If Industry 4.0 or smart industry technologies become a widespread phenomenon, it could help reduce operational costs and administrative burdens for manufacturers.

Pharma 4.0 is now a prevailing reality that has many advantages such as in-line and in-time control over manufacturing operations and faster decision-making (1-2). Nevertheless, the dangers of investing in wrong ways exist; investing in technologies that suit the company needs is strongly advised, that is, the ones that help provide the most efficient solutions to the problems faced by the company. Peter Guilfoyle writes that “the potential for Pharma 4.0 is so huge, and so wide, that a lot of pharmaceutical companies rushing to adopt the technology haven’t first paused to figure out the root goals that they are trying to achieve, and what main problems they are trying to solve”.

Launching a digitisation project indeed requires an approach to be chosen according to the expected benefits. However, all biopharma companies have at least two objectives in common: reducing operational supply chain costs and scaling down the data recording administrative burden. Investing in Pharma 4.0 technologies should aim to achieve these goals.

Buying Pharma 4.0 Technologies

If used for manufacturing sterile products, manufacturing and fill and finish (M/F&F) units should be designed in such a way that all operations are performed in GMP Grade A environments and encompass all equipment needed for manufacturing or filling the end products. The units should also contain all equipment required to control process and
environmental parameters, and should resist intensive use of decontamination products.

Flexibility in manufacturing is essential because processes are constantly evolving. It is important that M/F&F units can be modified easily and quickly to adapt to these evolutions. Flexibility is also needed in the integrated decontamination units; it should be possible to decontaminate one section of the unit while still working in the other sections.

M/F&F units should be coupled with a system that sequentially guides the operators through the operation steps. They should also be linked with an electronic document manufacturing system that provides the operators with appropriate working instructions in the form of text, schemes, pictures, and/or videos. The units should also be coupled with all equipment used for process and environmental control and for decontamination.

As many companies are still using paper-based master batch records (MBRs) and batch records (BRs) to collect huge volumes of M/F&F related data and to comply with regulatory traceability requirements, controlling MBRs and completing BRs are mostly notoriously cumbersome processes. Automating them by using technology that avoids completing the BRs by hand or via keyboard or tablet is needed to significantly reduce BRrelated costs and to speed up the products release process.

For ensuring the quality of the products, it is also vital to be able to follow the M/F&F processes, environmental parameters, and disinfection cycles remotely and in real time, especially when operations are performed by CMOs. In some cases, M/F&F units should be mobile too.

Designing Smart M/F&F Units

Designing, manufacturing, and validating such smart units require thinking outside the box; using nonclassical materials for building the units and developing innovative software solutions are prerequisites for designing smart M/F&F units.

Flexible Custom-Made Units

As already mentioned, M/F&F units should encompass all equipment needed for performing the operations and for controlling process, environmental, and disinfection parameters. They need, of course, to also maintain their integrity and withstand disinfection cycles (H2O2) over the years. Ergonomics is important too; operators should feel comfortable when working with the unit (isolator).

Nowadays, stainless steel is used as the main material in building isolators. Nevertheless, stainless steel corrodes when frequently in contact with cleaning/disinfection agents like H2O2; furthermore, it does not offer enough flexibility if the unit’s shape needs to be changed upon the user’s request or if new equipment must be integrated (as some operations have changed or are automated).

A more adequate material for building custom-made M/F&F units is poly methyl methacrylate (PMMA), as mentioned in a study wherein PMMA (an amorphous acrylic resin) has been compared to 316L stainless-steel (3). The following tests have been performed during that study:

• Contact with cleaning and disinfection agents: PMMA and 316L stainless-steel samples have been maintained during 3 months in Actril, Hexanios, IPA, and VHP (H2O2 35%). There were noticeable alterations in the stainless-steel samples put in VHP, while no visual adverse effects have been observed on any of the PMMA samples
• Roughness: when polishing PMMA samples with emery paper N° 4000 for five minutes or more, PMMA Ra value is equivalent to that of electropolished stainless-steel
• Fouling by products commonly used in cell culture manufacturing: PMMA and 316L stainless-steel are equivalent because, depending on the colourant, traces can remain in both
  cases. However, when using PMMA, a solution that cannot be used on stainless-steel is available to solve the stain problems, namely a polishing of the surface that eliminates any possible remaining stain and returns the resin to its original colour without damaging its surface
• Leak tightness: results show that the PMMA isolator is leak tight and that PMMA is suitable for building isolators wherein a positive pressure needs to be maintained
• Mechanical limits based on hardness and scratch tests: 316L stainless-steel and PMMA are not equivalent in terms of hardness and scratch tests. Resin is not as hard as 316L stainless. A periodic polishing of the surface is recommended to remove any scratch appearing on the working surfaces of the isolator

Study results: the possibility of moulding and ease of assembling (no welding) indicate that PMMA is more appropriate than 316L stainless-steel for building M/F&F units.

