1. Manufacturing of ATMPs

The European Regulation 1394/2007 defines advanced therapy medicinal products (ATMPs) as products used to restore, correct or modify physiological functions primarily through a pharmacological action.

The ATMP manufacturing process for clinical use must comply with the principles of good manufacturing practice (GMP) to determine how cell preparations are produced and controlled, from the collection and handling of raw materials to the processing of intermediate products and quality controls, storage, labeling, packaging and release.

GMP Annex 1 describes the appropriate classification required and assigned to pharmaceutical manufacturing areas, depending on the type of operations taking place in the facility:

• Grade D: Represents a clean area where the less critical stages of sterile manufacturing take place.
• Grade C: This area is accessible from Grade D and is associated with a clean area designated for less critical stages in the production of sterile products. Grade C requires higher air and particulate and microbiological surface quality than Grade D, while sharing similar temperature and relative humidity control.
• Grade B: For aseptic preparation and filling, this is the base environment for Grade A. Air pressure differences must be constantly monitored. Requires higher air and microbiological and particulate surface quality than Grade C, while sharing similar humidity and temperature control. Environmental contamination conditions must be constantly monitored.
• Grade A: an area of high-risk operations requiring aseptic conditions (e.g. filling, opening and closing of containers, such as vials or test tubes). These conditions are usually ensured by a homogeneous laminar airflow in the work environment and are monitored throughout the critical processes.

The guidelines also define two types of system in which aseptic production of drugs (in general and of ATMPs in particular) can take place:

• The open system is defined in general as an aseptic preparation and filling area in which the product is exposed to the environment and operator (for example when the product is handled in a laminar flow cabinet) ; in this case, according to the GMP guidelines, a grade A critical clean area inserted in a grade B background clean area is required (AinB).
• The closed system, on the other hand, involves the use of a physical barrier that absolutely separates the operator and the environment from the area in which the product is handled (Grade A Isolator); in this case, it is accepted that the background environment where the isolator is installed, is, always according to GMP guidelines, of Grade D (AinD).
• Due to its enormous complexity, the production of ATMPs has quite high costs, which mainly consist of direct costs, such as reagents, materials and products, garments, personnel and costs related to quality controls. However, this production has a significant impact also on indirect costs, which are related to qualifications and validations (e.g. media filling, cleaning and environmental controls) and to the entire structure, including energy costs, air conditioning costs, HVAC systems and environmental validation.

2. Methods

The analysis of the difference between open and closed systems was performed by comparing the Cell Factory of Regina Margherita (open system Figure 1) and the Centre de Production Cellulaire (CPC) located in Epalinges (closed system Figure 2) and belonging to the University Hospital of Lausanne (CHUV).

• Annual energy supply for ventilation of the controlled environments (kWh);
• Annual energy supply for the installed equipment (kWh);
• Costs of the twenty-one-day production cycle (in EUR);
• Greenhouse gas emissions (in CO2eq);
• An estimate of the construction costs for the open and closed systems.

The energy costs related to each controlled environment in the open and closed system were calculated based on the different surfaces and environmental classifications of the two Cell factories and the related hourly air changes.

The total air volume changes for each controlled environment in both open of 271m² and closed system layouts (108m²) have been calculated based on the different surface areas of the two CFs and the relevant Grade air changes per hour:

• Grade B: 55 changes per hour and
• Grade D: 35 changes per hour.

3. Cost analysis

A production cycle of 21 days/cycle was considered in both the open and closed systems.

These costs, provided by the Regina Margherita hospital for the open system, were divided into indirect and direct costs as follows:

• Indirect costs for the structure (Lighting/electricity of the equipment  ; Air conditioning/HVAC system ; Environmental validation; Annual qualification tools and products.)
• Indirect costs for production (Media filling for two operators ; CF cleaning (biocides + clothing) ; Qualification of the qualified operator’s dressing ; Qualification of the external operator’s dressing ; Material flow ; Environmental controls (monthly).
• Direct costs for production : Biocides ; Dressing ; Personnel (cost man/hour).

The data were measured in same season. However, the advantage using a closed system remains because the volume of fresh air which is thermally treated, at every cycle, is higher for the open system than for the closed system and therefore the energy consumed will be correspondently higher for the open system.