Pharmaceutical technology of advanced-therapy medicinal products 

Regulatory issues

In November 2007, the European regulation CE 1394/2007 creates a new class of biological medicinal products: the advanced therapy medicinal products (ATMP). This new regulation:

• Is lex specialis that modifies the existing community codes and procedures in particular: the directive 2001/83/EC on the Community code relating to medicinal products for human use than the regulation (EC) n° 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency;
• Institutes the "Committee for Advanced Therapies" (CAT) with particular responsibility for the classification of these products and the evaluation of authorization marketing dossier;
• Confirms the innovative character of drugs somatic cell therapy and gene therapy medicinal products;
• Institutes a legal definition of the products of tissue engineering and combined advanced therapy medicinal.

This regulation was transposed in French law by:

• Article 8 of Law No 2011-302 of 22 March 2011 containing various provisions of adaptation of legislation to the law of the European Union on health, labor and electronic communications;
• Decree No. 2012-1236 of 6 November 2012 on advanced therapy medicinal products, whose purpose is the "procedure and conditions for authorizing establishments manufacturing advanced therapy medicinal";
• Article L. 4211-9-2 of Law No. 2016-41 of 26 January 2016 modernizing the French healthcare system allowing, in derogation in the context of biomedical research, health care institutions, non-pharmaceutical, who have an authorization of ANSM to ensure the manufacture, import, export, distribution and exploitation of ATMP.

Furthermore, the Regulation defines two exceptions:

• « The ethical exception » in which the regulation of advanced therapy medicinal products at Community level should not interfere with decisions made by Member States on whether to allow the use of any specific type of human cells, such as embryonic stem cells, or animal cells. It should also not affect the application of national legislation prohibiting or restricting the sale, supply or use of medicinal products containing, consisting of or derived from these cells;
• And « the hospital exemption » creating the ATMP which is prepared on a non-routine basis (ATMP-pnrb) according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient, transposed in French law by:
• The order of 4 February 2013 fixing the content of applications for initial authorization, authorization renewal or amendment ATMP prepared on a non-routine basis and institutions or organizations which prepare these products may not be pharmaceutical;
• The decision of 20 May 2015 on the principles of good practice for preparation, storage, distribution and sale of ATMP prepared on a non-routine basis set at 17 ° of Article L. 5121-1 of the code of public health returns to the application of GMP.

At last, it does not derogate from the fundamental principles of the Directive 2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells, but introduces additional requirements.
Thus, Directive 2004/23 / EC applies to the donation, procurement and testing, tissue or cells to be used as starting material for the production of ATMP, but also for cell therapy preparations that are not medicinal products because they:

• Have not undergone substantial manipulation AND;
• are to be used for the same essential functions in the recipient and the donor;
• They have specific best practices described in the decision of 27 October 2010 rules of good practice for the preparation, preservation, transport, distribution and disposal of tissues, cells and cell therapy preparations.

What effects on hospital pharmacy?

Different cases defining the level of the pharmaceutical support or not are possible depending on i) whether an ATMP or ATMP-pnrb, ii) that it is part of a marketing authorization or as part of a clinical trial, and iii) whether a gene therapy medicinal product or not. Cell therapy preparations, used mainly in the context of hematological for « bone marrow transplant » are not, to date, in the pharmaceutical field.

The different levels of pharmaceutical care in conditions and/or with more or less normal operations in hospital pharmacy are:

• The circuit of medicinal product with:
• The reception, which can impose respect the regulatory requirements of the donation (Directive 2004/23 / EC) and its qualification if it is to produce an experimental drug as part of a clinical trial;
• Conservation may impose special conditions if the medication needs to be cryopreserved in nitrogen want it to be part of a marketing authorization or clinical trial of an ATMP or ATMP-pnrb;
• The dispensation which need a thawing operation for the same reasons mentioned in the previous point;
• At last, as part of a gene therapy medicinal product, marketed or in clinical trial will require the circuit of medicinal product takes into account the containment requirements including for waste if necessary.

• The production is optionally performed in the context of a clinical trial. It may require:
• The support of the donation, in compliance with the regulations of the gift mentioned earlier, with the entry of this potentially contaminated raw material in a controlled atmosphere zone;
• The application of « transformations » of the donation as: The substantial manipulation mentioned in Annex I of EC Regulation 1394/2007: cutting, grinding, shaping, centrifugation, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, cell separation, concentration or purification, filtering, lyophilization, freezing, cryopreservation and vitrification. But also trypsinization or another method for separating cells, plasma removal, erythrocyte removal, thrombocyte removal, genetic modification and thawing;
• Of course, the use of microbiological safety cabinets in controlled atmosphere zones in accordance with the recommendations of GMP;
• Packaging and labeling that it will comply with the recommendations of the guideline 13 GMP concerning the production of experimental drugs will also comply with the regulatory requirements of the donation (Directive 2004/23/EC) in particular for somatic cell therapy medicinal products for sampling the steps of receiving and storing;

- The quality control that can be qualified for a part of analytical biology because using analytical techniques such as multiparameter flow cytometry, high-throughput sequencing, technical "omics" and analysis of massive data generated by these high-throughput techniques.

• The vigilance :
  Although ATMP and ATMP-pnrb are medicinal product depend on pharmacovigilance, the multiplicity of materials used and their different status also requires the use of two other vigilances that are: biovigilance under the regulation of donation and Although MTI and MTI-pp is the medicine depend on pharmacovigilance, the multiplicity of materials used and their different status also requires the use of two other vigilance that are: biomonitoring under the regulation of donation and the vigilance of medical device.

So, this new regulation and the ATMP bring new challenges for the scientific and medical world, in particular for hospital pharmacy. Indeed, the European Parliament creates them to consider in his first argument that: « New scientific progress in cellular and molecular biotechnology has led to the development of advanced therapies, such as gene therapy, somatic cell therapy, and tissue engineering. This nascent field of biomedicine offers new opportunities for the treatment of diseases and dysfunctions of the human body. » Then, the hospital pharmacy and the pharmacists have to keep up to imagine and to build a « biopharmacy » for go with, for complete and for support the huge hopes of this « biomedicine ».