Devices incorporating
ancillary medicinal
substances

Medicinal dossier guidance
For devices which incorporate an ancillary medicinal
substance and fall under Rule 14 of EU 2017/745 (MDR)
For devices which incorporate an ancillary medicinal substance and fall under Rule 14 of EU
2017/745 (MDR), the quality, safety and usefulness of the substance shall be verified by analogy
with the methods specified in Annex I to Directive 2001/83/EC (the Medicinal Products Directive).
Annex IX, 5.2(a) of the MDR states the notified body should seek a scientific opinion from one of thecompetent authorities designated by the Member States in accordance with Directive 2001/83/
EC or from the EMA, on the quality and safety of the substance including the benefit or risk of theincorporation of the substance into the device.
Annex II, Section 6.2 (a) states the documentation shall identify the source of that substance andcontain the data of the tests conducted to assess its safety, quality and usefulness, taking accountof the intended purpose of the device.
In order to perform their assessment, the Medicines Competent Authorities (CA) prefer thedocumentation to follow the Common Technical Documentation (CTD) format. CTD is the format
used for pharmaceutical assessment of medicinal products and use of this format facilitates theCA review.

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Scope of this document
The purpose of this document is toguide the device manufacturer in thepreparation of this documentation
based on information provided by
the various Competent Authorities.
Please note different Competent
Authorities may have slightly
different requirements and where theCompetent Authority is known, specificadvice may be available on theirwebsites or via the BSI Medicinal team.

MEDDEV 2.1/3 rev 3 is the official
guidance on the content of themedicinal dossier. This BSI guide isintended to supplement the official
guidance based on information
published by the Competent Authorities
as well as feedback from ancillary
substance reviews conducted by BSI
on behalf of device manufacturers.
MEDDEV 2.1/3 is expected to besuperseded by a MDCG document in

the future and once available should be
consulted by the manufacturers.
Note the phrase ‘ancillary medicinal
substance’ is used throughout thisdocument. This document also applies
for ancillary human blood derivatives.
Where there are specific differences
these are highlighted.

Documentation Requirements
In order to facilitate review, typically performed by a quality, a non-clinical and a clinical assessor; it is necessary to provide
the dossier as separate, indexed and searchable (pdf) modules. Each module should be less than 100 MB to comply withCompetent Authority requirements. If necessary supportive information can be provided in Appendices to the Modules. Anindex showing the folder structures and document titles should be provided. See reference section below for more detailedguidance, in particular the EMA dossier guidance.

Module 1 Introduction
Introduction

A general description of the device, including the justification regarding purpose of incorporationof the ancillary medicinal substance in the medical device, in particular its ancillary nature, together
with a critical evaluation of results of the risk assessment and an assessment of benefit risk of theancillary substance.

GMP declaration

In module 1 a declaration from the manufacturer of the medical device must also be submitted
stating that the integral substance has been produced under Good Manufacturing Practices (GMP)
requirements. It is recommended by some Competent Authorities that this declaration be drawn
up in line with the QP declaration. For non-traditional APIs a justification of the quality, if not
manufactured in accordance with GMP requirements, should be provided.

Labelling and IFU

A copy of the labelling, including IFU. This should be clear and searchable.

Module 2 CTD Module Summaries
Quality overallsummary

The content of this section is to provide expert summaries of the information on the ancillary
medicinal substance. Overviews of the Quality sections, non-clinical and clinical sections.

Non clinicalsummary

Module 2 is expected to contain a clinical summary which focuses on a discussion of the clinicalusefulness of the integral medicinal substance, on the rationale for inclusion in the medical device
and on the safety of this substance..

Clinical summary

Module 3 Quality Documentation, can be split into two documents as described in the following tables.
Module 3 Drug Substance
Drug substanceinformation

If the ancillary substance has a Certificate of Suitability to the monographs of the EuropeanPharmacopoeia (CEP), a copy of the current, signed CEP declaration should be included.
If the ancillary substance has an Active Substance Master File (ASMF), a copy of the applicant’s partof the ASMF should be included together with a signed ‘Letter of Access’ to the closed part.
If ASMF or CEP are not available the information of the ancillary substance should be structured
according to Module 3.2.S of the CTD-format. See Annex I of CPMP/QWP/227/02 Rev 3/Corr. All
headings should be included. If not applicable, state this, with a rationale, rather than remove
the section.
Where applicable, reference shall also be made to the European Pharmacopoeia (Ph Eur) or in theabsence of a Ph Eur monograph to a national pharmacopoeia of one of the Member States. For
example, for reference standards or test methods. If no monograph is available from the Member
States reference may be to other national monographs or to the manufacturer's specification andmethods of analysis and a justification should be provided.
For ancillary human blood derivatives for which a Plasma Master File (PMF) already exists, therelevant information in module 3 already submitted as part of the PMF does not need to be provided
with the application dossier for the consultation procedure. In this case, a notification letter should
accompany module 3 from the medical device manufacturer. This letter should also include a
declaration that the device manufacturer will be informed of any changes to the manufacture of
the ancillary human blood derivatives and a declaration that the PMF holder has submitted the PMF
certificate, evaluation report and PMF dossier to the medical device manufacturer.
GMP certification, less than 3 years old, (or equivalent quality certification) should be provided forthe substance manufacturing site(s).

Module 3 -– Drug Product (Medical device with ancillary medicinal substance)
Note in CTD documentation the term drug product is used. In this case it refers to medical device with ancillary medicinalsubstance. The information on the incorporation of the ancillary substance in the device may include the following
CTD headings.

