EPM September/October 2023

IN HOUSE, IN CONTROL AND IN DEMAND COATING SOLUTIONS FROM NATOLI

Sep/Oct 2023 | Volume 23 Issue 5

REGULARS

5: EDITORS DESK

The Covid Comeback.

6: A SMALL DOSE

A round up of some of our favourite stories over the last two months!

12: COVER STORY

Kevin Queensen, Mechanical Engineer at Natoli discusses the various needs and many challenges presented in the tableting and encapsulation industries.

FEATURES

8: APIS & HPAPIS

Christiane Schuler, Communication Manager at Siemens explores the role Siemens has played in making their production plant one of the most modern and sustainable facilities in the world.

18: CONTRACT MANUFACTURING

Natalia Elizalde PhD, Chief Business Development Officer at VIVEBiotech discusses how the Company bridges the gap between R&D and commercialisation.

26: FORMULATION

Robert Newman, Chief Scientific Officer at FUJIFILM Irvine Scientific and Tom Fletcher, Director of Research and Development at FUJIFILM Irvine Scientific discuss the environmental impact of single-use technology.

32: REGULATION

Remco Munnik, Director at Iperion, explores ways of harnessing structured data to transform pharma processes.

34: Q&A

We caught up with Michael Shultz, Group Lead, Inhalation, at Lonza to ask him a few questions about dry powder inhalation.

36: CPHI BARCELONA PREVIEW

With CPHI Barcelona just around the corner, we look ahead to the show and a couple companies you won’t want to miss!

38: DRUG DELIVERY & PACKAGING

Laura Johnson, Senior Director of Sales Life Sciences at Loftware discusses the importance of the label.

42: TALKING POINTS

A strategy for game-changing post heart attack cardioprotection and AI in pharma takes another step.

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THE COVID COMEBACK

are being brought forward a month, with aims to begin the program September 11th. These new vaccination efforts will be specifically targeted at the most at-risk individuals, such as care home residents, elderly patients, and those who are immunocompromised.

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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 23 Issue 5 Sep/Oct 2023

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ISSN No - 2052-4811

For some, the close of the summer holidays will be a welcome change whilst for others, the summer months couldn’t last long enough. Whilst the sun has rarely shone over the breezy isle of Blighty, one familiar face has stepped into the spotlight. Covid-19 seems unable, as many experts predicted, to leave our lives. On Friday 18th August, the UK Health Security Agency (UKHSA) published a risk assessment of the SARS-CoV-2 variant BA.2.86 following detection of a new case in the UK.

This came alongside wider detection of this variant in Israel, Denmark and the

United States.

Come September 1st, and the UKSHA has released a Situational assessment for SARS-CoV-2 variant, reporting that: “Through the limited available global genomic surveillance, the variant is present in multiple countries on multiple continents, detected at a low prevalence amongst clinical cases or in wastewater. Although an increasing number of countries are reporting detection, there is as yet no clear signal of growth within any of these individual countries.” The report went on to outline that, as things currently stand, no laboratory

EDITOR’S DESK

data is currently available meaning that drawing conclusions remains a challenge.

Given the rise of Covid-19 cases over the summer months, the UKHSA has stated that Covid-19 surveillance will restart. This comes alongside the news that new vaccine rollouts

Commenting on the situation, UKHSA’s Director General of Data, Analytics, and Surveillance said: “Plans for the restart of Covid-19 surveillance for the winter season, when health pressures usually rise, is in progress and UKHSA will make a further announcement regarding surveillance plans for this winter shortly. Protecting the public from Covid-19 remains one of our top priorities.”

As things currently stand in the UK, the BMA have been in constant conflict with the relevant governing bodies, headed up by Conservative Steven Barclay MP, over fair pay. Consultant and junior doctor strikes are due to take place across the country from September 20th to October 5th, with the BMA explaining that emergency care will still be provided. Junior doctors and consultants have seen their pay drop in real terms by over a third in the past fifteen years. Having emerged from the pandemic in tatters, the NHS and its staff are within their right to demand an increase in their pay. Yet, with the possibility of a sharp increase in covid cases, the strikes may result in further complications down the line.

The hope and aim this time is that the pharma world will be better equipped this time around should Covid-19 rear its head on a nationwide scale. Those in positions of power need to facilitate this.

JAI MCINTOSH

A small dose

ITV Announces

Investment in Flarin: A New Pharma Programme

As part of ITV Adventures Invest, its Media for Equity investment fund, ITV has agreed to invest up to £5 million of advertising inventory across ITV’s channels and ITVX in return for a minority equity stake in the company. It follows ITV’s recent Media for Equity investments in architectural design company Resi plus pet health and wellness company PitPat, both announced earlier this year.

Flarin is a unique and patent protected antiinflammatory painkiller. Its lipid formulation has been clinically proven to be as effective as twice the dose of standard ibuprofen in patients with acute joint pain. Flarin is one of the fastest growing analgesics in the UK and offers consumers a targeted solution for joint and muscular pain relief. It is the only lipid formulated

MHRA

APPROVE NEW

INNOVATIVE SKIN DRESSING TRIAL

oral analgesic available in the UK.

Director of ITV AdVentures, Sheena Amin said: “It’s fantastic to be announcing our latest Media for Equity investment into Flarin. With its innovative and patented lipid technology, Flarin offers many unique benefits to those suffering from joint and muscular pain compared to any other product on the market. Flarin is already one of the fastest growing analgesics in the market and I am confident that we will see the company grow to new heights following a brand building campaign across ITV.”

ITV’s investment will help Flarin build mass market brand awareness by bringing the brand to millions of consumers via ITV platforms. This will be a step change in the size of the campaign and the approach to scaling the Flarin brand to date.

Healome Therapeutics has met a major milestone after the Medicines and Healthcare products Regulatory Agency (MHRA) approved a phase I trial for a scar-reducing wound dressing that uses the company’s technology. The approval means that a new bioactive dressing, developed by University of Birmingham researchers and designed to reduce the scarring of skin burns, can now be trialled on

25 patients being treated at the Queen Elizabeth Hospital in Birmingham for heat burns that cover between 3% and 20% of their body.

The bioactive dressing is a clear film that combines the benefits of a traditional dressing with new features that help to reduce the risk of scarring. It does this by delivering a synthetic version of a protein called decorin, which is naturally found in humans and plays a key role in wound

healing by reducing the inflammatory response and helping to organise new tissue as it is generated in the wound. Early lab work indicated that the dressing may reduce tissue fibrosis and inflammation and encourage tissue regeneration. Healome has since developed materials capable of delivering and retaining decorin across the body as well as delivering microenvironments to guide healing. This trial

NHS World First Rollout Of Cancer Jab Cuts Treatment Time By Up To 75%

Following being given the green light from the Medicines and Healthcare products Regulatory Agency (MHRA), the NHS in England will be the first health system in the world to roll out the seven-minute injection to hundreds of patients each year.

