Digital trust is crucial in modern cybersecurity, defined as users’ confidence in the ability of people, technology, and processes to create a secure digital environment.[1] It mirrors patients’ essential trust in pharmaceuticals; both scenarios involve an intrinsic relationship where the end user relies on a product’s safety, efficacy, and reliability. This parallel underscores a universal truth: trust is a vital currency in any sector where the consumer has limited visibility into the processes, whether it involves medications or technological services. In the pharmaceutical industry, trust is built over time through painstaking research, regulatory compliance, clinical trials, and ongoing evaluation through pharmacovigilance, all designed to assure patients and providers of a drug’s safety and effectiveness. Similarly, in IT services, particularly cybersecurity, trust hinges on best practices, transparent processes, and verifiable outcomes.
The CrowdStrike incident: a case study
The CrowdStrike incident on July 19, 2024, provides a poignant case study highlighting the crucial need for digital trust. An update to the Falcon sensor application led to widespread outages, impacting approximately 8.5 million Windows machines due to a substantial coding error. The responses post-incident unveiled vital factors that contributed to the outage: a flaw in a content validation process and the failure of specific testing protocols that could have identified the potential vulnerability.[2] The dynamics of the events resembled the Swiss cheese model of accident causation.[3] CrowdStrike’s response to the incident – committing to enhanced software testing and adopting a staggered deployment strategy – reflects approaches commonly employed in the pharmaceutical industry. As pharmaceutical manufacturers routinely revisit and refine their quality assurance processes, software vendors must continuously improve their development and release processes.
Lessons learned and recommendations
A key takeaway from the CrowdStrike incident is the risk associated with automated updates, which, although crucial for efficiency and maximum protection, can result in widespread failures. Cybersecurity solutions vendors should prioritize software testing processes to mitigate future incidents, emphasizing the importance of extensive and exhaustive code testing before deployment. Moreover, effective communication strategies are vital to maintain transparency during IT incidents. The CrowdStrike outage spotlighted organizations’ need to provide clear directions regarding the incident’s cause, immediate remediation actions, and preventive measures moving forward. Drawing parallels with the pharmaceutical industry, organizations must also foster a culture of accountability, demand adherence to ethical practices, and demonstrate a proactive stance toward the quality of processes and products. Building digital trust through more effective software testing or responsive communications is imperative for long-term success in today’s digital-centric marketplace.
In a post published on the association’s blog and signed by Alexander Olbrechts, director Digital Health, MedTech Europe turned the spotlight back on the possible impact of the AI Act, the new European legislation that aims to regulate the safety and quality aspects of artificial intelligence applications. An area that is presented to offer numerous opportunities in the field of medical technologies as well, side by side with just as many challenges in how to implement them.
First and foremost is the need to integrate the new provisions of the AI Act with what is provided by existing industry legislation, most notably the Medical Devices Regulation (MDR) and the In Vitro Diagnostics Regulation (IVDR). MedTech Europe’s goal here is to continue the dialogue with European legislators to ensure that the two strands of legislation actually complement each other, avoiding duplication of activities or conflict with procedures already in place.
One of the main goals of the AI Act, moreover, is to arrive at a smoothly flowing compliance process for AI-enabled medical technologies. A goal that, according to Olbrecht, should involve aligning compliance assessment with what is already in place in the MDR and IVDR regulations. The suggestion here is to maintain the existing technology codes for notifications to authorities and notified bodies, to which is added the possibility of assisting sectoral notified bodies with designation procedures under the AI Act, avoiding delays.
The MDR and IVDR regulations also introduced a strong component of clinical investigations and studies on device performance to support their efficacy and safety. According to Medtech Europe, the AI Act should serve as a facilitator in this regard, and a specific priority clause should be provided for the MDR and IVDR regulations in case of conflict with the provisions of the new AI legislation. MedTech Europe’s request is that it be definitively clarified that clinical and performance evaluations should be considered exempt from any requirement for CE certification under the AI Act, and thus continue to follow the pre-market testing rationale established of two medical device and in vitro diagnostic regulations.
Finally, there is no shortage of mention of the development of new digital therapies, in which AI models and data analytics play a key role in the development, for example, of innovative diagnostic solutions that can reduce the need for hospitalization.
An information note agreed between the European regulatory authorities and AIFA (the Italian medicines agency) reports the results of a retrospective study, according to which the risk of venous thromboembolism (VTE) is slightly increased in women using combined hormonal contraceptives based on chlormadinone acetate and ethinylestradiol.
The conclusion comes from the retrospective cohort study RIVETRCS, according to which the risk of venous thromboembolism increases 1.25-fold with this type of contraceptive compared to women taking combined hormonal contraceptives containing levonorgestrel. Based on these results, the annual risk of VTE in women taking chlormadinone acetate with ethinylestradiol is estimated at 6-9 cases of VTE per 10,000 women.
These data are compared with an annual incidence of 5-7 VTE cases per 10,000 women using low risk combined hormonal contraceptives containing levonorgestrel, norethisterone or norgestimate, and with 2 VTE cases per 10,000 women not using a combined hormonal contraceptive.
