Medical Devices Application Review Form
This form is used for:
Substantial Change
Non-substantial Change
Please check all the relevant DIRECTIVE(s)
DIRECTIVE
NSAI File No. (NSAI Use ONLY)
MDD (93/42/EEC)
252.
/
AIMD (90/385/EEC)
253.
/
TSE (2003/32/EC)
554.
/
Human Blood (2000/70/EC)
576.
/
For products covered by either the MDD or AIMD, is compliance with the
additional requirements of 2007/47/EC being claimed : Yes
No
NOTE : If “No”, please be aware that new certificates (original or renewal) will be issued
with an expiry date of 20-Mar-10, until compliance with 2007/47/EC has been
confirmed.
Please submit an unsigned version of this Application in Word as well as a
signed copy - either scanned/secured (pdf) copy.
Europe
N. America
NSAI
1 Swift Square,
Northwood,
Santry,
Dublin 9
Ireland
NSAI Inc.
402 Amherst Street
Nashua
NH 03063
USA
Phone : (01) 807 3929
Fax : (01) 807 3996
Medical.Devices@NSAI.ie
Phone : (603) 882 4412
Fax : (603) 882 1985
Medical.Devices@NSAIinc.com
NOTE : Only completed Applications will be reviewed.
RF-25-08 Rev 12
Page 1 of 31
DECLARATION(s) BY APPLICANT
Note: this page to be completed by all applicants
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:
--------------------
RF-25-08 Rev 12
Page 2 of 31
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/
MDD Classification:
Rule:
Conformity Route:
Annex
AIMD
Rationale
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
RF-25-08 Rev 12
Page 3 of 31
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
RF-25-08 Rev 12
Yes
Number(s)
Page 4 of 31
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
Table 2
Product / Product Family Name:
Intended Use:
Model/Catalogue
Number
Description
Classification
Schedule*
*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
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 5 of 31
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
significant
change to the :
Quality System
Product Range
Design Dossier
Class
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 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:
YES
NO
AGREED BY REVIEWER
REVIEWER
DATE
Pre-Clinical
Technical Requirements
Table 3 – Impact of Change
SECTION
Intended Use of the Device
Correct Classification &
Appropriate Annex
Labelling & IFU
Solutions to Essential
Requirements
Compliance to Harmonised
Standards
Performance/complaint
Analysis
Risk Analysis
Sterilisation
Stability – Device
Stability – Packaging
Biocompatibility
Medical Electrical Equipment
Medical Electrical System
Pre-clinical Testing - NonClinical (Bench)
Pre-clinical Testing - Clinical
(Animal Testing)
Clinical Evaluation
Design Dossier
(MDD Annex 2 Class 3)
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 14 below
- If section is applicable please complete each section (2 through 14 below) in full and
supply supporting documentation as required.
RF-25-08 Rev 12
Page 6 of 31
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
* As noted on page 1, if compliance with 2007/47/EC is not demonstrated, certificate expiry date will be
20-Mar-10.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 7 of 31
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. It is the intended use that is needed to fully
verify that the classification is correct. Intended use is always as defined by the manufacturer.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 8 of 31
Section 4 - Correct Classification and Appropriate Annex
Manufacturer’s Instructions
For MDD - Please enter the Classification of the device, along with the Rule & Rationale for the choice:
Class
Rule
Rationale
NSAI Review
The classification will be based on the Manufacturer’s intended use for the device.
For MDD : Review the Manufacturer’s classification rationale per Annex IX of the MDD 93/42/EEC and
the device classification guidelines, MDDEV 2.4/Rev. 8. * Also ensure that any classification changes
introduced by 2007/47/EC have been reviewed & implemented.
Ensure that the appropriate annex is referenced based on the classification rationale
For AIMDs : Ensure device falls under Directive 90/385/EEC & that the correct Annex used
* As noted on page 1, if compliance with 2007/47/EC is not demonstrated, certificate expiry date will be
20-Mar-10.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 9 of 31
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.
