PERSPECTIVE ON PHARMA e ture of pharma: How Industry 4.0 is driving pharmaceutical manufacturing

including sales forecasts, ordering raw materials, machine maintenance, floor plan operations, reporting, and last-mile delivery. The team ordering raw materials can access AI sales forecasts and adjust orders accordingly. Operators can access the same sales forecasts and adjust production line speed to avoid client stockouts. Likewise, when forecasts predict fewer incoming orders, maintenance can seize the opportunity to run machine maintenance.

Creating smart manufacturing starts by identifying which areas in the manufacturing process should be digitised first; not all pharmaceutical companies have the same digital maturity and needs. New pharma trends are emerging as processes and functions become interconnected, we review some of these trends below.

Increased Patient Safety

Patient safety has always been a focus for the pharma industry, so any technology that can reduce patient risks is important. Patient safety continues to be an industry 4.0 technology driver. Drugs must be stored and transported under certain conditions to ensure product quality. Changing ambient temperature, humidity, light, or air can contaminate raw materials and the final product. IoT sensorsan Industry 4.0 solution - were designed to track small ambient variations and have become a key player in patient safety. They can aggregate real- time data and transfer it to a centralised data hub, usually accessed by a group of users to monitor and take action to protect patients.

END-TO-END PRODUCT TRACEABILITY

Product traceability goes from ordering raw materials to lastmile delivery. New track-andtrace systems and serialisation solutions introduced in Industry 4.0 create additional transparency for pharma manufacturers, suppliers, and last-mile players to track every stage of the supply chain.

Product traceability has also been supported by the new DSCSA regulation that goes into effect by the end of 2023 and by new technologies like cloud labelling solutions and blockchain technology.

Pharmaceutical companies can leverage label management solutions to adhere to new label requirements. These solutions allowed working in a central platform to review, approve, and track labels across the supply chain. In a product recall, for example, pharmaceuticals know when and where a label was printed and can quickly locate the product batch. Blockchain will also be a key player in keeping drug batch records as specified in the DSCSA for at least six years.

Predictable Pharma Manufacturing Issues

Predicting what could go wrong, when, and perhaps most importantly, how to avoid things going wrong, is the desired outcome for any manufacturing floor. Industry 4.0 provides pharma with new ways to analyse previous, current, and future production conditions to predict outcomes using AI. Companies can run what-if scenarios to reduce downtime, streamline production lines with new operations, and test new facility layouts, for example.

Reshaped Workforce

As manufacturing facilities become more autonomous, human involvement will be reshaped. AI can be used to predict machine failure points before failures occur and trigger maintenance processes to reduce risk, removing the need for an operator to check on equipment. Instead, an operator’s new role will be to connect all the technical processes and ensure data is transferred correctly. Humans won’t be replaced by technology, but roles will evolve as technology use is widely adopted.

Protected Manufacturer Reputation

One of the challenges pharma has faced is counterfeit medicine, which affects patient safety and the manufacturer’s reputation. Using blockchain, another technology that is part of the fourth industrial revolution, manufacturers can add a new level of transparency to avoid being impersonated.

For example, perhaps Company X has manufactured a new drug. During the manufacturing process, a QR code to combine all the product properties is created and securely stored using blockchain. As the drug moves down the supply chain with its QR, parties add information, origin, destination, method of transportation, and so on. When the product reaches the consumer, he or she can use a QR enabler to access this information to confirm that the product is legitimate.

A late or poorly managed product recall is another item that can damage a pharma manufacturer’s reputation. In the last ten years in the US alone, more than 15,000 products have been recalled. Costs vary depending on the complexity of the recall, but according to Mc Kinsey, the average in 2010 was $600m per recall.

In the pharma industry, drugs go through multiple trials and tests, the results of which must be shared and approved. Blockchain provides secure sharing of highly sensitive information. If a product anomaly is detected, like a counterfeit drug, a recall can be done even before the counterfeit enters the supply chain, thereby protecting the brand’s reputation and patient safety.

A Holistic View Of Pharma Manufacturing Operations

The items discussed above create a holistic view of pharma manufacturing. Pharma’s highly regulated environment requires a high level of expertise and oversight at every production stage. In the past, these processes created data silos, scaling difficulties, and inefficient operations.

Industry 4.0 connects all stakeholders to create new levels of transparency, operations control, quick, informed decision-making, and an autonomous floor plan. Removing data silos reinforces data-driven decisions across an organisation, giving everyone access to the same validated data. Smart factories will allow pharma manufacturers to adapt to market and regulatory changes without putting patients at risk, while they become flexible and competitive by sending information to the right person at the right time.

Technical process advantages mean that continuous manufacturing could soon assert itself as an alternative to the batch-tobatch process. Market research institutes are forecasting high growth of around 10% for the years to come. Regulatory authorities such as the Food and Drug Administration (FDA) consider the process to be an innovative, quality-driven tool for modernising the pharmaceutical industry.

Continuous manufacturing is a central development area at Fette Compacting – with a focus on continuous direct compression. In particular, this can be attributed to a wide range of applications which can be combined with plant design optimised in terms of space and resources as well as precise process analysis. Direct pressing entails feeding the powder from the dosing and mixing module into the tablet press without any additional granulation.

Compared to granulationbased production, several production steps are no longer required, which is why spatial requirements are reduced and the process is leaner overall.

