Revolutionizing Medicine: Challenges & Future of Advanced Therapies

ADVANCED THERAPIES MEDICINAL PRODUCTS FRAMEWORK  

There is a continuous and rapid evolution in ATMPs research; every year an increasing number of clinical trials are started and new applications are found. 
An exponential development is expected in the near future, however, the effective potential of these therapies is not yet known. 

In 2009, REGULATION (EC) No 1394/2007 came into force in Europe to regulate the marketing authorization of these innovative therapies. This regulation defines four ATMPs categories: 

Somatic cell therapy medicinal product is a biological medicinal product which has the following characteristics: 

• Contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions, or structural properties relevant to the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor; 

• Is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing, or diagnosing a disease through the pharmacological, immunological, or metabolic action of its cells or tissues. 

This category also includes drugs produced from stem cells, capable of differentiating to form different tissues. 

Gene therapy medicinal product is a biological medicinal product which has the following characteristics: 

• Contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding, or deleting a genetic sequence; 

• Its therapeutic, prophylactic, or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence. 

There are two types of gene therapy, which differ in the route of administration: 

• In vivo - the "therapeutic gene" is administered directly into the patient's body, through an injection locally (target organ) or systemically (into the blood circulation); 

• Ex vivo - the correction occurs outside the patient's organism. The target cells are taken from the patient, genetically modified, and reintroduced into the patient himself. 

Genome editing techniques are part of gene therapy medicinal products, including the well-known CRISPR-Cas9 technique (Clustered Regularly Interspaced Short Palindromic Repeats, with CRISPR associated (Cas) gene 9). 

Tissue engineered product, which has the following characteristics: 

• Contains or consists of engineered cells or tissues (human or animal origin, or both); 

• Is presented as having properties for, or is used in or administered to human beings with a view to regenerating, repairing, or replacing a human tissue; 

• Contains cells or tissues of cells or tissues which may be viable or non-viable. 

Tissue engineered products may also contain additional substances, such as cellular products, bio-molecules, biomaterials, chemical substances, scaffolds, or matrices. 

Cells or tissues shall be considered ‘engineered’ if they fulfil at least one of the following conditions: 

• Are subject to substantial manipulation, so that biological characteristics, physiological functions, or structural properties relevant for the intended regeneration, repair, or replacement are achieved; 

• Are not intended for the same essential function or functions in the recipient as in the donor. 

This technique allows also to regenerate skin, bones and cartilage. 

Combined advanced therapy medicinal product, which has the following characteristics: 

• It must incorporate, as an integral part of the product, one or more medical devices or one or more active implantable medical devices;  

• Its cellular or tissue part must contain viable cells or tissues, or its cellular or tissue part containing non-viable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the devices referred to. 

FUTURE OF ATMPS IN POINT OF CARE MANUFACTURE 

The current human medicines legislation is geared towards traditional products which are manufactured at pharmaceutical companies’ sites (at one, or at a very small number of sites), with validated equipment, processes, and analytical methods: the manufacturing process is standardized and the finished product is analyzed according to predefined specifications and then released by the site’s QPs, for clinical or commercial purposes, and then supplied globally. 

Advanced Therapy Medicinal Products may have very short shelf-lives, or they may need to be highly personalized, so they must be manufactured on demand when the patient is present, likely in a health care facility or close to it. 

For these reasons, the strong need for a new decentralized production system has emerged in recent times. 

The Industry and Regulatory Authorities are thoroughly evaluating the advantages of decentralized production in Point of Care, which involves smaller production and flexible volumes in multiple locations, depending on the real need, also encouraging the development of personalized medicine. 

Along with the opportunities, just as many technical and regulatory challenges are being identified. 

The new regulatory framework will have to be based on the current regulatory systems for the approval of medicines and for clinical trials, with the essential evaluation of regulatory compliance at production sites and for safety monitoring. 

The safety, quality and effectiveness of the products manufactured at the Point of Care must be guaranteed, with the same levels required for manufacturing in pharmaceutical company sites, but there is a need for a certain flexibility and new strategies to obtain the required results, in a context different from the traditional one. 

New strategies are also necessary from a technological point of view, to guarantee a repeatable and consistent process across different sites to guarantee aseptic processing in a hospital context and to prevent risks of contamination and mix-ups in a healthcare facility where, ideally, different medicinal products can be manufactured for different patients. 

In addition to the challenges for the Industry, there will also be challenges for the Regulatory Authorities and there will be a need for new inspection strategies to authorize a very high number of centers, or "mobile" facilities, ideally in a short time, to meet the need to regulate production volumes based on requests.