–
–
–
–
Ensure the language requirements of the countries where the device is to be placed on the market
have been fulfilled
Ensure the requirements of EN 980 (Symbols for use in the labelling of Medical Devices) are
adhered to.
Ensure the requirements of EN 60601-1:2006 clause 7 (ME Equipment Identification, Marking and
Documents are adhered to.
If applicable, ensure the requirements of EN 60601-1-6 (General requirements for basic safety and
essential performance - Collateral Standard: Usability) is adhered to.
NSAI Review
Ensure that the labelling and the IFU comply with the requirements of:
Annex I Section 13 of MDD 93/42/EEC or
Annex I, Sections 14 and 15 of the AIMD 90/385/EEC and if applicable
EN 60601-1:2006 Clause 7 ME Equipment Identification, Marking and Documents
EN 60601-1-6 Usability Engineering Process – Results Satisfactory
Reviewer & date:
Queries?
No
Yes
Number(s)
If Applicable:
Symbols and Markings on ME Equipment/System are in accordance with Table D1 of EN 60601-1:2006
(Page 631) No
Yes
EN 60601-1:2006 – Accompanying Documents Satisfactory
RF-25-08 Rev 12
No
Yes
Page 10 of 31
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
In particular, ensure that for products covered by the MDD, any revised requirements introduced by
2007/47/EC are met. * As noted on page 1, if compliance with 2007/47/EC is not demonstrated,
certificate expiry date will be 20-Mar-10.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 11 of 31
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.
For MDD, see http://ec.europa.eu/enterprise/newapproach/standardization/harmstds/reflist/meddevic.html
For AIMD, see http://ec.europa.eu/enterprise/newapproach/standardization/harmstds/reflist/implmedd.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
EN ISO 13485:2003
EN ISO 14971: 2007
EN 980:2008
Compliant – YES/NO
YES
YES
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.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 12 of 31
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.
NSAI Review
Review complaints vs. units placed on the market and the nature of the reportable incidents/associated
corrective actions and complaint trends.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 13 of 31
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, human
blood derivatives or medicinal substances: see separate section(s)
– 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.
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.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 14 of 31
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
Number
Sterilization
Method
Sterilization
Location
Protocol /
Report No.
For EO Sterilization Only:
Please clarify if compliance with EN ISO 10993-7:2008 is being demonstrated -
Site Responsible
for Release
No
Yes
Please categorize the device according to the duration of contact, per EN ISO 10993-7:2008 / EN ISO
10993-7:1996
A – Limited Exposure
B – Prolonged Exposure
C – Permanent Contact
Please indicate if the following sections apply:
- Section 4.3.5 TCLs for surface contacting devices or implants for EN ISO 10993-7:2008
- Special Situations per EN ISO 10993-7:2008 Section 4.3.6, or EN ISO 10993-7:1996 Section
4.3.4
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.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 15 of 31
Section 11 – Pre-Clinical Evaluation
11.1 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 or
medicinal substances: see separate section(s)
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. packaging stability - EN ISO 11607-1/-2:2006.
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
RF-25-08 Rev 12
Yes
Number(s)
Page 16 of 31
11.2 Biocompatibility
Manufacturer’s Instructions
Confirm that the devices contact the patient’s body directly or indirectly?
Yes
If “Yes”, please provide biocompatibility data:
If biocompatibility data is required,-please confirm the categorization of the devices with respect to
Body Contact:
Surface-contacting devices
External communicating devices
Implant devices
Skin
Blood path, indirect
Tissue/bone
Mucosal membranes
Tissue/bone/dentin
Blood
Breached/compromised surfaces
Circulating blood
Duration of Contact :
Limited exposure (< 24hrs)
Prolonged exposure (>24hrs
<30 days)
Permanent contact
(>30 days)
Has biocompatibility testing been performed on the actual devices in question to demonstrate compliance
with EN ISO 10993-1:2003?
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)
Reviewer & date:
Queries?
