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Good practices for the preparation of human blood-derived biological products: Platelet Rich Plasma (PRP)

Daphne V. Dierman, PhD Pharmacist, Sanaa Benkirane, PhD Pharmacist Farid Gomri, Msc, Biologist, Antoine Turzi, CEO RegenLab.

Introduction

New innovative therapies characterized as autologous (organic substance whose donor and recipient are the same individual) are found on the market, their preparations are dependent on the use of medical devices allowing them to minimize the risks of contamination (infection) and to standardize the steps.
We will discuss the preparation of biological products derived from human blood for therapeutic purposes and specifically the preparation of platelet-rich plasma (PRP).

II/ Preparation of platelet-rich plasma (PRP)

It is still carried out today in some hospitals, clinics and private practices in an illegal manner, in violation of the intended use of certain devices that are intended for diagnostic procedures and not for therapeutic use.
Among the reasons for these prohibitions for therapeutic use It is important to emphasize the need to ensure patient safety and to provide proof of therapeutic efficacy based on clinical evidence proven by scientific studies that comply with health regulations.
Therefore, in vitro diagnostic (IVD) tubes cannot be used for the preparation of PRP, as they do not meet the necessary requirements to minimize the risk of side effects once the biological product is injected into the patient.

III/ Compliance with standards

Among these requirements we find Compliance with ISO10993 standards (Biological Evaluation of Medical Devices) in which numerous tests such as biocompatibility, pyrogenicity and chemical characterization are listed.  
In order to be used in a patient for therapeutic purposes, a Medical Device must comply with the European Medical Device Regulations: "The European Medical Device Regulation (MDR) 2017/745.
For this reason, one of the major manufacturers of in vitro diagnostic tubes, "Becton & Dickinson", has issued an official communication (Fig. 1) stating that the preparation of PRP should be performed using medical devices that comply with the above international regulations.

IV/The manufacturer of Medical Devices must consider the following parameters for the safety of a human blood-derived biological preparation, using medical devices, such as PRP

A / Have a Quality Management System in accordance with the ISO 13485: 2016 standard, meeting the requirements, in the past, to the Directive 93/42/EEC, with a grace period not exceeding May 2024.
After this deadline, the Quality System must also meet the additional requirements of the new MDR Regulation (EU) 2017/745.
  • Since 2019, a company with international activities must certify its quality system according to the MDSAP (Medical Device Single Audit Program), following the CIH (International Harmonization Conference established in 2001 !).
  • This unique audit program for medical devices is recognized by the authorities of the 5 participating countries: Australia, Brazil, Canada, United States and Japan.
  • As of January 1, 2019, Canada has made MDSAP mandatory. The United States of America, Brazil, Australia, Japan are expected to follow suit. Europe is currently only an observer of this program.
B/ Certify its Medical Devices according to the European Regulation (MDR (EU) 2017/745) on Medical Devices which replaces the Directive 93/42 EEC (MDD) on medical devices and the Directive 90/385/EEC on active implantable medical devices in force.
The MDR maintains the requirements of the MDD and introduces new ones. The MDR is more focused on safety. This word appears 290 times in the MDR (40 times in the MDD).
  • For each medical device, to provide un Technical File consistent with the new MDR 2017/745 requirements which includes the technical and functional specifications of the Device, and a clinical evaluation report (CER) performed with its medical device(s), allowing to prove their therapeutic efficacy and safety for the patient in the recognized therapeutic indications.
  • To set up a Post-market Surveillance Plan concerning the safety of the Medical Device throughout its life cycle.
This plan also includes the Post Market Clinical Follow up who will need to continually monitor and demonstrate certified clinical claims.
C/ The requirements of the biological product preparations (e.g. Platelet Rich Plasma) namely:
  • From sterile medical devices designed and certified by a notified body recognized according to the MDR 2017/745/EEC.
  • A closed-circuit preparation system, with a minimum of handling and at the patient's bedside (extemporaneous use), in compliance with strict asepsis techniques to guarantee the sterility of the sampling and administration whatever the indication of use.
  • PRP must be used in a single medical procedure, not stored or prepared elsewhere at a third-party facility.
  • The collection procedure must be performed by or under the supervision of a physician, and the PRP injections must be performed by a physician.
  • The concept of bioequivalence cannot be applied to biological preparations derived from human blood for therapeutic purposes because each medical device has its own performance in terms of cell isolation and therapeutic performance.
According to the French public health code, legislative parts, articles L1211-8 and 1242-1, blood samples for autologous therapeutic purposes are authorized provided that the samples are taken in compliance with the rules of Good Preparation Practices.

D/ Taking into account these different regulations and international standards, the preparation of blood derivatives, and more precisely the preparation of platelet-rich plasma, can only be performed using class IIb or III Medical Devices, certified and validated for this use.

E/ Thus, preparations using In Vitro Diagnostic - IVD devices (devices intended to be used only in vitro for the examination of biological samples, with the aim of providing information on the patient) subject to the new IVD 2017/746 standard, are prohibited for the preparation of PRP:

a) IVDs are not subject to biocompatibility and pyrogenicity tests according to ISO 10993-1 to 23.
(b) IVDs may not be promoted or used for medical use because they do not meet the safety and clinical evaluation prerequisites per MDR 2017/745. Their contents, even if sterile, cannot be re-injected into the patient.

V/ In clinical practice

The use of medical devices for the preparation of Platelet Rich Plasma is becoming more and more frequent for different indications, both in a purely aesthetic and therapeutic context. 

Indeed, PRP, by its strong presence and secretion of growth factor, allows to stimulate the regeneration of tissues by stimulating the production of collagen and stimulating the proliferation of fibroblasts, a biological stimulation that has been reported in many works, which allows a tissue renewal and a better quality skin.
From a therapeutic point of view, PRP has also demonstrated numerous benefits for certain pathologies such as androgenic alopecia.
Concerning the use of PRP in aesthetic medicine, the European Standard EN 16844:2017+A2 now defines all the requirements considered essential for the delivery of aesthetic medicine services (non-surgical medical treatments). 
This European Standard was adopted by the European Committee for Standardization (CEN) on 20 December 2017 and includes Amendment 2 adopted by CEN on 16 April 2019. 

This text specifies the level of risk according to the severity of possible complications. The risk levels are defined as follows:

A: Minimal risk (i.e., mild and transient signs/symptoms);
B: Mild disorders (i.e., moderate and transient signs/symptoms);
C: Cosmetic damage (permanent damage without functional restriction) ;
D: Disability (permanent damage with functional restrictions);
E: Death.

This standard qualifies platelet-rich plasma injections and comparable procedures:

  1. prepared in a closed system (like the Regen Lab process), Risk level A (minimal risk)

  2. and injections of platelet-rich plasma and comparable procedures, prepared in an open system, of risk level B.