The evolution of the regulatory framework for the plasma and plasma-derived medicinal products system in Italy

Introduction

In Italy, the plasma system is a part of the Blood System (BS) that is run under a thoroughly public governance scheme. The Italian National Blood Centre (NBC) (Centro Nazionale Sangue, http://www.centronazionalesangue.it) is designated as the Italian blood and blood product competent authority operating on behalf of the Ministry of Health (Ministero della Salute, MoH, http://www.salute.gov.it). It coordinates and supervises the 21 Regional Blood Transfusion Centres, with the aim of guaranteeing homogeneous standards of quality and safety across the 310 blood establishments (BEs) and 352 donor association collection units (with 1,867 collection points) (source: Italian Blood Information System, SISTRA database¹).

In 2012, the number of voluntary non-remunerated donors of whole blood and blood components amounted to approximately 1,739,712. The BS relied on 1,739,712 voluntary non-remunerated donors of whole blood and blood components: 1,443,770 (83%) repeat donors and 295,942 first-time donors². Based on a national definition, 666,479 of the repeated donors are considered “frequent donors” that means they donated at least once a year, every year, in the previous 5 years. There were 240,218 apheresis donors (13.8% of total). In the same year, 3,191,026 donations (53.7 donations per 1,000 population) were collected. Of the 7,224,409 blood components produced in 2012, 2,666,726 were red blood cell units (44.9 units per 1,000 population). Those transfused were 2,529,803 (42.6 units per 1,000 population). Every day, 8,719 blood components were transfused involving totally approximately 650.000 recipients (source: Italian Blood Information System, SISTRA database). In 2012, the volume of plasma sent to industry for fractionation was approximately 772,590 kilograms (source: Kedrion Biopharma SpA).

In February 2011, the MoH convened a panel of experts from the national competent authorities in the field of blood and blood products: the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA, http://www.agenziafarmaco.gov.it), the National Institute of Health (Istituto Superiore di Sanità, ISS, http://www.iss.it), the NBC and the MoH. The mission of the panel was to review and implement the current legislation and define proposals for regulations to comply with European directives and guidelines. Furthermore, efforts had to be put into the harmonisation of existing legislation, particularly for those aspects which were lacking and/or were not implemented: the production of plasma-derived medicinal products (PMPs) from Italian plasma, the opening up of the toll fractionation market to other contractors and the import/export of plasma and its products. The proposals, after approval of the State-Regions Conference, upon advice of the National Blood Technical Board and auditing of the Plasma Fractionators Association (Gruppo Emoderivati di Farmindustria), were signed by the Minister of Health on April 12^th, 2012^3–6.

The aim of this paper is to describe the main features of the Italian regulatory framework of the plasma system in the light of the recent changes of legislation, in particular related to the opening up of the toll fractionation market.

The Italian Blood System: founding principles and goals

BEs are responsible for every aspect of the collection, testing, processing, storage and distribution of human blood and blood components⁷. Moreover, in Italy they serve as Hospital Blood Banks by providing transfusion medicine (TM) services. All the mentioned activities are considered as an integral part of the National Health Service (NHS). According to Law No. 219 of October 21^st, 2005⁸, which is the main regulatory reference for the Blood Transfusion Services (BTSs) in Italy, they are provided as Basic/Essential Healthcare Services (Livelli Essenziali di Assistenza, LEA) to be homogeneously delivered nationwide - equitably, impartially and free of charge to any citizen. BTSs are based on voluntary, periodic, responsible, anonymous and non-remunerated donations that are recognised by the State as being of social and civic utility and an expression of human values and solidarity. Associations and federations of voluntary blood donors contribute to the promotion and development of blood and blood components donation and their activities are recognised in the law.

BEs are exclusively public and hospital-based. The only exception is provided by collection activities outsourced to units run by associations and federations of donors. Blood and blood components collection units perform their activities under the technical supervision and responsibility of BEs, following a licensing and accreditation process^7–10.

In addition, according to the aforementioned law, all these institutional bodies are involved in specific goals aimed at promoting, monitoring, assessing and auditing the appropriateness of the clinical use of blood components. The mandatory clinical assessment of the appropriate use of blood resources has a significant role in maintaining national self-sufficiency¹¹.

