To optimize industrial performance, SalamanderU has developed an integrated production unit under isolator with control via a voice-controlled electronic batch recording (EBR) system. Based on an industrial need, the company innovated on the material used, acrylic resin, and the voice control technology.

There is a need for optimization in terms of ready-to-use, quickly available and cost-effective production units. Two elements caught the attention of SalamanderU: first, the creation of production units under isolator using a material offering more flexibility, helping to guarantee longer integrity. The use of synthetic resins allows for the manufacture of custom-made isolators, so that all the equipment intended for production can easily be placed within the isolator. The second element of the integrated unit was control via a voice-controlled electronic batch record (EBR) system.

“In production, in the pharmaceutical sector, there is what is called a manufacturing record,” explains Claude Dedry, CEO of SalamanderU. “It is necessary to record all manipulations. Our system speaks the different stages of production using a voice synthesizer, while the operator announces aloud the treatments he is carrying out and what the results should be. The software, called SmartReg, records everything using voice recognition. This technology also makes it possible to perform calculations and generate optimized reports.”

The material used to manufacture the insulators is acrylic resin. Its flexibility and adaptability allow for the production of tailor-made insulators that are more robust than stainless steel and can be adapted to the manufacturing process.

Case study: RevaTis

RevaTis is a spin-off from the University of Liège (Belgium), founded in late 2013 and dedicated to advanced regenerative veterinary medicine and cell therapy. The company's growth is driven by its innovative and patented technology for obtaining pluripotent adult mesenchymal stem cells from minimally invasive muscle microbiopsy.

As part of its development and with a view to cost control strategy, it turned to a complete "turnkey" system that includes the quality management system and electronic batch recording. Everything is GMP compliant, and the isolator-based production unit is flexible and adaptable over time. The benefits shared by RevaTis are fourfold.

The strategy

In the animal sector, autologous cell therapy products have high production costs, so reducing these costs is a priority. With only one full-time equivalent in the integrated unit thanks to the voice-controlled EBR, human resource optimization is real. Furthermore, to ensure the sustainability of the integrated unit, it is necessary to be able to evolve the design with the development of the process and to use stable materials for as long as possible.

Project implementation

The flexibility of the construction material enabled agile project management. Implementing the insulator directly on site, with a 3D wooden mock-up, and the ability to cut it on site, ensured an optimal design the first time. The EBR and its MBR (Master Batch Record), including reduced IT interfaces, were deployed in a production room for five users in six weeks, from design to full qualification.

Routine mode

Voice interfaces are perceived as very user-friendly and intuitive. They contribute to user confidence, with the added bonus of less stress during a critical operation such as calculations. They also improved confidence for supervision and QA because SmartReg acts as a pilot. Users were very satisfied with the ease of use and the adaptability of the insulator material, allowing modifications until the end of the project. The system was thus fully aligned with their needs, evolving over time and during development.

The authorities

The authorities' response was less critical than expected, and the validation plan met GMP requirements. This building material is fully compliant, and the inspection raised no concerns.

A digital management solution: SmartReg

The creation of Master Batch Records (MBR) and the completion of Batch Records (BR), which contain information on premises, equipment, personnel, raw materials, operations and calculations performed, design qualification (QC) results, environmental monitoring results, etc., are examples of complex and dense processes, often considered too time-consuming and inefficient. Many companies still currently use these paper-based documents to collect huge volumes of data. Automating these processes would ease the administrative burden on the manufacturer, significantly reducing batch record management costs and reducing time to market.

In this context, a first step towards automation is to replace paper documents with electronic ones. Electronic batch recording (EBR) offers several advantages:

• an increase in the number of operations deemed “right the first time”;
• easier access to data, for example faster retrieval of information using search functions, a particularly interesting advantage during audits;
• faster data encoding and recording;
• easier and faster of these;
• reduced paper costs and irradiation costs in aseptic operations;
• an assurance of reliable traceability;
• a review of batch files by exception by quality assurance;
• support for sequential orientation of the operator throughout the manufacturing process;
• more efficient decision-making, with operators immediately informed of any deviations.

Despite the proven improvement in the transition from paper to electronics, traditional EBRs still require operators to use their hands to record data, leading to discomfort and frequent errors, especially when working in a sterile environment. Operators can now be accompanied by an intelligent pilot that guides them verbally and automatically records all actions on the operations they perform.

The proposed solution is a web-based voice-controlled EBR (speech recognition and speech synthesizer) that speaks to operators in their own language and listens to them, greatly simplifying manufacturing and recording operations. Instead of reading what is written in the BR, the operator listens to what the voice-controlled EBR tells them to do, and instead of writing down all the results of each operation step, the operator simply announces aloud what result they have obtained. The traditional stylus or keyboard is replaced by the operator's voice. The voice-controlled EBR thus acts as an infallible pilot that guides the operator through the operating steps.

Of course, it will also retain all the features of classic EBRs, but it could introduce other useful attributes, such as easy and intuitive preparation and validation of master batch records (MBRs), allowing rapid creation of BRs, and more.

This innovation multiplies the expected benefits of a traditional EBR, both in terms of optimizing resources allocated to this activity, but also in terms of quality and compliance. Implementation within an integrated unit is rapid and the benefits perceived by users are significant, as seen in the RevaTis case study.

Acrylic resin, an innovation in the insulator sector

Today, stainless steel is used as the main material in the manufacture of cleanroom equipment (work benches, chairs, shelves, etc.). However, it can suffer from corrosive degradation, mainly due to the types of cleaning and disinfection products used. Furthermore, it is not an easily adaptable material in the event that a shape change is requested by the equipment's users, or in the event of the integration of new equipment necessary for the manufacturing process.

