If Industry 4.0 or smart industrial technologies become more widespread, they could help reduce operational costs and administrative burdens for manufacturers.

Pharma 4.0 is now an unavoidable reality that offers many benefits, such as online, real-time control of manufacturing operations and faster decision-making (1-2). However, investing inappropriately carries risks; it is strongly recommended to invest in technologies that are tailored to the needs of the company, that is, those that provide the most effective solutions to the problems encountered. Peter Guilfoyle writes: “The potential of Pharma 4.0 is so vast and so broad that many pharmaceutical companies rushing to adopt this technology do not first take the time to determine the fundamental objectives they seek to achieve and the main problems they are trying to solve.”

Launching a digitalization project requires choosing an approach based on the expected benefits. However, all biopharmaceutical companies have at least two common goals: reducing operational costs in the supply chain and reducing the administrative burden of data recording. Investing in Pharma 4.0 technologies should aim to achieve these objectives.

Purchase of Pharma 4.0 technologies

If used for the manufacture of sterile products, manufacturing and fill/finish (F/F) units must be designed so that all operations are carried out in Grade A GMP environments and include all equipment necessary for the manufacture or filling of finished products. The units must also contain all equipment necessary for the control of process and environmental parameters, and must withstand extensive use of decontamination products.

Manufacturing flexibility is essential because processes are constantly evolving. It is important that F/F units can be modified easily and quickly to adapt to these changes. Flexibility is also essential for integrated decontamination units; it must be possible to decontaminate one section of the unit while continuing to work in other sections.

F/F units must be coupled to a system that sequentially guides operators through the steps of the operation. They must also be connected to an electronic document production system that provides operators with appropriate work instructions in the form of text, diagrams, images, and/or videos. The units must also be coupled to all equipment used for process and environmental control, as well as for decontamination.

With many companies still using paper-based Master Batch Records (MBRs) and Batch Records (BRs) to collect large volumes of finished product and end-use data and to comply with regulatory traceability requirements, MBR control and BR entry are notoriously time-consuming processes. Automating them with technology that eliminates manual, keyboard, or tablet entry is necessary to significantly reduce BR costs and accelerate the product release process.

To ensure product quality, it is also essential to be able to monitor manufacturing processes, environmental parameters, and disinfection cycles remotely and in real time, especially when operations are carried out by CMOs. In some cases, manufacturing, packaging, and packaging units must also be mobile.

Design of intelligent M/F&F units

The design, manufacturing, and validation of such smart units require innovative thinking. The use of unconventional materials and the development of innovative software solutions are prerequisites for the design of smart M/F&F units.

Custom-made flexible units

As mentioned earlier, M/F&F units must include all the equipment necessary to carry out operations and control process, environmental, and disinfection parameters. They must, of course, maintain their integrity and withstand disinfection cycles (H₂O₂) over the years. Ergonomics is also important; operators must feel comfortable working with the unit (isolator).

Nowadays, stainless steel is the main material used for the manufacture of isolators. However, stainless steel corrodes due to frequent contact with cleaning/disinfecting agents such as H₂O₂; moreover, it does not offer sufficient flexibility if the unit's shape needs to be changed at the user's request or if new equipment needs to be integrated (some operations have evolved or are automated).

Polymethyl methacrylate (PMMA) is a more suitable material for the construction of custom M/F&F units. One study compared PMMA (an amorphous acrylic resin) to 316L stainless steel (3). The following tests were conducted during this study:

Contact with cleaning and disinfecting agents: PMMA and 316L stainless steel samples were stored for 3 months in Actril, Hexanios, IPA, and VHP (H₂O₂ 35 %). Significant alterations were observed on the stainless steel samples placed in VHP, while no visual adverse effects were observed on the PMMA samples.

Roughness: After polishing PMMA samples with No. 4000 grit sandpaper for five minutes or more, the PMMA Ra val's wear resistance is equivalent to that of electropolished stainless steel.

Fouling by products commonly used in cell culture manufacturing: PMMA and 316L stainless steel are equivalent, as, depending on the colorant, traces may remain in both cases. However, when using PMMA, a solution not applicable to stainless steel can resolve staining problems: surface polishing, which removes any residual stains and restores the resin to its original color without damaging its surface.

Leaktightness: The results show that the PMMA insulator is leaktight and that PMMA is suitable for the construction of insulators requiring the maintenance of positive pressure.

Mechanical limits based on hardness and scratch resistance tests: 316L stainless steel and PMMA are not equivalent in terms of hardness and scratch resistance. Resin is less hard than 316L stainless steel. Periodic surface polishing is recommended to remove any scratches appearing on the working surfaces of the insulator.