Currently, patients receive the life-extending

immunotherapy atezolizumab

(Tencentriq) in hospital directly into their veins via a drug transfusion. It usually takes around thirty minutes to administer intravenous atezolizumab, but for some patients this can be up to an hour when it can be difficult to access a vein. But now and within weeks, hundreds of eligible patients

being treated with atezolizumab are set to have their experience improved by switching to the swifter and more comfortable under the skin (or subcutaneous) injection — freeing up valuable time for NHS cancer teams.

Atezolizumab is an immunotherapy drug that empowers a patient’s own immune system to seek and destroy cancerous cells. The treatment is currently offered by transfusion to NHS patients with a range of cancers, including lung, breast, liver and bladder.

It is anticipated the majority of the approximately 3,600 patients starting treatment of atezolizumab annually in England will switch onto the time-saving

will focus on a wound dressing format.

Dr Richard Williams, Chief Executive Officer, Healome Therapeutics, commented: “We are delighted to have been given the green light by the MHRA for our first ever phase I clinical trial. This is a major milestone for the company that will demonstrate the safety of

the dressing technology and be the first step towards evaluating how effective the decorin dressing is at healing wounds and reducing scarring. The trial will assess the product’s safety and early efficacy against another dressing commonly used by the NHS in the same type of wounds.”

injection. However, where patients are receiving intravenous chemotherapy in combination with atezolizumab, they may remain on the transfusion.

NHS National Director for Cancer Professor Peter Johnson said: “The world-first introduction of this treatment will mean that hundreds of patients can spend less time at the hospital and will free up valuable time in NHS chemotherapy units. Maintaining the best possible quality of life for cancer patients is vital, so the introduction of faster under-the-skin injections will make an important difference. This announcement is the latest in a series in the 75th year of the NHS that highlights how an innovation-driven health

service is securing the most advanced cancer treatments for patients.” The faster treatment comes at no extra cost to the NHS thanks to the existing commercial deal negotiated between NHS England and the manufacturer Roche. The world-first rollout of this new treatment is the latest example of how the NHS is rapidly adopting medical innovations to improve the efficiency of the health service and follows the publication last month of new guidance to optimise medicines use across the NHS as the health service is also set to save £7bn by the end of this year thanks to a five-year drug pricing agreement negotiated with the pharmaceutical industry.

e bioactive dressing is a clear lm that combines the bene ts of a traditional dressing with new features that help to reduce the risk of scarring.

e world- rst introduction of this treatment will mean that hundreds of patients can spend less time at the hospital and will ee up valuable time in NHS chemotherapy units.

HIGH, HIGHER, HIGHCON

Author: Christiane Schuler, COMMUNICATION MANAGER, SIEMENS.

U.S.pharmaceutical company Pfizer has opened a new high-containment plant in Freiburg, Germany, that’s capable of producing up to seven billion tablets per year. Along with several partner companies, Siemens played a role in making the production plant one of the most modern and sustainable facilities in the world.

The pharmaceutical industry is in a constant race against time. New diseases are always developing that require new medications and vaccinations. And common diseases like cancer are still among the most common causes of death, so the range of treatments is continuously being refined. One example is high-potency active pharmaceutical ingredients, or HPAPIs for short. In all of these cases, the key is to get medications onto the market as quickly as possible. And that’s not the only challenge: Interrupted supply chains, cost pressures and the demand for efficiency, short innovation cycles, high-quality products, and increased flexibility all have to be taken into account. And of course the world’s resources are finite, so there’s an urgent need for sustainability. As a result, the industrial world has never been as complex as it is today.

HIGH CONTAINMENT FOR HPAPIS

What distinguishes high-potency active ingredients is their

elevated pharmacological action at low doses as well as their high selectivity, which reduces the risk of adverse drug effects. Both of these factors contribute to the growing popularity of HPAPIs in medicine. But their use in medications means that the utmost precautions must be applied during their manufacture. When highly active toxic ingredients are used in manufacturing, it’s essential to ensure maximum cleanliness and safety for people and products in the production process. Highcontainment plants make that possible. What’s special about Pfizer’s new plant in Freiburg is that medications in category OEB4 can be made there, but employees only need protective clothing to the OEB3

When highly active toxic ingredients are used in manufacturing, it’s essential to ensure maximum cleanliness and safety for people and products in the production process. High-containment plants make that possible.

level – and that improves safety for the employees. This is made possible by a special containment concept and innovative technologies that are monitored and controlled by building services from Siemens.

SMART BUILDING MANAGEMENT

Desigo CC is the integrated, scalable, and open building management platform from Siemens for controlling highperformance buildings and clean-rooms. It can integrate diverse systems and devices and automate all processes. “Desigo CC enables a range of systems to communicate with each other and collaborate via a centralised control centre,” says Andreas Bühring, Vertical Sales, Siemens Smart Infrastructure. “That turns the platform into the technological backbone of a smart building infrastructure.” Desigo CC is linked to the SIMATIC WinCC Unified visualisation system used at Pfizer meaning data sharing is easy: Data relevant to production from the building management platform is transferred to the SCADA system via OPC UA. SIMATIC WinCC, the innovative, scalable process visualisation system, offers many powerful functions for monitoring automated processes. At the same time, information from other production systems can be fed

into Desigo CC and used for predictive control functions in the building automation systems. “Thanks to this link, building management data can be used in the central management system, and it can be accessed in the individual production areas at any time,” Bühring concludes. From power distribution to automation, technologies like Desigo PX integrate the various building systems in Pfizer’s new high-containment plant, including ventilation, airconditioning, and heating.

EXAMPLE OF SUSTAINABLE PHARMACEUTICAL PRODUCTION

“Thanks to the smart networking of machines and processes, production at the Pfizer plant in Freiburg can be faster and more flexible and can better conserve resources,” said Gunter Bechmann, head of the HighCon plant project at Pfizer. For example, networking and visualising data in the Desigo CC management system helps Pfizer’s new highcontainment production plant to consume about 40 percent less

energy than traditional plants. That’s an important contribution to energy-efficiency, because 40 percent of global primary energy consumption happens in buildings, and that figure is growing.

Germany’s Federal Environment Agency has recognised that Pfizer’s rigorous attention to its environmental footprint extends beyond the plant construction stage: The Freiburg location is also an example of a best practice in sustainable pharmaceutical production.

The ultramodern and highperformance high-containment plant in Freiburg offers a highly automated and also sustainable production process, from powder to tablet. The seven billion tablets that are produced here every year and supplied to more than 150 countries are ultimately contributing to greater global health.

is is made possible by a special containment concept and innovative technologies that are monitored and controlled by building services om Siemens.

WHY COAT YOUR TOOLING?

In the past, applying a coating to tools was the only defence available to reduce or eliminate corrosion to the tools when compressing caustic powders, such as chlorine and other chemicals. At the time, the available tool steels used to make punches and dies were low in chrome content, largely considered the most effective alloying element to fight corrosion.

Some tool steels, such as 440C with 16-18% chrome in its chemical composition, were utilised for compressing caustic powder, but due to the carbon and high iron content in the steel, did not provide 100% protection from corrosion. Coating the tools with a surface layer of chrome provided 100% protection and became the normal method to protect the tools from corrosion.

