EPM Jun/Jul 2022 by EPM Magazine

THE MOBILE TOOLS ADVANCING PHARMA

REVOLUTIONISING UPSTREAM BIOMANUFACTURING

FUTURE PROOFING WITH AUTOMATION

June/July 2022

CONTINUOUS MANUFACTURING

REINVENTED

DIRECT COMPRESSION FOR CONTINUOUS TABLET PRODUCTION

Health Science Health Inspired, Quality Driven

Nitrosamine Testing Solutions The presence of the nitrosamine, N-nitrosodimethylamine (NDMA), in certain sartan API’s has resulted in several regulatory warnings and recall of contaminated products. Concerns over the presence of this class of genotoxins has now widened to include other medicines such as the well-known diabetes drug, Metformin. The US Food & Drug Administration (USFDA) and European Medicines Agency (EMA) have responded by publishing documents for the pharmaceutical industry that address requirements and limits related to nitrosamine contaminants. Pharmaceutical Manufacturers are now taking a pro active approach to risk assessment and mitigation of genotoxic contaminants within global pharmaceutical supply chains. Central to these activities is a coordinated analytical capability to identify and quantify contaminants across global geographies and regulatory zones.

Why use SGS

About SGS

SGS Health Science has considerable expertise in the method development of nitrosamine determination in pharmaceutical products. SGS has established a specific method for NDMA which can be applied to various different matrices. Alternatively, a platform method, based on trace-level detection by LC-MSMS, is also available and provides rapid and simultaneous determination of up to ten different, targeted nitrosamines. Although with more limited application, the SGS network is also able to support specialist methodologies such as GC-MSMS. Our experience in optimizing extraction allows application of these methods to drug products, API’s, and raw materials.

SGS is the world’s leading inspection, verification, testing and certification company. We are recognized as the global benchmark for quality and integrity. With more than 96,000 employees, we operate a network of more than 2,600 offices and laboratories around the world. Our conveniently located network of laboratories and clinical trial facilities offer an array of integrated services and expertise, providing you with the knowledge, flexibility and ability to scale.

By establishing these nitrosamine methods within centers of expertise across a global laboratory network, SGS can provide an unrivaled service offering that incorporates a harmonized methodological approach together with flexible management of capacity and capability requirements.SGS offers a variety of partnership models and can collaborate in such testing programs using fee-for-service to outsourced staffing models all exploiting resources of the SGS network.

Wide-range of laboratories and clinical research sites and qualified partners. Size and diverse testing capabilities matching biologics and small molecules needs International network across America, Europe and Asia-Pacific

Contents Jun/July 2022 | Volume 22 Issue 4

REGULARS 5. EDITOR’S DESK: New beginnings.

6. A SMALL DOSE:

A brief round-up of some of the latest developments in the industry.

10. OPINION:

Panasonic TOUGHBOOK discusses the mobile tools that are advancing the pharma industry.

14. COVER:

Fette describes direct compression as an innovative system for tablet production.

22. PERSPECTIVE ON PHARMA:

Autostore highlights automation solutions for pharma supply chains.

26. TALKING POINTS:

Stories to consider and what to look out for in EPM over the coming weeks.

FEATURES 8. COATINGS & CAPSULES:

ACG highlights current trends in tablet coating

12. CONTAINMENT & CLEANROOMS: Vaisala discusses the role of temperature monitoring in the pharma cold chain.

16. CONTAINMENT & CLEANROOMS:

Genezen explores the challenges faced with cGMP-compliance in vector manufacturing.

18. CONTINUOUS MANUFACTURING:

Thermo Fisher discusses the implementation of continuous perfusion cell culture.

24. LOGISTICS & DISTRIBUTION:

ParkourSC explains the innovative solutions within real time supply chain operations.

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NEW BEGINNINGS

EDITORIAL acting editor ian bolland ian.bolland@rapidnews.com junior editor rebekah jordan rebekah.jordan@rapidnews.com publisher duncan wood

PRODUCTION

head of studio and production sam hamlyn

ADVERTISING robert anderton tel: +44 (0)1244 952359 robert.anderton@rapidnews.com vp sales & sales talent Julie Balmforth julie.balmforth@rapidnews.com

SUBSCRIPTIONS subscriptions@rapidnews.com qualifying readers Europe - Free, ROW - £249 outside qualifying criteria UK - FREE, ROW - £249 please subscribe online at www.pharmaceuticalmanufacturer.media Address changes should be emailed to subscriptions@rapidnews.com European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd. European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals. Volume 22 Issue 4 June/July 2022 While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed. All rights for European Pharmaceutical Manufacturer are reserved and reproduction in part or whole without written permission is strictly prohibited.

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It’s thanks to the hard efforts of the pharmaceutical industry that we are now in a position to be able to meet face-to-face again. I’d like to welcome you to this issue of European Pharmaceutical Manufacturer. It’s been a little over two months since I started as an editor to this magazine and already, I’ve learned so much. This is something of a new industry to me but one I have relished getting to grips with. From innovative drug

delivery devices, methods of developing new drugs, and the role that genomics will have on the future of the way we deal with healthcare issues, the pharmaceutical industry is an exciting field to be a part of, and indeed write about. Even through COVID (which I’m sure you’ll agree we’re all tired of talking

EDITOR’S DESK REBEKAH JORDAN about), the pharmaceutical industry has had to rapidly keep up with vaccine supply and demand, whilst maintaining a high level of consistency and accuracy. This is evident with the recent news of the sector having to adapt vaccines in order to combat new variants of the disease that left us

in multiple lockdowns over the past couple of years, as Pfizer/BioNTech have recently announced positive results following the development of their two Omicron-adapted vaccine candidates. As variants continue to emerge, this work is critical as the world combats any emerging health threats. Moreover, it would be interesting to see how the industry adapts to the prevalence of automation and digitalisation especially during the manufacturing and distribution processes, and the challenges posed. But it’s thanks to the hard efforts of the pharmaceutical industry that we are now in a position to meet face-to-face once again, for example trade shows are now back up and running as normal, and a hello to those who may be picking up this edition at ACHEMA. On a similar note, my recent visit to Pharmapack in Paris as a first-time attendee was certainly an intriguing one. Being able to observe the pinnacle of packaging and delivery devices first hand and discuss with the experts to gain insights into the field. It made me appreciate an experience that you can only really get with face-toface interaction as I’m sure I wasn’t alone in expanding my knowledge base in this particular part of the pharmaceutical supply chain. With all that being said, I hope you enjoy this issue and I can’t wait to see what CPHI has to offer in Frankfurt later on this year, in terms of the latest solutions and developments. Finally, I look forward to working with and meeting as many of you as possible during my tenure on European Pharmaceutical Manufacturer.

A small dose

Study launched to investigate Covid-19 vaccine protection in young, immunosuppressed people

HARMFUL CHEMICALS UNDETECTABLE IN SMOKING ALTERNATIVE NOW AVAILABLE IN UAE

U A

study into how well additional doses of the Covid-19 vaccine protects immunosuppressed people is set to be extended to include young people following a recent funding extension. The research project that was first launched in December of 2021 to evaluate third doses in adult patients was supported by a coalition of funders including Kidney Research UK, The Medical Research Council, Blood Cancer UK, Vasculitis UK and the Cystic Fibrosis Trust, and will now seek to examine the impact that the vaccines have on immunocompromised patients aged 12-17 years. Some smaller studies have suggested that immunocompromised people within this age group mount a stronger response to Covid-19 vaccinations than older immunosuppressed adults, but they are still thought to be more vulnerable than the general population.