On the other hand, acrylic resin has shown suitable characteristics when it comes to shaping modification capacity and has already been widely used in the manufacturing of kitchens, office equipment, etc.

Its characteristics (smooth finish, easy adaptability, etc.) make it easy to clean, it does not diffuse particles, and various other materials (glass, stainless steel, etc.) can easily be connected to it, allowing the integration of pharmaceutical process equipment. These very interesting characteristics make it an attractive candidate as a material for cleanroom equipment.

It should be added that manufacturing units should include all the equipment necessary for carrying out operations, controlling process parameters and the environment. In addition, they must maintain their integrity and withstand repeated disinfection cycles (H2O2 for example).

Ergonomics is also important: operators must feel comfortable working in the isolator. Finally, the units sometimes need to be mobile. This is the case, for example, when drugs to be used in clinical trials have a short shelf life.

Acrylic resin, or polymethyl methacrylate (PMMA), appears to be a suitable material for the construction of custom manufacturing units. It is an amorphous polymer with a glass transition temperature of 110 to 135 °C. It can be molded and is extremely rigid.

An internal study, sponsored by the Department of Development Technologies of the Walloon Region of Belgium, compared it to 316L stainless steel. The results are given in the rest of the article.

Contact with cleaning and disinfection agents

The PMMA and 316L stainless steel samples were kept for three months in Actril, Hexanios, IPA and VHP (H2O2 35 %) samples. A notable alteration was observed in the stainless steel samples soaked in the VHP solution: rust spots were found on both sides of the steel, on the section of the non-immersed samples and on the edges, while no visual effect was observed on the PMMA samples.

Roughness

The roughness value Ra of PMMA and 316L stainless steel samples was measured.

When polishing PMMA samples with N4000 emery paper for 5 minutes or more, the Ra value of PMMA is equivalent to that of electropolished stainless steel.

Products used in cell culture manufacturing

The objective of the test was to verify that PMMA can be cleaned in the same way as 316L stainless steel, starting from fouling by colored raw materials commonly used in cell therapy laboratories and clean rooms. The following colored raw materials were used: Alizarin Red (1,2-dihydroxyanthraquinone), blood, fetal bovine serum (FBS), trypan blue, and trypsin. PMMA and 316L stainless steel are equivalent: dyes can leave traces in both cases. However, when using PMMA, there is a solution to solve staining problems, which cannot be used on stainless steel. Indeed, periodic polishing (e.g. every
every six or twelve months) of the surface can remove any remaining stains and return the resin to its original color without damaging its surface.

Resin/material compatibility

The joining of materials commonly found in cell therapy or cell culture insulators (e.g. stainless steel, glass, glove rounds) with PMMA acrylic resin is feasible.

Waterproofing

The purpose of this test was to demonstrate that a PMMA insulator can maintain an internal pressure of 150 pascals, just like a 316L stainless steel insulator. This means that the resin and its connection with other materials do not generate any leaks. The results show that the PMMA insulator is leak-proof and that PMMA is suitable for the construction of insulators in which a positive pressure must be maintained.

Mechanical limits: hardness and scratch tests

Resin is not as hard as 316L stainless steel, and the impression mark left by scratching in resins is larger than that left in stainless steel. Periodic polishing (e.g., every six to twelve months) of the surface is recommended to remove any scratches appearing on the working surfaces of the insulator.

Study results

The results of the study indicate that PMMA has more advantages than 316L stainless steel for the construction of buildings and manufacturing units. Indeed:

• it can be molded (important to adapt the units to the needs, to encompass all the equipment and for ergonomics); • it is totally resistant to disinfection products such as H2O2;
• it has the same roughness as electropolished stainless steel;
• it is comparable to 316L stainless steel for cleanliness, but unlike the latter periodic maintenance by repolishing the PMMA surface can remove residual stains;
• it is easily repaired by simply repolishing the surface, even if it is softer and easier to scratch than 316L stainless steel;
• It can be assembled without welding.

Conclusion: the expected benefits of the integrated unit

• Accelerate the availability of manufacturing units while ensuring they operate according to the needs of users (full control of recipes) and authorities through digital solutions that must detail the process steps and sequentially guide operators through operations. In this context, the use of a voice-driven and tailor-made electronic batch recording (EBR) system is necessary. It will be supported by a manufacturing execution system (MES) also linked to an electronic document management (EDM) system and systems that control all equipment (including environmental control equipment).
• Make operations more reliable by providing operators with real-time work instructions consisting of text, diagrams, images and videos, the aim being to drastically reduce human errors.
• Optimize resources by automating the completion of batch registration forms using voice recognition and avoiding the need to complete them by hand or via a keyboard or computer tablet, while ensuring complete traceability of operations.
• Reduce drug release time and increase process reliability by automatically generating batch records in which certain critical issues are highlighted (e.g. nonconformities, deviations, critical steps, etc.).
• Reduce validation time because solutions are based on a generic version that is qualified at the supplier's premises so that the focus remains on performance qualification. Interfaces with existing IT equipment must be qualified on-site.
• Ensure data integrity.
• Maximize manufacturing infrastructure by using a structure that is both flexible in the integration of process equipment and adaptable over time with the ability to adjust the material.
• Maintain your production tool over time by the possibility of upgrading (polishing) the acrylic resin and reduce maintenance costs thanks to the material being more robust against decontamination.
• Reduce contamination risks by using custom-built integrated decontamination units.

This article is published in Clean Rooms No. 121, pages 38-42.