Secondary benefits of coating tools is to enhance product release and increase wear resistance. Product sticking to the face of the tools and picking within the embossing on the punch faces is often seen as a common issue with compressing many pharmaceutical products. Chrome coating provided a good solution with regards to minimising product sticking, resulting in reduced downtime cleaning tooling and increased production.

Chrome coatings are applied with the metalworking industry standard method of electroplating. However,

Author: Kevin Queensen, MECHANICAL ENGINEER, NATOLI.

the electroplating utilised an electrified chromic acid bath, which is plagued with obvious environmental challenges and occasional adhesion deficiencies.

Some tool manufacturers promote coatings but may not provide full disclosure of the actual coating that is applied.

TIME FOR A CHANGE

In the ever-evolving landscape of modern manufacturing, finding efficient, cost-effective, and high-quality solutions is vital to support the various needs and many challenges present in the tableting and encapsulation industries. The contemporary coating solution is cathodic arc deposition, a cutting-edge arc evaporation process for coating punches, dies and encapsulation parts. This article explores the merits of adopting this innovative technology, focusing on its cost-effectiveness, time-saving benefits, superior coating characteristics, and its ability to enhance product quality.

Cathodic arc deposition is a Physical Vapour Deposition (PVD) process that involves the deposition of ions from the cathode (solid metal target) onto the surface of the tooling (anode) to form a thin film coating. The cathode is energised with a high-current, low-voltage electric arc discharge, leading to the vaporisation of metal ions. The cathode may be combined with nitrogen, oxygen, or carbon-containing gas to form compound materials. These ions condense onto the tooling to form a thin, bonded layer, greatly improving appearance and durability, with exceptional adhesion properties, enhancing performance.

Traditional manufacturing practices often involved outsourcing coating services, leading to substantial expenses and excessive lead times. By adopting in-house cathodic arc deposition, manufacturers can eliminate the need to

rely on third-party coating providers. This allows your tool manufacturer to maintain dimensional integrity, provide higher quality control standards, reduce costs, decrease lead times, enhance security for branded product tooling, and pass the savings on to their customers.

In-house PVD coating capabilities allows for greater control over the deposition process ensuring high quality coverage and precise thickness of coating material is applied. Direct control of the coating process parameters, such as temperature, pressure, and ion energy ensure quality, consistency in coating thickness, uniformity, and surface finish across all production runs, ultimately allowing tool vendors to tailor solutions specific to their customer’s needs.

ENHANCED WEAR RESISTANCE (TIN)

Punches, dies and encapsulation parts are subjected to significant wear during the manufacturing process. Cathodic arc deposition allows for the application of exceptionally hard and wearresistant coatings. Titanium nitride (TiN) or chromium nitride (CrN), will increase the lifespan of these essential components by offering enhanced wear resistance. The higher surface hardness provided by these coatings imparts enhanced wear resistance without sacrificing the impact toughness and strength of the steel substrate.

IMPROVED CORROSION RESISTANCE (CRN)

Corrosion resistant coatings become essential when tableting or encapsulating products containing harsh or caustic compounds. Cathodic arc deposition of Chromium (Cr), Titanium (Ti) or Zirconium (Zr) metals will apply corrosionresistant coatings to protect tooling from degradation due to corrosive agents. These coatings

perform significantly better when subjected to the ASTM B117 salt spray test, which quantifies and ensures a materials’ corrosion resistance.

ANTI-STICK BENEFITS-REDUCED FRICTION AND ADHESION (CR, CRN & ZRN)

The most prevalent challenge in the tableting industry is sticking to the tool face. Sticking occurs when the adhesive forces of powder to the tool face are greater than the cohesive forces of particles to one another. Hard Chrome (Cr), Chromium Nitride (CrN), or Zirconium Nitride (ZrN) coating applied by cathodic arc deposition will significantly reduce friction, provide low adhesion properties, and enhance surface lubricity between the tool face and the powders being compressed. Decreased friction also offers an additional benefit for heat sensitive API’s as operating temperatures are reduced, significantly diminishing product sticking and picking on the contact surfaces. This helps ensure consistent product quality and therefore minimises tool cleaning and polishing.

ADAPTABLE COATING SOLUTIONS

Different manufacturing processes require specific coating characteristics. In-house coating capabilities allow tool manufacturers to customise coating formulations to suit unique requirements. This

ensures that punches and dies are optimised for specific tasks, resulting in better product quality. The most effective way to evaluate the efficacy of a coating is to test multiple coatings within one set of tooling during a single production/test run (the only gross variable is the tooling). This is best to do early in the development process as a way to identify deficiencies in the formulation using <USP 1062> guidelines.

CONCLUSION

Tool vendors with in-house PVD coating capabilities have developed game-changing solutions for coating punches, dies and encapsulation parts. The cost-effectiveness stemming from reduced outsourcing and increased yields empower manufacturers to allocate resources more strategically, while providing enhanced security and control of branded tooling. Most importantly, the ability to achieve superior product quality with wearresistant, corrosion-resistant, and low-friction coatings ensures customer satisfaction and longterm success.

By embracing this PVD coating technology, tooling manufacturers can offer a wide variety of solutions to best fit their customers’ unique needs. Ultimately, the end user will reduce their operating costs, minimise downtime, increase productivity and overall product quality.

BREAKING DOWN BARRIERS:

Use of highly potent active pharmaceutical ingredients (HPAPIs) is on the rise in the pharmaceutical industry. The market share of these was valued at $26.85 billion in 2023 and is forecast to grow to reach $41.83 billion by 2028. The ability of HPAPIs to effectively target and prompt a pharmacological response at low concentrations makes them promising drug candidates, especially those for oncology and orphan and rare disease indications.

As interest in HPAPIs continues to evolve, challenges surrounding their safe handling arise. These substances pose a significant risk to the operator throughout their use, and strict safety measures are required to minimise the risk of exposure.

Operator safety has always been a priority in the industry, but as substances become increasingly potent, more stringent, and robust safety control measures are required. These controls must also be designed to meet the regulatory expectations of the good manufacturing practice (GMP) guidelines that define the required standards for drug manufacture for ensuring patient safety.

In this article, Catherine Wilkes, Executive Director of Environmental, Health and Safety at Quotient Sciences, will explore how containment protocols shift when dealing with HPAPIs to meet the required safety standards.

TO ACHIEVE HPAPI MANUFACTURING SUCCESS

Catherine Wilkes, Executive Director of Environmental, Health and Safety at Quotient Sciences.

DETERMINING POTENCY OF AN API

Prior to identifying the safety control measures required for handling an active pharmaceutical ingredient (API), the potency must be evaluated. To do this, properties such as pharmacological activity, mutagenicity, carcinogenicity and reproductive toxicity need to be taken into consideration.

A good understanding of the toxicological characteristics of an API, allows occupational exposure limits (OEL) and acceptable workplace exposure limits (AWEL) to be calculated. OELs are regulatory values which indicate the level of a chemical substance in the air that an employee could be safely exposed to in the workplace. With these limits known, safety controls can be designed to ensure these limits are not exceeded during handling i.e., minimising the risk to operators to exposure levels which would not result in adverse effects to them.