Dr. Michelle Willicombe, the study lead at Imperial College London said: “Information on how young, immunosuppressed people have responded to vaccination and the protection it affords them from infection is currently lacking, so we are delighted for the additional support so we can include children in MELODY to provide ongoing evidence. If we can understand more about how this group of people respond to vaccines, then this will inform future vaccination strategies and also identify those young people who are most at risk of catching Covid-19.” Immunocompromised people have remained particularly vulnerable to the Covid-19 virus, leaving an estimated 500,000 people in the UK very much aware of their increased risk. The MELODY study was launched to provide vital insight into which patients remain vulnerable after

vaccination, which will help to develop bespoke strategies for exiting the pandemic for those who continue to remain most vulnerable. Dr. Aisling McMahon, executive director of research, innovation and policy at Kidney Research UK said: “We are starting to build a clearer picture on how vaccination has provided varying levels of protection within the immunosuppressed community, but we still have very little data on how well vaccines protect the younger members of this group. There cannot be a one size fits all approach to keeping all immunocompromised people safe and including data from this age group will allow for more effective strategies to be developed.” Michelle and her team in London are aiming to recruit 1,000 immunocompromised transplant recipients between the ages of 12 and 17 years.

AE tech company, Medad Technology, has launched an alternative to tobacco and e-cigarettes that produces no detectable carcinogenic agents, according to independent tests

conducted by medical experts in the United Kingdom and the United States. Now available in the UAE, NEB Mist uses its patented ultrasound technology to aerosolise a liquid containing pharmaceutical-grade nicotine into a mist unlike standard electronic nicotine delivery systems (ENDS), and other reduced risk alternatives to tobacco smoking, which rely on electronic heating elements such as heated coils to create a vapour. Mohammed Alshaiba Al Mazrouei, chief executive officer of Medad Technology said: “NEB

Insomnia medicine, QUVIVIQ, to decrease overactive wakefulness is granted approval

dorsia Ltd announced that the European Commission (EC) has granted marketing authorisation for QUVIVIQ (daridorexant), for the treatment of adult patients with insomnia characterised by symptoms present for at least three months and considerable impact on daytime functioning. Chronic insomnia disorder is one of the most prevalent sleep disorders in Europe, affecting between 6-12% of the adult population, and impacting both physical and mental health. With this approval, QUVIVIQ becomes the first dual orexin receptor antagonist (DORA) in

the European Union (EU) for the treatment of insomnia. Rather than inducing sleep through broad inhibition of brain activity, QUVIVIQ blocks only the activation of orexin receptors. Consequently, QUVIVIQ decreases the wake drive, allowing sleep to occur, without altering the proportion of sleep stages. Jean-Paul Clozel, MD and chief executive officer of Idorsia, commented: “As our first treatment authorised in the EU, the approval of QUVIVIQ marks a significant medical advancement in the management of insomnia and a big milestone for Idorsia. We expect to

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Mist, the world’s first ultrasonic cavitation smoking alternative, is the only product registered under both the EU’s Tobacco Products Directive and the UK’s Medicines & Healthcare Products Regulatory Agency that produces no detectable carcinogens, including formaldehyde and acetaldehyde.” UK and US studies also found no signs of eight other compounds identified as the main causes of smokingrelated illness and disease. “By eliminating the harmful, heatproduced chemicals from regular cigarettes

dose of the average e-cigarette,” he added. NEB Mist also has a built-in Bluetooth feature allowing users to connect to a dedicated mobile app to help monitor and reduce their nicotine intake. “While we will always encourage the reduction of nicotine consumption, we understand that quitting tobacco smoking can be an incredibly difficult task,” said Al Mazrouei. “By providing a credible smoking experience involving considerably less harm, our NEB Mist technology is potentially a gamechanger for millions of smokers worldwide.”

and e-cigarettes, we are reducing harm and improving the health of existing tobacco smokers, who are already consuming nicotine,” said Al Mazrouei of Medad Technology, which recently announced that it was investing U$150 million in ultrasound technology to support advances in smoking cessation and other medical treatments. “At the same time, we fully support efforts to reduce the amount of nicotine in both tobacco and alternative products, which explains why our NEB Mist e-liquid capsules, or Sonics, contain half the nicotine

The world’s first

VOICE ACTIVATED ISOLATOR

make it available in the first countries before the end of the year.” The EC decision is supported by robust Phase 3 results – published in The Lancet Neurology – which demonstrated that at the recommended dose, QUVIVIQ improved sleep onset, sleep maintenance and self-reported total sleep time in adults with chronic insomnia disorder. Patients reported feeling less mentally and physically tired, less sleepy and more energetic during the day, at months one and three compared to placebo, with a favourable safety profile. In clinical trials, the most frequently reported adverse reactions were headache and somnolence. Professor Damien Léger, Université Paris Cité, France, commented: “QUVIVIQ, which can be used long-term, effectively improves sleep parameters and people’s ability to function better during the day, while avoiding major safety concerns, fulfilling the major medical requirements for insomnia management. This is great news for the millions of adults and elderly people across the EU living with chronic insomnia.”

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COATINGS & CAPSULES

Author: Ajit Kanetkar, process technology head, ACG

TRENDS

IN TABLET COATING

harmaceutical dosage forms have been around for centuries. Tablet dosage forms have dominated the sector as they are easy to manufacture, cost-effective and achieve improved acceptability and patient compliance. Tablet coating was originally introduced to mask the bitter taste and odour of some medicines. At first, simple sugar coatings were applied, followed by shellac which provided additional protection to ingredients that are sensitive to atmospheric moisture, light and oxygen. Coatings continue to evolve and today’s drivers include product identity to help with promotion and product recall, protecting patients from the effects of active ingredients (APIs), drug loading, release profiles and modified release dosage forms. Advanced film coating is currently the most widely used today. The new versions of coating materials allow a much higher concentration of coating materials in suspensions, where the solid content can be as high as 30% or more which drastically reduces processing times. Environmental and operational safety have contributed to a move towards aqueous-based coatings.

The choice of coating materials includes new options such as cellulosic, acrylic and other polymers offering a range of drug release profiles. The growing demand for coated tablets has focused pharmaceutical companies on equipment to handle large volumes of innovator products and generics. Continual improvement in airflow design, drying and spraying systems has produced more efficient systems. Delivering spraying capability of maximum droplet size in a narrow band improves coating quality and consistency whilst minimising spray drying time and losses of expensive coating materials. In addition to the regulator’s needs and user expectations of recipe management, access control, data compilation, trend analysis and new features are being added to controls. For equipment management, these include incorporating operating manuals and troubleshooting guidelines and drawings to facilitate ease of ordering parts and spares. Control of intricate process parameters, increasing levels of automation and having critical information, easily available at any point in time, work towards better compliance to Quality by Design (QbD) and ICH guidelines delivering process optimisation and consistent results. The application of ICH guidelines like Critical Material Attributes (CMA), Critical Process Parameters (CPP) and Critical Quality Attributes (CQA) contribute to achieving Quality Target Product Profile (QTPP). Supported by Process Analytical Technology (PAT) tools complete a robust and reliable coating system. Evolving concepts in tablet coating include flexibility to produce multiple products in smaller volumes where equipment accommodates high to low batches with fast changeovers, continuous manufacturing, reduction in the residence time of tablets in equipment, increasing use of new modelling systems to study process

parameters using data analysis and Industrial Internet of Things (IIoT). Other concepts include the adoption of low-cost generics and utilising coated tablets to extend the generics life-cycle, improved coating materials, and binding an insoluble API with a hydrophilic polymer to improve solubility and permeability. Finally, new coating materials without titanium dioxide are being developed following the European Food Safety Authority (under the broader European Commission) ban which is likely to trigger a review by regulators on its use in medicines and may invite a similar ban. The introduction of products such as personalised and precision medicine, and targeted delivery will continue to drive innovation and development in coating technologies, materials and processing.