Indeed, the main self-declared goals of the BS are to reach national self-sufficiency of blood, blood components and PMPs, as well as the delivery of uniform levels of services nationwide and the development of TM in order to guarantee the most efficient protection of the citizens’ health in terms of quality and safety of blood and its products⁸. These goals must be in compliance with the pertinent national and European regulatory provisions.

Compliance with the European legislation on blood and medicinal products

As a Member State of the European Union (EU), Italy is required to transpose, through its own regulations, all European Directives on human blood and blood components and on medicinal products for human use, in order to comply with all standards and to ensure the same levels of quality and safety in the production of PMPs for all EU citizens. The Directives on human blood apply to “the collection and testing of human blood and blood components, whatever their intended purpose, and to their processing, storage, and distribution when intended for transfusion” (Table I)^7,9,12–18.

Table I.

European legislation and national transposition legislation regarding blood and blood components.

Blood and blood components
European legislation	Transposing legislation
Directive 2002/98/EC7 “setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components amending Directive 2001/83/EC”	Legislative Decree no. 261 of December 20th, 20079 “Revision of legislative decree 19/08/2005 n. 191, on the implementation of directive 2002/98/EC setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components”
Directive 2004/33/EC11 “implementing Directive 2002/98/EC of the European Parliament and of the Council as regards certain technical requirements for blood and blood components”	Ministerial Decrees of March 3rd, 200514,15 - “Protocols for assessing the suitability of donors of blood and blood components” - “Characteristics and methods for donating blood and blood components”
Directive 2005/61/EC12 “implementing Directive 2002/98/EC of the European Parliament and of the Council as regards traceability requirements and notification of serious adverse reactions and events”	Legislative Decree no. 207 of November 9th, 200716 “Implementation of directive 2005/61/EC implementing Directive 2002/98/EC of the European Parliament and of the Council as regards traceability requirements and notification of serious adverse reactions and events”
Directive 2005/62/EC13 “implementing Directive 2002/98/EC of the European Parliament and of the Council as regards Community standards and specifications relating to a quality system for blood establishments”	Legislative Decree no. 208 of November 9th, 200717 “Implementing directive 2005/62/EC implementing Directive 2002/98/EC of the European Parliament and of the Council as regards Community standards and specifications relating to a quality system for blood establishments”

The Directives and regulations on medicinal products apply to “the process, storage and distribution of plasma intended for fractionation” (Table II)^19–23. The transposition of the European legislation in addition to the national one makes the regulatory framework that governs the Italian system of plasma and PMPs particularly complex.

Table II.

European legislation and national transposition legislation regarding the production of plasma-derived medicinal products.

Plasma-derived medicinal products
European legislation	Transposing legislation
Directive 2003/63/EC18 “amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use”	Ministerial Decree of September 24th, 200421 “Provisions on documentation which must accompany applications for marketing authorisation for medicinal products for human use in implementation of directive 2003/63/EC of the Commission of 25 June, 2003”
Directive 2001/83/EC19 “on the Community code relating to medicinal products for human use” Directive 2003/94/EC20 “laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use”	Legislative Decree no. 219 of April 24th, 200622 “Implementation of Directive 2001/83/EC (and subsequent amendment directives) on a Community code relating to medicines for human use, as well as Directive 2003/94/EC”

In order to make the BS fully compliant with the above-mentioned European legislation, a qualification pathway for BEs was started in December 2010 from the definition of the minimum structural, technological and organisational requirements to perform transfusion activities¹⁰ for both BEs and Blood Collection Units (BCUs). Furthermore, a template for blood inspections^7,9 for authorisation and accreditation purposes of BEs and BCUs was defined^7,8,10. According to the current legislation⁹, in Italy the competent authorities in charge of inspections are the Regional Health Authorities. However, the inspection team must include at least one national qualified inspector belonging to the NBC list of qualified inspectors²⁴. By law, the requirements of BEs and BCUs must be fully implemented and the first round of inspections completed by December 31^st, 2014^10,25.

During the period that will lead to the complete compliance with European legislation and European Pharmacopoeia^26,27, plasma collected by Regional BTSs may be processed for the production of PMPs only by national marketing authorisation holders (MAHs) and only if they use exclusively national plasma⁶. All the relevant information and documentation related to the quality and safety of national plasma must be submitted by MAHs, entitled of the tool agreement with Italian Regions, to the AIFA according to the provisions of the guidelines of the European Medicines Agency (EMA) on the European Plasma Master File^28–31.

