European Medicines Agency

Veterinary Medicines and Inspections

London, 15 April 2005

EMEA/CVMP/134/02 Rev 1
CPMP/QWP/227/02 Rev 1

COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS

(CPMP)
COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS
(CVMP)

GUIDELINE ON ACTIVE SUBSTANCE MASTER FILE PROCEDURE

DISCUSSION IN THE QUALITY WORKING PARTY Jan 2000-

Jan 2002

TRANSMISSION TO CPMP/CVMP February 2002

RELEASE FOR CONSULTATION February 2002

DEADLINE FOR COMMENTS August 2002

DISCUSSION IN THE QUALITY WORKING PARTY June 2003

October 2003

TRANSMISSION TO CPMP/CVMP January 2004/

February 2004

ADOPTION BY CPMP/CVMP January 2004/

February 2004

DATE FOR COMING INTO OPERATION 31 August 2004

Note:

Clarifications have been attached to this document (see last page) in relation to its applicability to
well-defined active substances only and its non-applicability to biological active substances. In
addition, corrections are introduced in the Annex 1, sections 3.2.S.2 and 3.2.S.2.1. These changes have
been endorsed by CHMP and CVMP at their March and April 2005 meetings.

Public
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E-mail: mail@emea.eu.int http://www.emea.eu.int
©EMEA 2005 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
 GUIDELINE ON ACTIVE SUBSTANCE MASTER FILE PROCEDURE

1. INTRODUCTION
The main objective of the Active Substance Master File (ASMF) procedure, commonly
known as the European Drug Master File (EDMF) procedure, is to allow valuable
confidential intellectual property or 'know-how' of the manufacturer of the active substance
(ASM) to be protected, while at the same time allowing the Applicant or marketing
authorisation (MA) holder to take full responsibility for the medicinal product and the quality
and quality control of the active substance. Competent Authorities/EMEA thus have access to
the complete information that is necessary for an evaluation of the suitability of the use of the
active substance in the medicinal product.
This Guideline is intended to assist Applicants/MA holders in the compilation of the active
substance section of their dossiers for a marketing authorisation application (MAA) or a
marketing authorisation variation (MAV) of a medicinal product. It is also intended to help
EDMF holders in the compilation of their EDMFs. This Guideline is not intended to give
instructions to the Competent Authorities/EMEA in the administrative and scientific handling
of EDMFs and related MAAs and MAVs.

2. CONTENT OF THE ACTIVE SUBSTANCE MASTER FILE

The overall content of the EDMF should contain detailed scientific information as indicated
under the various headings of the relevant Notice to Applicants for Marketing Authorisations
for Medicinal Products in the Member States of the European Union (NtA). EDMFs linked to
human medicinal products should be presented in the format of the Common Technical
Document (CTD), see Annex 1 table 1. EDMFs linked to veterinary medicinal products
should be presented in accordance with Annex 1 table 2. EDMFs for veterinary medicinal
products may also be presented in CTD format after consultation with the Competent
Authorities/EMEA.
The scientific information in the EDMF should be physically divided into two separate parts,
namely the Applicants Part (AP) and the Restricted Part (RP). The AP contains the
information that the EDMF holder regards as non-confidential to the Applicant/MA holder,
whereas the RP contains the information that the EDMF holder regards as confidential, see
Annex 1. It is emphasized that the AP is still a confidential document that cannot be
submitted by anyone to third parties without the written consent of the EDMF holder. In all
cases the AP should contain sufficient information to enable the Applicant/MA holder to take
full responsibility for an evaluation of the suitability of the specifications for the active
substance to control the quality of this active substance for use in the manufacture of a
specified medicinal product. The RP may contain the remaining information, such as detailed
information on the individual steps of the manufacturing method (reaction conditions,
temperature, validation and evaluation data of critical steps) and the quality control during the
manufacture method of the active substance. The Competent Authorities/EMEA may not
accept that particular information has not been disclosed to the Applicant/MA holder. In such
cases, the Competent Authorities/EMEA may ask for an amendment to the AP.

