Good practice in the preparation of human blood-derived biological products such as Platelet Rich Plasma (PRP)
Antoine TURZI.
President of REGENLAB
President of REGENLAB
New innovative therapies characterized as autologous (organic substance whose donor and recipient are the same individual) are now on the market.
Their preparation depends on the use of medical devices that enable them to be prepared in a way that minimizes the risks of contamination and infection, and standardizes the preparation steps.
Here, we focus on the preparation of human blood-derived biological products for therapeutic purposes, and more specifically on the preparation of platelet-rich plasma.
The preparation of platelet-rich plasma is still carried out illegally in some hospitals, clinics and private practices, in breach of the intended use of certain diagnostic devices.
In fact, these devices are intended solely for diagnostic use in patients, and not for medical use: i.e., not for reinjection of this biological material into patients.
There are many reasons for this. These include the need for patient safety and proven clinical evidence.
In vitro diagnostic (IVD) tubes cannot therefore be used for the preparation of platelet-rich plasma, as they do not meet the necessary requirements to minimize the risk of side effects once the biological product has been injected into the patient.
These requirements include compliance with ISO10993 standards (Biological Evaluation of Medical Devices), which list numerous tests such as biocompatibility, pyrogenicity and chemical characterization.
In order to be used on a patient, the Medical Device must comply with the European Medical Device Regulation (MDR) 2017/745.
This is why one of the leading manufacturers of in vitro diagnostic tubes, Becton & Dickinson, has issued an official communication (Image below) explaining that the preparation of Platelet Rich Plasma must be carried out using medical devices that comply with the aforementioned international Regulation.
When it comes to the safety of a biological preparation derived from human blood using medical devices, such as PRP, there are several parameters and stakeholders to consider.
THE MANUFACTURER
The manufacturer of Medical Devices must :
1. Have a Quality Management System compliant with ISO 13485:2016, meeting the requirements of Directive 93/42/EEC in the past, with a grace period not to exceed 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 program (Medical Device Single Audit Program), following on from the CIH (International Conference on Harmonization set up in 2001!).
This single audit program for Medical Devices is recognized by the authorities of the 5 participating countries: Australia, Brazil, Canada, Japan and the United States.
As of January 1, 2019, Canada has made the MDSAP mandatory. The United States, Brazil, Australia and Japan are expected to follow suit. Europe is currently only an observer to the program.
2. To certify its Medical Devices according to the European Regulation (MDR (EU) 2017/745) on Medical Devices, which replaces Directive 93/42 EEC (MDD) on medical devices and Directive 90/385/EEC on active implantable medical devices. 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).
3. to provide a Technical File for each medical device, in line with the new MDR 2017/745 requirements, which includes the device's technical and functional specifications and a Clinical Evaluation Report (CER) carried out with its medical device(s), making it possible to prove their therapeutic efficacy/s and safety for the patient in the recognized therapeutic indications.
4. To set up a Post-market Surveillance Plan concerning the safety of the Medical Device throughout its life cycle.
This plan also includes Post-Market Clinical Follow-up to continually monitor and demonstrate certified clinical claims.
REQUIREMENTS FOR BIOLOGICAL PRODUCT PREPARATIONS E.G. PLATELET-RICH PLASMA (PRP)
Sterile medical devices designed and certified by a notified body and recognized in accordance with MDR Regulation 2017/745/ EEC.
A closed-circuit preparation system, with minimal handling and at the patient's bedside (extemporaneous use), in compliance with strict asepsis techniques to guarantee sterility of collection and administration whatever the indication of use.
PRP must be used for a single medical intervention, without being stored or prepared elsewhere in a third-party facility.
The act of collection must be performed by, or under the supervision of, a physician, and PRP-based injections must be carried out by a physician.
The concept of bioequivalence cannot be applied to biological preparations derived from human blood for therapeutic purposes, as each medical device has its own specific characteristics in terms of cell isolation and therapeutic performance.
According to the French Public Health Code, legislative parts, articles L 1211-8 and 1242-1, autologous blood sampling for therapeutic purposes is authorized on condition that the samples are taken in compliance with the rules of Good Preparation Practices.
Taking into account these various regulations and international standards, the preparation of blood-derived products, and more specifically the preparation of platelet-rich plasma, can only be carried out using class IIb or III Medical Devices, certified and validated for this use.
Thus, preparations using In Vitro Diagnostic devices (devices intended to be used solely in vitro for the examination of biological samples with the aim of providing patient information) subject to the new IVD 2017/746 standard, are prohibited for the preparation of PRP :
IVDs are not subject to biocompatibility and pyrogenicity tests in accordance with ISO 10993-1 to 23.
IVD devices, cannot be promoted or used in medical use as they do not comply with the safety and clinical evaluation prerequisites according to MDR 2017/745.
Their contents, even if sterile, cannot be re-injected into the patient.
IN CLINICAL PRACTICE
The use of medical devices for the preparation of "Platelet-Rich Plasma" is becoming increasingly common for a variety of indications, both purely aesthetic and therapeutic.
PRP, with its high presence and secretion of growth factors, stimulates tissue regeneration by stimulating collagen production and fibroblast proliferation, a biological stimulation that has been reported in numerous studies, resulting in tissue renewal and better-quality skin.
From a therapeutic point of view, PRP has also demonstrated numerous benefits for certain pathologies, such as androgenic alopecia.
With regard to the use of PRP in aesthetic medicine, European Standard EN 16844:2017+A2 now defines all the requirements deemed 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 December 20, 2017, and includes Amendment 2, adopted by CEN on April 16, 2019.
In particular, the text specifies the risk level of treatments according to possible complications.
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: Aesthetic damage (permanent damage without functional restriction);
D: Disability (permanent damage with functional restrictions);
E: Death.
This standard classifies platelet-rich plasma injections and comparable procedures, prepared in a closed system (such as the RegenLab process), as risk level A (minimal risk), and platelet-rich plasma injections and comparable procedures, prepared in an open system, as risk level B.
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