欧盟ASMF递交法规及相关模板

31 May 2013

Committee of Human Medicinal Products CHMP/QWP/227/02 Rev 3/Corr *

Committee of Veterinary Medicinal Products EMEA/CVMP/134/02 Rev 3/Corr *

Guideline on Active Substance Master File Procedure Final

Discussion at the HMPC November 2005 – January 2006 Adoption by the HMPC 22 January 2006 Draft agreed by Quality Working Party 9 February 2006 Adoption by CHMP for release for consultation 23 March 2006 Adoption by CVMP for release for consultation 20 April 2006 End of consultation (deadline for comments) 30 August 2006 Agreed by Quality Working Party 1 December 2011 Adoption by CHMP for release for consultation 15 December 2011 Adoption by CVMP for release for consultation 12 January 2012 End of consultation (deadline for comments) 12 March 2012 Rev. 03 Agreed by Quality Working Party 04 May 2012 Rev. 03 Adoption by CVMP 14 June 2012 Rev. 03 Adoption by CHMP 21 June 2012 Rev. 03 Date for coming into effect 1 October 2012 This guideline replaces guideline CPMP/QWP/227/02 Rev 2 (EMEA/CVMP/134/02 Rev.2).

Keywords Active substance master file, ASMF, letter of access, submission letter 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom

Note:

The corrections introduced to this guideline aim to support the Working Group on Active Substance Master File Procedures in their initiatives to improve the ASMF procedure across the European Regulatory Network. To this end, the annexes to the guideline have been revised, and one new annex introduced. Some minor textual changes in the main part of the guideline have been introduced as a consequence of the revised annexes.

* The correction concerns a clarification in:

?Annex 1, detailing which manufacturing sites are to be declared in section 3.2.S.2.1;

?Annex 3, detailing the need to declare the salt form, water content and grade of the active substance, as applicable.

Table of contents

Executive summary (4)

1. Introduction (background) (4)

2. Scope (4)

3. Legal basis (4)

4. Content of the Active Substance Master File (5)

5. Use of the Active Substance Master File Procedure (5)

6. Content of the MA-dossier when the Active Substance Master File Procedure is used (7)

7. Changes and updates to the Active Substance Master File (7)

ANNEX 1 (9)

ANNEX 2 (14)

ANNEX 3 (15)

ANNEX 4 (19)

ANNEX 5 (20)

ANNEX 6 (21)

ANNEX 7 (22)

Executive summary

1. Introduction (background)

The main objective of the Active Substance Master File (ASMF) procedure, formerly 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. National Competent Authorities/EMA 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.

2. Scope

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 ASMF holders in the compilation of their ASMFs.

ASMF Procedure and herbal substances/preparations

In accordance with Directive 2001/83/EC as amended, the quality of traditional herbal medicinal products for human use has to be documented in accordance with existing European legislative requirements. These criteria are laid down in the following guidelines (which are applicable for all Human and Veterinary Herbal Medicinal products): ‘Guideline on quality of herbal medicinal

products/traditional herbal medicinal products’ (CPMP/QWP/2819/00, EMEA/CVMP/814/00, in their latest revisions) and the ‘Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/ traditional herbal medicinal products’ (CPMP/QWP/2820/00, EMEA/CVMP/815/00, in their latest revisions).

It should be noted that the principles which are outlined in table 3 of Annex 1 in relation to traditional herbal medicinal products are equally applicable to other herbal medicinal products, both for Human and Veterinary use, which do not follow the simplified registration procedure.

References:

1. ‘Guideline on quality of herbal medicinal products/traditional herbal medicinal products’

(CPMP/QWP/2819/00, EMEA/CVMP/814/00, in their latest revisions);

2. ‘Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal

preparations and herbal medicinal products/ traditional herbal medicinal products’

(CPMP/QWP/2820/00, EMEA/CVMP/815/00, in their latest revisions);

3. ‘Guideline on summary of requirements for active substances in the quality part of the dossier’

(CHMP/QWP/297/97, EMEA/CVMP/1069/02, in their latest revisions).

3. Legal basis

Annex I to Directive 2001/83/EC as amended Part I, 3.2 Basic principles and requirements, (8) Active Substance Master File (for Human medicinal products) and Annex I to Directive 2001/82/EC as

amended, Part 2.C.1 General Requirements, 1.1. Active Substances (for Veterinary medicinal products).

4. Content of the Active Substance Master File

The overall content of the ASMF 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).

ASMFs linked to human medicinal products should be presented in the format of the Common Technical Document (CTD), see Annex 1 table 1.