The decision to prescribe a combined hormonal contraceptive must therefore take into account the individual woman’s risk factors for VTE and be based on a comparison with the VTE risk of other combined hormonal contraceptives. AIFA also points out that the risk is highest during the first year of use of any combined hormonal contraceptive or upon resumption of treatment with combined hormonal contraceptives after a break of 4 weeks or more.
Quality Culture has evolved into a critical component for biopharma and medical device companies since it was initially established in the early 2000s, when both regulatory agencies and industry were focused on increasing quality throughout the entire life cycle of product development. It has become clear that, whatever an employee’s position is – from technician to C suite executive – every department of the company should be built around quality so that the end goal is to ultimately provide the end-user – the patient – a quality drug or medical product.
Over the past 10-20 years, companies have developed the work required to develop a Quality Culture; some have accomplished this, but some have not. Initiatives taken to advance towards Quality Culture include working on regulatory deficiencies and all issues that can trigger the receipt of FDA warning letters; these initiatives require hard work to actually equate all work done to true Quality Culture. Everyone in the organization must be fully knowledgeable about quality; the quality concept must be instilled as a critical requirement in their jobs.
In addition to ensuring training and educating all employees on the importance of Quality Culture, another challenge, especially for older companies, is bringing their facilities thoroughly up-to-date, including equipment, computer and document management systems, digitalization, etc.; that can be costly and time-consuming. New facilities and those being planned should focus particularly on current and future trends, equipment, and digital capabilities.
For a solid 25 years, PQE Group has been tackling these challenges head-on. But this year, they’re stepping up their game with some slick docu-videos delving into the vital realm of Quality Culture. Picture this: shining a spotlight on everyday heroes – patients leading ‘normal’ lives, courtesy of cutting-edge meds and devices. Prepare to uncover the origin story of the ‘Q’ factor straight from the company DNA, revealing why it’s an absolute game-changer.
The question to you, reader, at this point is: Does your Company have the “Q factor”? Find the answer through the story of :
Eva – “Veterinarians: Ensuring Quality Care for Animals”
Eva, a Tuscan veterinarian, has a special bond with pets and livestock. Her work is a source of love and fulfillment, but it also carries great responsibility: identifying diseases and conditions and ensuring the administration of correct and high-quality medication. For animals as well, the Quality Culture intrinsic to the medication they take is invaluable.
Alessandro – “Learning to Hear at 30” –
Alessandro has recently emerged from a world of silence, thanks to a cutting-edge cochlear implant. We’ll delve into how top-tier medical devices, like Alessandro’s implant, can profoundly enhance patients’ lives. The documentary highlights the vital role of quality culture within companies to guarantee dependable and impactful products. It showcases the fusion of technology and corporate dedication in delivering transformative medical solutions. Join us on this journey celebrating hope, progress, and the imperative of investing in innovation for a better tomorrow.
Elisabetta: “Elevating Hope: Advocating for Cannabinoid Therapy”
Elisabetta is an amazing Italian woman affected by several pathologies, including Arnold Chiari, Ataxia, and Small Fiber Neuropathy, which cause chronic pain, tremors, and severe headaches. Having experienced significant benefits from using medical cannabis, she has long been advocating for institutions to recognize the importance of cannabinoid therapy. It’s crucial to highlight the significance of managing medical cannabis across all stages and ensuring Quality Culture to deliver the best possible product for patients.
Be sure to visit PQE Group’s Quality Culture page to view these informative, and important, videos to stay on top of new and exciting industry developments that utilize Quality Culture clicking on the QR Code here below!
In an area covering almost 1,400 sqm, the Pharmaceutical Divisions of IMA Group and its specialists are glad to introduce IMA Pharma, the All-In-One supplier specialized in the design and manufacture of innovative machines and complete lines for the processing and packaging of pharmaceutical and nutraceutical products, medical devices assembling, as well as projects concerning digitalisation, sustainability, and customer service solutions.
Meeting the Divisions at the show
IMA Active is the ideal partner for each solid dose processing phase: granulation, tableting, capsule filling and banding, weight checking, coating, handling and washing. On show AQUARIA, the new all-in-one solution to wash components and machine parts of different sizes and volumes in completely automatic mode, ensuring greater efficiency and respect for the environment; the Continuous Direct Compression Line (CDC Line), a very lean, efficient and flexible tablet-manufacturing technology that, in combination with PAT, allows easy adoption of a QbD approach, ensuring excellent operation performance and avoiding waste during startup and shutdown; the CROMA continuous coater, designed to cover a range of throughputs and a range of coating weight gains thanks to its innate modularity; a single CROMA module works in ranges between 20 and 100 kg/h and with an average weight gain of 2-4%, depending on tablets and film types; the ADAPTA 50 capsule filler, featuring innovative technical solutions to manage complex solid dosage forms such as product combination in hard gelatine capsules or powder micro-dosing for Dry Powder Inhalers. The ACCELA CTC 500 continuous coater by Thomas Processing is designed to manage high production throughputs in a range of 100-1,000 kg/h of large batch sizes of tablets to process in continuous mode, being the only coater on the market manufactured with an integrated cooling chamber that eliminates the need for additional cooling systems, reducing the footprint of the equipment and streamlining the coating process. On show also the IMA Active Competence Center, a specialised and centralised hub for knowledge and resources, providing support, training, and guidance in the oral solid dose field.
