf life (if applicable) : 4. Approval conditions :

ROLE Name DateFile ManagerExpert OpinionBiomechanical ReviewElectrical ReviewClinical ReviewTSE ExpertOutcome 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

PRESENTED TO THE TECHNICAL REVIEW COMMITTEE MEETING ON:

Outcome of Meeting: Follow Up required No YesIf “Yes” please provide details –

APPROVAL DEMONSTRATED by SIGNING APPROVAL AMENDMENT RECORD

GRF-25-30 Rev. 3.2 Page 28 of 28

GRF-25-30 Rev. 3.2 Page 29 of 28

Section 13 - Medical Devices Supplemental Review Form

This form is used to supplement applications/change notifications for: Medical Devices incorporating Tissues of Animal Origin (722/2012EU) Medical Devices incorporating Human Blood Derivative (2000/70/EC) Medical Devices incorporating Medicinal Substance (2001/83/EC)

THIS IS NOT A STAND ALONE DOCUMENT

Please submit an unsigned version of this Supplemental Application in Word along with the relevant NSAI review form.

Europe N. America

NSAI1 Swift Square,Northwood,Santry,Dublin 9Ireland

Phone : (01) 807 3929Fax : (01) 807 [email protected]

NSAI Inc.402 Amherst StreetNashuaNH 03063USA

Phone : (603) 882 4412Fax : (603) 882 [email protected]

GRF-25-30 Rev. 3.2 Page 30 of 28

mailto:[email protected]

APPENDIX A

Medical Devices incorporating tissues of animal origin, covered by the TSE Directive 722/2012 EU only

Manufacturer’s InstructionsPlease complete the table below:Appendix 1 Table 1Starting tissue used Species Used Geographical sourcing Veterinary controls Feeding restrictions Evidence of compliance with regulation 1609(where the raw material or intermediates are imported or processed in the EU)

GBR rating of tissue Details of collagen, tallow or gelatine used.

Details of source establishments

Scope of Site(s): EDQM Certificate (Yes / No)

# : Expiry Date : (please supply copy)

Note – NSAI Certificate will not exceed the expiration date of the EDQM certificate

If no valid EDQM Certificate held, please supply:Details of harvesting of the animal tissueTSE infectious agents inactivation stepsTSE infectious agents clearance validationSource establishmentsCopy of compliance to Regulations 1609Details of the source of tissue - geographical location, open/closed herds, feeds, pre and post mortem inspection.

NSAI ReviewReview the information provided, and verify the suitability of the scope of the site(s).

Based on the presence/absence & content of the EDQM Certificate, is C.A. Distribution required?

No Yes

Reviewer & date: GRF-25-30 Rev. 3.2 Page 31 of 28


TSE ONLYRationale on justification

Manufacturer’s InstructionsPlease provide a detailed rational on the use of the use of the animal tissue in the specific application, comparing the device with materials sourced from other animals, or made with alternative non-animal derived material and the expected clinical benefit.

NSAI ReviewReview the data supplied.

Reviewer & date: QUERIES No Yes Number(s)

Auditing Source Establishments

Manufacturer’s InstructionsPlease information on the auditing of source establishments &/or third party supplier for the animal material used by the medical device manufacturer including details of feeding restrictions:



Harvesting and TSE infectious agents inactivation of the animal tissue

Manufacturer’s InstructionsPlease provide details on the harvesting of the animal tissue and relevant TSE infectious agents inactivation steps performed on the animal tissue prior to its incorporation into the device.The TSE infectious agents clearance validation study of the animal tissue, protocol and report, should also be supplied – conformity to EN ISO 22442-1, -2, & -3 must be demonstrated:

NSAI Review

GRF-25-30 Rev. 3.2 Page 32 of 28

Review the data supplied, and ensure compliance with EN ISO 22442-1, -2 & -3:2007


Description of production steps

Manufacturer’s InstructionsPlease provide details of all production steps in which the animal tissue is present including a description of the key elements adopted to minimise the risk of infection:



Summary Evaluation Report

NSAI Review

RF-25-13 completed: . No Yes(Summary Evaluation Report on the Assessment of a Medical Device by the Notified Body for conformity with Council Directive 93/42/EEC and Commission Directive 722/2012EU)

Comments:


GRF-25-30 Rev. 3.2 Page 33 of 28

APPENDIX B

Medical Devices incorporating Human Blood Derivative only

Manufacturer’s InstructionsPlease compile the technical dossiers in the volumes detailed below:

