Single use components may simplify the design of manufacturing plants, the execution of cleaning procedures and reduce the risk of cross contamination and the global costs of production
Single use technologies (SUT) are coming more and more central in modern pharmaceutical manufacturing design, as they may improve the change towards new production’s models characterised by enhanced safety and simplified operations. The overall efficiency of the process, including reduction of manufacturing costs, is a driver pointing towards the adoption of single use technologies, even though doubts still remain about some practical aspects. The implementation of SUT systems requires a deep study of the manufacturing layout and possibly some modifications of the already existing installations.
«The word “revolution” is often referred to single use technologies, as they introduce very innovative elements compared to the traditional approach», explains Marco Sanvito, Marketing Manager of Pall Corporation BioPharmaceuticals Division. Pharmaceutical plants based on traditional steel solutions requires additional activities to set up and maintain the production line: activities that are not needed with SUTs. «If properly evaluated, the overall costs are lower than the current situation because the cost of goods decreases. They are not if you compare only the costs of consumables», adds Sanvito. A good production desing need to take into consideration and quantify all the activities that are currently necessary, but shall not longer be while improving single use technologies. Costs’ evaluation should include the items summarized in Table 1.
Cleaning and cross contamination
One of the most relevant features of single use technologies is the central role they may play to avoid cross-contamination, a typical issue arising during shifts from one production campaign to the next or from one batch to the next. SUTs are closed, ready-for-use systems sterilized by irradiation before supply. «This characteristic greatly reduces the potential risk of microbiological contamination, which is traditionally linked to the sterilization steps run in-house pre-use, assembly and post-use cleaning – tells Marco Alberio, Engineering, Maintenance & EHS Manager of Pharmintraco and board member of ISPE Italy Affiliate. – SUTs are not “operator dependent” and their plug-and-play technology avoids errors during the assembly steps». The number of connections needed in single use technologies-based manufacturing lines is very low if not absent since kits are pre-assembled and tested for integrity by the supplier. With the traditional design, for example, the assembly of transfer systems for solutions in a filling line are highly depended from the manual skills of the operators. «Today we need simply to connect the single use kit to the existing system, virtually eliminating all mistakes linked to the preparatory phase», adds Alberio. The pre-assembled systems also allow to reduce the time needed to build and operate a new facility or a new line compared to a traditional steel one. «This is very important, for example, for a contract manufacturer. Furthermore, the use of SUTs allows to arrange dedicated lines for each customer: if we consider a mixer or a dissolver, there is just need for a common hardware in order to accommodate different customers, each of which shall have its dedicated mixing bag», tells Sanvito.
A different layout for manufacturing
Single use technologies have introduced the possibility to design modular production plants. “Ballroom” and “dance floor” are terms which have entered the common technical language to identifying respectively (according to the definition of Wolton and Rayner, Pharmaceutical Engineering, vol. 34, n . 4, 2014) “a large manufacturing that has no fixed equipment and minimal segregation due to the use of functionally closed systems” and “a smaller and more defined space, is being considered as an alternative to the ballroom’ concept”, where single use production modules are placed and operate.
The compatibility of existing filling systems with single-use elements needs to be checked, explains Marco Sanvito: «The use of SUTs which integrate with aseptic filling systems within isolators shows a consistent trend of growth». Final filling systems often need to be adjusted in order to fit with single use technologies, further tells Marco Alberio: «Filling systems, as the time-pressure ones, for example, are not suitable for SUTs. Today the single use technologies cover upstream, downstream and formulation & filling applications: bioreactors, and bi- or tridimensional containers for storage, delivery and formulation are available, as well as sterile connectors and disconnectors, depth and sterilizing filters, chromatography membranes, beta bags for insulators, needles for final filling. Plastic valves able to undergo the “steaming in place” process (SIP) represent, for example, a link component between traditional systems and SUTs».
The regulatory point of view
The use of single use technology in the general framework of commercial scale GMP manufacturing is the new challenge for the pharmaceutical and biopharmaceutical industry, as its implementation would allow to increase the manufacturing capacity while reducing the extension of the facilities, including grade A manufacturing plants. «The issue – explains Alberio – could relate to the changes made to already existing manufacturing process, as such a variation would result in the request of new validation studies».
From the regulatory point of view, international agencies are very positive towards the adoption of SUTs, an event that would require changes to the regulatory dossier of the medicinal product with respect to the manufacturing process. «International regulatory authorities ask to assess the impact of single use systems on the product. Validation should assess compatibility and the presence of the so called extractables or leachables», further tells Marco Sanvito.
Extractables and leachables
The term extractables identify known additives, their degradation products, oligomers and polymers. Extractables are the result of a worst case situation, where a contact occurred between plastic materials and model solvents under conditions worse than those of the real process.
Leachables are known extractables and extractables modified as a result of product formulation (a very rare event). They are the result of the contact between plastic materials and process solution, under normal process conditions. They are usually part of the extractables pool.
BPSA, Recommendations for extractables and leachables from single-use systems
There are several reference guidelines available, even though some are not specific for single use technology (Table 2), as for example, the one describing requirements for materials in contact with the product. PDA TR 66 is a specific publication entirely dedicated to the evaluation and adoption of single use technology.
To achieve validation, single use components have to meet some minimum requirements, among which, for example, the compliance to USP Class VI biocompatibility, the execution of studies to identify the extractables core, the characterization of the chemical-physical properties and the availability of functional tests. «The risk assessment should take into consideration the generic data that characterise the SUT systems, to check if that are applicable to the specific case and application. Any gap should be filled by running specific tests. The debate is ongoing between users and suppliers about minimum data requirements, and it involves organizations such as the Bioprocess Systems Alliance (BPSA) and the Bioforum Operations Group (BPOG)», comments Sanvito.
Many advantages and some disadvantage
Single use technologies holistically optimize the manufacturing process: the increased productivity and sterility, the containment of the product, the reduction of overall manufacturing costs and the safety for environment and operators are the main advantages of the method. The economic value of the products is a fundamental parameter to assess the real economic advantage potentially deriving from SUTs. Lot size, number of batches per year and total number of different products should be also considered. «The drawbacks, excluding the non-applicability to certain lines, are often not so real as they are perceived. A proper evaluation of SUTs has to look at the whole process. A decrease of flexibility in the choice of alternative suppliers is one possible disadvantage, since validation activities involve costs to be afforded for a second time in the case of change», tells Alberio.
High value products are often linked to difficult cleaning procedures, risk of cross-contamination and high disposal costs, together with the possible reduction of the environmental impact and of energy consumption and the disposal of waste water resulting from the process. The adoption of single use solutions could become very interesting in such instances. «SUTs increase solid wastes – tells Sanvito – but this contribution is negligible and plastic materials might undergo recycling or be used for energy production».
The key to fully understand the potential impact single use technologies is linked to the extreme flexibility they can offer. Persistent doubts include the integrity of SUT systems such as biocontainers, the reliability of the supply chain, how to manage extractables and leachables and, not least, the fear of becoming dependent on just one supplier. «Tools are available to test the system for loss before use SUTs. There is no doubt that suppliers play a key role, even more than with conventional technology. Activities and responsibilities, such as the validation of g-ray sterilization, have to be delegated to them, something that might be perceived as a limitation», says Marco Sanvito.
«The impact and flexibility of single use technologies may be optimized through a reasoned approach, assessing the adoption of this technology from different perspectives», concludes Marco Alberio.