IMA Life offers a comprehensive product portfolio to process liquids and powders in aseptic and non-aseptic environments. Solutions include washers, depyrogenating tunnels, liquid and powder filling and closing machines for vials, ampoules and Ready-To-Use (RTU), freeze dryers and relevant automatic loaders/unloaders, isolation technologies, labellers for vials and cartons and ancillary equipment. On show, the integrated line composed by NEBULA, the high speed-decontamination tunnel which integrates seamlessly with IMA Life aseptic fill-finish lines, ensuring 100% sterility of RTU material and INJECTA 36, advanced robotic fill-finish solution which raises the bar for the high-speed processing of RTU syringes. Introducing an innovative solution for 100% In-Process Control and check-weighting, INJECTA 36 is further proof of the key role played by IMA Life in the Ready-To-Use segment for automatic filling & closing machines, able to maximise production performance. In a segregated area of the booth, you will be able to discover in world premiere TILE-X, IMA Life’s ground-breaking innovation in the field of fill-finish processing for small batch production. Based on electromagnetic levitation, TILE-X is a compact, Grade A, gloveless modular processing unit for high-value pharmaceuticals such as ATMPs. Also on show, MODULA 300, the assembly machine for pre-filled glass syringes capable of performing several operations: plunger rod insertion, labelling, backstop assembly, and a dedicated hub for isolation technology. Our aseptic processing experts will introduce you our isolation solutions: highly configurable, they adapt to different production environments, enhancing versatility and applicability to different manufacturing contexts including high-containment scenarios. At the LAB4LIFE Lyo development Laboratory corner, IMA Life’s experts will present KryoAir, our new 100% green refrigeration technology for freeze dryers using the ultimate natural refrigerant: air.
Along with the equipment displayed at the fair, customers will have the opportunity to experience firsthand various digital solutions aimed at reducing maintenance costs and downtime. These solutions leverage real-time monitoring, event forecasting, and fault prevention through the analysis of vast amounts of process and equipment data, ultimately leading to an increase in overall equipment effectiveness and compliance with current regulations.Along with the equipment displayed at the fair, customers will have the opportunity to experience firsthand various digital solutions aimed at reducing maintenance costs and downtime. These solutions leverage real-time monitoring, event forecasting, and fault prevention through the analysis of vast amounts of process and equipment data, ultimately leading to an increase in overall equipment effectiveness and compliance with current regulations.
GIANT5-A96
Specialised in primary and secondary packaging, IMA Safe creates blister-packaging machines, capsule and tablet counters, sachet and stick-packaging machines, tube fillers and cartoners. End-of-line solutions, from robotics, handling, overwrapping to case-packing and palletizing are provided by the IMA EOL hub. On show the GIANT5-A96 integrated blister and cartoning line, which redefines the parameters in terms of flexibility, speed and compactness; the RED250-A96 deep draw thermoforming and cartoning line, a compact solution for medium-speed production of small batches requiring frequent format changes. Thanks to the robotic handling system, RED250 allows careful and precise manipulation of any type of product, introducing it into the tray with a wide range of possible configurations; the MINILINE bottle transport, filling and capping system able to integrate all the functions required to form a complete counting line with a simple and superior footprint: desiccant insertion, tablet or capsule counting, cotton insertion and capping, and can be configured for any product or container requirement and BETA 360 a high-performance vertical sachet packaging machines for 4-seal sachets, able to handle all types of products from paste products to fluid products, powders, free and non-free-flowing products, objects and accessories such as wipes.
The End of Line Hub’s experts will be also present to discuss and highlight the latest solutions available from IMA, completing the line. These include a wide range of options, from bundling and wrapping machines, case packers, palletizers and depalletizers, to state-of-the art, integrated systems featuring robotic solutions for enhanced flexibility and efficiency.
IMA AUTOMATION designs and manufactures advanced technological systems for the handling and assembly of a variety of components for diverse applications and in different sectors: automotive, E-mobility, electrical motors, medical devices, caps & closures, eye care, electro-mechanics and watchmaking. On show the X-PEN, the standard modular platform for pen and autoinjector final assembly. With the latest robust technologies, labelling as standard incorporated into the machine, quick time-to-market and compact design concept, the X-PEN system uses state-of-the-art, at your fingertips technology and ensures fast ROI.
Visitors will also have the chance to discover dedicated areas covering hot topics like Sustainability, Digitalisation and Customer Service Solutions.
Our specialists will be glad to provide with an overview of the initiatives we conduct to improve sustainability, including our OPENLab network where we develop and test the latest eco-friendly packaging materials alongside our customers.
IMA will showcase a diverse array of digital tools and virtual applications, beginning with machines equipped with IMA Sentinel connectivity. This will include a comprehensive suite of Artificial Intelligence solutions such as Sandbox and Algomarket, enhanced by advanced analytics. The event will also offer an opportunity to present IMA’s latest proof-of-concept in generative artificial intelligence, aimed at improving training, troubleshooting, and monitoring activities.
Additionally, targeted services like training opportunities, troubleshooting support, and a broad range of platforms for machine management will be highlighted, including the customer service portal, services provided globally to the pharmaceutical industry to maintain the highest production standards.
An Industry 4.0 control platform is made up of a complex architecture that integrates the functions of the different systemsincluded within it.
