Blood products are medicines produced from human blood or plasma, coming from voluntary donations, through industrial manufacturing processes.
In Italy, the National Blood Center carries out functions of coordination and technical scientific control of the national transfusion system on behalf of the Ministry of Health. The requirements and criteria for the collection and control of human blood and its components intended for the pharmaceutical production of blood products are equivalent to those provided for both blood and blood components intended for transfusion.
In order to be marketed in Italy, blood products, as well as all other medicines, need to obtain the marketing authorization issued by AIFA following the scientific assessment of the quality, safety and efficacy requirements of the medicine. Furthermore, since blood products are biological medicines, the production processes provide for further processing and control phases to better guarantee the safety of these products.
Companies authorized to produce blood products for the import/export of blood and its components are required, in compliance with current legislation, to obtain prior authorization from AIFA or to submit a notification to the Agency (you can find in the “forms” section the operating instructions and reference models to file notifications/annual reports).
How they are classified and how they work
Albumin is a plasma protein produced by liver cells. Lower-than-normal values of albumin (albumin concentration in the blood) are, in most cases, due to a reduced production of albumin by the liver. Albumin is mostly indicated in the treatment of various liver diseases and occasionally in other clinical conditions with a reduction in blood volume.
Immunoglobulins are used in the replacement therapy of immunodeficiencies and in the treatment of autoimmune diseases or systemic inflammatory processes. Immunoglobulin preparations, produced from human plasma pools, contain structurally and functionally intact IG, with normal half-life and proportion of subclasses.
Antithrombin is a plasma glycoprotein produced by the liver. Antithrombin is the most powerful natural coagulation inhibitor and plays a fundamental role in the balance of haemostasis. Antithrombin preparations are indicated in congenital deficiencies of this glycoprotein.
Coagulation factor VIII is used in the replacement therapy of haemophilia A, a rare, hereditary, sex-linked recessive haemorrhagic disease, which causes a deficiency in FVIII. According to the level of activity of the circulating FVIII, it is possible to distinguish severe, moderate and mild forms of haemophilia A.
Coagulation factor IX is used in the replacement therapy of haemophilia B, a rare, inherited, sex-linked recessive haemorrhagic disease, which causes a FIX deficiency. According to the level of activity of the circulating factor, it is possible to distinguish severe, moderately severe and mild forms of haemophilia B.
Coagulation factor VII is a glycoprotein that plays an essential role in triggering blood clotting and used in therapy to replace a severe and rare bleeding disorder due to an autosomal recessive inherited chromosomal abnormality.
Coagulation factor XIII, also called fibrin stabilizing factor, is used in the replacement therapy of the congenital deficiency of the protein itself, an autosomal recessive disease. According to the level of activity of the FXIII, it is possible to distinguish severe, moderate and mild forms.
Prothrombin complex concentrates are used for the correction of temporary deficiency of prothrombin complex factors. Through appropriate techniques, complex products consisting of three or four factors can be produced.
Fibrinogen is one of the most abundant coagulation factors in plasma and is the main component of the coagulation phase. A lack of fibrinogen results in a decreased ability of the blood to clot, resulting in an increased tendency to bleed. Fibrinogen is mainly used in the treatment and prophylaxis of bleeding partially or totally caused by severe fibrinogen deficiency.
In order that an immunological medicine or a medicine derived from human blood and plasma be marketed in an EU country, each individual batch must pass the State Control procedure by obtaining a "batch release" certificate from the Official Laboratory of Control (Official Medicines Control Laboratory, OMCL) of a Member State or of a State with which mutual recognition agreements are in force. The Official Control Laboratory in Italy is the Istituto Superiore di Sanità (ISS).
Batches without the release certificate cannot be marketed in any EU country and related information is shared through the official OMCL network or the Network Official Control Authority Batch Release (OCABR).
Upon requesting AIFA to market a specific batch of an immunological drug or medicinal product derived from human blood or plasma, the MAH and/or the licensee is required to send the following documentation to the Product Quality and Pharmaceutical Crime Counteracting Office, through the certified email address email@example.com .
Information on the documentation to be submitted to AIFA
If the applicant is a MAH, all the documentation relating to the Batch Release request must be prepared by the MAH and sent through the licensee. The latter is required to notify the office of the MA, specifying it on the request cover and attaching all the documentation certifying this authorization.
The official start of the procedure (start-up) is marked by the date and the protocol number assigned to the request that are sent by e-mail from the Product Quality and Pharmaceutical Crime Counteracting Office to the applicant.
AIFA has deemed it useful to define two different procedures: ordinary and urgent. The ordinary procedure must be completed by 7 working days, at the end of which, if AIFA has not raised any objections (silent consent), the batch can be marketed. The urgent procedure, justified by particular situations, such as the risk that a shortage on the market may occur relating to a particular medicine, must instead be completed within 3 working days, at the end of which, following the release of the authorization by AIFA, the batch can be marketed.
If the documentation does not comply with the requirements, AIFA sends the MAH and/or the licensee a request for clarification and/or additional documentation. This request suspends the terms of the procedures which start from scratch upon receipt of the necessary additional documentation. The new terms are notified to the applicant via certified email (PEC).
Batch release for seasonal influenza vaccines
The procedure concerning influenza vaccines follows a specific process, as the marketing of these is subject to the entry into force of the AIFA resolution relating to the updating of influenza viral strains for the current season.
The MAHs can still submit to the office the marketing authorization requests for influenza vaccines prior to the publication of the AIFA resolution and before the issue of the specific annual circular by the Ministry of Health, using only the ordinary procedure.
However, up to the date of publication of the AIFA resolution, the release procedure cannot be considered concluded with the “silent consent” mechanism.
- Copy of the Batch Release (CBR) certificate, certificate issued by the OMCL of a Member State (including Italy) or of a State with which mutual recognition agreements are in force, if applicable also to this sector.
- Marketing Information Form (MIF), a model of notification of the applicant's intention to market a specific batch, in which all the information relating to the batch is reported (e.g. trade name, batch number, validity date, expiry date, etc.).
- Batch Release procedure cover, which identifies the type of procedure requested, which can be identified as ordinary or urgent.
The Plasma Master File (PMF) is a document providing detailed information on the origin and characteristics of human plasma used as a raw material and/or subsidiary for the production of medicines derived from human blood or plasma. The certification is optional and does not represent an authorization of the medicine, therefore its applicability is bound to its inclusion in the medicine authorization dossier.
The technical scientific evaluation is carried out by the European Medicines Agency (EMA), which issues a certification valid throughout the European Union. In cases where the PMF applies to products authorized in a single Member State, the certification is issued by the competent national authority (in Italy, AIFA, supported by the Istituto Superiore di Sanità and by the National Blood Center).
AIFA may authorize, on a case-by-case basis and in the absence of similar valid therapeutic alternatives, the import of vaccines or medicines derived from blood or plasma not registered in Italy, but legally marketed in the country of origin (pursuant to Art.8 of Ministerial Decree of 02/12/2016).