2 European Definitions, Current Use, and EMA Stance on Use of Platelet-Rich Plasma in Sports Medicine

10.1055/b-0035-123573

2 European Definitions, Current Use, and EMA Stance on Use of Platelet-Rich Plasma in Sports Medicine

Stefano Fiorentino, Alice Roffi, Giuseppe Filardo, Maurilio Marcacci, and Elizaveta Kon

2.1 Introduction

Platelet-rich plasma (PRP) has been the focus of much attention over the last few years, as an appealing biological approach to favor the healing of tissues otherwise doomed by a low healing potential. Since PRP is a blood-derived product, its use is strictly regulated in Europe, to ensure the control of all the aspects related to preparations, storage, and distribution, and therefore the quality and safety of PRP products.

This chapter aims to focus on the regulatory framework related to the products derived from the manipulation of whole blood (PRP) through medical devices for separation, without specifying the regulations concerning the development and marketing of the devices (generally falling in the category of medical devices within the European Directive 93/42), which often have completely different risk categories due to the heterogeneity of manufacture, assembly, and operating instructions, and require specific and nonuniform regulatory pathways for obtaining the CE mark.

2.2 The Current Reference Regulatory Framework in Europe

In Europe, the regulatory framework concerning the blood system is currently disciplined by the Directive 2002/98/EC of the European Parliament and Council, January 27, 2003, which sets out quality and safety rules for collecting, controlling, processing, preserving, and distributing human blood and its components, acknowledged in the various States of the Union with internal regulations.

The salient contents of the European regulatory framework aim to ensure, at community level, a high level of protection of human health.

The fundamental principles of the text are the following:

License for hematological centers. Member states must ensure that activities concerning the collection and control of human blood and its components are performed only by hematological centers that have obtained a designation, authorization, accreditation, or a license for this purpose from the appropriate authority, recognized by each member state according to its own institutional setup.
Nominating a head of the transfusion service. The head of the transfusion service, under his/her own responsibility, will have to, among other things, ensure that each unit of blood or blood product, for any intended use, be collected and controlled and, if intended for transfusion, be processed, preserved, distributed, and assigned in compliance with the regulations in force.
Qualified staff. The staff who participates in collecting, controlling, processing, preserving, distributing, and assigning human blood and blood products must have the qualifications required by the regulations in force to carry out these functions and receive, in due time, adequate professional training, periodically updated.
Quality system. Member states must adopt the necessary measurements so that the transfusion service and the collecting units form and maintain a quality system based on the principles of good practice and according to the regulations in force.
Using a rigorous penalty system to stop nonauthorized transfusion services.

2.3 The European Commission’s Position

In the Summary Report following the Meeting of the Competent Authorities on Blood and Blood Components (held on October 11–12, 2012, in Brussels) concerning PRP, the Commission indicated that after consultation with the legal service SANCO (Directorate-General for Health and Consumer Protection), the procedure should fall within the scope of the directives on blood, although the appropriate national authorities have highlighted how in practice it is difficult to bring this procedure fully in line with what is envisaged by the 2002 Directive. The legal service SANCO has therefore reported that this procedure will in future be the subject of specific and unitary regulations by the European Union. This position was confirmed in the Meeting of the Competent Authorities on Blood and Blood Components (held on April 17–18, 2013, in Brussels) and it is one of the audited annual regulatory agenda of European authorities competent in the field of organ and tissues.

2.4 Execution of the Regulations in Italy

From a legal point of view, we can clarify some salient points that qualify the procedure for employing blood components for noninfusion/transfusion use (topical).

The term “topical” is equivalent, from a legal point of view, to “noninfusion/transfusion” and indicates all therapeutic applications in which blood components are not transfused into the patient but are used directly in the pathologic area through different ways (intra-articular/deep-tissue injection in orthopedics, cutaneous in dermatology, subcutaneous in plastic surgery, etc.).

2.4.1 Blood Components, Non-Hemoderivatives

A big advantage of this procedure is to obtain the final product by harvesting a very limited amount of blood from the patient. With that in mind, the preparation of concentrates or platelet gels is not considered as the production of blood derivatives, but as fractionating the blood itself by simple and/or physical means to obtain blood components.

Currently, it is technically possible, once authorized by the competent/specific authorities, for any orthopedic surgeon to prepare concentrated platelets, even in an outpatient setting, by using appropriate machines, in some cases in a closed circuit or more commonly in asepsis, with the CE mark, that can centrifuge and/or filter the blood harvested from the patient and separate completely autonomously the plasma part rich in platelets for therapeutic use.

2.4.2 Safety, Use, and Preparation (Minimum Manipulation)

Minimum manipulation refers to blood components that do not interact with other drugs and are prepared quickly. The only risk, in the case of autologous donors, can be malpractice in the preparation system. Concerning their use, in the case in question the blood components have a topical therapeutic indication and therefore beyond the classic infusion/transfusion administration.

Concentrated platelets are, without doubt, prepared by simple physical means (centrifugation, separation), provided that the practice itself is not used for experimental purposes or somatic cell therapy. This is also supported by two more considerations:

The manipulation in question can be considered minimum (even in the hypothesis where there is not a simple centrifugation of the autologous blood but the platelet concentrates are made into a gel by adding autologous cryoprecipitate, sterile calcium gluconate, and batroxobin).
These manipulations do not produce any cell proliferation because the platelets are cell elements without nucleus, which release cytokines after shape modifications, albeit to a lesser extent, in all apheresis procedures.

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