Module 3 Drug Product (Medical device with ancillary medicinal substance)
3.2.P.1 Description
and Compositionof the Drug
ProductA description of the device and its composition should be provided, including the quantitative detailsof the ancillary substance.

3.2.P.2
Pharmaceutical
Development

This section should cover development of the device, including choice of the ancillary substance.
The composition of the device and any excipients used should be stated. Also a summary of thepackaging and materials

3.2.P.3
Manufacture

The name, address, and responsibility of each manufacturer, including contractors, and each
proposed production site or facility involved in manufacturing and testing should be provided.
The quality system of each manufacture should be included. Certificates may be placed in theappendix.
A flow chart and description of the manufacturing process including batch size. In-process tests
and critical process parameters should be listed.

Module 3 Drug Product (Medical device with ancillary medicinal substance) – Continued
3.2.P.4 Control ofExcipients

Excipients involved in the application of the ancillary substance, for example to aid with coating or
ensure a specific release rate should be listed, together with their specifications.
The control of excipients (or materials) related only to the device rather than the ancillary substance,e.g. dressing layers, or stent delivery materials do not need to be described in this document.

3.2.P.5 Control ofDrug Product3.2.P.5.1 The specifications and tests from incoming goods, in-process tests and final release should
be listed.
3.2.P.5.2 The test methods should be specified.
3.2.P.5.3 Validation of test methods used.
3.2.P.5.4 Batch data from 3 recent production scale batches should be included.
3.2.P.5.6 A justification of the specification for the tests used for the ancillary medicinal substanceshould be included.

3.2.P.6 ReferenceStandards orMaterialsAny reference standards used in the testing of the ancillary substance should be included.
Justification should be provided if PhEur standards are not used.

3.2.P.7 ContainerClosure System

A description of the primary and secondary packaging. This will be assessed, for the device, by the
Notified Body; however, the Competent Authority will need to understand the packaging from themedicinal substance point of view.

3.2.P.8 Stability

Include a clear statement of the claimed shelf life of the device and if applicable any in-use shelf-life.
Include stability protocols, reports and data relevant for the ancillary medicinal substance stability. Ifrelevant, the fate of known impurities on stability should also be discussed.

Module 4 Non-clinical data
Module 4

Data used to support biocompatibility of the device may be used here. The purpose of this section isto provide a critical assessment of the non-clinical safety of the ancillary substance, which should asa minimum include , pharmacology/ pharmacodynamics, pharmacokinetics and toxicology including
local tolerance.
Relevant literature and pre-clinical testing related to the ancillary substance should be included inthis section.

Module 5 Clinical data
Module 5

The CER may be used to support clinical data; however, the purpose of the review is to assess therisk benefit of the ancillary medicinal substance, not the device as a whole. Therefore it is useful if
the CER is supplemented by a document directing the reviewer to the clinical data which is directly
important for substantiating the safety and usefulness of the integral substance. This may take theform of literature or clinical data. A conclusion on the risk/ benefit of adding the ancillary substanceto the device should be included. If the device covers multiple strengths or indications, risk benefit
for each variant should be included.

Useful references
The references below are useful as further reading when collating the medicinal dossier and have been used in the creationof this document.

Title

LinkDescription

MEDDEV 2.1/3
rev 3

http://www.meddev.info/_documents/2_1_3_
rev_3-12_2009_en.pdf

Borderline products, drug-delivery products andmedical devices incorporating, as an integral
part, an ancillary medicinal substance or an
ancillary human blood derivative.
Note this document is expected to besuperseded by a MDCG document in 2021.

EMA dossierrequirements

https://www.ema.europa.eu/documents/
regulatory-procedural-guideline/emarecommendation-procedural-aspects-dossierrequirements-consultation-ema-notified-bodyancillary_en.pdf

European Medicines Agency dossierrequirements.

EMA Consultation
procedure forancillary medicinal
substances inmedical devices

https://www.ema.europa.eu/en/humanregulatory/overview/medical-devices/
consultation-procedure-ancillary-medicinalsubstances-medical-devicesOverview and further links from EMA for
Consultation procedure for ancillary medicinal
substances in medical devices.

EMA Presentationand formatof the dossierCommon TechnicalDocument (CTD)

EudraLex Notice to Applicants Volume 2B(Presentation and content of the dossier – CTD).

Comprehensive description of CTD dossier,modules and sub-sections to be used.

EMA Guideline onActive Substance
Master File

Guideline on Active Substance Master File
procedure (EMEA/CVMP/134/02 Rev 3/Corr;
CPMP/QWP/227/02 Rev 3/Corr). Please note
this guideline is not applicable for biologicalactive substances.

EMA Guideline on Active Substance Master File.

Note some Medicines Competent Authorities have dossier requirements listed on their websites. If the Competent Authority
is known the manufacturer is encouraged to look at this as well.

Navigating your transition to the IVDR and MDR
The MDR brings with it more scrutiny of Technical Documentation,
addressing concerns over the assessment of product safety
and performance by placing stricter requirements on clinicalevaluation and post-market clinical follow-up. The IVDR brings
with it significant changes to the regulatory requirements for IVD
medical device manufacturers and introduces a new rule-basedclassification system with stricter notified body oversight, as
well as significant changes to the depth and requirements of theassociated Technical Documentation.

The Medical Devices Regulation (MDR) (EU) 2017/745 has atransition period of four years starting from May 2017, after
which the Regulation now applies. The In Vitro DiagnosticRegulation (IVDR) (EU) 2017/746 entered into force on the25 May 2017 marking the start of a five-year transition period.
Manufacturers have the duration of the transition periods toupdate their Technical Documentation and processes to meetthe new requirements if they want to place medical devices
and in vitro diagnostic medical devices on the market in theEuropean Union.

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