The Hazel® smart environment-control platform, for example, while enabling the integration of different systems according to user-defined rules and permitting their management through a web based software – also from mobiles equipped with a dedicated app – contains several devices that can also be operated as autonomous elements, such as the wall clock Hazel® Tempus.
This industrial clock has been specifically designed by Dos & Donts to be used in sterile manufacturing facilities– but it also proves useful in other industrial and non-industrial work environments – and it can be supplied and used independently from the integrated platform.
High precision to comply with pharmaceutical requirements
The need for the pharmaceutical industry to close each production batch filling out a Batch record compliant to GMP rules requires a strict control of exact times along the entire manufacturing process, with monitoring of all its phases and cycles. The Batch record contains detailed information on the time of starting and ending of the production, and other information describing each single passage of the industrial process, e.g. temperatures and concentrations and all the different materials and intermediates used for it. The signature of the Batch record by the in-charged person goes together with documenting also the specific date and time.
To meet the GMP’s requirements, a precise and synchronized time indication through all manufacturing departments is needed.In the Industry 4.0 architecture, this demand has been catched up by Dos&Donts by proposingHazel® Tempus,a wall clock developed according to the new paradigms and specifically studied to be placed into clean rooms.
The clock can be freely integrated with smart systems different than Hazel®, and can receive inputs and exchange informationallowingfor the carrying out of actions at specific time viathe TCP/RTU Modbus protocol. Time synchronization across the clocks present in the different manufacturing units, as well as across the different equipment’s and devices operating along the production chain, is provided by connecting to a NTP server or to a BMS via TCP/RTU Modbus.
The time indicated by Hazel Tempus is clearly visible at each moment to operators thanks to its wide and bright LED 4-digit display. Offering an input and an output, the wall clock also provides actuations functionalities, that can be activated or disabled by a pre-defined time schedule or upon achievement of a specific event .
Furthermore, the auxiliary serial connection allows to use the wall clock in conjunction with otherdevices, for example a printer to print out start and ending of a specific operation
The technical characteristics
Hazel® Tempus is characterised by a very thin layout (just 41 mm) and can be easily installed into the wall; its stainless steel structure houses a coplanar display, creating a completely flushstructure highly resistant to common sanitizing agents used in clean rooms, and making the wall clock ideal to be used within controlled contamination environments.
Once placed on the wall and connected to the facility’s LAN network, connection to Hazel® Tempus through a specific interface enables the necessary configurations setting.
Hazel® Tempus can be poweredPoE or 24Vdc; it can provide an alarm in case of synchronization fail with the NTP server. Thanks to the internal battery, the current time is not lost even in case of power fail. Four different alerts are available, which can be pre-set at established times in order to automatically activate – for instance – lights, fans, acoustic alarms or send a signal on Modbus.
If integrated with other systems, Hazel® Tempus allows to activate specific actions – i.e. video recording, emission of light or sound signals, opening of interlocked doors, etc. – upon the achievement of a pre-determined time or event.
The keywords of the third millenium are digitalisation and interconnectivity: the new paradigm of automation is based on the wide availability of data from digitally integrated systems allowing for greater traceability, flexibility, adaptability and efficiency of the smart factory. Pharma 4.0 reference model of vertical and horizontal integration relies on enabling tecnologies such as IoT, augmented reality, additive manufacturing, simulation, data analytics, cloud computing, smart robots,cyber security.
In a holistic approach, these technologies can be profitably applied not only to the Pharma process but also to the production environment, where different control systemsinteract between them and with the process.
Many different modules for Environment controls
Diverse environment controls are required in Pharmaceutical manufacturing to grant the compliance to GMP standards and to support optimized product quality, especially in the strictly regulated cleanroom environment.
This includes controls to be put in place to match the sometimes conflicting needs ofproduction quality (GMP) and personnel safety (HSE) as for instance at the level of operated doors, interlocks, personnel access, doors interaction with AGVs, critical environmental parameters, communication between areas.
All these systems can be interconnected between them providing data alarms andprompt information on any anomalous situation affecting production or operator safety. Under the Industry 4.0 approach, an environment control platform should be able tocommunicate using technologies such as Lan and IoT, to easily integrate with building systems (i.e. Scada and Dc systems). Data can be collected, logged and managed in compliance with CFR21 Part 11 requirements, cloud data storage can be profitably used for integration with other platforms.
A complete, and open, multi-layer platform
This approach requires the availability of platforms to host and operate the different functions and controls. An example in the field of environment control is the Hazel® multi-layer platform developed by Dos & Donts: each of its small intelligent modules is dedicated to a specific function and is able to communicate with the others through WiFi/Lan connections. The final result are “tailor-made” complete and easy scalable systems that can be designed to reflect all different applicative needs, simply plugging together multiple basic units to form increasingly complex systems. Hazel® is also an “open” platform, as additional systems can be integrated at all times. The modular approach also provide benefits to reduce the hidden costs for installation, management and maintenance.
A user-friendly MMI
The interaction between the different units can be regulated by user-defined rules; easy of use is increased by the possibility to set the units working parameters using a mobile device equipped with the dedicated App.