Further Development Via Quality By Design

In an effort to further develop the continuous direct pressing process, Fette Compacting has been pursuing a Quality-byDesign approach for some years now which has also contributed toward a versatile process design. Ultimately, culminating in the FE CPS dosing and mixing unit. In combination with a rotary tablet press and a central operating panel, it forms a comprehensive continuous direct pressing line. The entire plant can be integrated on a single level in existing production rooms.

On its way to becoming a finished tablet, the powder (or premixture) goes through several flexibly adjustable

The technology used in continuous pharmaceutical manufacturing has matured even further in recent years. Within the scope of tablet production, one major focus is on direct compression, which combines a particularly lean plant design with process analysis technology. The FE CPS dosing and mixing unit sets new standards in the continuous direct compression process.

CONTINUOUS TABLET MANUFACTURING:

How The Powder Starts To Flow

process steps: from the inlet ports for the materials to the outlet port for the mixture, which is in turn connected to the inlet of the downstream tablet press. The continuous product flow can be summarised and described in the following steps:

1. MATERIAL FEED

The dosing and mixing unit features up to six inlets for the material feed. Each inlet can be used for an individual ingredient or a premixture of several ingredients. A premixture is used when the total number of ingredients exceeds six or the concentration of an ingredient in the formula is particularly low. Each feeder is equipped with an automatic refill system (ARS) which feeds the material reliably and at consistent intervals to the next process step. As this first step is decisive for the correct operation of the line as a whole, Fette Compacting has developed its own refill system with special screws. These can convey very complex raw materials into the dosing process, both reliably and consistently.

2.

Dosing

Dosing is at the heart of the new technology, so to speak. Up to six gravimetric (loss-in-weight, LIW) powder dosing units are used here. For each feeder, the concentration of the respective material in the formula is stored in the cross-plant product recipe. Combined with the required plant throughput, the control system automatically calculates the requisite flow rate. The LIW feeders use twin screws to feed material to the next process step with the required feed rate and minimal feed variability.

3. MIXING PROCESS

In the next step, a specially developed horizontal powder mixer is used. It has two successive but independent mixing zones – without a dead zone in between. This allows mixing processes with high and low shear energy to be combined in a single mixer and to achieve the best mixing results depending on formulation requirements. The mixer is equipped with four inlet ports: two in the first mixing zone and two in the second. The various ingredients are directed from the LIW feeders to the mixer inlets using a combination of downpipes and transfer hoppers. Each specific hopper configuration determines which outlet of the feeder is connected to which mixer inlet. The mixing duration for the respective ingredient is thereby specified. Various hopper configurations are available as format parts, offering a great deal of flexibility. This enables users to achieve the optimal process setting of shear intensity and mixing duration for a wide range of recipes.

4. INLINE QUALITY CONTROL

Embedded process analytical technology (ePAT) can be used at the output of the mixer. A near-infrared spectroscopic sensor checks, among other things, the homogeneity of the mixed powder and the concentration of the active ingredient. In this way, the system can be permanently monitored, and quality deviations can be discovered without delay. Especially in process development, it is important to continuously record and optimise the mixing process. Further ePAT sensors are located at the tablet press, which enables continuous in-process monitoring at high speed.

5. CONVEYING

In the last step before tableting, the powder mixture is conveyed evenly and without the risk of segregation to the inlet of the tablet press. For this purpose, a powder transport system was developed, which conveys the product by dense phase conveying over a distance of up to ten meters without the risk of segregation. Via a conveying hose, it reaches the conveying arm of the FE CPS, which can be flexibly aligned with the inlet of the tablet press. This ensures that the thoroughly mixed powder reaches the tablet press without interference and is compressed in the usual quality. The mixing conveyor system also allows a two-room set-up of the direct pressing line: the FE CPS can be set up in one room while the tablet press is in an adjacent room. This can be interesting if the system is to be installed in an existing tablet production line.

In this combination, these process steps open up new perspectives for efficiency and product quality in tableting. Thanks to its lean plant design and a process analysis technology adapted to it, the FE CPS offers a compact yet reliable solution for continuous manufacturing.

The European Commission in December issued the first approval of an allogeneic T-cell therapy in the world, a significant milestone for the cell and gene therapy sector. The landmark approval reflects the potential promise of pharmaceutical products currently in development and also highlights a broader industry trend: a growing percentage of products – from vaccines to cell and gene therapies – require cold chain storage and handling.

The global market for cold chain products (e.g. temperatures ranging from 2 to 8 °C or lower) is expected to increase from $366 billion in 2021 to $480 billion in 2027, driven in part by the projected influx of biopharmaceutical products. Recent reports suggest cold chain products will continue to grow at twice the rate of non-cold chain products through 2024, creating a heightened demand for cold chain logistics, including temperaturecontrolled distribution and storage. While these products offer tremendous promise for patients worldwide, they rely on a secure cold chain – any exposure to temperatures outside the specified range can threaten a product’s viability, resulting in product wastage, lost revenue and, most importantly, delayed patient access.

As significant R&D investments and scientific advances power breakthroughs in medicine, biopharma companies and their logistics partners need to build end-to-end strategies to ensure the products can reach patients who need them – no matter where they throughout Europe, with recent investments in France, the Netherlands and the United Kingdom to meet the heightened demand.

Nick Porter, president of World Courier, and Chris Williams, senior vice president and international managing director of Alloga Europe and ICS (all a part of AmerisourceBergen), discuss the growing trends for cold chain and cryogenic storage in transporting ATMPs, and the technology investments needed to safeguard the supply chain.

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