However, this can be challenging for drugs in the early stages of development, where little of this toxicological data is available and meaningful OELs and AWELs cannot be calculated. This is

where occupational exposure banding (OEB) systems are helpful. There are numerous OEB systems in use which have been designed to help categorise API with limited data available, based on any known toxicological properties and predicted potency.

One OEB system is the Performance-Based Level of Exposure Classification or Control (PBLEC) system. In this system API are assigned to one of five categories:

WHEN IS AN API CLASSIFIED AS HIGHLY POTENT?

Defining whether an API is classified as highly potent is complex, especially when handling novel compounds with limited data. Extensive analysis and characterisation are required to better understand these API to define where they fall in terms of potency. At Quotient Sciences, API which either default into (due to limited data) or where a calculated OEL places them into the PBLEC 4 or PBLEC 5 categories, are considered highly potent for handling. When considering the corresponding OELs (<10µg/ m3), it is at these low OEL

Once assigned to a PBLEC category, appropriate levels of handling controls are put in place to control risk of operator exposure and facility contamination. The controls should be designed to reduce operator exposure to the bottom end of the corresponding OEL range.

levels where powder particles in the air are invisible to the naked eye which makes safe handling all the more challenging.

OVERCOMING HPAPI CONTAINMENT CHALLENGES

Once an HPAPI has been classified, the control measures employed for safe handling must be sufficient to control operator exposure to below the calculated OEL or the bottom end of the OEB band. Effective engineering controls designed to contain substances at the point of use are essential for primary protection of operators, supported by further facility/ administrative controls and personal protective equipment (PPE) as secondary and tertiary controls, respectively.

Primary containment strategies (e.g. closed transfer systems,

flexible / hard shell isolators, ventilated balance enclosures etc.) will differ depending on the unit processes involved and the scale of handling. For example, the controls required for manipulating solutions will be different to those required for manipulating solids in the development and manufacturing of tablets. Similarly, the controls required to manage analytical scale work will be different to those required at the development and manufacturing scale.

The PBLEC system is supported by matrices which define all the controls required to safely conduct tasks for each PBLEC category at each scale. To further assist with this, each unit process is assigned a risk category (low, medium, or high) with respect to the potential of operator exposure to the API.

This must all be backed up by a robust and comprehensive training program for operators, which should include regular refresher training.

In addition, control performance target (CPT) testing is required to quantitatively assess and evaluate the effectiveness of the containment strategies in place. The results from this testing enables us to understand the limitations of a control, support risk assessments and guide discussions as part of a continuous improvement safety program.

With these systems in place, the risks to the operator from handling these substances is significantly minimised, as well as the risks associated with cross-contamination within a GMP facility.

GUIDING HPAPI MANUFACTURE

Navigating the HPAPI space to ensure appropriate safety controls are in place is essential.

Partnering with a specialist contract development and manufacturing organisation (CDMO) can help to overcome the challenges of HPAPI

containment. With access to specialised knowledge and guidance on determining API potency, classification, and how to establish safe working practices, meeting safety regulations is assured. Outsourcing to a CDMO with the appropriate facilities and practices in place can help to meet these requirements cost-effectively, assuring safety measures are adhered to, and the production of high-quality HPAPIs at speed.

At Quotient Sciences, we have over thirty years of experience in developing and manufacturing small molecule HPAPIs. Our facilities in the US and UK are configured with the necessary controls required for the handling and processing of these types of molecules and we offer our customers a complete, global end-to-end development solution from early phase drug substance and formulation screening through clinical and commercial manufacturing. We are able to handle PBLEC 1 through to 5 depending on the type of compound, dosage form, manufacturing process and batch size required and consider ourselves to be a trusted partner when it comes to supporting our customer’s highly potent molecules.

A good understanding of the toxicological characteristics of an API, allows occupational exposure limits (OEL) and acceptable workplace exposure limits (AWEL) to be calculated.

AN INNOVATIVE APPROACH TO PRIMARY PACKAGING FOR BIOLOGICS AND OTHER SENSITIVE FORMULATIONS

The growing demand for biologics and other sensitive drug formulations is shifting the dynamics of the pharmaceutical market. Biologics are increasingly transforming the treatment of many diseases. However, the new market landscape poses a range of challenges as well as new opportunities –particularly when it comes to drug containment solutions.

The patient-centric trend

towards self-medication at home and outpatient care rather than hospitalbased treatment promises improved adherence, cost reduction, and enhanced quality of life. For this to work, simplified and userfriendly injection methods are essential. At the same time, pharma manufacturers must pivot from stability to agility – accommodating changes, managing smaller

production batches, and expediting time-to-market, all while maintaining steady production.

Meanwhile, biologics and other sensitive formulations introduce complexities such as heightened viscosity and larger doses, and chemical interactions with containers are now more likely due to increased drug sensitivity and concentration. Drug formulations thus now have

sensitivity issues – reacting to one or more elements of their primary packaging and losing their stability. The problem can be caused by several factors – silicone oil sensitivity; the interaction between the drug and the surface of the primary container, leading to protein aggregation; the particles generated by rubber in the closure system; or surface delamination, especially in glass vials.

TECHNOLOGY EXCELLENCE CENTERS IN ITALY AND USA

Stevanato Group’s analytical services teams thus have a crucial role to play at the start of the development process for drug delivery devices. Early selection of the appropriate drug containment solution can avoid expensive issues and delays further down the line. With Technology Excellence Centers (TEC) in Italy and Boston, USA, Stevanato Group’s experts are perfectly positioned to help pharma customers anticipate challenges, navigate complex regulations, and make wellinformed decisions.

ALBA® AND NEXA® STATEOF-THE-ART SOLUTIONS

Prefilled syringes are one example of Stevanato Group innovation in action and its Nexa® platform has been specifically designed for high-value drug products. As well as optimizing the stability of the drug, Nexa® offers higher mechanical resistance than a standard container, and superior cosmetic quality. It also expedites the regulatory approval process as a dependable secondary source and facilitates scalable manufacturing.

In addition to the Nexa® glass container solutions, the latest addition to the company’s syringe portfolio is the Nexa FlexTM presterilized polymer syringe – available in both cyclic olefin polymer (COP) and cyclic olefin copolymer (COC) materials. Nexa FlexTM has an optimized silicone-oil distribution along the barrel that improves gliding performance while minimizing particles – while its 100% camera inspection guarantees consistent cosmetic quality. It also uses

a tungsten-free polymer molding process to guarantee compatibility with even the most sensitive drugs.

But that’s not all. Stevanato Group’s biopharmaceutical partners can adopt a platform approach and transfer from Nexa® to Alba® platform, if improved silicone functionality is required, enabling concerns to be addressed without major disruptions to, or investment in, the development and manufacturing process.