All data collected by each unit are real time transferred to the dedicated webserver unit Hazel® core, equipped with “Sigma”, a web based software which provides the data log and allows for real-time monitoring, statistics elaboration, triggers and interaction rules among connected units while operating as “system manager”. Data stored into the webserver are readily available to the BMS via a Tcp Rtu Modbus interface; in alternative, data can also be
accessed through the dedicated Hazel® cloud portal. Data security is safeguarded by the use of encryption protocols.
Smart bricks to personalise the systems
Each different industrial plant has its own, specific needs as for Environment control, that should be captured and reflected by the architecture of the control systems (see figure).
Each different function is managed by a specific “smart brick”, which can work autonomously or can be connected to the Hazel® core server.
Among the smart bricks Hazel® Visio, a touch screen Led display, and Hazel® Aditum, an access control reader, both specifically designed for cleanroom environments. Motion within the cleanroom can be monitored using the Hazel® Moveo smart cam, while the combination of different modules of the Hazel® Janus smart door controller permits to create powerful and flexible door interlock systems. Hazel® Acta I/O smart interface can convert digital I/Os to be transmitted on a Tcp or WiFi data line. It can be used to collect data from sensors and to drive outputs according to defined specifications. The I/O controller provides an acoustic signal for local event notification.
The Hazel® platform easily integrates with many other Dos & Donts systems, i.e. the Ilock M16 panel that can manage from one to twelve interlocked doors, and the Multigates 12 web-based access control software for cleanroom
In this context, the aim of my PhD project was to study the combination of flow chemistry and biocatalysis in order to develop greener and scalable routes for the synthesis of high values chemicals and active pharmaceutical ingredients (APIs), e.g., Captopril, an angiotensin-converting enzyme (ACE) inhibitor widely used for the treatment of hypertension. In particular, my attention was focused on continuous flow biocatalyzed redox reactions.
Methods
During my PhD, I performed heterogeneous reactions using immobilized biocatalysts (either whole microbial cells or enzymes) in packed bed reactors, also introducing a gas inlet when necessary. In many cases, the products were purified in-line, using scavengers or exploiting catch and release strategies, or performing in-line extractions and liquid/liquid separations. In this way, traditional work-up and chromatographic procedures were not necessary, the operational times were reduced and less amount of organic solvents was used, thus obtaining faster and greener procedures.3
Results
Here below, I summarize three different applications exploited during my PhD thesis that clearly demonstrate the potential of performing biotransformations in a continuous flow fashion: 1. Chemo-enzymatic continuous flow synthesis of Captopril
A chemo-enzymatic route for the synthesis of the antihypertensive drug Captopril [i.e., (S)-1-((S)-3- mercapto-2-methylpropanoyl) pyrrolidine-2-carboxylic acid] was developed in a continuous flow reactor. The process consists of four steps: the first one was a biocatalyzed regio- and stereo-selective oxidation (using Ca-alginate-immobilized cells of A. aceti) of a cheap commercially available prochiral diol (i.e., 2- methyl-1,3-propandiol, 1, Scheme 1). This reaction was performed with a segmented air-liquid flow stream. The air was necessary to guarantee the oxygen required for the reaction.
After isolation of the obtained carboxylic acid 2, the first step was followed by three chemical reactions (i.e., chlorination, amide coupling and nucleophilic substitution).
Scheme 1. Biocatalyzed oxidation of prochiral 2-methyl-1,3 propandiol
The continuous flow process leads to different advantages compared to the batch one: first, the overall reaction time was dramatically reduced from 3 days (batch) to 100 minutes (flow), increasing the overall yield from batch (45%) to flow (65%). In addition, it was possible to perform in-line purification procedures as in-line quenching and liquid/liquid separations, avoiding in this way the traditional, time-consuming work-ups and purification of intermediates. Only one column-chromatography purification was performed at the end of the process (Scheme 2).
Scheme 2. Schematic representation of continuous flow synthesis of Captopril after isolation of compound
2. Stereoselective reduction of di-ketones using an immobilized ketoreductase/glucose dehydrogenase mixed bed reactor
The stereoselective biocatalyzed reduction of di-ketones was optimized in flow to obtain the mono-alcohol products, some of them key intermediates for the synthesis of hormonal contraceptives (e.g., compound 6c, Scheme 3). The reactions were performed in a reactor packed with two immobilized enzymes, a ketoreductase (KRED1) from Pichia glucozyma and a glucose dehydrogenase (GDH) from Bacillus megaterium. The KRED1 performs the reductive reaction, while the glucose dehydrogenase was necessary to regenerate the cofactor used, that is NADP+. The BmGDH was able to do so by oxidizing glucose to gluconic acid.
Scheme 3. Di-ketones substrates and corresponding products
Reaction parameters (i.e., stoichiometry, concentration, temperature, pressure, residence time) were optimized and a complete conversion was observed with residence times between 7 minutes and 3 hours to form the enantiopure mono-alcohol. For all the substrates, the reaction was carried out in continuously for 15 days with no significant change of the chemical composition of the outflow solution. Noteworthy, after 6 months of operation, the flow reactor only lost 30-32% of the original activity 3. Oxidation of amines to aldehydes using an immobilized form of pure transaminase from Halomonas elongata
Benzylamine-derivatives were oxidized into the corresponding aldehyde-compounds using an immobilized transaminase from Halomonas elongata in a flow reactor (Scheme 4). This class of molecules is commonly employed as flavour and fragrance component in food, beverage, cosmetics and pharmaceuticals.