RF-25-08 Rev 12
No
Yes
Number(s)
Page 17 of 31
11.3 Medical Electrical Equipment (ME Equipment) & Medical
Electrical Systems (ME Systems)
Definitions:
ME Equipment – electrical equipment having an applied part or transferring energy to or form the
PATEINT or detecting such energy transfer to or from the patient and which is:
a)
b)
provided with not more than one connection to a particular supply mains; and
intended by its manufacturer to be used:
1) in the diagnosis, treatment, or monitoring of a patient; or
2) 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 MEdicial Device Product (i) ME Equipment
(ii) ME System
Yes
Yes
No
No
Have the applicable requirements of EN 60601-1:2006, including the mandatory risk assessment to EN
14971 been applied to the ME Equipment/ME System 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 which of the following EN 60601-1-X Collateral Standards have been applied to validate the
proposed change(s):
TABLE 5
EN 60601-1-X
EN 60601-1-2:2007
EN 60601-1-3:1994
EN 60601-1-6:2004
EN 60601-1-8:2007
EN 60601-1-10:2008
RF-25-08 Rev 12
Document Title
Medical electrical equipment - Part 1-2: General
requirements for basic safety and essential
performance - Collateral standard:
Electromagnetic compatibility - Requirements
and tests
Medical electrical equipment - Part 1-3: General
requirements for basic safety and essential
performance - Collateral Standard: Radiation
protection in diagnostic X-ray equipment
Medical electrical equipment - Part 1-6: General
requirements for safety - Collateral standard:
Usability
Medical electrical equipment - Part 1-8: General
requirements for basic safety and essential
performance - Collateral Standard: General
requirements, tests and guidance for alarm
systems in medical electrical equipment and
medical electrical systems
Medical electrical equipment - Part 1-10:
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
Page 18 of 31
General requirements for basic safety and
essential performance - Collateral Standard:
Requirements for the development of
physiologic closed-loop controllers
If applicable, please list any EN60601-2-X Particular Standards which have been applied to validate the
proposed change(s):
TABLE 6:
EN 60601-2-X
Document Title
In respect of the ME Equipment/ME System, please provide each of the following as applicable:
 Test Report to EN 60601-1:2006
 The associated Risk Management File
 The EN62304 Software Development Process and Validation Report, as well as the software
Risk Assessment
 Test Reports to the applicable EN 60601-1-X Collateral Standards
 Test Reports to the Applicable EN 60601-2-X Particular Standards
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 60601-1:2006 for the proposed change(s).
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 19 of 31
Section 12 – Pre-Clinical Evaluation (continued)
(FOR CLASS 2B IMPLANTABLE AND CLASS 3 REVIEWS ONLY)
Section 12.1 – Non-Clinical Testing (Bench Testing)
Manufacturer’s Instructions
For the proposed change(s):
 Please supply design input/output document which clearly outlines each device attribute, the design
specification, location of data, etc; for example supply the Product Requirements Document (PRD), or
Design Description Document (DDD)
 Please populate Table X with relevant information – Note when utilizing non-harmonized standards
(ASTM, AAMI, internal test methods, etc) please justify applicability
TABLE 7 – SAMPLE DESIGN DESCRIPTION TABLE
1
Device Attribute
(Design Input)
Harmonized
Std
Accelerated
Durability – Dynamic
atigue
Coating Thickness
ISO25539
N/A
2
Non-Harmonized Std
Doc Ref
(Design Input)
NSAI
N/A
Justification: N/A
RP-12345
Yes
In-house Validated Method
Justification:
No harmonized standard or
ISO/ASTM/AAMI standard
available. Hence in-house
method was developed
and validated per internal
procedures; validation
reference VR-1234.