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Opinion THE MOBILE TOOLS ADVANCING THE PHARMACEUTICAL INDUSTRY

For those working in the Cold Chain, transportation technology needs many of the same qualities as in mobile computing: reliability, accuracy, and ruggedness.

Author: MIKE WILLETT, key account manager of manufacturing and logistics, UK & Ireland for Panasonic TOUGHBOOK.

n the last few years, the public has truly come to understand just what an undertaking the global pharmaceutical industry’s operations are. Now valued at around $1500 Billion, the pharmaceutical industry’s success relies on a series of well-oiled processes and highly efficient workers. Even the smallest considerations can make a real difference to a pharmaceutical company’s success. Like many industries today, the pharmaceutical industry has undergone a considerable digital transformation. As the industry shifts towards paperless processes across manufacturing and distribution, mobile computing devices are becoming as essential as the test tube, and decision makers must select technology as flexible and reliable as the workers themselves. But from lab technicians and manufacturers to logistics and distribution workers, each stage has its own unique needs. Any successful device needs to fulfil a specific set of challenges:

OBILE YET POWERFUL • M Pharma users need a device that is light enough to move with them around the lab or production environment but also has the processing power and memory to cope with complex data sets and information. To support the long worker hours, a device with a long battery life and hot-swappable capabilities is also essential to support a worker through a day. • SANITISATION-READY Pharma environments demand regular, easy sanitisation. Buyers should look for devices that are built for operation in this environment: capacitive touch screens are designed to be easily used when wet, and by gloved hands or with a Digitiser Pen – avoiding user frustrations and inaccuracies. • HIGHLY RUGGEDISED Computing devices in a pharma environment suffer from all the usual knocks and scrapes of any workplace, so buyers should look for rugged devices with the strongest warranties, a European repair centre and a local network of engineers for peace of mind. • TAILORED TO EACH USER’S NEEDS Alongside these, the varying processes along the production and distribution journey demand that any mobile devices can adapt to each users’ needs. Barcode readers, for example, are vital for those logging ingredients or those working in the supply chain, and smartcard readers offer security identification to ensure the integrity of the product throughout. • DESIGNED FOR EXTREME TEMPERATURES The nature of the pharmaceutical industry and its products necessitates temperature-resiliency more than most. Rugged devices like Panasonic TOUGHBOOK tablets can operate in temperatures as low as -29 °C, and as high as +60 °C, to meet the extreme temperature requirements of the products being manufactured, shipped, or distributed.

The IQVIA institute found that the biopharma industry loses approximately $35 billion annually to temperature failures in the manufacturing, logistics and distribution stages. Well-selected thermal storage solutions can mitigate errors, protecting the hard work of the pharmaceutical industry and shoring up losses for reinvestment and development. The crucial hardware selected for these operations must therefore create and maintain exact temperatures for extended periods of time. Panasonic’s solution, VIXELL, uses the latest generation in-built thermal storage units, to accurately set and sustain temperatures from -75°C to 15°C for up to 18 days. VIXELL is a step forward in transportation unit technology, replacing the Vacuum Insulated Panelling (VIP) with a patented Vacuum Insulated Casing (VIC), removing gaps to create a more secure insulation layer. A wireless vacuum sensor unit also enables remote location and temperature monitoring, so workers can respond to any errors or changing requirements instantly. As the pharmaceutical industry goes increasingly digital, equipping workers with the right mobile technology is key to streamlining and protecting their vital work.

CONTAINMENT & CLEANROOMS

THE VITAL ROLE OF TEMPERATURE MONITORING IN THE PHARMA COLD CHAIN

he rollout of COVID-19 vaccines has highlighted the importance of temperature monitoring and control in the pharmaceutical supply chain, whilst also raising awareness and understanding of the different temperature requirements of products. This article from global measurement technology provider Vaisala will discuss the challenges and describe solutions for both static and dynamic temperature monitoring. BACKGROUND Pharmaceutical manufacturers must qualify temperaturecontrolled storage areas and provide evidence of continuous temperature monitoring in storage areas to regulatory agencies and clients. Temperature mapping, refrigeration equipment maintenance, and the calibration of sensors are also necessary. Following manufacture, pharmaceutical products generally reach end users through a complex cold chain with multiple stages. It is therefore vital that each stage is monitored accurately and reliably. All parties within the cold chain seek the successful delivery of the product, without harming its quality or integrity. A continuous temperature monitoring system should therefore provide all parties with the information they need. Regulations are generally created by national regulatory agencies, other regulatory bodies such as IATA and the ICH, while international

organisations such as the WHO create guidelines. Regulatory pressures are strongest at the manufacturer’s end of the supply chain, with comprehensive temperature monitoring being undertaken by drug manufacturers and documented in quality agreements with their downstream supply chain partners. Examples of national regulatory agencies include the USFDA, the European Medicines Agency and the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK. These organisations issue guidelines such as the MHRA publication ‘Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2017’ which provides detailed requirements for the calibrated accuracy of temperature monitoring.

The cost of highquality sensors is negligible in comparison with the value of the assets and goods that they protect.

TEMPERATURE CONTROL REGULATIONS The USFDA’s Federal Food, Drug, and Cosmetic Act states that a drug is adulterated if the facilities or controls used for its ‘manufacture, processing, packing or holding’ do not conform with Current Good Manufacturing Practice (cGMP). The term ‘holding’ refers to any way in which a drug is ‘distributed, transported, or warehoused for distribution or transfer.’ Maintaining temperature control is a GMP requirement; if goods are not maintained in specified conditions throughout all stages, they are considered adulterated. The ICH Q9 ‘Guideline on Good Manufacturing Practices (GMP)’ also requires that manufacturers ensure the transporters of products follow appropriate transport and storage conditions.

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Temperature Control Regulations’ published by IATA cover the shipping of temperature-sensitive products. IATA outlines the importance of temperature monitoring in its ‘Guidance for Vaccine and Pharmaceutical Logistics and Distribution’. STATIC TEMPERATURE MONITORING At various points in the cold chain, pharmaceutical products are static – stored in a warehouse or distribution centre awaiting dispatch. For static stages in the cold chain, a wide variety of monitoring solutions are available to reduce the risk of noncompliance in GxP-compliant holding areas. For example, Vaisala’s viewLinc continuous monitoring system has been continuously developed for over two decades for critical monitoring applications such as pharmaceutical distribution. As such, the viewLinc monitoring platform represents a blueprint for GxP-compliant monitoring because it includes key features designed to meet regulations: • R eal-time monitoring and alarms with customisable reports • Alarm notifications by email, SMS, voice call, lights and sirens • Gap-free monitoring (even during power and network outages) • Intuitive, easy to validate software • Easy network connectivity via Ethernet, Wi-Fi, or VaiNet wireless technology (over 100m) • Browser based access for global environmental management • Simple installation and validation, with optional IQ/OQ protocols