Study results: Moldability and ease of assembly (weld-free) indicate that PMMA is more suitable for the construction of M/F&F units than 316L stainless steel.

Electronic and paper batch documents

Many companies still use paper-based MBRs and BRs to collect large volumes of data. Automating these processes would reduce the administrative burden, significantly reducing BR control costs and product delivery times.

A first step towards automation is replacing paper documents with electronic ones. Electronic batch records (e-BRs) offer many advantages (4). Unfortunately, they do not solve one of the main problems faced by operators working in aseptic environments: they still have to use their hands to record data, which generates discomfort, wasted time and frequent errors.

voice-controlled e-BR

It is time to take a real step forward in the control of MBRs and BRs by adopting a solution that allows us to forget the days when operators had to read and write, and which offers them the support of an infallible pilot who guides them orally and automatically records all their statements concerning the operations they carry out.

Instead of reading what is written in the BR, the operator listens to the instructions of the voice-controlled e-BR. Instead of writing down each result of each step, they simply say the result aloud. The traditional pen, keyboard, or tablet are replaced by the operator's voice.

Preparation and validation of MBRs

A voice-controlled e-BR must contain a module offering intuitive functionalities for controlling MBRs subject to a strict validation cycle.

Batch execution features

A voice-controlled e-BR should be designed so that all types of personnel (e.g., operators, dubbers, supervisors) can interact with it in real time during operations, each with their own access rights. It should be noted that one of the financial advantages of a voice-controlled e-BR is the saving of a staff member whose main task is to record operator operations in the BR during production.

Operators must have voice access to operations and be able to record and manage all entered values by voice. They must also be able to easily access documents, diagrams, images, and videos that help them perform operations.

In the event of an incident during operations, the operator must be able to open an "incident" to record a voice comment and suspend the execution session pending a supervisor's decision to continue or interrupt the execution.

Creation and approval of the BR

All raw data generated during batch execution must be recorded and subjected to a strict validation cycle. Therefore, the voice-activated e-BR must be designed to highlight specific process inconsistencies and draw the attention of reviewers and approvers to, for example, non-conformities, incidents, etc. The traditional and time-consuming process of reviewing all data must disappear.

Comments from reviewers or approvers, such as the rationale for their decisions, should also be included in the BR. Final BRs should be easily generated on demand in a suitable format.

IT infrastructure

The voice-controlled e-BR server infrastructure must be a platform located in the customer's private infrastructure. It will host the database, automatic speech recognition and speech synthesis services, a WebRTC gateway, as well as the voice-controlled e-BR web application. At the user's request, it must be able to operate autonomously without connection to existing equipment or IT systems (standalone option), or be integrated into existing equipment and IT systems (e.g., ERP systems).

Remotely controllable operations

Outsourcing manufacturing, and even quality control operations, is common in the pharmaceutical industry. It can save money, whether in terms of purchasing on-site equipment or in operational costs (maintenance, etc.).

The disadvantage, however, may be to increase the risk of drug falsification and the threat of counterfeiting.

In reality, and more generally, an operational and uncompromising solution must be found to the following central problem: ensuring a high and uniform quality standard for the multiple manufacturing/filling units at different sites, wherever they are located. The solution lies in a system that collects, in real time, all manufacturing/filling and environmental data and stores it in a secure cloud, allowing total remote control of all CMOs.

Quick and easy validation

Validation specifications and documentation are extremely important when purchasing a voice-enabled e-BR. To expedite the validation process, a voice-enabled e-BR vendor should provide documents such as the validation plan, user requirement specifications (URS), URS for e-BR deployment, risk analysis, functional specifications, design specifications, factory accepted tests, installation qualification, operational qualification, performance qualification, and traceability matrix.

Conclusion

Although Industry 4.0, or "smart industry," has become a widespread phenomenon in many industrial sectors, it should not be forgotten that automation and digitalization technologies should help reduce operational costs in the supply chain and ease the administrative burden.

Pharma 4.0 M/F&F units must be flexible (easily and quickly adaptable) to accommodate constantly evolving manufacturing and filling techniques. They must be connected to software that verbally guides operators, provides them with all necessary instructions, relieves them of administrative tasks related to BR registration, and collects all batch-related data. The software must also allow for remote control of all operations in real time, even when performed by CMOs.

This article is from “Pharmaceutical Manufacturing and Packing Sourcer,” November 2019, pages 57-60. © Samedan Ltd.

References

1. ispe.org/initiatives/pharma-4.0
2. www.rdmag.com/article/2018/10/pharma-40industry-40-applied-pharmaceuticalmanufacturing
3. www.salamanderu.com
4. www.pharmtech.com/electronic-batch-records-offeradvantages-beyond-automation