Alba®, in fact, represents a groundbreaking advancement in biologics packaging through its innovative cross-linked silicone coating. This effectively minimizes the release of particles, thereby addressing potential silicone-related concerns. It also improves gliding and break-loose forces, while simultaneously establishing a robust protective barrier to ensure the stability of the drug within the container. This combination of purity and protein stability is designed to support even the

most delicate biologics. And, in addition to a substantial reduction in sub-visible particles, Alba® glass primary packaging maintains consistent performance throughout the shelf life of the drug. Alba® is offered in three formats: 0.5 mL, 1 mL, and 2.25 mL, where the 2.25 mL option has gained significant traction in developing innovative therapies requiring larger volumes.

Alba® and Nexa® syringes are compatible with the majority of leading autoinjectors on the market – to meet the growing demand for drug products that patients can selfadminister from the comfort of their own homes. Together, the innovative packaging solutions offer unrivaled quality and reliability for even the most demanding biologics and other sensitive drug formulations.

VIVEbiotech is a GMP Contract Development and Manufacturing Organisation (CDMO) fully specialised in lentiviral vectors working according to both EMA´s and FDA´s regulations operating since 2015 for more than 40 international clients in Europe, US, Asia and Australia.

Specifically, the company is specialised in the manufacture of lentiviral vectors that are being used for the development of both gene-modified cell therapy products -ex-vivo administration- as well as for gene therapy products -invivo administration.

VIVEbiotech has a wellestablished manufacturing platform that is employed from developmental phases to GMP production. More than 100 batches in reactors have been manufactured in a scalable, timely, and costeffective manner, adhering to EMA and FDA GMP regulatory standards and adapting to the specific scale required for each phase.

There are two main reasons why the company fully specialised on lentiviral vectors: the growing market demands, from one side, and the high technical expertise that is required to manufacture this kind of viral vectors, from the other.

Referring to the market growing demands, it is important to highlight that the cell & gene therapy (CGT) area is forecasted to be the fastest growing segment within the pharmaceutical market. Indeed, the current

market value stands tall at $758 Bn in 2020, with the potential for a significant growth beyond $1.200 Bn in 2026. The CAGR for the CGT market is expected to be around 50% by 2026 while that of the overall pharmaceutical sector is predicted to be around 8%.

There is indeed a scarcity of players with the capacity to offer end-to-end manufacturing services. This is why CDMOs like VIVEbiotech, which bridge the gap between R&D and commercialisation, are experiencing an increasing demand. Moreover, a significant number of pharmaceutical and biotechnology companies currently do not possess the capability to internally manufacture CGT. This is the driving factor behind the projected growth of outsourced lentiviral vector supply, expected to achieve a Compound Annual Growth Rate (CAGR) of 15% from 2020 to 2026.

This expected growth can be easily justified linked to the fact that more and more CGT approvals are happening in the last years – there have been more approvals in the last 3 years than in the prior 15 years- among which lentiviral vectors have been the gene transfer technology used in 8 of these marketed therapies.

The CGT pipeline is getting stronger with 2,061 ongoing clinical trials globally at 1H´22, with immuno-oncology the most common therapeutic area under study. Specifically, lentiviruses are the main vector used for immuno-oncology applications as they are very efficient in gene delivery, they guarantee long-lasting transfer gene expression, they have improved safety features and present low immunogenicity.

As reflected in the latest H1 2023 ARM report, immuno-oncology remains at the forefront among all ongoing clinical trials (+50%) of which the majority consist of T-cell and NK cell therapies (+90%). This is somewhat expected considering that there is an increase in the number of people being diagnosed with cancer and is expected to grow by a further 50% compared to 2020, exceeding 28 million people.

Moreover, CGTs are progressively expanding beyond rare diseases. Increasingly more frequent or prevalent diseases are being treated with lentiviral vectors which are being used for manufacturing vaccines or viral like particles, among others. Indeed, currently lentiviral vectors are being used in 48% of total clinical trials, which is more than double the usage for AAVs.

All of this information taken together makes it clear that lentiviral vector manufacturing capacity is a pivotal factor in the development of these therapies. Therefore, the scarcity of experienced CDMOs with established virology expertise is the primary reason why it can be asserted that viral vector manufacturing constitutes a critical bottleneck for the industry, affecting both cost and the high-quality provision of vectors at a suitable scale for every phase.

Speaking of the significant technical expertise involved, the manufacture of lentiviral vectors is a highly intricate process that

demands skilled personnel possessing knowledge in both virology and GMP regulations for the production of sterile products. Viral vectors are highly sensitive; therefore, limiting their exposure to harsh environments is necessary to minimise product loss.

Lentiviral vectors are sensitive to factors such as pH, temperature, shear, and chemical composition (salt), necessitating controlled conditions during both processing and storage.

Ensuring that the process is regulatory compliant, scalable, and cost-effective from the very early stages, and executing it in a timely manner, is indeed crucial for the successful

VIVEBIOTECH:

A Lentiviral Vector Specialist

Bridging the Gap Between R&D and Commercialisation

manufacture of a given therapy at a commercial scale. Thus, VIVEbiotech has specialised Technological Innovation, Upstream and Downstream Optimisation departments whose objective is adapting to the very specific requirements of our partners to make sure that the vector that is being produced is scalable and cost-effective, and high titers and pure vectors are obtained from the very beginning. Moreover, some of the ongoing innovative projects that VIVEbiotech is working on include various pseudotypes, modified cells, and/or stable cell lines, among others.

Moreover, in the global landscape of the lentiviral

vector space, there exists a very limited number of fully specialised players. VIVEbiotech is the sole GMP CDMO fully specialised in lentiviral vectors in Europe.

Taken together, these factors clearly demonstrate an interest in CDMOs leveraging their unique expertise to bridge the gap between R&D up to commercialisation. In this regard, VIVEbiotech stands out by adapting to the real needs of the market in a rational and sustainable growth mode, aligned with current demands offering specialised services in lentiviral vectors, covering the entire spectrum from the initial phases to GMP-compliant commercial scale.

NATALIA ELIZALDE PHD – Chief Business Development Officer

Increasingly more equent or prevalent diseases are being treated with lentiviral vectors which are being used for manufacturing vaccines or viral like particles.

manufacturing

BENEFITS OF A SINGLE SOURCE PROVIDER FOR DEVELOPMENT THROUGH TO COMMERCIALISATION

The development and manufacturing of drugs requires a complex and interconnected process involving Active Pharmaceutical Ingredient (API) development, drug product development and manufacture, clinical trial management, and commercialisation.

Traditionally, these functions have been outsourced to multiple providers, leading to challenges in coordination, communication, and efficiency. However, a growing trend is emerging towards utilising a single source provider that offers end-to-end solutions.

One of the primary benefits of a single source provider is streamlined communication and collaboration. By consolidating the multiple activities required to one outsourcing contractor, it eliminates the need for coordination between multiple providers and ultimately the gaps in communication this creates.

Critically, when inevitable challenges arise, particularly within chemical and formulation development, having the scientific expertise of multiple teams within one organisation creates natural problem-solving groups which enables the identification and implementation of quicker and more creative solutions. Scientific excellence and continuity through the drug development process cannot be understated and reduces many uncertainties inherent in a multi-supplier, multi-site process, resulting in improved coordination and efficiency

with reduced time to clinic and ultimately to the market.

