Electronic management of the GMPAPI Office documentation

From 15 September 2020, the GMPAPI Office has implemented the electronic management of the documentation and applications to be sent to the GMPAPI Office and related documents issued.
All correspondence and requests addressed to the GMPAPI Office, with the sole exception of requests for information at Italian level, for which the email infoGMPAPI@aifa.gov.it will remain active, and requests for information at an international level, for which the email gmpapirequest@aifa.gov.it has been activated, must be sent only electronically, to the certified e-mail address protocollo@pec.aifa.gov.it .

For the submission of applications, companies are invited to use the appropriate forms in the updated version, published in this section.

Please note that, in all cases where the total size of the documents to be transmitted exceeds 40 MB, not allowing their electronic transmission, it will be possible to carry out direct delivery (by hand, by courier, etc.) on electronic media (the exclusive use of USB Drives is recommended) at the AIFA Mail Room, (by hand, by courier, etc.) along with the (paper) form accompanying electronic media.

In order to allow the proper upload of the documentation into the Agency's IT systems and to avoid the interruption of the terms of the procedure, the size of each file contained on the USB Drive must not exceed 10 MB. As for files in.PDF format, they must have a resolution of 200 dpi for all black/white or colour combinations and, if possible, they must not exceed 12 MB. Please note that all documents can also be scanned only in black and white if they exceed 12MB; only documents that strictly need it should be scanned in colour. After each scan, it is recommended to check the quality of the digital image created, with particular reference to the correctness of the framing, the integrity of the text and the intelligibility of the content.

The documents issued by the GMPAPI Office shall be produced and digitally signed in accordance with Legislative Decree 82/2005 and sent by certified e-mail.

As for the stamp duty, please note that, pursuant to the D.P.R. 642/1972 (note 1-quater to art.4 of the duty, first part), for the deeds and measures issued electronically, this tax is due in the flat rate of € 16.00 for each deed, regardless of the size of the document and of the number of pages.

The payment of the stamp duty for the submission of the application and for the issuance of the deed/s can be made in the following ways:

• compilation and payment of the F23 form of the Revenue Agency 
• purchase of the paper stamp duty
• payment with virtual stamp duty, paid to the Revenue Agency, if the applicant has a specific authorization from the same Revenue Agency. 

For details, please refer to the AIFA communications of 25 June 2021, 06 October 2020 and 24 november 2022

Activation of new manufacturing plants

To register a new manufacturing/import plant of non-sterile and/or non-biological active substances and/or not deriving from tissues, organs, human and animal fluids, also for clinical trials, the Companies must submit an application for activation by filling in the Form 391/01 and send the documentation listed in the above form. Form 031/04 must also be completed and sent.

To request the authorisation of a new manufacturing/import plant of sterile and/or biological active substances and/or deriving from tissues, organs, human and animal fluids, also for clinical trials, the Companies must submit an application for activation by filling in the Form 392/01 and send the documentation listed in the above form. Form 031/04 must also be completed and sent.

Authorization for manufacturing/import of active substances (also for phase III clinical trials and/or bioequivalence studies)

Requests for modification of the authorisation must be sent using, for specific cases, the forms: 392/03 (manufacturing of new active substance), 392/02 (import of active substances), 392/05 (manufacturing of new active substances for phase III clinical trials and/or for bioequivalence).

Registration for manufacturing/import of active substances (also for phase III clinical trials and/or bioequivalence studies)

Requests for changes to the registration deed must be sent using, for specific cases, Form 391/02 (manufacturing of new active substance), Form 391/03 (import of active substances), Form 391/05 (manufacturing of new active substances for phase III clinical trials and/or for bioequivalence).

Notifications for manufacturing/import of active substances for phase I and phase II clinical trials 

Companies must submit the notification of manufacturing of active substances for phase I and II clinical trials, in previously activated plants, through Form 390/01 and the notification of the import of active substances through Form Mod.390/03 for phase I and II clinical trials by active substance manufacturing plants or medicinal product manufacturing authorisation holders.

Requests for changes to the conditions under which the import of active substances was authorised/registered

Requests for changes to the conditions under which the import of active substances was authorised/registered must be submitted using the following forms.

Non-essential changes

For the communication of "non-essential" changes to the authorisation, plants must use the following form:

Annual communication of the list of “non-essential” changes 

For the annual communication of the list of "non-essential" changes, the manufacturing/import plants of non-sterile and/or non-biological active substances and/or those not deriving from tissues, organs, human and animal fluids must use the following form:

Essential changes

Requests for essential changes affecting the quality or safety of non-sterile and/or non-biological active substances and/or not deriving from manufactured/imported tissues, organs, human and animal fluids must be submitted using the Form 391/06 (notification of essential changes).

