ASMF: active substance master file

The ASMF procedure is described in the EMA guideline on the active substance master file procedure (CHMP/QWP/227/02 Rev 4) and is the EU implementation of what other regions call a drug master file. Its purpose is to protect the intellectual property of the active substance manufacturer while letting the marketing authorisation applicant rely on its data. The manufacturer, as ASMF holder, splits the Module 3.2.S information into an Applicant's Part, which the applicant receives and includes in its dossier, and a Restricted Part containing the detailed synthesis, process controls and other confidential information, which goes directly to the authorities. A letter of access from the ASMF holder authorises the authorities to assess the Restricted Part for the named application.

The procedure can be used for new active substances, for existing substances not covered by a pharmacopoeial monograph, and for pharmacopoeial substances where the applicant wishes to rely on the manufacturer's data; it cannot be used for biological active substances. Each ASMF is identified by an EU ASMF number requested from EMA, and the CMDh runs an ASMF worksharing procedure so that one assessment of a master file can be reused across mutual recognition and decentralised procedures instead of being repeated in each. Assessment reports on the ASMF are shared between the authorities involved.

In the dossier the applicant submits the Applicant's Part together with its own summary of the active substance specification and the control tests it performs on receipt. The ASMF holder submits the Restricted Part and the Applicant's Part in eCTD format to each authority, with a cover letter referencing the application. When the master file changes, the holder must inform both the applicants and the authorities, and the applicant may then need a variation if the change affects the Applicant's Part or the specification.

What goes wrong: the Applicant's Part submitted by the applicant is an older version than the one the ASMF holder sent to the authority; the letter of access names the wrong product, procedure or holder; the ASMF holder updates the Restricted Part without telling its customers, so a Type IB variation is filed years later than it should have been; the same substance has several ASMF versions in different Member States because worksharing was not used; and an applicant assumes a certificate of suitability would have been simpler without checking whether the monograph controls the impurities of that route of synthesis.