With a sole provider, vital quality control measures are implemented consistently across all stages of the development and manufacturing process. This ensures that each process adheres to the highest standards, reducing the risk of quality-related issues and ensuring compliance with regulatory requirements.

Consolidating development, clinical trials, and commercialisation to a single

source mitigates the risk associated with managing multiple vendors. The sole provider instead oversees responsibility for ensuring regulatory compliance, maintaining quality control, and meeting timelines. If unforeseen challenges arise, they can be handled quickly and efficiently, reducing potential delays and minimising the impact for the client, and ultimately the patient.

Utilising a single source CDMO can also lead to significant cost and time savings. Instead of managing multiple

partners, clients can focus on a single partnership, reducing overall costs and simplifying the procurement process. Additionally, development through to commercial manufacture with a sole provider ensures scientific continuity of your product, reducing the risk of errors and delays. This streamlined approach accelerates the overall timeline, allowing pharmaceutical companies to gain competitive advantage by potentially launching their products faster.

In an industry where efficiency, experience, and adherence to strict guidelines is key, this option presents numerous benefits. Streamlined communication, enhanced quality control, cost and time savings, better resource allocation, risk mitigation and simplification of the supply chain are strong reasons to consider this model. By embracing a single source provider, drug development companies can optimise their operations, focus on their pipeline, and accelerate the delivery of safe and effective drugs to patients in need.

With over 50 years’ industry experience and 7,000 skilled individuals globally, Almac Group provides a wide range of end-to-end solutions utilising a wealth of knowledge and expertise. Working in true partnership with clients to deliver a unique, integrated service model tailored to specific product needs, Almac can support your drug pipeline through part, or all of its lifecycle.

Brian Eastwood (Top), Global Head of Business Development, Almac Pharma Services Simon Hamilton (Right), Head of Global Business Development, Almac Sciences.

ENSURING HIGH-QUALITY ACCELERATED BIOLOGICS MANUFACTURING

JINHYEOK JEONG AND JOHN THOMAS, SENIOR DIRECTORS OF DP INSPECTION & PACKAGING AND DP MSAT.

As the pharma industry evolves and advanced therapeutics such as gene therapies and cell-based products gain momentum in the market, the demand for rapid timelines from development to commercialisation is rising. Development and manufacturing speed is critical for drug manufacturers to expedite medicines that have the potential to change patients’ lives. In addition, they need to demonstrate a return on investment to investors to keep developing and driving products forward.

Optimising development and manufacturing processes to accelerate biologics production while keeping costs down is essential to meeting market demand. Streamlining drug product (DP) manufacture helps to shorten timelines for biologics production, but this process requires expertise and experience.

In this article, Jinhyeok Jeong and John Thomas, Senior Directors of DP Inspection & Packaging and DP MSAT, explores the major areas of DP manufacturing that can accelerate timelines from development to commercialisation, along with the necessary qualities that should be sought after in a specialist service-providing partner.

THE NEED FOR SPEED TO MARKET

In the highly competitive biopharmaceutical industry, bringing a product to market at speed positions an organisation

for commercial success and ultimately helps improve patient outcomes as quickly as possible.

On-time delivery is of the utmost importance. Clients need to be competitive by reaching the market fast. For healthcare professionals, ontime delivery of therapeutics is essential to facilitate seamless healthcare planning and, importantly, continuity of care. Finally, and perhaps most significantly, for patients, quick access to life-changing therapies can improve outcomes and prognosis. However, bringing a drug product to market quickly can be complex. Drug developers

must balance the urgency of getting effective treatments to patients with the need to ensure safety, efficacy and regulatory compliance. Rushing through the development process can increase the risk of potential safety issues, and insufficient testing or validation can lead to subpar products that do not deliver the desired therapeutic benefits.

Rapidly scaling up production and distribution to meet increased demand can also strain the supply chain, with shortages in materials and manufacturing issues impacting the availability of the drug.

STRATEGIES TO CONSIDER FOR ACCELERATED TIMELINES

To reach milestones quickly and overcome potential challenges, drug developers in DP manufacturing should consider several strategies. The strategies to streamline manufacturing speed include:

• Establishing a Robust Supply Chain

With more outsourcing, new modalities and high demand for therapeutics, it is essential to establish a strong supply chain. Reliable access to materials during drug development and manufacturing can minimise delays that can be caused by long lead times.

• Maintaining Efficient Technology (Tech) Transfer Companies can benefit from a streamlined tech transfer process that ensures seamless communication through every stage of a drug development project. Timely tech transfer supports commercial-scale quality and the production goals of the project. Implementing tech transfer strategies will expedite therapy production and improve patient outcomes.

• Reducing Risks During Production

By identifying time constraints and process limitations that could lead to delays further down the development pipeline, areas can be identified that may need additional attention to detail. This allows for a

mitigation plan to be put into place to preempt possible manufacturing challenges and allow for a solution to be implemented to then accelerate the path to commercialisation.

• Meeting Changing Regulatory Requirements and Guidelines

A strict quality management system (QMS) should be implemented throughout manufacture so that every raw material, component of drug production and manufacturing process is well characterised and defined to meet all good manufacturing practice (GMP) regulations. Integration of QMS will ensure the quality, safety and efficacy of all therapeutics reaching commercialisation.

• Ensuring Efficient and Timely Batch Release

Once a commercial batch has been manufactured, it should be released within the defined time frame of 30 days. Quality control (QC) testing should take place to confirm that GMP guidelines have been followed. At this point, information spanning all processes, procedures, drug formulation and equipment details should be collated and filed, so a batch can be released immediately. Continuous process verification (CPV) should be conducted for each commercial batch. The critical quality attributes should also be monitored throughout to ensure the commercial production process remains in compliance with regulatory guidelines.

• Maintaining

Flexibility

Having flexibility through the conditional release of a therapeutic during commercialisation allows for

DS batch release and DP manufacture to run in parallel. This can help balance the demand for critical treatments with patient safety. In addition, this can highlight the competitive advantage of end-to-end batch manufacturing.

• Encouraging Open Communication

Effective communication between the biologics developer and contract development and manufacturing organisation (CDMO) should be maintained from the beginning of the delivery process. Working together as a single unit allows for production goal alignment and incorporates originator client and CDMO expertise into technical and strategic planning workflows. This does not just maintain expectations of both entities throughout, but positions the project for success.

ENGAGING WITH AN EXPERIENCED CDMO

Developing a DP is complex and comes with scientific, technical and regulatory challenges that can slow the progress to market. Therefore, companies are increasingly outsourcing activities to CDMOs to overcome development and manufacturing challenges, such as:

• The need to scale up biologics production.

• Maintaining product quality through to commercialisation.

• The requirement for specialised equipment and expertise.

The CDMO outsourcing market is predicted to increase by $287 billion between 2023 and 2030, at a compound annual growth rate of 9.2%. With demand in the market for therapeutics increasing, it is becoming more and more advantageous for manufacturers to align with an experienced CDMO from the beginning of development.