Volume 1: Completed EMEA application form (Doc. Ref. EMEA / CHMP/ 434094/ 2005)Volume 2: Product Information and LabellingVolume 3: Appendix II (ref Doc. Ref. EMEA/CHMP/401993/2005)Volume 4: Quality Summary of the ancillary medicinal substance as integrated into the medical device in accordance with MEDDEV 2.1/3 rev 2, section B2, a–q.Volume 5: Quality Summary of the ancillary medicinal substance in accordance with Module 2.3 of Volume 2B, CTD of the Notice to Applicants (Eudralex).Volume 6: Tabular summaries for non-clinical and clinical studies.Volume 7: Quality, non-clinical and clinical documentation in accordance with MEDDEV 2.1/3 rev 2 for the ancillary medicinal substance as integrated into the medical device section B2, a – q.Volume 8: Relevant parts of Module 3 of Volume 2B, CTD of the Notice to Applicants for the ancillary medicinal substance and a copy of the latest PMF annual update.

NOTE - Please be advised that following review of the application by the NSAI, amendments may be requested to the technical dossiers prior to their submission to the EMEA.

The number of hard and soft copies of the technical dossiers required by the EMEA will vary depending on the appointed Rapporteurs, it is the responsibility of the Medical Device Manufacturer to prepare these as directed by the NSAI.

Please complete the table below:

Please complete the table below:Appendix B-Table 1Derivative(s) Supplier: Supplier Address: Test laboratory used: Laboratory Address: Laboratory Approvals: Contract company used

GRF-25-30 Rev. 3.0 APPENDIX-B - HUMAN BLOOD ONLY

for bioavailability or bioequivalence trailsContact person in the EEA for product recall and defects

Approval Certs for above sites:

EMEA Scientific Opinion:

NSAI ReviewReview the information provided, and in particular ensure that the laboratory is an approved facility for the testing and batch release of Blood Derivatives in accordance with Annex III of EC Administrative Procedure for OCABR (EDQM).

Based on the presence/absence & content of the EDQM Certificate, is C.A. Distribution required?

No Yes


Details of human blood derivative(s) used

Manufacturer’s InstructionsPlease provide a detailed description of derivative. The quantities of product derived from human blood should be expressed by mass or international units of biological activity appropriate to the product concerned.

Does the Human Blood Derivative has a Ph. Eur. Certificate of Suitability? No YesIf so, please supply a letter of access to the related Drug Master File or a copy of the Ph. Eur. Certificate of Suitability for the component.

Please supply PMF Master Files certificates for the human blood derivative (this should include the original certificate and the latest annual up-date)

NSAI Review


Review the information provided on the qualitative & quantitative composition of the material.Review the Certificate(s) supplied


Justification for use of human blood derivatives

Manufacturer’s InstructionsPlease provide an in-dept rational justifying the use of tissue in specific application, including a comparison with materials sourced from non-human derivatives, and expected clinical benefit.

NSAI ReviewReview the rationale/justification provided.

Clinical Review


Verification of Usefulness of Device

Manufacturer’s InstructionsIn addition to the justification above, please provide a review of currently available devices & technologies, confirming medical necessity based on an expert clinician recommendation & review:

NSAI ReviewClinical Review of the information provided.



Human Blood Derivative Manufacture

Manufacturer’s InstructionsPlease supply:

A copy of the Manufacturing Authorisation for the Ancillary Medicinal Substance containing Human Blood Derivatives.

A statement from the Competent Authority which carried out the inspection of the Human Blood Derivative manufacturing sites.

Written confirmation from the manufacturer of the ancillary active substance that the applicant will be informed in the case of any modification of the manufacturing process or specifications.

Written confirmation from the manufacturer of the human blood derivative to inform the medical device manufacturer in the case of any modifications to the PMF.

Written confirmation from the manufacturer of the human blood derivative to complete look back procedures in the event of product recalls.

NSAI ReviewReview the information provided.


Human Blood Derivative Supplier(s), Collection and Controls

Manufacturer’s InstructionsPlease complete the table below:Appendix B- Table 2Details on the control of suppliers

Source of blood/donor control

Nature of donation – pooled or single donation

Details on the collection of source materials

NSAI Review


Review the information provided.


Derivative Manufacturing steps

Manufacturer’s InstructionsPlease outline the derivative manufacturing steps:

NSAI ReviewDoes the information provided demonstrate the ability to guarantee batch-to-batch consistency & absence of viral contamination, to the extent that the state of technology permits?


Inactivation steps

Manufacturer’s InstructionsPlease document the production steps used to minimise risk of infection and provide the necessary viral clearance validation studies:

NSAI ReviewHave the production steps used to minimise the risk of infection been adequately validated? Does the data demonstrate the suitability of the inactivation steps taken to minimise the risk of infection?