STM-0234
VR-1234
Yes
3
TABLE 7 - SAMPLE DESIGN DESCRIPTION TABLE
Device Attribute
(Design Input)
1
2
3
4
5
6
7
8
9
10
11
Harmonized
Std
Non-Harmonized Std
Doc Ref
(Design Input)
NSAI
Justification:
Justification:
Justification:
Justification:
Justification:
Justification:
Justification:
Justification:
Justification:
Justification:
Justification:
12
RF-25-08 Rev 12
Page 20 of 31
Justification:
Note – please add rows depending on number of attributes for specific device

Please supply the following if applicable:
o Computer modelling Reports – Finite Element Analysis (FEA), Computational Fluid Dynamics
(CFD), etc
o All relevant bench test Protocols and Reports which should include, but not limited to, justified
test parameters per relevant standards, sample size justification, acceptance criteria, justified
deviations, etc
Note - Depending on type of the device of this submission, physical testing can include, but is not limited
to, static and dynamic accelerated durability, bond strength, coating integrity, coating durability, corrosion,
simulated use testing etc.
NSAI Review
Review the physical device test results to assess design inputs versus outputs versus relevant standard
requirements.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 21 of 31
Section 12.2 – Clinical Testing (animal model)
Manufacturer’s Instructions
Please indicate if acute/chronic animal studies have been completed to substantiate the in vivo safety
and/or effectiveness of the device design, including the proposed change(s) of this submission?
No
Yes
If “No” please justify Please include all relevant animal reports associated with the device design related to this submission.
Section 12.2 (a)
Pre-Clinical Performance (In Vivo Acute/Long-term)
Manufacturer’s Instructions
If applicable to the proposed change(s):
Please supply detailed information on all studies in animal models, i.e. study objectives, methodology,
results analysis and conclusions including rational for selection of the model(s), which substantiate the
stated intended use.
NSAI Review
Review the pre-clinical study results to assess the adequacy and validity of the documentation supporting
the pre-clinical evaluation.
Reviewer & date:
Queries?
No
Yes
Number(s)
Section 12.2 (b)
Acute In-Vivo Device Performance
Manufacturer’s Instructions
If applicable to the proposed change(s):
Please provide summary data of acute in vivo device performance against pre-defined requirements,
and/or clearly define location of the relevant data within each animal report
NSAI Review
Review the device pre-clinical study results to assess the adequacy and validity of the documentation
supporting the pre-clinical evaluation.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 22 of 31
Section 13 – Clinical Performance (Human Model)
Section 13.1 – Clinical Evaluation
Manufacturer’s Instructions
Please indicate if a clinical evaluation has been completed to substantiate the in vivo safety and/or
effectiveness of the device design, including the proposed change(s) of this submission?
No
Yes
If “No” please justify -
NOTE –
Revisions to the MDD 93/42/EC by 2007/47/EC have implications for the clinical data & the evaluation of
the data to be provided by Manufacturers to the Notified Body, to demonstrate the clinical safety &
performance of the medical device.
Clinical data must always be documented for all medical device classifications.
MedDev 2.7.1 (2009) provides guidance on the procedure to be adopted by the Manufacturer to evaluate
clinical data. See NSAI Guidance document for further information.
Please provide the necessary clinical evaluation report to support the safe use of the device
NSAI Clinical Review
Evaluation is in accordance with:
For MDD: Annex X of MDD 93/42/EEC, ISO 14155-1 & -2, Notified Body Guidance Document NBMED/2.7/Rec 3 (Evaluation of clinical data) and MedDev 2.7.1 (2009).
In cases where results have been derived from clinical investigations, the Notified Body shall ensure that
the conclusions drawn by the manufacturer are valid in the light of the plan of clinical investigations
submitted to the Competent Authority. Review details of the post market clinical follow-up
NSAI Clinical Assessment: (Chronology of review)
Date:
RF-25-08 Rev 12
Page 23 of 31
Review of Clinical Evaluation
#
1
Signed & dated clinical evaluation provided
2
Competence of the author justified
3
Scope of the evaluation outlined
Yes
No
Comments
Literature Review: : If not Applicable – Clinical Investigation to be reviewed.