In addition to the AP and RP, the EDMF should contain a table of contents, and a separate
summary for the AP and the RP. In cases where the EDMF is provided in the CTD format,
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both summaries should be presented as a Quality Overall Summary (QOS). In cases where the
old human or current veterinary NtA format is used, each summary should be made in the
form of a written and tabulated expert report (ER). The AP and RP should each have a
version number. The structure of the version numbers should be unique and follow a logical
order. Preferably the following structure is used.
Name EDMF holder / Name active substance / AP or RP/ version number / date in yyyy-mm-dd.

3. USE OF THE ACTIVE SUBSTANCE MASTER FILE PROCEDURE

An EDMF can only be submitted in support of an MAA or MAV. The relationship between
the quality of the active substance and its use in the medicinal product needs to be justified in
this MAA or MAV. Although the EDMF procedure is developed to keep intellectual property
of the ASM confidential, it is also permissible to use the procedure when there is no
confidentiality issue between the Applicant/MA holder and the ASM (e.g. when the
Applicant/MA holder synthesises the active substance himself). It is expected that the ASM is
also the holder of the EDMF.

The EDMF procedure can be used for the following active substances (except biological
active substances, see the CHMP procedural announcement at the last page of this Guideline),
i.e.:
A. New active substances
B. Existing active substances not included in the European Pharmacopoeia (Ph. Eur.) or
the pharmacopoeia of an EU Member State
C. Pharmacopoeial active substances included in the Ph. Eur. or in the pharmacopoeia of
an EU Member State

The EDMF holder may have an EDMF as well as a CEP for a single active substance.
Generally, it is however not acceptable that the Applicant/MA holder refers to an EDMF as
well as to a CEP for a single active substance of a particular MAA. In cases where the CEP
contains too little information (e.g. stability) the Competent Authorities/EMEA may decide
that additional information should be provided in the dossier. In such case it may be
acceptable to refer both to an EDMF and a CEP.
The EDMF holder should give permission to the Competent Authorities/EMEA to assess the
data in the EDMF in relation to a specific MAA/MAV, in the form of a ‘Letter of Access’,
see Annex 2.

The EDMF holder should submit to the Applicant/MA holder:

- a copy of the latest version of the AP.
- a copy of the QOS/ ER on the latest version of the AP
- the letter of access where this letter has not been submitted earlier for the product
concerned.
In addition, the EDMF holder should submit to the Competent Authorities/EMEA:
- the EDMF accompanied by a covering letter, see Annex 3.
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- the Letter of Access where this letter has not been submitted earlier for the product
concerned.

The EDMF holder should submit the EDMF to the Competent Authority/EMEA either for
each MAA and each MAV or only once according to national requirements. The submission
of the relevant documentation by the EDMF holder to the Competent Authority/EMEA must
be synchronised to arrive at approximately the same time as the MAA or the MAV.
Where the EDMF procedure is used, the Applicant/MA holder should submit the MAA or
MAV to the Competent Authorities/EMEA together with the Letter of Access where this
Letter has not been submitted earlier by the MA holder/Applicant himself or by the EDMF
holder for the product concerned.
Where the same active substance is used in a number of applications for different products in
one or more Member States, the EDMF holder should submit identical documentation to
every Competent Authority/EMEA. Consequently, the Competent Authorities/EMEA may
require that any EDMF updates made in relation to one MA should apply to all. It is the
EDMF holder’s responsibility to notify the MA holders and Competent Authorities/EMEA
concerned about any changes to the AP and/or RP, so that the MA holders can update all
affected MAs accordingly.

4. CONTENT OF THE MA DOSSIER WHEN THE ACTIVE SUBSTANCE

MASTER FILE PROCEDURE IS USED
The Applicant/MA holder is responsible for ensuring that he has access to all relevant
information concerning the current manufacture of the active substance.

The specifications used by the Applicant/MA holder to control the correct quality of the
active substance should be laid down unambiguously in the MA dossier (NtA CTD format
section 3.2.S.4.1 and 3.2.S.4.2 or old human/veterinary NtA format part IIC1). The
Applicant/MA holder should include a copy of the AP in the MA dossier (NtA CTD format
section 3.2.S or NtA old human/veterinary format part IIC1). The version of the AP in the
MA dossier should be the most recent and it should be identical to the AP as supplied by the
EDMF holder to the Competent Authority/EMEA as part of the EDMF. The Applicant/MA
holder should include all relevant details from the AP in the QOS/ER of the MA dossier.
Issues of the EDMF that are specifically relevant to the product under consideration should be
highlighted in the QOS/ER of the MA dossier.