Plants subject to authorisation shall submit requests for essential changes by using Form 392/04. 

Registration for the primary manufacturing/import of medicinal gases 

The request for registration of the primary manufacturing/import activity of active substances in the form of medicinal gases must be made using the forms available in the section "Registration for the manufacturing/import of active substances (also for clinical trials)" Form 391/02 and 391/03; for submission of essential and non-essential changes, reference must be made to the sections: "Non-essential changes" Form 392/11, 391/11 and "Essential changes" Form 391/06.

Please note that carbon dioxide is to be considered an active substance and, therefore, the manufacturing/import activities, including the distribution, are subject to a registration regime. Nitrogen, on the other hand, is to be considered an excipient and is not subject to a registration regime.

Finally, it should be noted that for the primary manufacturing plants of medical gases that also fill fixed hospital tanks, the GMPAPI Office, in addition to being responsible for the manufacturing/import of active substances, also checks and authorises compliance with GMPs for the filling of fixed hospital tanks and issues, in the specific case, a hybrid resolution of registration/authorisation. 

Import Registration/ Authorisation for MAHs

For MAHs, the new registration/authorisation regime applies as of 1 March 2018, as per the communication of 28/02/2018. The forms for submitting applications by MAHs, who are not also manufacturing authorisation holders, are 392/13 for applications for authorisation to import sterile and/or biological and/or active substances derived from tissues, organs, human and animal fluids and 391/13 for registration applications for the import of non-sterile and/or non-biological and/or non-tissue-derived active substances, organs, human and animal fluids.

Registration/Import Authorisation for Medicines Manufacturing Authorisation Holders

The forms to submit applications for the import of active substances according to the new registration/authorisation regime by the medicines authorisation holders is available as communicated in the notice published on 01/03/2016.

Qualified persons

The GMP Inspections and Manufacturing Authorisations of APIs Office issues the Authorisations for the appointment, replacement, addition of Qualified Person at authorised/registered plants.

Companies can submit their requests using the following forms:

Administrative changes

The Companies can communicate the change of the company name or ownership of the manufacturing/import plant, the change of the Company's registered office or the change of address of the plant using the following forms:

GMP certificates

The GMP Inspections and Manufacturing Authorisations of APIs Office issues the GMP certificate to manufacturers/importers of active substances who comply with the Good Manufacturing Practice Guidelines.

The request for a GMP certificate for manufacturing/import plants of active substances subject to a registration regime must be submitted using forms 391/09 and 391/10. The request for copies of the GMP certificate must be made using Form 028/02. The GMP Inspections and Manufacturing Authorisations of APIs Office issues the GMP certificate to manufacturers of active substances located in third countries and inspected by AIFA as a supervisory authority and who comply with the Good Manufacturing Practice Guidelines.

Upon request of the interested parties, an authentic copy is issued of the GMP certificate: the request must be submitted using the forms: Form_ Richiesta di copia di certificato GMP per officine di produzione di sostanze attive situate in paesi terzi (in Italian) or Form_ Request for authentic copy of GMP certificates for pharmaceutical production manufacturing site (APIs) (in English).

Inspection requests to non-EU plants

The inspection request for active substance manufacturing plants located in non-EU countries must be submitted using Form 101/03.

Upon successful completion of the inspection, the GMP Inspections and Manufacturing Authorisations of APIs Office will issue the relevant original GMP certificate on EudraGMDP.

CPP certificates

The request for the Certificate of Active Substance (CPP-API) used in medicinal products that do not have a Marketing Authorisation in Italy, intended exclusively for export, must be submitted using the Form CPP-API/EN. The certificate request form must be completed by the applicant in all its parts in English and sent in paper format to the GMP Inspections and Manufacturing Authorisations of APIs Office.

This certification is issued by the Agency according to the model recommended by the WHO for medicines lacking the marketing authorization (MA) and the related guideline for the implementation of the certification scheme "WHO pharmaceutical starting materials certification scheme (SMACS)". Pursuant to Art. 156 of Legislative Decree no. 219/2006, the certification is issued for application as part of a regulatory procedure (registration, renewal, extension, variation, revision) in the country of destination of the product, with the aim of certifying the compliance with GMPs by the manufacturer of the active substance.