Laboratory Test Details – derivative

Manufacturer’s Instructions


Please provide details of the laboratory tests and also provide the necessary validation(s):

NSAI ReviewReview the adequacy of the tests & technology used. Have tests been adequately validated? Does the technology represent ‘State of the Art’?


Quality Control of derivative

Manufacturer’s InstructionsPlease provide details of the in-process & final test procedures:

NSAI ReviewReview the adequacy of the test procedures


Procedures for batch release of derivative

Manufacturer’s InstructionsPlease provide details of the batch release procedures for derivative(s):

NSAI ReviewReview the adequacy of the procedures



Derivative Storage & Stability(in addition to the Device stability covered previously)

Manufacturer’s InstructionsPlease confirm the shelf life of the derivative: Please provide details of the storage & transport requirements along with stability studies and validation for the derivative:

NSAI ReviewReview the adequacy of the data


Device Manufacturing Steps

Manufacturer’s InstructionsPlease provide details of the manufacturing steps & any relevant procedures for the device using derivativeIs) along with the relevant validation of the effect on quality & viral safety on the finished device:

NSAI ReviewReview the adequacy of the data & validation(s) provided.


Device Testing & Quality Control

Manufacturer’s InstructionsPlease provide details of the device in-process and final test(s) & any relevant procedures:

NSAI ReviewReview the adequacy of the tests, in particular regarding the safety of the device.



Device Batch Release

Manufacturer’s InstructionsPlease provide copies of the batch release procedures for finished devices:

NSAI ReviewReview the procedures to ensure that responsibilities & authorities are adequately defined, and that the system requires batch release notification to be sent to NSAI.


Packaging components

Manufacturer’s InstructionsPlease provide details of the packaging components including a description from which the material is constructed using current standard terms – European Pharmacopeia where applicable:

NSAI ReviewReview the data supplied to ensure that the description includes the following details – package size, proposed shelf life (unopened and in use), & proposed storage conditions.


Previous Existing Legislation - additional

Manufacturer’s InstructionsPlease provide details of the applications for the same derivative both in and out of the EEA including those which are authorised, pending and refused.


If the device does have other applications for the same derivative please provide details of the country, the trade name, date of submission/suspension and the reason for suspension where appropriate:

NSAI ReviewReview the Marketing Authorisations or Device approval in the EEA. Ensure that the following details are included; the authorisation/approval number, the date of authorisation/approval


Risk analysis - additional

NSAI ReviewEnsure that the risk analysis includes a statement of acceptability of residual risks in view of the clinical use and benefits of the device in comparison to other existing devices with similar intended use.It should comprise of a qualitative or quantitative estimate of the risk arising from the use of the product, taking into account the likelihood of contamination of the product, the nature & duration of patient exposure, and the route of administration.


Labelling and IFU - additional

NSAI ReviewEnsure that the labelling & IFU include a statement indicating that the device incorporates human blood derivative, as per E.R. 13.3(n) & 13.6(a) of 93/42/EEC



APPENDIX C

Medical Devices incorporating Medicinal Substance only

Manufacturer’s InstructionsPlease provide a dossier detailing the medicinal substance prepared in compliance with MEDDEV 2.1.3 section B3 (A-Q).

Please complete the table below:

Appendix C- Table 1Name of Medicinal Substance

Name & address of Medicinal Substance manufacturerName & address of Medicinal substance supplier

Function of Medicinal Substance within medical device

EDQM Certificate for Medicinal Substance (Yes / No)

Note – NSAI Certificate will not exceed the expiration date of the EDQM certificate

If no EDQM certificate is available, please supply the drug master file for the medicinal substance

NSAI ReviewIs the dossier provided complete, as required by MEDDEV 2.1.3 Section B3 (A-Q)?If an EDQM cert. is supplied, is it valid for the medicinal substance?


Qualitative and quantitative particulars of the constituents

Manufacturer’s InstructionsPlease provide a description of the substance and the amount (giving a range where appropriate) of the medicinal substance incorporated into each medical device. If the substance is modified during its incorporation into the device, please provide relevant information:

GRF-25-30 Rev. 3.2 Appendix C –MEDICINAL SUBSTANCE ONLY

NSAI ReviewIs the data provided sufficient?


Description of method of manufacture

Manufacturer’s InstructionsIn addition to the overall description supplied, please provide details of the incorporation of the medicinal substance into each medical device.If the medicinal substance is altered in any way prior to its inclusion into the device, please provide relevant information:

NSAI ReviewIs the data provided sufficient?