ASMFs linked to veterinary medicinal products should normally be presented in accordance with the format given in Annex 1 table 2, however in accordance with Parts 1.C and 2 of Directive 2001/82/EC as amended, all parts of such ASMFs (AP, RP, and their summaries) may be presented in the CTD format in the following circumstances1:

?Where the active substance has been included in a medicinal product for human use authorised in accordance with the requirements of Annex I to Directive 2001/83/EC as amended;

?In the case of any application for an animal species or for indications representing smaller market sectors;

?Where the competent authority has publicly announced this possibility.

The scientific information in the ASMF should be physically divided into two separate parts, namely the Applicant’s Part (AP) and the Restricted Part (RP). The AP contains the information that the ASMF holder regards as non-confidential to the Applicant/MA holder, whereas the RP contains the information that the ASMF 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 ASMF 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 specification 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 of the active substance. The National Competent Authorities/EMA may not accept that particular information has not been disclosed to the Applicant/MA holder. In such cases, the National Competent Authorities/EMA may ask for an amendment to the AP. In addition to the AP and RP, the ASMF should contain a table of contents, and separate summaries for both the AP and the RP. In cases where the ASMF is provided in the CTD format, both summaries should be presented as a Quality Overall Summary (QOS). In cases where the veterinary NtA format is used, they should be detailed and critical summaries. Each version of the AP and RP should have unique and independent version control numbers.

5. Use of the Active Substance Master File Procedure

An ASMF 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.

1A correlation table should also be provided for ASMFs for Veterinary applications presented in the CTD format.

Although the ASMF 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 ASMF.

The ASMF procedure can be used for the following active substances, including herbal active substances/preparations. 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. Pharmacopeial active substances included in the Ph. Eur. or in the pharmacopoeia of an EU Member

State.

The ASMF procedure cannot be used for biological active substances, see Annex 5.

The ASMF holder may have an ASMF as well as a Certificate of Suitability (CEP) issued by EDQM for a single active substance. Generally, it is however not acceptable that the Applicant/MA holder refers to an ASMF as well as to a CEP for a single active substance of a particular MAA/MAV. In cases where the CEP contains too little information (e.g. stability) the National Competent Authorities/EMA may decide that additional information should be provided in the dossier. In such case it may be acceptable to refer both to an ASMF and a CEP.

The ASMF holder should give permission to the National Competent Authorities/EMA to assess the data in the ASMF in relation to a specific MAA/MAV, in the form of a ‘Letter of Access’, see Annex 2.

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

? a copy of the latest version of the AP (and, if applicable, responses to deficiency letters on the AP from a NCA/EMA if not already incorporated into the AP);

? a copy of the QOS or detailed and critical summary, as appropriate, on the latest version of the AP;

? a copy of the Letter of Access where this letter has not been submitted earlier for the product concerned.

In addition, it is an essential requirement that the ASMF holder should submit to all National Competent Authorities/EMA involved in the MAA/MAV procedure:

?the ASMF (and, if applicable, responses to deficiency letters from a NCA/EMA if not already incorporated into the ASMF), accompanied by a Submission Letter and Administrative Details, see Annex 3. This also applies to the ASMF holder's responses to deficiency letters from a NCA/EMA; ?the Letter of Access where this letter has not been submitted earlier for the product concerned. The ASMF holder should submit the ASMF to the National Competent Authority/EMA either for each MAA and each MAV or only once according to national requirements. The submission of the relevant documentation by the ASMF holder to the National Competent Authority/EMA must be synchronised to arrive at approximately the same time as the MAA or the MAV i.e. not more than one month before and not after the intended MAA/MAV submission date.

Where the ASMF procedure is used, the Applicant/MA holder should submit the MAA or MAV to the National Competent Authorities/EMA together with the Letter of Access where this Letter has not been submitted earlier by the MA holder/Applicant himself or by the ASMF 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 ASMF holder should submit identical documentation to every National Competent Authority/EMA. Consequently, the National Competent Authorities/EMA may require that any ASMF updates made in relation to one MA should apply to all. It is the ASMF holder’s responsibility to notify the MA holders and National Competent Authorities/EMA concerned about any changes to the AP and/or RP, so that the MA holders can update all affected MAs accordingly.

6. 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 specification used by the Applicant/MA holder to control the correct quality of the active substance should be laid down unambiguously in the MA dossier (CTD format section 3.2.S.4.1 and 3.2.S.4.2 or old human/veterinary NtA format part 2.C.1). The Applicant/MA holder should include a copy of the AP in the MA dossier (CTD format section 3.2.S or veterinary NtA format part 2.C.1). 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 ASMF holder to the National Competent Authority/EMA as part of the ASMF. The Applicant/MA holder should include all relevant details from the AP in the QOS/detailed and critical summary of the MA dossier. Issues of the ASMF that are specifically relevant to the product under consideration should be highlighted in the QOS/detailed and critical summary of the MA dossier.