Engaging with a CDMO early in the drug development process ensures that goals are clearly defined so that the needs and outcomes of the project are considered when establishing a timeline. Embedding strict milestones into the timeline will ensure streamlined production with continued project momentum. Forming a supportive and communicative partnership with a CDMO can propel the manufacture of biologics. Access to expert knowledge and specialised equipment can be gained through collaboration with a CDMO with experience driving therapeutics to commercialisation. In addition, it is essential to align with a CDMO that is at the forefront of developments in the biologics space, such as automated manufacturing and AI systems that are streamlining processes and data analysis, providing real-time insights that can further accelerate life-saving therapies to market.

Drug developers must balance the urgency of ge ing e ective treatments to patients with the need to ensure safety, e cacy and regulatory compliance.

COMMITTED TO SUSTAINABILITY!

Since its creation, Nemera has been resolutely focused on the well-being of patients, true to the motto, “We put patient first” and the health and safety of the people who work for the company. When we built Nemera’s sustainable development roadmap, it seemed obvious to us that to better serve these two missions, we needed to think of on much more, notably on our impacts: limiting our impact on the environment and having a positive impact on society. This is why we articulated our sustainable development strategy around 4 priority areas: labor and human rights, environmental protection, our impact on

society and on our value chain. Through our roadmap and the concrete actions that follow, we want to initiate a strong dynamic on these 4 pillars within our sphere of influence. And we will not be able to do it alone! It is only by creating solid partnerships with our customers and suppliers that we will be able to achieve our goals.

REDUCING OUR IMPACT ON THE ENVIRONMENT, A KEY CRITERIA INCLUDED IN OUR BUSINESS CHOICES

Nemera’s main environmental impact is electricity consumption. In 2019, we chose to find new partners to supply us with green or

decarbonized electricity. Since 2023, 100% of our factories have been using green or decarbonized energy! This has resulted in a reduction of more than 80% of our C02 emissions from scopes 1&2.

In parallel with the work on energy supply contracts, each plant is developing an energy saving plan. Work on LED lighting and the reuse of heat produced by the machines to heat the premises has been underway for several years now. Today, we are making major investments in more efficient heating and cooling equipment and in production machines that consume less energy. We already have

two ISO 50001 (Energy Management System) certified sites and a third will be certified by the end of 2023.

To go even further down the road to decarbonization, we have made a commitment to the SBTi in 2021 to set our CO2 reduction targets and to contribute, on our own scale, to limiting global warming to 1.5°C in 2030 compared to the pre-industrial era. This is a very strong commitment because we must reduce our CO2 emissions from scopes 1&2 by 90% and CO2 emissions from our indirect activities (scope 3) by 55%. We are designing and developing action plans for

2023, targeting the various categories of emissions that will enable us to achieve these objectives. This is a multi-disciplinary effort that is once again being developed with our supplier and customer partners.

(Main Image)

Another major area of development for us is the eco-design of our products. Led by Insight, our R&D team, this year we are going to carry out our first life cycle analysis on one of our own products, Novelia®. The aim of this process is to quantify the environmental impact of this product and to identify the best levers for action to make it more sustainable and more easily recyclable. Given the development cycles for pharmaceutical equipment, which can take 10 years, this is a long-term task, but one that is essential to complete the 2030 decarbonization plan for our activities.

While we are freer to choose the actions to be taken on our own products, we are also engaging in discussions with our CMO customers. Indeed, our development teams as well as our production teams are ready to work on low-carbon resins or reuse of production scraps on the shop floor. We are looking forward to bringing our skills on these innovative projects for the pharmaceutical sector!

EMBARKING VARIOUS STAKEHOLDERS TO INCREASE OUR IMPACT

We do not want to limit this sustainable development dynamic to our own activities. The beneficial effects of our strategy will be particularly amplified if we succeed in convincing our suppliers, customers and financial partners to participate in

our initiatives at their level. This is not the easiest part because we have to explain our strategy and convince our stakeholders.

Let’s take the example of greenhouse gas emissions. Scopes 1 and 2 emissions are directly linked to our activities and we have a direct influence on them. Following the actions implemented at each of our production units, we will have reached our reduction targets by the end of 2023. We have acted quickly and effectively.

Thus, our indirect emissions from our value chain, also known as scope 3 emissions, will represent more than 70% of our carbon footprint by 2023. The real challenge is here. We need to work on the carbon footprint of the products we buy as well as the transportation of raw materials and finished products. This requires building strong relationships with our suppliers and customers so that they accept the changes we propose. A virtuous circle is then set up in which our suppliers will also have to bring their own suppliers on board. This is the effect we are looking to produce.

LEVERAGING INTERNATIONAL AND SCIENTIFIC INITIATIVES TO PROVIDE TRANSPARENCY

In 2019, our sustainability road map was assessed for the first time by EcoVadis. This allows us to be evaluated annually by an independent third party and our efforts are translated into a score in a completely transparent way. Since 2019, we have carried out many projects and our score keeps increasing. We were Silver in 2021 and 2022, that means, in the top 15% of companies in our industry with the highest

score; and thanks to the projects conducted this year, we will certainly be Gold, in the top 5%.

In 2021, we have made a commitment to the SBTi to validate our greenhouse gas emission reduction targets. This guarantees that our ambition is in line with the global challenge of limiting global warming to 1.5° by 2030 compared to the preindustrial era.

Finally, at the beginning of 2023, we signed up to the UN Global Compact in order to contribute to the 17 sustainable development goals defined by the United Nations. The next step is to analyze our strategy with regard to these 17 objectives and identify any gaps or define a higher ambition.

The regulations relating to sustainable development are evolving very quickly. We are actively preparing for the upcoming new guidelines on non-financial reporting by companies by putting in place robust and repeatable CSR indicators and data collection

processes. The whole company will be involved, which is what makes our business so attractive.

I’m very happy to share that we published our first ESG report in 2023! This is an important step for us because it brings together in a single document all our initiatives and inspiring testimonials from our teams. This report will evolve into an improved version in 2024, as we will also be producing our double materiality matrix this year. The results will determine the architecture of our next report and the indicators we will publish annually.

We are certainly at the beginning of our journey, but the involvement of our employees and our management team is already visible. We are putting particular energy into engaging our stakeholders to maximize our positive impact on the environment and society. I am confident that we are on the right track in our contribution to a better world for future generations.

*tCO2/added value

OPTIMISING BIOPROCESSING WORKFLOWS: Sustainability and Environmental Impact of Single-Use Technology

Robert Newman is Chief Scientific O cer at FUJIFILM Irvine Scientific and Tom Fletcher is Director of Research and Development at FUJIFILM Irvine Scientific, a company that specialises in the development, manufacture and supply of cell culture media for Bioprocessing and Cell and Gene Therapy applications.

While the global demand for new sustainability measures continues to be a focus, it is important to identify ways to reduce risks associated with handling, managing raw materials, and maximising the impact of limited resources by improving efficiency with simplified cell culture media and buffer preparation methods and resource allocations that optimise productivity. An efficient, sustainable bioprocessing workflow is crucial for the timely production of biologics and therapies to both the manufacturer and patients.