4
Literature search protocol provided
5
Rationale for selection/relevance of published literature
provided
6
Validity of data with respect to author, study design & state of
the art technologies, addressed by the manufacture
7
Copies of actual papers and references provided
8
Clinical data appraisal criteria pre-defined
9
Clinical data analysis & conclusion provided, to address safety
& performance of device, compliance with ERs & risk benefit
analysis of device
10
Is the pre-clinical with clinical data sufficient to demonstrate
compliance with ERs (safety & performance under normal
conditions of use)
11
Are gaps identified in demonstration of compliance with ERs
12
Are gaps identified in demonstration of equivalence
13
Are labelling claims substantiated by the clinical data together
with the pre-clinical data provided
14
Are the manufacturer’s conclusions valid
Conclusion:
Internal & External Assessors:
Signature:
Date:
RF-25-08 Rev 12
Page 24 of 31
Section 13.2 – Acute In-Vivo Device Performance
Manufacturer’s Instructions
If applicable to the proposed change(s):
Please provide summary data of acute in vivo device performance against pre-defined endpoints, and/or
clearly define location of the relevant data within clinical evaluation report
NSAI Review
Review the device pre-clinical study results to assess the adequacy and validity of the documentation
supporting the pre-clinical evaluation.
Reviewer & date:
Queries?
RF-25-08 Rev 12
No
Yes
Number(s)
Page 25 of 31
Section 14 – Design Dossier – Design Verification & Validation
(MDD Annex II Class III or AIMD Annex II only)
NSAI Review
Briefly state the outcome of the review against:
1. The Essential Requirements
2. The safety and efficacy of the device as demonstrated by the Risk Analysis
3. The clinical safety of the device
4. Design outputs shall meet the input requirements for design and development. Verify that the
laboratory results obtained and the conclusions made are applicable to the design specifications and
performances claimed.
5. Design validation demonstrates that the product is capable of meeting the requirements for its intended
use. Verify that the validation programme and the results obtained are consistent with all the claimed
properties and the/or intended uses and conform to the applicable essential requirements.
Reviewer & date:
Queries?
No
RF-25-08 Rev 12
Yes
Number(s)
Page 26 of 31
Additional Information
Manufacturer’s Instructions
Please use this section to document any additional information not already covered:
NSAI Review
Review (if applicable).
Reviewer & date:
Queries?
No
Yes
Number(s)
-----------------------------------------------------------------------------
NOTE:
Please indicate which, if any, of the following appendices apply to this submission.
Please complete the relevant appendix.
TABLE 8 – APPLICABLE APPENDICES
Appendix
Directive
Description
Devices containing Tissue of Animal
Origin
A
2003/32/EC
B
2000/70/EC
Devices containing Human Blood
Derivative(s)
C
2001/83/EC
Devices containing Medicinal
Substance
Applicable
Yes
No
Yes
No
Yes
No
-----------------------------------------------------------------------------
RF-25-08 Rev 12
Page 27 of 31
NSAI Queries
Company Query #1 -
Company Response:
Response Disposition:
Company Query #2 -
Company Response:
Response Disposition:
Company Query #3 -
Company Response:
Response Disposition:
Company Query #4 -
Company Response:
Response Disposition:
Company Query #5 -
Company Response:
Response Disposition:
Company Query #6 -
Company Response:
Response Disposition:
RF-25-08 Rev 12
Page 28 of 31
Company Query #7 -
Company Response:
Response Disposition:
Company Query #8 -
Company Response:
Response Disposition:
Company Query #9 -
Company Response:
Response Disposition:
Company Query #10 -
Company Response:
Response Disposition:
Company Query #11 -
Company Response:
Response Disposition:
Company Query #12 -
Company Response:
RF-25-08 Rev 12
Page 29 of 31
Response Disposition:
Company Query #13 -
Company Response:
Response Disposition:
Company Query #14 -
Company Response:
Response Disposition:
Query
RF-25-08 Rev 12
Disposition
Date
Page 30 of 31
Conclusion of Assessment
NOTIFIED BODY STATEMENT
Conclusion:
File Manager:
Expert Opinion by:
Biomechanical Review by:
Electrical Review by:
Clinical Review by:
TSE Expert Review by:
Outcome of Competent Authority Review
(where applicable)
Date :
Date :
Date :
Date :
Date :
Date :
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:
RF-25-08 Rev 12
Page 31 of 31
APPENDIX A
Medical Devices incorporating tissues of animal origin,
covered by the TSE Directive 2003/32/EC only
Manufacturer’s Instructions
Please complete the table below:
Appendix 1 Table 5
Starting tissue used
Species Used
Geographical sourcing
Veterinary controls
Feeding restrictions
Evidence of compliance with
regulation 1774 (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 tissue
Viral inactivation steps
Viral clearance validation
Source establishments
Copy of compliance to Regulations 1744
Details of the source of tissue - geographical location, open/closed herds, feeds, pre and post mortem
inspection.