• O ptional GxP documentation package for GAMP-style validation • Reports compliant with 21 CFR Part 11 and EU GMP Annex 11, delivered by email • Encrypted data and audit trail • Monitoring data can be shared with other systems via OPC UA & API • Unlimited parameter integration with Modbus and analog devices • Intrinsically safe options for hazardous/explosive areas • ICH-compliant calibration options One of the most important features of a temperature monitoring system, like view Linc, is its ease of use; not only for set-up and operation, but also for user training, system validation, sensor calibration. These features ensure fewer errors, less deviations, and considerable time savings. The most common measurement parameters are temperature, relative humidity, carbon dioxide, differential pressure, and door contacts. However, this wishlist of features is redundant if the sensors are not accurate, stable, and reliable. This is a fundamentally important aspect of Vaisala technology, because the cost of high-quality sensors is negligible in comparison with the value of the assets and goods that they protect. DYNAMIC TEMPERATURE MONITORING The temperature control of goods in transit can be considered the dynamic part of the pharmaceutical cold chain. Because goods cross borders and use a variety of transport methods, dynamic monitoring is complex. Prior to the COVID-19 pandemic, Envirotainer, a world leader in air-transportation solutions for temperature-

sensitive pharmaceuticals, identified clear needs for shipping containers that were either not currently met, or fully optimised. Based on their analysis of survey results, Envirotainer initiated a product development program that resulted in the 2021 launch of their Releye RLP container. This new shipping container had an enormous impact in the market, providing fast, reliable deliveries around the world with a wide range of features beyond accurate, verifiable temperature control. The Releye RLP employs active temperature control, which adjusts the temperature inside the container to maintain the specified temperature range. This monitoring is supported by eight internal Vaisala temperature sensors, one of which also measures humidity. In addition, there are two external Vaisala sensors monitoring ambient temperature and humidity. The Vaisala sensors were chosen for their high performance, long-term measurement stability, low power consumption, and fast response. Each Releye RLP is supplied with its own rechargeable power supply, so that it is able to operate autonomously for over 170 hours (over a week) without recharging. This is an important feature because these containers ship over continents and can undergo changes of route and delays at customs or during handovers. The ability to maintain effective temperature control during unforeseen delays is therefore a major advantage. Temperature settings, such as limit values or pre-conditioning, can be managed by an intuitive keypad/screen on the Releye RLP, but users are also able to connect with their containers remotely and securely using any smart device. This live monitoring of position, temperature, battery level, humidity, door openings etc., allows users to continuously track shipment conditions as well as the status of their cargo. CONCLUSION Pharmaceutical cold chains are complex, with multiple stages in both static and dynamic conditions that increase the risk of noncompliance with global regulations. It is vitally important therefore that accurate, reliable, verifiable monitoring is undertaken at every stage. While technologies for data collection, transmission, processing, and display, have advanced in recent years, the key factors affecting the value of that data, are still the ease with which it can be used and the accuracy/reliability of the sensor.

t is a well-known fact that continuous manufacturing offers numerous advantages for the production of medicines and food supplements: integrated processes increase both efficiency and process reliability. Compared to batch processes, process time is also reduced, while the specific production output increases. Another advantage is the higher speed of market launches and more flexible production, overall. In addition, continuous production is a quality-driven technology. Thus, it fulfils all regulatory requirements. According to the Food and Drug Administration (FDA), continuous manufacturing is even capable of making a significant contribution to modernising the pharmaceutical industry. This is due mainly to the high product quality and patient safety that go hand in hand with increased process control. LEAN DESIGN, EASY OPERATION In recent years, there has been a growing acceptance of continuous direct compression in tableting. It appears attractive in terms of process technology and can be realised with a leaner plant design as compared to batch-to-batch production. Nevertheless, many manufacturers continue to rely on the latter. The reasons for this lay primarily in enduring reservations about continuous systems. One central concern stems from the often large footprint and room height necessitated by existing continuous systems, as this is often accompanied by modifications to existing buildings or even the need for new builds. In addition, many companies fear long lead times for design and production, while at the same time tending to invest heavily in customised facility designs. Since scientific staff are required for such

COVER STORY

In recent years, machine manufacturers have been working at making continuous pharmaceutical and nutrition production ready for the market. At Fette Compacting, too, the focus of development has been on continuous manufacturing. Now the company has achieved a breakthrough, with direct compression proving to be a target-oriented process. This is mainly due to a lean plant design that can be combined with highly efficient process analysis. The result is an innovative modular system for continuous tablet production.

CONTINUOUS MANUFACTURING

REINVENTED

DIRECT COMPRESSION FOR CONTINUOUS TABLET PRODUCTION

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installations, and specially trained users for the operation, manufacturers also shy away from anticipated complexity. This is further compounded by the assumption of lengthy cleaning and refitting times, which could threaten smooth operation due to extended downtime. As a result, many companies anticipate disproportionate investment and operating costs. LOW CAPITAL EXPENDITURE THANKS TO LEAN DESIGN Fette Compacting has developed a continuous tableting system from scratch that serves to eliminate the reservations outlined above. The system comprises a closed dosing-mixing unit with powder transport system (FE CPS) as well as a rotary tablet press and an operating terminal. Full integration of the system into existing production areas is on one level only and largely dispenses with the requirement for structural investments and modification. The range of formulations covers throughputs from about 5 to 200 kilograms per hour. This allows flexible use both with both smaller batches and large-volume production. The FE 55 tablet press used enables longer pressure holding times at a lower pressure via three compression stations rather than two.

Separation of the process and technical areas facilitates cleaning and conversion of the dosing-mixing unit.

DESIGN PRINCIPLE FOR SAFETY AND EASY OPERATION The process area of the FE CPS was designed to be dust-tight, and its closed construction – including sealed glass panes and negative pressure in the process area – provides additional protection for operators. Cleaning and changeover, which were previously considered time-critical steps in continuous systems, are also carried out with less effort in Fette Compacting’s new design. This is due mostly to the dosingmixing unit being designed with significantly fewer parts and interfaces, and having separate, easily accessible process and technical areas. The process parts of the refilling stations, the dosing stations, and the specially developed mixer are located in the process area. The drives, the electronics, the cabling, and other components are housed in the dust-tight, and separate, technical area. All components are thus easily removed from the process area for cleaning. Additionally, the design principle of the direct compression line makes operation, changeover and maintenance particularly easy. Central to the design is a Human Machine Interface (HMI) that provides, on a single terminal, an overview of all parameters for dosing, mixing, tableting, and process analysis – including recipes, logs, events

Ultrasound enables a uniform powder flow even with different formulations.

and diagnostics. Continuous operation of the HMI is very user-friendly and thus quickly learned. PROCESS ANALYSIS, NOT ONLY FOR SPECIALISTS The quality and efficiency of continuous production depend above all on the appropriate process analytical technology (PAT). PAT is not yet widely used in tablet production because the complex integration of software from third-party systems often means safe and efficient handling can only be achieved through the employment of experienced specialists. Here, too, the continuous direct compression line takes a completely new approach: an innovative technology for inline process analysis (embedded PAT, or ePAT for short) is used to monitor the most critical quality attributes. Sophisticated sensors are integrated into the process units and can be positioned at four points for continuous monitoring of production parameters: at the outlet of the mixer, at the inlet of the tablet press, at the Fill-O-Matic, and in the process area of the tablet press. Corresponding inline measurements, which take place directly in the production flow, allow swift reactions to quality deviations and direct

adjustment of the production process. The system also enables data acquisition and analysis in real time and thus significantly higher measurement and reaction speeds. The particularly efficient measuring method used is near-infrared spectroscopy (NIRS), which is particularly good at detecting many active substances in this spectral range. The infrared rays penetrate deep into the tablet without causing any damage. NIRS ensures ultrafast quality checks on larger sample quantities and is thus ideal for tablet presses such as the FE 55 and the upstream mixer. The result is a systematic unity of plant and process analysis – and thus continuous manufacturing, which is – finally - economically viable.

A new user interface provides an overview of the parameters of the entire continuous process.