In the case of a single supplier and where the ASMF procedure or CEP procedure is used, the specification for the active substance provided by the Applicant/MA holder in the MA dossier should in principle be identical to that of the ASMF holder or the CEP holder. However, the Applicant/MA holder does not need to accept redundant tests in the specification, 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 ASMF, both methods should be validated. Technical tests in the specification that are relevant for the medicinal product, but which are normally not part of the specification in the ASMF (e.g. particle size), should be part of the specification of the Applicant/MA holder.

In cases where there is more than one supplier, the Applicant/MA holder should have one single compiled specification that is identical for each supplier. It is acceptable to lay down in the 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).

7. Changes and updates to the Active Substance Master File

As for medicinal products, ASMF holders should keep the content of their ASMFs 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.

ASMF holders shall not modify the contents of their ASMF (e.g. manufacturing process or specifications) without informing each Applicant/MA holder and each National Competent

Authority/EMA. This obligation remains valid until the Letter of Access has been withdrawn by the ASMF holder, see Annex 4. ASMF holders should provide the updated ASMF to all interested parties with reference to the revised version number.

Any change to the ASMF should be reported by every MA holder to the relevant National Competent Authority/EMA by means of an appropriate variation procedure. A Submission Letter should be provided (Annex 3).

In cases where the contents of the ASMF cannot be changed for a certain period of time because of other procedural provisions (i.e. mainly because of on-going MRP procedures), the ASMF holder should still provide the aforementioned data to the MA holder and National Competent Authorities/EMA making reference to this reason and requesting a later date of implementation.

At the occasion of the 5-year 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 CHMP/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/EMA.

MA holders should therefore verify with their ASMF 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 National Competent Authority/EMA, the necessary variation procedure should be initiated without delay.

ANNEX 1

OVERVIEW ASMF CONTENTS Table 1 CTD format

Applicant’s

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)2

x 3.2.S.2.2 Description of Manufacturing Process and Process controls

a) b) 3.2.S.2.3 Control of Materials

X 3.2.S.2.4 Control of critical steps and intermediates c) d) 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 e) 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 f) 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

2

Including all companies involved in the manufacture of the active substance, including quality

control/ in process testing sites, intermediate manufacturers, milling and sterilisation sites.

Table 2 NtA veterinary format Applicant’s

Part Restricted

Part

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

2.C.1.1 Specifications and routine tests x

2.C.1.2.1 Nomenclature x

2.C.1.2.2 Description x

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

2.C.1.2.3 Detailed description manufacturing method X

2.C.1.2.4 QC during manufacture c) d)

Process validation and evaluation of data X

2.C.1.2.5 Development Chemistry x

Evidence of structure x

Potential Isomerism x

Physiochemical characterisation x

Analytical validation x

2.C.1.2.6 Impurities x e)

2.C.1.2.7 Batch analysis x

2.F.1 Stability x

a) 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 Applicant’s Part (in cases where there is no further sterilisation of the final product).

b) Detailed information.

c) As far as the information is also relevant for the Applicant/MA holder.

d) As far as the information is related to the detailed description of the manufacturing process and as

far as this information is not relevant for the Applicant/MA holder.

e) In so far as the information is related to the detailed description of the manufacturing process and

in so far as the ASMF holder sufficiently justifies that there is no need to control these impurities in the final active substance.

f) As far as the information is related to the detailed description of the manufacturing process, control

of materials and process validation.

Table 3 NtA CTD format3

Herbal Active Substances/ Preparations Applicant’s

Part

Restricted Part

3.2.S.1 General information X

3.2.S.1.1 Nomenclature X

For herbal substance:

Binomial scientific name of plant (genus, species,

variety and author), and chemotype (where

applicable)

Parts of the plants

Definition of the herbal substance

Other names (synonyms mentioned in other

Pharmacopoeias)

Laboratory code

For herbal preparations

Binomial scientific name of plant (genus, species,

variety and author), and chemotype (where

applicable)

Parts of the plants

Definition of the herbal preparation

Ratio of the herbal substance to the herbal

preparation

Extraction solvent(s)

Other names (synonyms mentioned in other

Pharmacopoeias)

Laboratory code

3.2.S.1.2 Structure X

- Physical form

- Description of the constituents with known

therapeutic activity or markers (molecular formula,

relative molecular mass, structural formula, including

relative and absolute stereochemistry, the molecular

formula, and the relative molecular mass).

- Other constituent(s)

3.2.S.1.3 General properties X

3.2.S.2 Manufacturer(s)

For herbal substances

The name, address, and responsibility of each

supplier, including contractors

each proposed site or facility involved in

production/collection and testing of the herbal

substance should be provided, where appropriate.