NSAI Review
Review 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:
Queries?
No
RF-25-16 Rev. 10
Yes
Number(s)
Appendix A - TSE ONLY
Page 1 of 3
TSE ONLY
Rationale on justification
Manufacturer’s Instructions
Please 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 Review
Review the data supplied.
Reviewer & date:
Queries?
No
Yes
Number(s)
Auditing Source Establishments
Manufacturer’s Instructions
Please 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:
NSAI Review
Review the data supplied.
Reviewer & date:
Queries?
No
Yes
Number(s)
Harvesting and viral inactivation of the animal tissue
Manufacturer’s Instructions
Please provide details on the harvesting of the animal tissue and relevant viral inactivation steps
performed on the animal tissue prior to its incorporation into the device.
The viral 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
Review the data supplied, and ensure compliance with EN ISO 22442-1, -2 & -3:2007
Reviewer & date:
Queries?
No
RF-25-16 Rev. 10
Yes
Number(s)
Appendix A - TSE ONLY
Page 2 of 3
Description of production steps
Manufacturer’s Instructions
Please 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:
NSAI Review
Review the data supplied.
Reviewer & date:
Queries?
No
Yes
Number(s)
Summary Evaluation Report
NSAI Review
RF-25-12 completed: . No
Yes
(Draft 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 2003/32/EC)
RF-25-13 completed: . No
Yes
(Final 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 2003/32/EC)
Comments:
Reviewer & date:
Queries?
No
RF-25-16 Rev. 10
Yes
Number(s)
Appendix A - TSE ONLY
Page 3 of 3
Appendix B
Medical Devices incorporating Human Blood Derivative only
Manufacturer’s Instructions
Please 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 Labelling
Volume 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:
Table 6
Derivative(s) Supplier:
Supplier Address:
Test laboratory used:
Laboratory Address:
Laboratory Approvals:
Contract company used for
bioavailability or
bioequivalence trails
Contact person in the EEA for
product recall and defects
Approval Certs for above sites:
EMEA Scientific Opinion:
RF-25-16 Rev.10
Appendix B – Human Blood ONLY
Page 1 of 8
NSAI Review
Review 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
Reviewer & date:
Queries?
No
Yes
Number(s)
Details of human blood derivative(s) used
Manufacturer’s Instructions
Please 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
Yes
If 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
Reviewer & date:
Queries?
No
Yes
Number(s)
Justification for use of human blood derivatives
Manufacturer’s Instructions
Please 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.
RF-25-16 Rev.10
Appendix B – Human Blood ONLY
Page 2 of 8
NSAI Review
Review the rationale/justification provided.
Clinical Review
Reviewer & date:
Queries?
No
Yes
Number(s)
Verification of Usefulness of Device
Manufacturer’s Instructions
In 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 Review
Clinical Review of the information provided.
Reviewer & date:
Queries?
No
Yes
Number(s)
Human Blood Derivative Manufacture
Manufacturer’s Instructions
Please 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 Review
Review the information provided.
Reviewer & date:
Queries?
No
RF-25-16 Rev.10
Yes
Number(s)
Appendix B – Human Blood ONLY
Page 3 of 8
Human Blood Derivative Supplier(s), Collection and Controls
Manufacturer’s Instructions
Please complete the table below:
Table 7
Details 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.