In the case of a single supplier and where the EDMF procedure or CEP procedure is used, the
specifications of the Applicant/MA holder in the MA dossier should in principle be identical
to those of the EDMF holder or the CEP holder. The Applicant/MA holder does however not
need to accept redundant specifications, unnecessarily tight specification limits or outdated
analytical methods. In cases where the Applicant/MA holder uses a different analytical
method than that described in the EDMF, both methods should be validated. Technical
specifications relevant for the medicinal product, which are normally not part of the
specifications in the EDMF (e.g. particle size), should be part of the specifications of the
Applicant/MA holder.
In cases where there is more than one supplier, there should be one single compiled
specification that is identical for each supplier. It is acceptable to lay down in the

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specification more than one acceptance criterion and/or analytical method for a single
parameter with the statement ‘if tested’ (e.g. in case of residual solvents).

5. CHANGES AND UPDATES TO THE ACTIVE SUBSTANCE MASTER FILE

As for medicinal products, EDMF holders should keep the content of their EDMFs updated
with respect to the actual synthesis/manufacturing process. The quality control methods
should be kept in line with the current regulatory and scientific requirements. EDMF holders
shall not modify the contents of their EDMF (e.g. manufacturing process or specifications)
without informing each Applicant/MA holder and each Competent Authority/EMEA. Before
implementation, any change to the EDMF should be reported by every MA holder to the
relevant Competent Authority/EMEA by means of an appropriate variation procedure. A
covering letter should be provided. In cases where the contents of the EDMF cannot be
changed for a certain period of time because of other procedural provisions (i.e. mainly
because of ongoing MRP procedures), the EDMF holder should still provide the
aforementioned data to the MA holder and Competent Authorities/EMEA making reference
to this reason and requesting a later date of implementation.

The EDMF holders’ covering letter to the Competent Authorities/EMEA should contain the
following information (if available):
- A tabular list summarising the changes carried out since the first compilation of the
EDMF.
- An overview comparing the old and new content of the EDMF.
- Information as to whether the change has already been accepted, rejected or withdrawn
by another Member State.
- The names of the relevant Applicants, MA holders and MAs.
- The new AP and/or RP with each the new version number.
- An updated QOS/ER if relevant.

At the occasion of the 5-yearly renewal of a medicinal product, MA holders are required to
declare that the quality of the product, in respect of the methods of preparation and control,
has been regularly updated by variation procedure to take account of technical and scientific
progress, and that the product conforms with current CPMP/CVMP quality guidelines. They
will also declare that no changes have been made to the product particulars other than those
approved by the Competent Authority/EMEA.
MA holders should therefore verify with their EDMF holders whether the above declaration
can be met in respect to the active substance particulars. In case changes have not been
notified to the MA holder and Competent Authority/EMEA, the necessary variation
procedure should be initiated without delay.

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ANNEX 1: OVERVIEW EDMF CONTENTS

Table 1 NtA CTD format Applicants Part Restricted Part

3.2.S.1 General information x

3.2.S.1.1 Nomenclature x

3.2.S.1.2 Structure x

3.2.S.1.3 General properties x

3.2.S.2 Manufacture x X

3.2.S.2.1 Manufacturer(s) x

3.2.S.2.2 Description of Manufacturing Process and Process controls 1) 2)

3.2.S.2.3 Control of Materials X

3.2.S.2.4 Control of critical steps and intermediates 3) 4)

3.2.S.2.5 Process validation and/or Evaluation X

3.2.S.2.6 Manufacturing Process Development X

3.2.S.3 Characterisation x

3.2.S.3.1 Elucidation of Structure and other Characteristics x

3.2.S.3.2 Impurities x 5)

3.2.S.4 Control of Drug Substance x

3.2.S.4.1 Specification x

3.2.S.4.2 Analytical procedures x

3.2.S.4.3 Validation of analytical procedures x

3.2.S.4.4 Batch analysis x

3.2.S.4.5 Justification of specification x 6)