Scheme 4. Schematic representation of the oxidative reaction
For all the substrates, conversions ≥ 90% were reached within a residence time between 3 and 10 minutes. The products were directly purified in-line, with acidification and extraction with ethyl acetate. In some cases, the aldehyde product remained attached to the support used for the immobilization of the enzyme and an adjustment in the flow configuration was necessary. In these cases, a liquid/liquid biphasic system with toluene and buffer was used and an extraction with toluene was performed. The bioreactor was stable after several weeks of continuous work.
Conclusion
Flow chemistry and biocatalysis offer a broad spectrum of new and interesting possibilities that can change the idea of organic chemistry. During my PhD, I developed new chemo-enzymatic routes for the synthesis of pharmaceutically interesting intermediates, APIs and fragrances that can be considerable alternatives to the traditional chemical pathways. In all cases, the reactions were completely stereoselective, conversions were higher and productivities were increased compared to batch procedures, thus reducing the waste by reusing the biocatalysts for several cycles.
References
1) Ley, S. V. On being green: Can flow chemistry help? Chem. Rec. 2012, 12, 378–390 2) Tsubogo, T.; Oyamada, H.; Kobayashi Multistep continuous-flow synthesis of (R)- and (S)-rolipram using heterogeneous catalysts S. Nature 2015, 520, 329–332; 3) Bryan M. C., Dillon B., Hamann L. G., Hughes G. J., Kopach M. E., Peterson E. A., Pourashraf M., Raheem I., Richardson P., Richter D., Sneddon H. F., Sustainable Practices in Medicinal Chemistry: Current State and Future Directions, J. Med. Chem, 2013, 56, 6007-6012
Author affiliation
PhD in Chemistry at the University of Milan.
Department of Pharmaceutical Sciences (DISFARM), University of Milan, via Mangiagalli 25, 20133, Milan, Italy. E-mail: federica.dalloglio@unimi.it
A complete range of packaging services for all pharmaceutical forms, with reliability guaranteed by over 30 years of success and cutting-edge solutions. A slender partner that combines the flexibility of a SME with metrics and industrial approaches of a large company and has a clear target: helping pharmaceutical companies to overcome all those small and big obstacles related to packaging preventing them to focus on high value activities or to develop new initiatives, as explained by Federico Casaglia, one of CIT directors.
What is the philosophy of your company?
Our philosophy is written in the history of the group.
CIT was founded in 1986 and has remained true to its spirit for over 30 years: the awareness of the importance of being good helper in order to bring out a distinctive result for our customers and for us.
Today CIT is going through a period of strong discontinuity, with the aim of aligning its portfolio of services to what the market will require in the coming years and looking both at serialization and at future further automation to be prompted by the need to carry out processes increasingly integrated with each other in view of Pharma 4.0. We have implemented and will continue in the future to implement a truly impressive investment plan.
What kind of services do you offer?
We offer GMP services. In addition to traditional secondary and tertiary packaging services, to which serialization is added, CIT also provides value-added ones capable of satisfying a specific customer need: to get to the market in an appropriate way and in challenging times. For this reason CIT offers support in defining and managing the artworks, in procuring packaging materials through a validated network of suppliers, in releasing batches to the market and in managing the supply chain up to customer warehouses all over the world.
Which segments of the pharmaceutical market do you target?
CIT wants to be a one-stop shop. At present, we deal with many segments: ethical drugs, high activity drugs and antibiotics in controlled premises, biological drugs, OTC drugs, medical and diagnostic devices, as well as dietary supplements in segregated area. But it is still not enough for us. In the coming months we will
start clinical packing services for clinical trials and we will move towards the new frontiers of biotechnologies and “tailor-made drugs”. These activities require a high level of professional specialisation and extreme attention to product quality. Lastly, we will soon be ready to handle veterinary drugs as well.
What kind of technology do you use and what are your industry standards?
As today examples, I’d like to mention the integration between Erp and the serialization system, and emphasize that, in a logic of integration, we have prepared a qualified ICT infrastructure and a series of processes ensuring adequate governance. In addition, we have always had a policy of investing in young people to work with persons of proven experience responsible for transferring their knowledge and developing the most appropriate skills in order to meet the challenges ahead.
What distinguishes your production lines from those of other companies?
Our production lines are based on a 30-year partnership with the market leaders on packaging lines and we carefully follow their continuous evolutions. CIT has always used a network of suppliers that are qualified and recognized as best-in-class. This choice allows us to guarantee the business continuity of our customers and to have a reliable and scalable technological base. We have been pushing hard on Pharma 4.0 in recent years. The starting point was the risk analysis and the related qualification of IT infrastructure. There are no Industry 4.0 approaches without a solid, validated IT infrastructure: it would be like building a beautiful house without the foundations. That is why, in recent years, we have focused on this aspect and we consider it a fundamental and distinctive strength.
Are you able to expand the range of packages you offer?
Yes, absolutely. CIT is an evolutionary partner: in over 30 years, it is the third plant we build in order to follow the evolution of market demands. We have 2 ISO-8 areas available and qualified for integrations also in primary packaging.
We will soon be entering the clinical supply and integrating clinical trials. We are also starting Biotech part. Within a few months we plan to complete these new segments to represent in the market a single interface, able to address all types of packaging with high added value.