CONTAINMENT & CLEANROOMS

DESIGNING VIRAL VECTOR MANUFACTURING FACILITIES FOR CGMP-COMPLIANCE Natasha Rivas, vice president of quality and regulatory, and Jose Cruz, director of vector manufacturing at Genezen, explore the difficulties in ensuring cGMP compliance is achieved throughout viral vector production. Examining best practice production suite design, they also highlight the key safety considerations needed when manufacturing these new therapeutic tools. production of these products currently involves many challenges.

s effective tools in facilitating vectormediated gene transfer, viral vectors – including gammaretrovirus and lentivirus – are playing an integral role in the advancement of cell and gene therapies (C&GTs). Viral vectors are commonly used in the development of chimeric antigen receptor (CAR) therapies. The growing potential of CAR therapies particularly in the oncology space - has been realised by the biopharma industry. CAR-T therapies now represent 48% of genetically modified cell therapies in the pipeline, with 98% of these in development for cancer indications. With the C&GT market predicted to grow between 2021 and 2028 at a compound annual growth rate (CAGR) of 12.4% to reach a value of $13.8 billion, reliance on viral vector development and manufacturers will rise. However, C&GTs are relatively new, meaning safe and regulatory-compliant

CGMP COMPLIANCE WITH AMBIGUOUS REGULATIONS Considering the surge in demand for C&GTs, regulations around their development and manufacturing have been relatively slow to manifest in comparison. Consequently, viral vector producers have had to shoulder the

responsibility of ensuring that their processes are safe and robust enough to remain compliant with new regulations as they arise. Conforming to ambiguous regulations written with traditional biologics in mind requires developers and manufacturers to assess how these might apply to viral vector production. Current production processes differ

significantly from those typically used for other well-established therapeutics, so it is important for viral vector developers

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to demonstrate careful consideration of the risks, as well as the application of suitable measures to ensure safety. IDENTIFYING THE RISKS There are a number of potential risks that are specific to viral vector production. An in-depth understanding of the risks is essential in determining the proper safety measures required to ensure the protection of both the handlers and the patients that will be receiving the final product. Predominantly, these risks are: • H azards inherent to viral vectors Typically, viral vectors will be carefully designed to reduce the health risks associated with potential infection. This includes techniques to ensure that vectors are replication-defective and use self-inactivating (SIN) transfer plasmids. However, even when working with viral vectors that are replication-defective, there is still the potential for infection to occur and for the target gene to be transfected. Viruses can also become replication-competent if exposed to wild-type viruses. • E xposure risk with open processes Although cell expansion is a common process in the development and manufacturing of many biologics, there are several additional “open processes” involved in viral vector production, which results in handlers being at more risk of coming into contact with biological hazards. These include transfection steps and manual processes involved in harvesting vectors from

adherent producer cells grown in 2D culture chambers. • Cross-contamination For manufacturers working on multiple viral vector projects concurrently, it is essential to implement measures to prevent cross-contamination, as this could lead to serious risks to patient safety. Steps must also be taken to ensure that there is no contamination of adventitious viruses that could be present throughout production. DETERMINING THE SAFETY MEASURES NEEDED Determining biosafety levels (BSLs) will help to identify the protective measures needed in a development and manufacturing setting in order to protect workers and the environment. In the US, BSLs have been defined (BSL-1 to BSL-4) by the Centres for Disease Control and Prevention (CDC), with the same levels applicable to the EU, as defined in a directive. Although by default, the BSL level for recombinant viruses is BSL-2, BSLs should be determined by risk assessment, as a lower biosafety containment level may suffice for incomplete viruses cultured in vitro. Different safety measures will be required as projects progress to commercial scale. For example, at early stages of R&D, lower grade materials may be used. These will eventually need to be replaced by higher grade materials for products to safely be used in clinical trials with patients. BEST PRACTICE FOR DESIGNING CGMP VIRAL VECTOR PRODUCTION SUITES It is important that viral vector production suites

are designed with the aim of reducing the identified risks and correlating safety measures needed as projects progress. There are several ways developers can apply best practices when designing their production suites: • D esign to prevent crosscontamination In conjunction with appropriate decontamination procedures, production suites should be built to prevent crosscontamination with carefully designed heating, ventilation, and air conditioning (HVAC) systems, and cleanrooms that adhere to set ISO standards. For viral vector production, there will often be a need for ISO 7 (<352,000 PPC [particles per cubic meter] at 0.5 μm) and ISO 8 (<3,520,000 PPC at 0.5 μm) cleanrooms. By designing HVAC systems whereby air is drawn and exhausted through separate pathways, the appropriate number of air changes can be achieved while minimising the risk of contamination between rooms. This provides flexibility to organisations working on different viral vector projects within the same facility. • P repare for potential hazards In the event of an unplanned release of bioactive materials, for example from bioreactors, production suites should be designed to ensure hazard containment. Isolating and dedicating airflow between different suites helps to ensure that personnel in surrounding areas will be protected from exposure. Additionally, systems for monitoring room conditions should be used to raise awareness of detrimental changes to airflow, differential

17 pressures across different areas, or temperature fluctuations that could lead to safety risks. • Rely on expertise With ambiguous regulations, working with experts that possess a strong understanding of the risks involved in viral vector manufacturing, as well as previous regulatory experience in various therapeutic areas, can ensure the right safety measures are put in place. As regulations evolve, experts in viral vector production will likely be those that can effectively anticipate changes and properly prepare for them. PREPARING FOR THE FUTURE As the C&GT space continues to grow, it can be expected that the regulations and cGMP requirements surrounding viral vector production will continue to evolve. When designing a viral vector production suite, developers must ensure continued compliance with these changes to ensure the safety of both handlers and patients. With demand for C&GTs continuing to expand, there will likely be an increased reliance on experienced contract development and manufacturing organisations (CDMOs) offering viral vector production services in facilities designed according to best practices. These organisations will offer the additional capacity and capabilities required for cGMP manufacturing, the viral vector expertise and experience needed to anticipate regulatory changes, and the ability to design production suites that can withstand the evolving requirements.

CONTINUOUS MANUFACTURING

REVOLUTIONISING UPSTREAM BIOMANUFACTURING: Supporting the implementation of continuous perfusion cell culture

stablishing continuous manufacturing (CM) workflows is becoming increasingly popular for intensifying manufacturing processes within the pharmaceutical industry. This is particularly true for small molecule drug manufacturing, following the successful regulatory approval of several CM processes. However, for biopharmaceutical manufacturers, implementation of CM is more complex. Because biotherapeutics are produced using living cells, manufacturing requires highly specific process conditions. This is essential to maximise productivity and, most importantly, ensure the molecules produced fulfil the critical quality attributes (CQAs) which validate their safety and efficacy. A solution to meeting these required process parameters while intensifying production is a type of bioprocessing known as perfusion cell culture. By using a cell retention device and a cell culture media exchange system, this method enables manufacturers to maintain a high cell density under constant conditions for an extended period. This can improve productivity and allow for a smaller footprint. There are a number of different perfusion processes; the most suitable for integration into upstream CM workflows is continuous perfusion. ADVANTAGES OF CONTINUOUS PERFUSION As media exchange replenishes nutrients and removes waste products, a cell bleed prevents excess cell density. This allows continuous perfusion

to maintain a steady-state bioreactor environment. This state enables high cell densities and viabilities to be preserved for long periods of time—often for around 30–90 days—and product of consistent quality to be produced. By enabling manufacturers to intensify production, continuous perfusion can provide significant productivity benefits. Additionally, by removing the product of interest throughout the manufacturing process, improvements in overall product quality can also be achieved. These advantages can reduce overall cost of goods compared to traditional batch or fed-batch processes over the lifetime of the process.