3.2.S.5 Reference standards or materials x

3.2.S.6 Container Closure System x

3.2.S.7 Stability x

3.2.S.7.1 Stability summary and conclusion x

3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment x

3.2.S.7.3 Stability data x

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Table 2 NtA veterinary format / old human format Applicants Part Restricted Part

IIC.1 Name(s) and site(s) of ASM x X

IIC.1.1 Specifications and routine tests x

IIC.1.2.1 Nomenclature x

IIC.1.2.2 Description x

IIC.1.2.3 Brief outline of the manufacturing route (flow chart) x

IIC.1.2.3 Detailed description manufacturing method X

IIC.1.2.4 QC during manufacture 3) 4)

Process validation and evaluation of data X

IIC.1.2.5 Development Chemistry x

Evidence of structure x

Potential Isomerism x

Physiochemical characterisation x

Analytical validation x

IIC.1.2.6 Impurities x 5)

IIC.1.2.7 Batch analysis x

IIF1 Stability x

1) Flow chart and short description is regarded as sufficient, if detailed information is presented in the
Restricted Part. However, full validation data on the sterilisation process may be requested in the
Applicants Part (in cases where there is no further sterilisation of the final product).
2) detailed information.
3) In so far as the information is also relevant for the Applicant/MA holder.
4) In so far as the information is related to the detailed description of the manufacturing process and in so
far as this information is not relevant for the Applicant/MA holder.
5) In so far as the information is related to the detailed description of the manufacturing process and in so
far as the EDMF holder sufficiently justifies that there is no need to control these impurities in the final
active substance.
6) In so far as the information is related to the detailed description of the manufacturing process, control of
materials and process validation.

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ANNEX 2: TEMPLATE LETTER OF ACCESS

[Address of Competent Authority/EMEA]

[Date and place]

LETTER OF ACCESS

Number of Active Substance Master File: [if known, or to be given by the Competent
Authority/EMEA or procedure reference number/community reference number in Centralised
Procedure ]
Manufacturing site: [name and address]
Active Substance Master File holder: [name and address]

The aforementioned Active Substance Master File holder hereby authorises the [name of
Competent Authority/EMEA including all CPMP or CVMP Members and their experts] to
refer to and review the above mentioned Active Substance Master File in support of the
following Marketing Authorisation Application(s) or Marketing Authorisation Variation(s) 1
submitted by [name /Marketing Authorisation holder/Applicant] on [planned date of
submission]:

[Name of product and Marketing Authorisation number, if known]

[Name of Applicant or Marketing Authorisation holder]

The aforementioned Active Substance Master File holder commits to ensure batch to batch
consistency and to inform [name of Marketing Authorisation holder/Applicant] and
Competent Authority/EMEA of any change in the Active Substance Master File.

Signature for the Active Substance Master File holder

[Name and address]
[Signature]

1
i.e. to introduce a new EDMF from a new AS manufacturer.

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ANNEX 3: PART OF COVERING LETTER

This Active Substance Master File is submitted in relation to the Marketing Authorisation
Application/Marketing Authorisation Variation:
[Number of national, centralised or mutual recognition procedure]
[Name of product in national, centralised or mutual recognition procedure]
[Name of Applicant/Marketing Authorisation holder for the application concerned]
[Concerned Member States in mutual recognition]

And describes <changes to> the manufacturing process and specifications of the (or one of
the) active substance(s) of this Marketing Authorisation Application or Marketing
Authorisation Variation.
[Name active substance]

The version number of this Active Substance Master File is

Applicants part: version [version number]
Restricted part: version [version number]

This Active Substance Master File has previously been submitted for assessment in
combination with a Marketing Authorisation Application/ Marketing Authorisation Variation
for a medicinal product within the European Union:
‰ No
‰ Yes, within the following National, Centralised or Mutual recognition procedure:
[Number of National, Centralised or Mutual Recognition Procedure]
[Name of product in National, Centralised or Mutual Recognition Procedure]
[Authorisation number and date of approval of the products concerned]
[Rapporteur or Reference Member State]
[Concerned Member States in Mutual Recognition]
[Version number Applicants Part]
[Version number Restricted Part]

Note:
Information in italic font can be left blank if not known.
Information in normal font is always required.