What role does your team of qualified persons (QPs) play within the company?
Qualified persons (QPs) play a vital role in bringing products into the European market. Our QP team ensures fast and competent management of specific issues and technical challenges across the entire spectrum of pharmaceutical dosages. We are very demanding with our QP team: they deal with traditional activities of GMP insurance, but also with audits to third parties and with the release of product on the market.
Our QPs have a strong design and business component ranging from Pharma 4.0 to the opening of new business segments.
They are in charge of the major projects referring to the company change with the exact aim of designing native GMP processes. For example, there are several interesting new Industry 4.0 technologies. It is risky to adopt them and then try to fit them into a GMP frame, as it often happens. That is why we have put our QPs at the head of our evolutionary projects, supported by multidisciplinary teams: they have to draw an evolutionary path born and developing harmoniously with our quality processes.
Although we are dealing with a final phase of the pharmaceutical process, I am convinced that being today a QP in CIT is a very involving challenge and one of the most interesting opportunities for managerial growth in our sector.
Do you also provide distribution and supply chain services?
Usually a customer does not want a packaged product, but a marketable one. We package the product, but we are also able to add subsequent value-added services, such as batch release and transport from our factory to customers’ warehouses all over the world. From an operational point of view, this takes place by sharing the individual specific procedures based on the standards of the customer himself.
How do you deal with your customers?
Customers are always at the heart of our processes and we tend to try to customize processes specifically to each one of them. Our only constraints are GMP dictates: within this framework we rely exclusively on customer requirements to guide our processes.
What does quality mean for CIT?
We believe that quality has to do with another concept: integrity. It means doing things in a certain way even when you are not checked or when, apparently, it does not show up in the service.
Quality as compliance to specifications and requirements is not a differentiating factor for us: it is taken for granted, it is a necessary condition. Our vision starts here and goes beyond: it has to do with twenty-year relations without obstacles or surprises. It has to do with tranquillity.
Mergers and acquisitions (M&A) continue to represent one of the preferred tools for companies in the pharmaceutical and life sciences sectors to create new business opportunities, consolidate their pipelines, and create value for investors.
After a decline in the number of deals in Q1 2018, the second quarter of the year saw a meaningful increase of operations close to the levels of 2016-2017, according to the report from PwC “Global pharma & life sciences deals insights: Q2 2018” .
The megadeal that saw Takeda acquiring Shire for a total value of $ 81.7 billion spiked the +200% increase in volume observed for the pharmaceutical sector in Q2 vs Q1 2018. Other important operations involved Novartis’ acquisition of AveXis for $ 8.7 billion and Celgene’s acquisition of Juno Therapeutics for $ 9 billion.
A feature of M&A that is often overlooked when evaluating the total deal value is the role and contribution of the brands involved. It is a prominent role that should be correctly addressed at the beginning, to avoid possible drawbacks and failures due to brands’ incompatibility. We spoke about how to deal with brands and their value during the M&A process with Helen Westropp, managing partner at London-based branding stalwart, Coley Porter Bell.
A high risk of failure
“2018 looks to be a bumper, if not record-breaking year, for global pharma M&A,” says Westropp. “The pace and intensity of these acquisitions reflect a category in which sustainable innovation capabilities and success are hard to identify, maintain, and manage in the long term. It’s worth noting that historically, close to 90% of M&A deals never get off the ground. And seven in 10 fail to create long-term shareholder value,” she adds.
Last-generation innovation models are focused on research activities being concentrated within academia or small biotech companies. Thes latter are often acquired by big pharma companies once the projects reach the proof-of-concept stage.
A recent example of this comes in the form of Denmark-based Novo Nordisk’s acquisition of Ziylo, a small UK biotech company spun out of the University of Bristol that developed a synthetic glucose binding molecules platform.
“It is an unusual deal that could eventually be worth more than $ 800 million if a series of milestones are met,” says Westropp. “It’s a striking example of a trend that’s set to grow, namely, high-stakes partnerships between stalwart incumbents and disruptive minnows”.
Competitive service providers within the same fields are also looking to gain more market share and benefit from the synergies inherent in a partnership or merger, adds Westropp. While pharma and biotech companies work toward the same basic objectives, they are very different in nature.
Biotechs are often smaller and more flexible than pharmaceutical companies, and possess a great ability to expand things quickly,” insists Westropp, adding: “Their most coveted assets tend to be their scientific minds and proprietary technology. When they come to these mergers, pharmaceutical companies contribute to the partnerships mainly with regulatory, sales and marketing expertise”. But how is brand usually considered during M&A deals?
The current approach to managing brands during M&A
The way brands are managed during mergers and acquisitions depends on whether the deal is a hostile takeover or a friendly deal, according to Westropp. “Most of the time,” she says, “the focus is on things they are looking to gain from a business point of view. Most mergers in pharma and biotech seem to be about expertise, pipeline, portfolio synergies, portfolio expansion, or market share.
“You have huge amount of due diligence on financial balance sheets and legal aspects, and yet, brand, and brand strategy, are either overlooked or evaluated only when the deal has almost gone through. This is symptomatic not just of the biotech industry, but of most business-to-business sectors. I think it is symptomatic of the fact that within B2B, brand is still something people are only recently starting to properly understand. In the consumer sector, this has been understood for a long time”, Westropp tells NCF.