WHERE IS CONTINUOUS PERFUSION NOW? Although there is significant interest focused on implementation of continuous perfusion processes, challenges remain. One of the primary obstacles currently facing manufacturers is the lack of comprehensive regulatory guidance. Although many regulatory groups are actively supporting the transition to CM and are continuing to issue advice to support its implementation, there is not yet a full set of “default” standards to which manufacturers can refer. This uncertainty makes many manufacturers hesitant to fully commit to implementing a continuous process. Outside of regulatory

challenges, there are also limitations with existing bioprocessing equipment, as many installed fed-batch workflows are not capable of facilitating continuous perfusion. There has been significant innovation to help support manufacturers, however, that requires installing new equipment in some cases. INNOVATIONS TO SUPPORT CONTINUOUS PERFUSION Process development solutions One of the primary challenges for manufacturers looking to establish continuous perfusion processes is the limited ability of current small-scale development tools. Specifically, existing small-scale bioreactors and high-throughput solutions are often unable to support

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the mass transfer needs of highdensity cell cultures as well as continuous media exchange. To overcome this challenge, R&D teams across the industry have developed approaches to simulate perfusion processes. Although many of these remain labour intensive and have limitations around the conditions that can be achieved, they are playing a vital role in developing the knowledge needed for progression towards continuous perfusion processes. There are also novel equipment solutions becoming available, including microbioreactors that are specifically designed for intensified and continuous process development, which could have a transformative effect. Single-use technology Compared to batch and fed-batch processes, initial continuous perfusion process development is often more time consuming. However, once the process has been established, this can be offset by productivity advantages. These advantages include allowing for smaller scale-up production operating volume targets, enabling manufacturers to reach clinical production volumes more easily. These benefits can be amplified using single-use bioreactors. By using lower volume single-use equipment, manufacturers can reduce their capital expenditure costs compared to stainlesssteel alternatives. Additionally, the process itself can become easier to replicate. Consequently, parallel small-scale set-ups can be established in multiple locations rather than needing a large central facility, lowering costs and possibly lead times, in the long term. Bioreactor design Due to the high cell densities that perfusion achieves, existing equipment can struggle to meet the necessary mass transfer and agitation requirements of the cells. To help support perfusion processes, equipment

manufacturers now offer bioreactors with specific features that can overcome these challenges. This includes appropriately sized mass flow controllers to regulate gas flow at higher rates and better designed spargers to optimise oxygenation. Agitation design is also a critical factor as agitators need to provide increased movement without causing cavitation, sheer stress issues, or excessively influencing sparge behaviour. Process analytics Advances in process analytical technology (PAT) are also enhancing perfusion workflows due to their crucial role in helping to achieve, and then maintain, an optimal steady-state environment. In particular, spectroscopy and capacitance-based solutions are continuing to see increased use. One recent PAT development that has simplified the monitoring of perfusion processes is increased use of autosamplers. These can play a major role as, due to the relatively slow changes in steady-state cell culture conditions, they are able to make pseudo, real-time process adjustments. Feedback from at-line instruments can enable manufacturers to automate identification of any deviations using the same at-line instrumentation they already use to qualify their processes. Media formulation In addition to the process equipment, another crucial element of perfusion workflows is the cell culture medium used. This is important as the medium provides the essential compounds and nutrients required for maintaining high cell density and achieving maximum productivity throughout the process. Crucially, the requirements for a cell culture medium used for perfusion are distinctly different to those used in batch and fed-batch processes. For example, a perfusion

medium must be formulated with a higher osmolality to offset the drop associated with typical perfusion workflows. It must also balance running richly on highly consumed components and lean on components that risk build-up in cells in a way that minimally inhibits cell growth rate. To simplify process development, it is also optimal for the same medium to be used throughout the workflow—from initial seed-train steps through to steady-state perfusion. To meet these requirements, media manufacturers have developed commercially available media products specifically designed for use in perfusion processes.

Author: CHRISTOPHER BRAU, R&D process development manager, Thermo Fisher Scientific

FUTURE OF CONTINUOUS PERFUSION CELL CULTURE Although there remain several key challenges preventing widespread uptake of CM within the biopharmaceutical industry, significant progress has been made over recent years. By combining the latest technological innovations with increasing process development knowledge and regulatory guidance, implementation of continuous perfusion is becoming increasingly achievable for manufacturers. Through continued development in these areas, the biopharmaceutical industry has the opportunity to embrace the CM revolution alongside small molecule manufacturers and achieve fully intensified biologic manufacturing.

There is not yet a full set of “default” standards to which manufacturers can refer. This uncertainty makes many manufacturers hesistant to fully commit to implementing a continuous process.

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End-to-End High Potent Solutions with PCI Author: David O’Connell, director of scientific affairs at PCI Pharma Services Tredegar site Drug products containing high potency active pharmaceutical ingredients (HPAPIs) continue to be a major driving force in the global pharmaceutical market. Consequently, Contracted Development and Manufacturing Organisations (CDMOs) that are able to provide end-to-end solutions for the development and manufacture of highly potent solid oral dosage forms remain a vital part of the pharmaceutical outsourcing industry. Recent data suggest that between 2021 and 2026, the small molecule drug discovery market will register

a compound annual growth rate (CAGR) of 8.05 percent, indicating a growing need for these dosage forms. Oncology remains at the forefront of this demand, accounting for approximately 38 percent of all new small molecule drug candidates1, with around three‑quarters containing HPAPIs.2 For an active pharmaceutical ingredient (API) to be considered highly potent, it requires an operational exposure limit (OEL) of less than 10 μg/m3. Whereas it can be safely assumed that many, if not all, small molecule oncology therapies may fall

within this category, in reality many HPAPIs in development register a potency far greater than this. The greater the potency, the more targeted the medicine becomes, which is understandable given the innate complexity of oncologyrelated diseases, for example. PCI has developed and manufacture potent products since the 1980s, and in 2013 the Contained Manufacturing Facility (CMF) in Tredegar, South Wales was launched to increase our capabilities in this field. The CMF was originally built to fulfil a relatively unmet need for highly potent solid oral dosage forms, and was

designed in accordance with the latest safety, scalability and regulatory guidelines. After gaining almost a decade of operational experience with the first CMF, PCI has now expanded the Tredegar facility with a second CMF, essentially doubling our capacity for high potent development and manufacture. Combined with a new state-of-the-art high potent packaging facility, the Tredegar site is well-placed to deliver precision small molecule therapies to the market at commercial scale. Using oncology as an example, such medicines are often classified as extremely potent,

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which means they would fall within operational exposure band (OEB) 4 or 5. A molecule with an OEB 5 classification would register an OEL of less than 1 μg/m3. The design of the CMF, which prioritised engineered containment systems, allows for the safe handling of HPAPIs down to an OEL of 0.01 μg/m3. This ensures not just the safety of our operators when handling these molecules, but also the protection of our clients’ products. In order to on-board such potent drug substances with confidence, PCI routinely partners with recognised industry expert groups such as Affygility and Safebridge for the assignment of OELs to new molecules. By performing robust assessments of new molecules, PCI ensures the safe handling of the product throughout its lifecycle. Like many CDMOs, PCI is a multi-product facility. In order to prevent crosscontamination when using our equipment for development and manufacturing activities, a robust approach to cleaning verification and validation is essential. Establishing permitted daily exposure