The self-sufficiency program

The achievement of self-sufficiency -of PMPs as well as of blood and blood components- recognised as a role of “national, superregional, above-local healthcare management and indivisible interest” is one of the strategic goals of the BS⁸. This achievement is entrusted to the synergy between Regions and healthcare facilities.

The MoH attains this goal through: the Annual National Programme for Self-sufficiency⁸ and the Programme on the development of plasma collection in both blood services and blood collection units, as well as the promotion of an appropriate and rational use of PMPs⁹.

The first Programme is aimed at identifying historical consumptions, real demand, necessary production levels, resources, funding system criteria, interregional exchanges, import and export levels^32–34. NBC has to provide a technical proposal for this programme after consultation of all relevant stakeholders like Regional Blood Centres and Donor Associations and Federations. It may include recommendations, indications and objectives both on blood’s and PMPs’ demand and on blood collection and plasma production. It may take into consideration issues like need assessment and auditing of appropriate use, seasonal and regional shortages and surpluses, possible emergency/critical situations, as occurred with emerging virus outbreaks (e.g. Chikungunya virus, West Nile virus, etc.)^35,36, regional services performance, quality and safety.

The second Programme provides a specific tool for medium-long term planning of the plasma and PMPs system⁹.

The production of plasma-derived medicinal products from Italian plasma

The plasma system is an integral part of the BS although it has some peculiarities with respect to the European system. Regions and Autonomous Provinces (henceforth referred to as “Regions”), individually or in consortium, send the plasma collected by Blood Services to Kedrion Biopharma SpA (Castelvecchio Pascoli, Lucca, Italy) (henceforth referred to as Kedrion), nowadays the only manufacturer authorised under a toll fractionation agreement^37–39. The Regions retain ownership/property of the raw materials and the equivalent derived products throughout all the process. Both the management and control of the production process and the distribution of plasma for third-part processing are carried out by Regional BTSs.

Currently, there are two interregional agreements in force in Italy: the Consortium Lombardy-Piedmont-Sardinia (LPS) and the Interregional Agreement on Plasma-Derivation (IAPD) involving 14 Regions (on a total of 21), that contribute to around 75% of the plasma sent to fractionation (747,982 kilograms in 2011)⁴⁰. Interregional agreements for plasma fractionation are a fundamental instrument for promoting regional and national self-sufficiency of PMPs and also a virtuous model of cooperation between Regions aimed at achieving optimal distribution in terms of quantity, continuity and flexibility of medicinal products obtained from fractioning national plasma.

The current toll agreement between Regions and Kedrion provides for the production of the following PMPs: human albumin solution, polyvalent immunoglobulin for intravenous administration, factor VIII concentrates, factor IX concentrates, prothrombin complex concentrates and antithrombin.

The opening up of the toll fractionation market

A new scenario for PMP manufacturing came into effect in April 2012^4–6. According to the new context, the MoH identifies, by means of a decree, the companies authorised to process Italian plasma, among the suppliers that submit an intention to tender application by the 30^th of September of each year. Fractionators are requested to meet the following technical and regulatory pre-requirements: 1) adequate industrial size; 2) advanced technology working cycle; 3) plasma fractionation in EU countries in conformity with European legislation, i.e. plasma is not transferred for profit and it is not manufactured in a monopoly market; 4) marketing authorisation for PMPs in Italy; 5) appropriateness of all fractionation plants, in accordance with national and European legislations. The inclusion of ethical requirements, e.g. location of the fractionation plant in an European country where plasma is not transferred for profit, confirms the ethical nature of the system and meets the need, expressed in particular by Donor Associations and Federations, to preserve the BS founding principles and values^8,41,42.

Furthermore, a template of the service Convention between Regions and fractionators has been formally adopted³. It sets out the essential contents of the contract as regards the pre-processing stage and the plasma fractionation as well as the production, distribution and safety of PMPs. For the purposes of the tender notice, the production of at least human albumin, factor VIII concentrates and polyvalent immunoglobulins for intravenous administration has to be considered.