The importance of culture and soft elements
One of the key disruptive elements in the M&A sector is culture, adds the branding expert. “If you think about the differences that are likely to be in culture between a large, established pharmaceutical company and a small, nimble, biotech company, they are potentially quite different. We believe the process of due diligence is the ideal time to consider the real worth of soft factors such as brand and culture,” she says.
According to a research from KPMG, about 92% of M&A clients admit their deal would have been more successful if they had a better cultural understanding before the merger. “That’s why looking at brand, and soft elements around brand, is of huge importance early on in a merger deal. You have to understand the more subtle items within the deal that can be deal breakers.
“We often see brands that were the very reason for the initial acquisition weakened or destroyed because of a lack of understanding of what the brand stood. So often the focus is on their financial worth alone,” says Westropp.
Trend in M&A pharma deals, 2016-2018 (Source: PwC, su dati S&P Capital IQ)
The points for a successful deal
To achieve partnership ‘bliss’, thus, each party must understand the other’s business at all levels. The value proposition brought by each to the table is also a factor sometimes overlooked, according to Westropp. “Importantly,” she says, “these subtle nuances can ultimately make or break a deal”.
Many of the risks associated with piecing together the brand puzzle during M&A stem from a need to homogenise different organisational structures and ways of working, and to re-engage employees who have different ways of doing thing. “Companies may have fast cultures or slow cultures. You need to focus on long-term sustainability vs short-term profit. Very often you find that the approach might be quite different. This tends to be one of the most common reasons for failed mergers. Are they top-down, hierarchical, formal organisations? Or are they an informal organisation?”, says the expert. The first model is typical of traditional big pharma companies, while smaller entities tends to be very informal.
Another important point that impacts on brand management during M&A deals is whether the value is placed on the acquirer or the acquired. “It seems to me, given the current growth of the sector, that another danger might be a sense of self-fulfilling prophecy. The more companies that are bought and sold within one particular group, the greater the complexity of any potential restructuring, and therefore the more likely it is that a CEO will seek more acquisitions, rather than trying to build a truly joined up coherent group.
“Because of time constraints, one thing we see often is that after the the deal is done, the focus goes elsewhere. A lot gets forgotten about, because of the length of time you need to close the deal and to really sort everything out. It is very difficult to get organisations to really focus on that longer term perspectiv,” adds Westrop.
The possible risks
An important risk factor is thus the drive for short-term cost-cutting or synergies rather than answering the critical question: ‘When we actually own this asset, what are all the ways we can create value with it?’.
The problem is identifying how the brand fits with the portfolio and how it can be further developed. “Companies are very often unaware there is a big danger they will end up destroying the very reason they bought the brand in the first place,” warns Westropp. This goes hand-in-hand with the risk of missing untapped growth opportunities of the acquired brand, or the combined brands, to provide long-term growth and benefit.
Loss of staff must also be taken into account but is often overlooked in M&A deals according to Westropp, as employees may feel distrustful, disillusioned or disenfranchised. The opportunity to leverage and commercialise the acquisition is another point requiring consideration, due to the many remaining risky and time-sensitive regulatory issues and patent limitations. “Again, time tends to be the essence in a lot of these mergers, but that does not necessarily means companies get the time to consider all the facts they would really need to consider,” she says.
How to manage overlapping or competing brands
Making clear the motives behind the M&A are fundamental to properly address this sort of issue. Sometime the reason for buying a competing brand is to kill it; sometimes it is because they have something that is slightly lacking in their own brand. “It’s not possible to just force brands to fit together, that never works. I think the most important thing is to look at the vision you want for your brand portfolio,” says Westropp.
This must work in conjunction with timing to achieve the requisite portfolio, and the valuation of the brand within this portfolio. “Does the brand you have acquired have more brand value that others you have already got? Or vice-versa? If you actually put the two together, can you create a significantly greater brand value? Many different options are possible: you could back the strongest brand over the other(s), you can keep both, you could create something new, you could divest one, create an endorsement strategy,” explains the managing partner of Coley Porter Bell.
No less important is the differing brands and logos, the latter being much more than a simple visual assett. According to Mrs Westropp, in business-to-business contexts, and while dealing with non marketing people, often there’s a confusion between the two terms. “A logo is not a brand: it’s part of a toolkit to help grow the brand, and the personality of the organisation. A real brand has a proper sense, a core idea and purpose, a proper proposition. Notwithstanding, it has some values. It has a logo as well, but a logo is just a visual expression of what that brand is, its sense”.
The creation of a new brand identity for the company implies what the value proposition for customers, stakeholder, and employees is, and how to express it. “It certainly goes through logo, but it goes through the personality, culture, behaviour, visual elements (logo, imagery , colours, typefaces …), tone of voice you use, where you use it to communicate and how. All these things make up a brand and the perception of a brand”, is the conclusion of Helen Westropp. “Despite the current failure rate for M&A, the outlook needn’t be so grim. The key is to bring the brand into business strategy discussions in advance of the deal and carry it forward well past the transaction itself into genuine integration. Incorporating brand at all phases of a merger, from discussions to implementation to integration, undoubtedly forces difficult discussions and decisions but it ensures that people act in direct response to their business strategy and their unique position in the market».
