New ASMF - Aim to support and improve the ASMF procedure across the European Regulatory Network

EMA has released the new ASMF guideline, which is effective from 1 October 2012. 

Updates: 

• 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 This obligation remains valid until the Letter of Access has been withdrawn by the ASMF holder. ASMF holders should provide the updated ASMF to all interested Authority/EMA. This obligation remains valid until the Letter of Access has been withdrawn by the ASMF holder. 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.

• 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.

Reference: Guideline on Active Substance Master File Procedure

Do you Know about Sister File??

Sister File: There are cases when a manufacturer has been granted a CEP for a substance and where they apply for a second CEP for the same substance to cover an alternative process, generally because the existing one cannot cover the new process/conditions. Any differences compared to the approved CEP from a content point of view could be considered as revisions. These applications will be called sister files.

Since the original dossier has already been approved, it is proposed to treat sister dossiers with a fast track procedure and focus the evaluation on the variations compared to the approved CEP dossier. 

This is applicable typically in case of changes of solvents used in the final purifications steps or processes carried out in two sites belonging to the same company, if the company wants to have both situations covered by CEPs.

Note: Sterile and TSE applications are outside the scope of this procedure. 

Conditions:

• The original application should already have been approved by EDQM and the CEP granted
• The manufacturer should be the same for both applications
• Differences described in the new dossier compared to the already granted CEP can be classified and hence treated as a revision.

Documentation:

• New application according to the current procedures
• Reference to the already approved dossier and explanation of differences
• A comparative table of the affected dossier sections for both the approved and the new application
• A subtitle for the CEP of the sister application, in order to differentiate both CEPs

Further Information: Sister File

Routes for registration of Active Pharmaceutical Ingredients (API) in EU

Active pharmaceutical ingredient: Any substance or mixture of substances intended to be used in the manufacture of the medicinal product and that, when used in the production of the drug, becomes an active ingredients of the medicinal product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of diseases or to affect the structure and function of the body.

In EU, API's classified as:

• New active substances
• Existing active substances not included in the European Pharmacopoeia (Ph.Eur.) or the pharmacopoeia of an EU Member State
• Active substances included in the Ph.Eur. or in the pharmacopoeia of an EU Member State

Feasible ways to submit the required information:
Depending on the kind and classification of the active substance, the required data may generally be submitted in one of the following

a. Certificate of suitability to the monograph of the European pharmacopoeia (CEP)b. Active Substance Master File (ASMF) procedure or EDMFc. Full details of manufacture

1. For new active substances option (b) or (c) would apply.
2. For existing substances option (a) would apply, it has the advantage of generally avoiding any subsequent reassessment. Option (b) and (c) are also apply.

Scope:

CEP - Applicable to Pharmacopoeial substances only (active substance or excipient)

ASMF - Applicable to active substances only ( new or pharmacopoeial)

Differences between CEP & ASMF:

ASMF: 

• Full dossier sent by API manufacturer to National Authorities
• It consists two parts: Open part and closed part
• Applicant’s part sent by API manufacturer to MA applicant or holder of medicinal Product
• Letter of access (to be sent by API manufacturer)
• Assessment of ASMF by each national authority in the context of assessing a specific marketing authorisation application or variation for medicinal products.

CEP:

• Full dossier sent directly by manufacturer to EDQM
• Single evaluation centralised at EDQM
• By assessors nominated by national authorities / Certification Steering Committee
• Independent from marketing applications of medicinal products
• Certificate including annexes (additional tests to be performed) granted to manufacturer who supplies a copy of it to its users

Advantages of the CEP

• Easier management of RA documentation for API manufacturer (no open part)
• Savings of time and resources
• Easier management of MAA - replaces main part of 3.2.S
• CEP accepted in all Ph. Eur. Member states (36) + others (eg. Canada, Australia, Morocco, New Zealand etc.)

References:

1. Certification of suitability to the monographs of the European Pharmacopoeia

2. Guideline on Active Substance Master File procedure