Reviewer & date:
Queries?
No
Yes
Number(s)
Derivative Manufacturing steps
Manufacturer’s Instructions
Please outline the derivative manufacturing steps:
NSAI Review
Does 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?
Reviewer & date:
Queries?
No
Yes
Number(s)
Inactivation steps
Manufacturer’s Instructions
Please document the production steps used to minimise risk of infection and provide the necessary viral
clearance validation studies:
RF-25-16 Rev.10
Appendix B – Human Blood ONLY
Page 4 of 8
NSAI Review
Have 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?
Reviewer & date:
Queries?
No
Yes
Number(s)
Laboratory Test Details - derivative
Manufacturer’s Instructions
Please provide details of the laboratory tests and also provide the necessary validation(s):
NSAI Review
Review the adequacy of the tests & technology used. Have tests been adequately validated? Does the
technology represent ‘State of the Art’?
Reviewer & date:
Queries?
No
Yes
Number(s)
Quality Control of derivative
Manufacturer’s Instructions
Please provide details of the in-process & final test procedures:
NSAI Review
Review the adequacy of the test procedures
Reviewer & date:
Queries?
No
Yes
Number(s)
Procedures for batch release of derivative
Manufacturer’s Instructions
Please provide details of the batch release procedures for derivative(s):
RF-25-16 Rev.10
Appendix B – Human Blood ONLY
Page 5 of 8
NSAI Review
Review the adequacy of the procedures
Reviewer & date:
Queries?
No
Yes
Number(s)
Derivative Storage & Stability
(in addition to the Device stability covered previously)
Manufacturer’s Instructions
Please 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 Review
Review the adequacy of the data
Reviewer & date:
Queries?
No
Yes
Number(s)
Device Manufacturing Steps
Manufacturer’s Instructions
Please 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 Review
Review the adequacy of the data & validation(s) provided.
Reviewer & date:
Queries?
No
Yes
Number(s)
Device Testing & Quality Control
Manufacturer’s Instructions
Please provide details of the device in-process and final test(s) & any relevant procedures:
RF-25-16 Rev.10
Appendix B – Human Blood ONLY
Page 6 of 8
NSAI Review
Review the adequacy of the tests, in particular regarding the safety of the device.
Reviewer & date:
Queries?
No
Yes
Number(s)
Device Batch Release
Manufacturer’s Instructions
Please provide copies of the batch release procedures for finished devices:
NSAI Review
Review the procedures to ensure that responsibilities & authorities are adequately defined, and that the
system requires batch release notification to be sent to NSAI.
Reviewer & date:
Queries?
No
Yes
Number(s)
Packaging components
Manufacturer’s Instructions
Please provide details of the packaging components including a description from which the material is
constructed using current standard terms – European Pharmacopeia where applicable:
NSAI Review
Review the data supplied to ensure that the description includes the following details – package size,
proposed shelf life (unopened and in use), & proposed storage conditions.
Reviewer & date:
Queries?
No
Yes
Number(s)
Previous Existing Legislation - additional
Manufacturer’s Instructions
Please 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:
RF-25-16 Rev.10
Appendix B – Human Blood ONLY
Page 7 of 8
NSAI Review
Review 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
Reviewer & date:
Queries?
No
Yes
Number(s)
Risk analysis - additional
NSAI Review
Ensure 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.
Reviewer & date:
Queries?
No
Yes
Number(s)
Labelling and IFU - additional
NSAI Review
Ensure 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
Reviewer & date:
Queries?
No
RF-25-16 Rev.10
Yes
Number(s)
Appendix B – Human Blood ONLY
Page 8 of 8
Appendix C
Medical Devices incorporating Medicinal Substance only
Manufacturer’s Instructions
Please provide a dossier detailing the medicinal substance prepared in compliance with MEDDEV 2.1.3
section B3 (A-Q).
Please complete the table below:
Table 7
Name of Medicinal Substance
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 Review
Is 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?
Reviewer & date:
Queries?