Control of starting materials

Manufacturer’s InstructionsPlease provide the specification for the medicinal substance. Where applicable, reference shall be to the European Pharmacopoeia or in the absence of an EP monograph to a national pharmacopoeia of one of the Member States. If no monograph is available from the Member States reference may be to other national monographs or to the manufacturer's specification and methods of analysis.

For new active substances and certain known substances additional information will be required which may be provided in the form of a Drug Master File. The guideline "Requirements in relation to active substances"(1) may be of assistance in providing circumstances where reference to a Pharmacopoeia monograph may need to be supplemented by further information:

NSAI ReviewDoes the specification for the medicinal substance reference the EP?If not, is a National Pharmacopeia from one of the EU Member States used?


If not, what is used?

Is a Drug Master File required and supplied?


Control of tests carried out at intermediate stages of the manufacturing process of the medical device

Manufacturer’s InstructionsIf necessary, please supply information regarding the control of tests carried out at intermediate stages of the manufacturing process.

NSAI ReviewThis information is only necessary if it is directly relevant to the quality of the substance as incorporated in the medical device


Control tests on finished product

Manufacturer’s InstructionsPlease supply details of the qualitative and quantitative tests carried out to control the medicinal substance in the device.

NSAI ReviewAre adequate controls in place?


Toxicity

Manufacturer’s InstructionsPlease provide reference to the known toxicological profile of the medicinal substance.


In the case of new active substances, the results of the toxicity tests should be supplied

NSAI ReviewReview the toxicological profile provided. This may include information on toxicity and biocompatibility of the medical device which may be available from evaluation in accordance with the EN ISO 10993 series of standards.


Reproductive Function

Please provide reference to the known profile in relation to reproductive function, of the medicinal substance.In the case of new active substances, the results of the appropriate tests should be supplied

NSAI ReviewReview the profile provided, similar conditions to Toxicity apply.


Embryo/foetal and perinatal Toxicity

Manufacturer’s InstructionsPlease provide reference to the known embryo/foetal & perinatal toxicological profile of the medicinal substance.In the case of new active substances, the results of the toxicity tests should be supplied




Mutagenic Potential

Manufacturer’s InstructionsPlease provide reference to the known mutagenic potential of the medicinal substance.In the case of new active substances, the results of the relevant tests should be supplied



Carcinogenicity Potential

Manufacturer’s InstructionsPlease provide data on the carcinogenicity potential of the medicinal substance.

NSAI ReviewThe need for data on carcinogenicity should be addressed taking account of available information on the medicinal substance, the results of genotoxicity testing, the chemical structure of the medicinal substance, and the duration of potential exposure to the substance.


Pharmacodynamics

Manufacturer’s InstructionsPlease provide information on the intended action of the medicinal substance in the context of its incorporation into a medical device.

NSAI ReviewReview the data provided to ensure that this addresses the intended action of the medicinal substance in the context of its incorporation into a medical device.



Pharmacokinetics

Manufacturer’s InstructionsPlease provide details on the pharmacokinetics – addressing some or all of the points below as appropriate:description of the pattern of local and systemic exposure to the medicinal substance, where the level of exposure fluctuates, the maximum level and duration of exposure should be considered, where it is considered possible that potential levels of systemic exposure may present a safety concern, maximum peak plasma concentration should be established, taking due consideration of individual variability, new active substances will require information on the release from the device, and, if relevant, its subsequent distribution and elimination.

NSAI ReviewIt is anticipated that pharmacokinetic studies will not be required in the majority of cases. Have the areas above been addressed as appropriate?


Local tolerance

Manufacturer’s InstructionsPlease provide details on the local tolerance of the medicinal substance.

NSAI ReviewThis is of particular relevance since the route of exposure to the medicinal substance may be different from its conventional application. The relevant results of device testing according to EN ISO 10993 should be provided, or, where appropriate, information from the scientific literature.


Risk Analysis - additional


NSAI ReviewReview the risk analysis supplied to ensure that it includes a critical appraisal of the safety of the drug/device combination.


Stability – additional

NSAI ReviewReview the stability data supplied to ensure it shows that the medicinal substance maintains its desired function throughout the defined shelf-life of the device, taking account of the manufacturer’s recommended storage conditions.


Competent Authority Review

NSAI ReviewDetails of Consulting Competent Authority: Date consultation sought: Date opinion received: Summary of Competent Authority Opinion:


Documents

Applicant - NSAI - The National Standards Authority of Ireland Web viewCompleted application form (Word format, .doc or .docx) Application (min. Signed Declaration page(s)) scanned