(PDE) cleaning limits – known in the US as acceptable daily exposure (ADE) – early in the product lifecycle ensures no significant API carryover to the next product on the equipment train. An accurate risk assessment would include an understanding of the PDE/ ADE, equipment contact areas, batch sizes, API concentration and maximum carry over (MACO) data. Our experience with the original CMF places PCI in a strong position to ensure a strong NPI process, which In the current market, there is a strong desire to work with fewer outsourcing partners throughout a product’s lifecycle. The top 5 CDMOs occupy just 15% of the market share, with the remaining 85% experiencing a high level of fragmentation3. With this fragmentation comes a large number of CDMOs who are not able to offer end-to-end services, from clinical development to commercial launch. PCI’s ability to support clients by scaling-up from development to commercial volumes is of central importance when positioning us as a

true commercial CDMO. By utilising geometrically similar equipment and mathematical scaling models, this provides a greater success rate during this phase of process development. As increasing numbers of these precision medicines move from development to commercialisation, PCI’s ability to offer clients long-term partnership is hugely beneficial in terms of product knowledge and supply chain security. Our success with the original CMF and the recent site expansions positions PCI as a CDMO capable of growing with our clients and their products. As the market continues to evolve with increasing numbers of highly potent molecules in development, it is important to understand the requirements for the safe processing of such molecules, the differing regulatory requirements across the world, and – above all – the safety of employees REFERENCES

and the environment. For pharmaceutical developers looking to outsource the development and manufacture of products containing HPAPIs, the challenge is finding a CDMO with the right technical capabilities, knowledge and experience to successfully manage the project. At PCI, we believe that applying in excess of 30 years’ experience of managing highly potent molecules, combined with our purpose-built CMF and high potent packaging suite, is the key to success making PCI the logical partner of choice. We pride ourselves on being able to offer a true end-to-end supply chain solution, allowing clients to move seamlessly from late-stage clinical manufacture to commercial launch and ongoing market supply. https://pci.com/pharmaceutical-manufacturing/?utm_ source=EPM-Magazine&utm_ medium=Article&utm_campaign=EPM-Growing-HP-07-22

1. Small Molecules, Sizable Market Opportunities [Internet]. The Medicine Maker. 2022 [cited 28 June 2022]. Available from: https://themedicinemaker.com/manufacture smallmolecules-sizable-market-opportunities 2. Why Small Molecules Are Still a Big Deal [Internet]. The Medicine Maker. 2022 [cited 28 June 2022]. Available from: https://themedicinemaker.com/manufacture/why-smallmolecules-are-still-a-big-deal 3. L ess is more: Significant CDMO consolidation expected as pharma looks to work with fewer suppliers [Internet] Outsourcing Pharma [cited 28 June 2022] Available from: www.outsourcing-pharma.com/Article/2018/10/22/Top-5CDMOs-hold-15-of-the-market-as-industryconsolidation-is-expected-tocontinue

PERSPECTIVE ON PHARMA Future proofing the pharmaceutical industry through automation creating effective supply chains

ne of the largest growing areas for the supply chain industry is pharmaceutical logistics. With consumers taking a hands-on approach to their healthcare and medication being more personally prescribed, the demand for pharma products has rapidly increased since 2019. Pharmaceutical companies are now taking more of a consumer approach, for example GSK recently split the business into two distinctive sides through the launch of its consumer arm, Haleon. Once an industry driven by B2B trading, now faces the challenge of staying ahead of the curve by jumping on the pandemic induced e-commerce boom, quickly and effectively to maximise business outputs. Online pharmacies are scaling up stock from recognised brands in order to meet customer demand, but currently there is a lag due to this being a developing service for UK consumers. Whilst the pharmaceutical industry remains largely profitable, there is more opportunity to be had with the implementation of smart automation into its supply chains to significantly improve lead times. AUTHOR Jon Brewin, business development manager, AutoStore.

Fortunately, there are many technical applications that can support future proofing a business. Warehouse automation is one of the main drivers. A current challenge is space, with commercial property being in high demand

and limited options, businesses need to think strategically how they can store and export their products without reducing margins because of costs of commercial property and wait times. We are seeing this with onshoring, normally heavily

reliant on overseas shipments and limited warehouse space to store stock, by keeping more stock onshore utilising existing footprints these can be upscaled through smart storage. Technologies such as automated storage and retrieval systems

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Technologies such as automated storage and retrieval systems for picking can increase uptime by over 99%.

for picking can increase uptime by over 99%, providing accuracy and flexibility in turn around times. These systems can also adapt to business growth, easily expanding to meet capacity requirements in tune with order fulfilment demands without compromise on location. E-commerce sales increased by 14% in 2020. With bricks and mortar still taking a large percentage of the market share, e-commerce is on a healthy incline and industries need to be readily equipped to adapt to this. We have seen a drive in directto-consumer deliveries for over the counter and prescription medicines. This is putting pressure on pharma wholesalers and smaller medical centres to adapt their existing distribution processes to meet this surge in demand for next day delivery. Outside of e-commerce, pharmaceutical companies need to be able to cater to their existing base of manufacturers, clinics, hospitals, practices and nurseries meaning they have to be able to grow and continue to provide the same, or a better level of service. AutoStore offers a system that ensures the safety of its users and can be implemented in an optimal environment for a variety of medicines and sterilised products. With controlled environments, an automated system can house products at a range of temperatures and humidities to reduce the risk of contamination and product waste, whilst maintaining the strict standards and regulations required for the storage of healthcare products. Manufacturer and distributor of medical supplies, Medline Industries, was an early adopter of AutoStore systems in 2013. Due to the business growing exponentially, Medline saw

23 the opportunity to invest in automation which would meet the businesses growth and firm its position in a competitive market. Investing in 56,000 m2 of grid system, housing 47 robots and 28,000 bins, Medline was able to overcome three challenges. Increasing item picking, decreasing dispatch times to fulfil orders, and run a successful enterprise in a shortlaboured market. What made the Medline operation particularly challenging is, besides the large customers who order in bulk, there are also thousands of customers who put in small orders. These small orders are as much of a priority to Medline as are their big orders from organisations. Medline worked on distributing goods in two ways: bulk cases - which make up 30–40% of Medline’s sales - were transported by forklift to the staging areas to be manually picked the correct quantity of items for shipping and distribution. The second part of the picking and distribution process involved the AutoStore system for individual orders following the success of the first install Medline have since invested in several other sites as a result of the increase in uptime and efficiency. Medline are one of many global examples taking advantage of this natural next step for the pharmaceutical industry companies are posed with the challenge of standing out in a highly oversaturated market, and need to address this by increasing operational efficiency through the investment of supporting systems. Automation adoption will not only better their economic growth in the long run but contribute to excellent brand awareness, driving further investment from consumers and partners alike.

LOGISTICS & DISTRIBUTION

Author: Mahesh Veerina, president and CEO, ParkourSC

Innovations in Real Time Supply Chain Operations Can Solve Logistics and Distribution Challenges

hocks to the global pharmaceutical supply chain are more frequent and have a bigger impact than ever before. Pandemic disruptions, labour shortages, logistics and distribution challenges, human error, operational inefficiencies, geopolitical crises and more have all conspired to create significant hurdles that have stymied supply chain operations for countless organisations.