No
Yes
Number(s)
Qualitative and quantitative particulars of the constituents
Manufacturer’s Instructions
Please 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:
NSAI Review
Is the data provided sufficient?
Reviewer & date:
Queries?
No
RF-25-16 Rev.10
Yes
Number(s)
Appendix C – Medicinal Substances ONLY
Page 1 of 6
Description of method of manufacture
Manufacturer’s Instructions
In 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 Review
Is the data provided sufficient?
Reviewer & date:
Queries?
No
Yes
Number(s)
Control of starting materials
Manufacturer’s Instructions
Please 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 Review
Does 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?
Reviewer & date:
Queries?
No
Yes
Number(s)
Control of tests carried out at intermediate stages of the manufacturing process
of the medical device
Manufacturer’s Instructions
If necessary, please supply information regarding the control of tests carried out at intermediate stages of
the manufacturing process.
RF-25-16 Rev.10
Appendix C – Medicinal Substances ONLY
Page 2 of 6
NSAI Review
This information is only necessary if it is directly relevant to the quality of the substance as incorporated in
the medical device
Reviewer & date:
Queries?
No
Yes
Number(s)
Control tests on finished product
Manufacturer’s Instructions
Please supply details of the qualitative and quantitative tests carried out to control the medicinal
substance in the device.
NSAI Review
Are adequate controls in place?
Reviewer & date:
Queries?
No
Yes
Number(s)
Toxicity
Manufacturer’s Instructions
Please 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 Review
Review 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.
Reviewer & date:
Queries?
No
Yes
Number(s)
Reproductive Function
Manufacturer’s Instructions
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
RF-25-16 Rev.10
Appendix C – Medicinal Substances ONLY
Page 3 of 6
NSAI Review
Review the profile provided, similar conditions to Toxicity apply.
Reviewer & date:
Queries?
No
Yes
Number(s)
Embryo/foetal and perinatal Toxicity
Manufacturer’s Instructions
Please 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
NSAI Review
Review the profile provided, similar conditions to Toxicity apply.
Reviewer & date:
Queries?
No
Yes
Number(s)
Mutagenic Potential
Manufacturer’s Instructions
Please 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
NSAI Review
Review the profile provided, similar conditions to Toxicity apply.
Reviewer & date:
Queries?
No
Yes
Number(s)
Carcinogenicity Potential
Manufacturer’s Instructions
Please provide data on the carcinogenicity potential of the medicinal substance.
RF-25-16 Rev.10
Appendix C – Medicinal Substances ONLY
Page 4 of 6
NSAI Review
The 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.
Reviewer & date:
Queries?
No
Yes
Number(s)
Pharmacodynamics
Manufacturer’s Instructions
Please provide information on the intended action of the medicinal substance in the context of its
incorporation into a medical device.
NSAI Review
Review 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.
Reviewer & date:
Queries?
No
Yes
Number(s)
Pharmacokinetics
Manufacturer’s Instructions
Please 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 Review
It is anticipated that pharmacokinetic studies will not be required in the majority of cases. Have the areas
above been addressed as appropriate?
Reviewer & date:
Queries?
No
RF-25-16 Rev.10
Yes
Number(s)
Appendix C – Medicinal Substances ONLY
Page 5 of 6
Local tolerance
Manufacturer’s Instructions
Please provide details on the local tolerance of the medicinal substance.
NSAI Review
This 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.
Reviewer & date:
Queries?
No
Yes
Number(s)
Risk Analysis - additional
NSAI Review
Review the risk analysis supplied to ensure that it includes a critical appraisal of the safety of the
drug/device combination.
Reviewer & date:
Queries?
No
Yes
Number(s)
Stability – additional
NSAI Review
Review 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.
Reviewer & date:
Queries?
No
Yes
Number(s)
Competent Authority Review
NSAI Review
Details of Consulting Competent Authority:
Date consultation sought:
Summary of Competent Authority Opinion:
RF-25-16 Rev.10
Date opinion received:
Appendix C – Medicinal Substances ONLY
Page 6 of 6