Import and export of plasma and plasma medicinal products

In Italy, the MoH is the authority competent for the release of the authorisation to import and export blood and blood components when intended for transfusion while AIFA is the authority in charge of regulating the import and export of plasma intended for fractionation, plasma intermediate products and PMPs^5,8. The new regulation⁵ introduces the possibility for companies with fractionation plants in Italy to import plasma and blood products destined for the production of medicinal products to be marketed exclusively in third countries (i.e. non-EU countries) in accordance with the new provisions of Annex 14 of Good Manufacturing Practices (GMPs)⁴³. Furthermore, it allows for the processing of national plasma abroad, in order to make feasible the opening up of the market to fractionators located outside Italy. It also consents to the exportation of plasma products exceeding national needs “in relation to specific agreements, programmes and plans, which may foresee the supply of plasma medicinal or intermediate products of plasma processing with recovery of production costs and in any case without financial profit” and after declaration of conformity of the projects by the NBC. A recent State-Regions Agreement has reinforced the promotion and implementation of collaboration agreements intended for the export of PMPs for humanitarian purposes⁴⁴ in line with the international recommandations⁴⁵. Examples of activities to be encouraged are: organisation/implementation of blood systems in the countries of destination, education and training of human resources, and support to both the planning and implementation of healthcare networks for patients with haemophilia and other congenital bleeding disorders. Furthermore, the Agreement calls for the involvement of the Ministry of Defense in undertaking the transport of blood-derived products in emergency or war situations, and the Ministry of Foreign Affairs in promoting and supporting the above-mentioned agreements, programs and projects within the general framework of elaboration and implementation of both cooperation and health policies.

Conclusions

Both the progressive adaptation of the plasma and PMPs system to European regulations and the opening up of the national plasma processing market will likely create new challenges and opportunities in terms of ethics, planning, economy, organisation and coordination of the BS, as well as create offer of new services and products (Table III)^{3–6,8,23,24,46}.

Table III.

Summary of Decrees of the Minister of Health April 12^th, 2012 and May 24^th, 2011 concerning the plasma and plasma-derived medicinal products system, with the related legislative acts of origin.

Legislative acts	Ministerial decrees envisaged by the legislation
Law 219/20058art. 15 modified by Law 96/201046	“Scheme of Convention between Regions, Autonomous Provinces and fractionators for the fractionation of plasma collected in Italy”3 “Decree identifying centres and companies authorised to stipulate conventions for the fractionation and production of blood derivatives” (to be issued)
Law 219/20058art. 16	“Provisions on the import and export of human blood and its products”5
Law 10/201124(Milleproroghedecree)	“Institution of a national list of inspectors of blood establishments and blood collection units”23 “Transitional provisions for marketing blood-derived medicinal products produced from human plasma collected in Italy”6 “Dispositions on the submission and evaluation of the requests for the authorisation to enter into contractual agreements with Regions, in order to produce blood-derived medicinal products through the fractionation of plasma collected in Italy”4

The effective opening up of the toll fractionation market will introduce new elements to the Regions that could supposedly benefit from a stronger competition in terms of qualitative and quantitative supply of all toll fractionation products, with potential variations of industrial yields and PMPs self-sufficiency levels, and an adequate management of the product surpluses.

The new contracts with fractionators will probably lead to a re-definition of interregional aggregations/consortia for plasma process with the purpose of forming new homogeneous groups on the basis of various criteria, with a view to achieve a better management and greater savings in the production of PMPs. Some elements to take into account will be: similar raw material quality, the effective achievement of the critical amounts necessary for the processing, the level of regional organisation, as well as both the demand and supply of the products with reference to the mechanisms of distribution and product exchanges within the agreements.

The new dispositions allow companies on national territory to import blood-derived products destined for the production of medicines to be marketed exclusively in non-EU countries in order to provide non-EU patients with access to medicinal products whose quality and safety are the same as those of the medicinal products available for EU patients.

In conclusion, the national regulatory framework is continuously changing in order to keep up with the EU legislation and with the evolving needs of a complex system as the Italian one. Notwithstanding this evolution, the core strength of the Italian blood system, i.e. the legislative provisions establishing that appropriate use of blood resources must be promoted and applied nationwide, is stable and continues to play a significant role also in the adequate supply of PMPs.