For reasons we’ll explore, pharmaceutical supply chains are particularly hard hit. Fortunately, the right modernisation efforts can help ensure resilience and spur ongoing innovation in the face of these challenges. In this article, we examine how this is possible through solutions that bring improved levels of digitisation, visibility and control to pharmaceutical supply chain environments. STEEP SUPPLY CHAIN CHALLENGES IN PHARMA In the past few years, the pharmaceutical industry has faced highly visible challenges, particularly relating to the development and distribution of COVID-19 vaccines. The

numbers are significant and the instances many. On a global scale, the World Health Organisation estimates that up to 50% of vaccines are wasted every year. Extrapolated to the scale of COVID-19, this spoilage rate could waste a billion or more vaccine doses – a staggering waste of health care resources. The United States Center for Disease Control (CDC) reported that at least 15 million doses of the COVID-19 vaccine were wasted in just a 6 month period last year. That’s a conservative estimate that doesn’t even cover all places that handle, store and administer vaccines. And then there are cases where vaccines don’t pass quality inspection to

begin with – including a New York Times account of nearly 400 million doses scrapped by a manufacturer due to poor quality control. Much of this waste can be attributed to shortcomings in logistics to support an unbroken cold chain. Failures in the pharmaceutical cold chain alone cost the industry an estimated $35 billion (around £29 billion or €33.7 billion a year). That’s because temperature variations in transit, warehouse delays and other breakdowns that might constitute moderate inconveniences in a typical supply chain can have devastating impacts for pharmaceutical cold chains. A single anomaly can cause entire

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batches of product to be ruined, contributing to the statistics cited above. Whether it’s environmental conditions, tight product expiration windows or any of the more common pain points all industries endure in their supply chains, the central challenge is visibility and the ability to take real-time action to correct excursions. Many pharma companies struggle with a lack of visibility across the full supply chain journey of drugs and therapeutics, from development to patient, and every step in between. This lack of visibility manifests in poor planning, inaccurate predictions and delayed decision-making – all of which increases risk, leads to waste, and erodes value for the organisation. THE POWER OF DIGITAL TWINS Across the whole supply chain logistics ecosystem of customers, suppliers and transportation modalities, what’s needed are new technologies for supply chain visibility and control. One particularly powerful approach for mitigating losses and positioning the organisation not just for resilience, but for ongoing innovation, is to implement digital twin technology. A digital twin is a virtual representation of the entire supply chain ecosystem – a virtual map of assets across operations and business processes that’s built from vast amounts of accessible, real-time, ground truth data flowing across connected systems. By digitising and monitoring the end-to-end supply chain, the resulting digital thread of connected data allows supply chain constituents to model and optimise operations. Digital twins enable the

generation and sharing of deep data intelligence drawn from numerous sources across every supply chain constituent. The modelling happens virtually, so digital twins can be safely and economically deployed to enable real-time supply chain operations. The enhancements in visibility, control and decision support help pharmaceutical manufacturers meaningfully tackle new and legacy challenges – and actively course correct using a “real-time, all the time” approach to bridge the gap between plan and execution. Supply chain executives can model and run simulations and whatif scenarios for failure planning, disruptions and supply-demand fluctuations. When implemented across the extended network of suppliers, production, transportation and other partners in the extended value chain, digital twin can optimise operations and accelerate value through live, real-time collaboration portals – convening stakeholders across the enterprise in a collective effort to safeguard quality and ensure compliance in drug substance and drug product integrity and security. ORCHESTRATING DATA AND ASSETS TO REAP MAXIMUM VALUE Critical to the success of digital twin capabilities are the standards and processes around the data that make up the digital thread – the orchestration of data that shapes how the digital twin modelling process itself will work. A key categorical distinction to make here is between tracking so-called “hard attributes” and “soft attributes” in the supply chain. Whereas tracking hard attributes involves visibility into the location and condition of goods and supplies in real time as they move through the supply chain, tracking soft attributes accounts for the business processes and workflows that apply throughout this journey. When pharmaceutical enterprises pursue visibility through tracking both hard and soft attributes together, they can achieve more granular visibility into business processes and are quicker at flagging any exceptions or organisational bottlenecks. They also have more robust data sets to fuel more proactive, and even predictive, digital twin modelling scenarios. Each form of tracking is unique: Hard attribute-based tracking uses IoT sensors and contextual systems to capture and interpret the ground truth on raw materials, components and finished goods in real time. This gives visibility into delays or temperature excursions in transit, or whether a component at rest is damaged at the factory or warehouse. Soft attribute tracking, meanwhile, focuses on events from workflows involving orders, shipments, documentation like trade clearance, quality and compliance, customs etc. and whether this

The World Health Organisation estimates that up to 50% of vaccines are wasted every year.

25 paperwork and processes are running smoothly – flagging any discrepancies in pricing, delivery schedules, contract terms or related processes. Taken together, the combination of hard and soft attribute tracking drives digital twins toward a fuller picture of supply chain health – one that enables faster identification and resolution of problems. Data from incidents are fed into deep machine learning and reasoning algorithms to support real-time decision-making and even predictive analysis and issues resolution. CONCLUSION Powered by strong digital threads and optimal data standards and asset management, digital twin solutions can enable unprecedented visibility and intelligence into minuteby-minute adjustments for continuous supply chain optimisation in life sciences. And thanks to low-code/no-code scripts, AI and machine learning algorithms, and collaboration technologies, digital twins can be shared securely across partner networks to enable predictive intelligence and automated workflows across the entire supply chain. Ultimately, robust digital twin implementations can help life sciences companies monitor changing conditions and incorporate ground truth to optimise operations across the ecosystem – from initial sourcing to the last mile delivery. While this specialised industry may have especially steep supply chain challenges, those in charge of keeping production moving and profitable can take heart in the increasing power of technologies such as digital twins.

Wastewater is anything but a waste – it could even prevent the next pandemic

esearchers are using innovative technologies and artificial intelligence tools to study the contents of our sewers. Sewers hold a detailed record of a community’s health, containing the substances consumed and expelled by the population. That’s why researchers and health officials are using wastewater analysis to glean information about the health of citizens and the environment, to detect diseases, and trace their spread early on. The outbreak of COVID-19 two years ago triggered an explosion of interest in wastewater for the study of epidemics, through the analysis of microbial bodies and substances that stem from the human digestive track and proliferate in sewage systems. Now, two years into the pandemic, two things are clear: first, that a global effort must be made to develop and implement even more proactive monitoring systems that can be used to track and hopefully prevent other potentially deadly diseases down the line. And second – that our sewers may hold the answer. Read the full article on the EPM website at: https://www. epmmagazine.com.

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CALL FOR GOVERNMENT TO TURBOCHARGE UK CANNABINOID INNOVATION Check out the latest news and interviews from our recently held Med-Tech Innovation Expo, the leading event for medical device and supply chain intelligence, at: www.med-technews.com.

new published report sets out 20 key recommendations which, upon implementation, would set the UK on a path to become the global leader in cannabinoid innovation. From Containment to Nurturing: How the UK can become a world leader in cannabinoid innovation was commissioned by The Centre for Medicinal Cannabis and the Association for the Cannabinoid Industry. It is authored by renowned regulatory thinker, professor Christopher Hodges and draws on wide ranging inputs from leading industry players, academics, patients, consumers and investors. The report views the

cannabinoid sector through the lens of Outcome-Based Cooperative Regulation, a regulatory philosophy pioneered by Hodges. He argues that for regulations to be effective, they need to be based in trust and collaboration. Included in the recommendations are calls for GPs to be allowed to prescribe medicinal cannabis, updates to hemp farming rules, modernisation of the Proceeds of Crime Act and the creation of a national patient registry for all cannabis-based medicines prescribed in the UK. Read the full article on the EPM website at: https://www. epmmagazine.com.

BE SURE TO LISTEN TO The latest episode of The MedTalk Podcast features Oli Hudson from Wilmington Healthcare discussing procurement in the NHS and what it means for the medtech industry.

14 & 15 September 2022 | Geneva, Switzerland

The new event at the heart of European pharma dedicated to innovative packaging, drug delivery systems, CDMO/CMO and filling & assembling processes

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COME TO THE RESCUE! Tooling & Tablet Design I Tablet Presses I Replacement Parts & Accessories Tablet Press Refurbishing I Technical Training I Consulting Services Encapsulation Change & Spare Parts I Instrumentation & Software I Laboratory Services

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Articles inside

TALKING POINTS

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COATINGS & CAPSULES

CONTINUOUS MANUFACTURING

CONTAINMENT & CLEANROOMS

A SMALL DOSE

LOGISTICS & DISTRIBUTION

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PERSPECTIVE ON PHARMA