Electronic and Paper Batch Records

Many companies are currently still using paper-based MBRs and BRs to collect huge volumes of data. Automating these processes would relieve the administrative burden, significantly reducing BR control costs and shortening the delivery time of the products.

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

Voice-Controlled e-BRs

It is now time for a real leap in MBR and BR control by moving on to a solution that allows forgetting the era when operators had to read and write, and which proposes them to be accompanied by an infallible pilot that orally guides them and automatically records all of what they say about the operations they are implementing. 

Instead of reading what is written in the BR, the operator listens to what the voice-controlled e-BR is telling them to do, and instead of writing down every result of each operation step, the operator just says out loud which result they’ve obtained. The traditional pen or keyboard/tablet is replaced by the operator’s voice.

MBR Preparation and Approval

A voice-controlled e-BR must contain a module that proposes intuitive features for controlling MBRs that must undergo a strict validation cycle.

Batch Running Features

A voice-controlled e-BR must be designed in such a way that all types of staff (e.g., operators, double-checkers, supervisors) can interact with it in real time during operations, all with their own access rights. It should be noted that one of the cost-related advantages of a voicecontrolled e-BR is the saving of a staff member whose job is mainly to record in the BR what the operators have done during manufacturing.

Operators must have vocal access to the operations and be able to vocally record and manage any input values. They must also have easy access to documents, schemes, pictures, and videos that can help them perform the operations.

In case of an incident during operations, the operator must be able to open an ‘incident’ to record a voice comment and pause the execution session awaiting a supervisor’s decision to either continue or abort.

BR Creation and Approval

All raw data generated when running a batch must be recorded and undergo a strict validation cycle. Therefore, the voice-controlled e-BR must be designed to highlight specific process inconsistencies and draw the attention of verifiers and approvers to, for example, non-conformities, incidents, and so on. The traditional tedious process of verifying all data must disappear.

Comments made by reviewers or approvers – such as justifying the decisions they take – must also be part of the BR. Final BRs should be easily generated on request in an appropriate format.

IT Infrastructure

The server infrastructure for the voicecontrolled e-BR should be a platform located in the customer’s private infrastructure. It will host the database, audio automatic speech recognition and text-to-speech services, a WebRTC gateway, as well as the voice-controlled e-BR web application. Upon the user’s request, it must be able to operate autonomously without being connected to an existing equipment or computer system (stand-alone option), or to be integrated with existing IT equipment and systems (for example, ERP systems).

Remotely-Controllable Operations

Outsourcing manufacturing and even quality control operations is quite common in the pharma industry. This can indeed save money either for the on-site purchase of equipment or at the level of operational costs (maintenance and personnel). The flip side can, nevertheless, be increasing the risk of drug falsification and the threat of counterfeit drugs.

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

Easy and Fast Validation

Specifications and validation documentation are extremely important when buying a voice-controlled e-BR. To fasten the validation process, a voice-controlled e-BR supplier must deliver documents such as validation plan, user-requirement specifications (URS), URS for e-BR deployment, risk analysis, functional specifications, design specifications, factory accepted test, installation qualification, operational qualification, performance qualification, and traceability matrix.

Conclusion

Even if Industry 4.0 or ‘smart industry’ has become a wide-spread phenomenon in many industrial sectors, it should not be forgotten that automation and digitisation technologies should help reduce operational supply chain costs and scaling down the administrative burden.

M/F&F units for Pharma 4.0 need to be flexible (easily and quickly adapted) to consider constant evolution of manufacturing/filling techniques. They should be linked to software that orally guides operators, provides them with all necessary instructions, relieves them of the administrative tasks related to BRs recording, and collects all batchrelated data. Software should also be used to remotely control all operations in real time even when they are performed by CMOs.

This article is taken 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