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ANNEX 4: LIST OF ABBREVIATIONS

Abbreviation Full text

AP Applicants Part (of EDMF)
ASM Active Substance Manufacturer
ASMF Active Substance Master File
CEP European procedure for a certificate of suitability of monographs of the
European pharmacopoeia (here on chemical purity)
CTD Common Technical Document
EDMF European Drug Master File
EDQM European Directorate for the Quality of Medicines
EMEA European Medicines Evaluation Agency
ER Written and tabulated expert report (refers to MA dossiers in old human or
existing NtA veterinary format)
ICH International Conference on Harmonisation

MA Marketing Authorisation
MAA Marketing Authorisation Application (including line extensions)
MAV Marketing Authorisation Variation
NtA Notice to Applicants
Ph. Eur. European Pharmacopoeia
RP Restricted Part (of EDMF)
QOS Quality Overall Summary (refers to MA dossiers in NtA CTD format)

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ANNEX 5: GLOSSARY

Item Definition
Active Substance Manufacturer A party involved in the manufacturing chain of the
active substance, including agents, brokers, traders,
distributors, repackers or relabellers.
Active Substance Master File This is the company that has the ultimate responsibility
holder for the Active Substance Master File.
Applicant This is the company requesting a Marketing
Authorisation for a medicinal product.
European Drug Master File The old name of the Active Substance Master File
Marketing Authorisation holder This is the company that is responsible for the medicinal
product on the market
Manufacturing chain A clear flow chart or written text explaining the
manufacturing and distribution route of the active
substance from the first starting materials to the final
active substance as delivered to the
Applicant/Marketing Authorisation holder.
New active substance According to ICH Q6A new drug substance that is
The designated therapeutic moeity, which has not
previously been registered in a region or Member State
(also referred to as a new molecular entity or new
chemical entity). It may be a complex, simple ester, or
salt of a previously approved drug substance.
Quality According to ICH Q6A that is
The suitability of either a drug substance or drug
product for its intended use. This term includes such
attributes as the identity, strength and purity.
Specification According to ICH Q6A that is
A list of test, references to analytical procedures, and
appropriate acceptance criteria which are numerical
limits, ranges or other criteria to which a drug substance
or drug product should conform to be considered
acceptable for its intended use. Conformance to
specifications means that the drug substance and/or drug
product, when tested according to the listed analytical
procedures will meet the listed acceptance criteria.
Specifications are critical quality standards that are
proposed and justified by the manufacturer and
approved by regulatory authorities.

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CHMP procedural announcement published with CHMP Monthly report October 2004

• Non applicability of Active Substance Master file (ASMF) concept to biological active
substances

Marketing Authorisation Holders (MAH) and applicants are advised that the concept of Active
Substance Master files, as laid down in Directive 2001/83/EC, as amended, cannot be applied in the
context of biological medicinal products.

The characterisation and determination of biological active substances’ quality requires not only a
combination of physico-chemical and biological testing, but also extensive knowledge of the
production process and its control.

The MAH/applicant for a biological medicinal product could therefore not comply with the requirement
to ‘take responsibility for the medicinal product’ without having full and transparent access to these
quality-related data.The use of an ASMF would prevent such access, and should therefore not be
allowed for biological active substances.

In addition, active substances, which are present in certain medicinal products such as vaccines or
cell-therapy medicinal products, do not fit with the concept of a ‘well-defined’ active substance.

• Non-applicability of ASMF concept of open and closed parts to Vaccine Antigen Master file
(VAMF) and Plasma Master file (PMF)

The legislation does not provide for the use of open/closed parts in the Vaccine Antigen Master file
(VAMF) and Plasma Master file (PMF). The concept of open (non-confidential) and closed
(confidential) parts is specific to the Active Substance Master file.

Regarding the VAMF the legislation specifies that the VAMF holder cannot differ from the
MAH/applicant for the concerned medicinal product: there is hence no rationale for an ‘open/closed’
parts system.

For the PMF the legislation specifies that where the MAH/applicant differs from the holder of the PMF,
the PMF shall be made available to the MAH/applicant for submission to the competent authority.

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