For herbal preparations

The name, address, and responsibility of each manufacturer, including contractors, and each proposed manufacturing site or facility involved in manufacturing and testing of the herbal preparation should be provided, where appropriate. X

X

3.2.S.2.2 Description of critical steps and intermediates Flow chart Detailed

information 3ASMFs for Veterinary herbal medicinal products should be presented in accordance with section 4.1 above.

For herbal substances

Information should be provided to adequately

describe the plant production

and plant collection, including:

Geographical source of medicinal plant

Cultivation, harvesting, drying and storage conditions

For herbal preparations

Information should be provided to adequately

describe the manufacturing

process of the herbal preparation, including:

Description of processing

Solvents, reagents

Purification stages

Standardisation

3.2.S.2.3 Control of materials X

X 3.2.S.2.4 Control of critical steps and intermediates If also relevant

for the MA

holder/applicant

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

3.2.S.2.6 Manufacturing Process Development X

A brief summary describing the development of the

herbal substance(s) and herbal preparation(s) where

applicable should be provided, taking into

consideration the proposed route of administration

and usage. Results comparing the phytochemical

composition of the herbal substance(s) and herbal

preparation(s) where applicable used in supporting

bibliographic data and the herbal substance(s) and

herbal preparation(s) where applicable described in

S1 should be discussed, where appropriate.

3.2.S.3 Characterisation X

3.2.S.3.1 Elucidation of structure and other characteristics X

For herbal substances

Information on the botanical, macroscopical,

microscopical, phytochemical characterisation, and

biological activity if necessary, should be provided:

For herbal preparations

Information on the phyto- and physicochemical

characterisation, and biological activity if necessary,

should be provided:

3.2.S.3.2 Impurities X

3.2.S.4 Control of drug substance X

3.2.S.

4.1 Specification X

3.2.S.

4.2 Analytical procedure X

3.2.S.

4.3 Validation of analytical procedure X

3.2.S.

4.4 Batch analysis X

3.2.S.

4.5 Justification of specification X X 3.2.S.5 Reference standards of 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

ANNEX 2

(< FROM ACTIVE SUBSTANCE MASTER FILE HOLDER ON HEADED PAPER>)

TEMPLATE LETTER OF ACCESS

[Address of Competent Authority/EMA]

[Date]

Number of Active Substance Master File:

Name of Active Substance:

Internal API Code (if applicable):

Active Substance Master File holder: [name and address]

The aforementioned Active Substance Master File holder hereby authorises the 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)6 submitted by [Name of Marketing Authorisation Holder/Applicant] on [planned date of submission]:

[Name of product7 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/EMA of any change in the Active Substance Master File.

The aforementioned Active Substance Master File holder hereby is informed of and accepts that the EEA National Competent Authorities, the EMA including all CHMP and CVMP Members and their experts, and the Certification of Substances Division of the European Directorate for the Quality of Medicines & Healthcare may share the assessment reports of the above mentioned Active Substance Master File amongst themselves.

Signature for the Active Substance Master File holder

[Name and function]

[Signature]

4 EU/ASMF/XXXXX reference number is allocated from the CTS ASMF assessment report repository (when available) by the Competent Authority/EMA

5 The national ASMF reference numbers is allocated by the Competent Authority and should be used for national Marketing Authorisations only or when the EU/ASMF reference number is not allocated

6 i.e. to introduce a new ASMF from a new AS manufacturer.

7If no invented name has been agreed at the time of submission for this product: it should be indicated ‘INN + Marketing Authorisation Holder name’

ANNEX 3

(< FROM ACTIVE SUBSTANCE MASTER FILE HOLDER ON HEADED PAPER>)

Template Submission Letter and Administrative Details for documents relating to an Active

Substance Master File (ASMF)8

From:

Town>

To:

Subject: Submission of documents relating to an ASMF

for - 10

Dear Sir or Madam:

This Active Substance Master File is submitted in relation to the following product:

Yours faithfully,

8

To be submitted together with the ASMF in conjunction with every MAA/variation submission as one document

9

EU/ASMF/XXXXX reference number is allocated from the CTS ASMF assessment report repository (when available) by the Competent Authority/EMA 10

The national ASMF reference numbers is allocated by the Competent Authority and should be used for national Marketing Authorisations only or when EU/ASMF reference number is not allocated 11

If no invented name has been agreed at the time of submission for this product: it should be indicated ‘INN + Marketing Authorisation Holder name’

Medicinal product

Allocated procedure number (as applicable)

(Intended) Submission date of the marketing

authorisation application or variation (if known) 11