The bioprocessing industry plays a pivotal role in the life sciences sector by providing cells, culture media and other essential materials necessary for the rapid advancement of innovations such as cell and gene-based therapies and biologics. As the demand for advanced therapeutics continues to grow, so does the need for optimised bioproduction workflows that ensure consistent, largescale, and cost-effective manufacturing. Coupled with the requirements for dramatically expanded outputs, the industry has seen mounting pressure to establish environmentally sustainable processes, with some pushing to move away from ‘singleuse’ technologies – but is the solution as clear cut as it seems?

Reflecting on the trajectory of the industry thus far, it becomes important to examine the latest

trends and successes, and the key workflow challenges that remain within the bioprocessing sector. The demands and risks associated with handling and processing raw materials are multi-faceted, particularly when considering how to maximise resources, simplify and optimise media and buffer preparation. These next-generation solutions must be developed to address pressing concerns related to environmental impact, which in themselves are complex.

MOVING TOWARDS SUSTAINABLE MANUFACTURING WORKFLOWS

In line with the advances of the bioprocessing industry, the optimisation and evolution of high performance cell culture media formulas and their manufacturing is key. Use of custom optimised culture media formulas can elevate process efficiency, to achieve higher titers, consistency, and improved product quality, leading to a significant reduction in waste – all components essential to the overall push to more sustainable manufacturing practice.

One pivotal advancement in increasing process efficiency is the move towards using chemically- defined cell culture media, which has enabled researchers’ full control over their media formulas. Removing all undefined or animal-derived components ensures the consistency of culture media formulas, with minimal risk of impurities from biological and variable materials, enabling therapeutic developers to effectively operate within strict regulatory landscapes and adhere to necessary safety requirements. Chemically-defined culture media not only enhance process control but also establish a foundation for reliable and sustainable manufacturing practices.

When seeking to address sustainability in any industry, effective and responsible waste management is key; not only minimising it, but also appropriate disposal. In bioprocessing workflows, these by-products could be solid waste from consumables (packaging), or liquid produced by the process itself or via system cleaning. Process optimisation provides a primary strategy to minimise this waste. However, as the stages of bioproduction demand careful and individualised fine-tuning, this is not a simple solution. Balancing waste reduction efforts with the intricacies of complex bioprocessing stages underscores the need for comprehensive waste management strategies.

The integration of increasingly sophisticated and intricate technologies, in combination with the development of process analytical technologies (PATs) and the artificial intelligence (AI) revolution has resulted in a surge of advanced automation technologies to optimise bioprocessing workflows. Harnessing AI, these systems enable critical parameters to be monitored during continuous manufacturing. This real-time data analysis facilitates ongoing process optimisation that would not be possible using traditional manual techniques. In addition, automated manufacturing minimises the possibility of human error, a risk that can significantly impact workflow efficiency or, in the worst case, cause a batch to

An e cient, sustainable bioprocessing work ow is crucial for the timely production of biologics and therapies to both the manufacturer and patients.

fail entirely. By introducing automation, laboratories can ensure batch-to-batch consistency, accelerate and streamline processes, to maximise resources and reduce waste output. Furthermore, sustainable management technologies, such as membrane bioreactors for wastewater purification can be integrated to address waste that cannot be eliminated in culture media preparation workflows.

SINGLE-USE TECHNOLOGIES

Contamination poses significant challenges in the development of biologics and therapies, not only risking human health, but also efficiency and cost of manufacture. Once detected, contaminated batches, and any other materials at risk, are disposed of - depending on how far into the process this occurs, it could result in a large amount of wasted raw material, energy, and time, significantly impacting a biopharmaceutical manufacturer’s output and carbon footprint. As such, efforts to eliminate risk of contamination are essential to manufacturers.

The adoption of singleuse technologies (SUTs) has become an integral part of modern bioprocessing, both across manual and automated workflows. Often composed of disposable plastic, these consumables eliminate the risk of cross-contamination, as opposed to conventional, reusable stainless steel or glass systems which require extensive cleaning and sterilisation between culture media preparation workflows. Not only does the cleaning process use additional resources, time and manual labour in comparison to SUTs, it drives up energy and water use. Despite these efforts, contamination may still occur. Latest advances in automated media and buffer preparation systems harness SUTs with pre-packaged media

cartridges, eliminating the need for bag installation and constant monitoring, to further maximise efficiency and reproducibility.

Addressing the challenge of disposable plastics is imperative when integrating them into sustainable workflows. Globally, there is increasing pressure on governments to impose stricter regulations on recycling and single-use materials, particularly around new plastic production, in an effort to minimise landfill and avoid toxicities when the materials break down into microplastics, which pose threat to all ecosystems. In the United States alone, an estimated 40 million tons of municipal plastic waste were generated in 2021, with at least 85% sent to landfill sites, of this, an estimated 30,000 tons of biopharma single-use products. Recycling such specialised plastics can be more complicated than standard waste, often containing different polymers, multi-layer films and potentially hazardous materials, which must be sterilised and appropriately disposed of.

The indispensability of plastics is recognised universally in the medical sector, owing to their high versatility and ability to be sterilised, and therefore raises the question: in what instances is single-use plastic appropriate? And when the benefits are substantial, how can we mitigate the impacts of new production? Consequently, efforts are

being made within the industry to demonstrate these materials are not predestined for landfill. With SUTs, there are two main routes for recycling – energy production and material production. For example, the Biopharma Recycling Program, launched in 2015, where scrap materials are recycled into various grades of plastic lumber, used in landscaping, speed bumps and garden furniture, and many other applications. And in 2018, Novo Nordisk announced that 94% of its manufacturing waste materials were recycled, harnessing waste materials for local energy production infrastructure.

LOOKING FORWARD

The discussion surrounding sustainability in the biopharmaceutical industry is extensive, demanding careful considerations between maximising workflow efficiency to advance innovation and mitigating environmental impacts. Realistically, this balance is also paired with perspectives in relation to local and corporate priorities, including the societal shift in environmental-consciousness and the growing expectations of customers towards manufacturers.

When assessing the impact of SUTs, reducing cost of workflows, and sustainability, key industry leaders are increasingly recognising that environmental considerations are interwoven: if natural resources are not protected, supply of raw materials cannot be secured. Consequently, more attention should be given to responsible operations and assessing overall carbon footprint and water usage, such as, the potential energy savings achievable with SUTs, to offset the added impact of plastic. By prioritising social responsibility, many companies have outlined ongoing sustainability initiatives, for example, FUJIFILM Irvine Scientific’s new purpose-built facility in Tilburg, Netherlands, that prioritises specific strategies that adhere to the Fujifilm Sustainability Value Plan 2030 for sustainable growth.

Demand is driven by customers, but as the bioprocessing industry continues to expand, collaborative solutions are required at all points in the supply chain to address current and future issues in SUT and the industry’s environmental impact as a whole. The implications of pharmaceutical waste entering the environment must also be effectively communicated to patients; the largest contributions being from patient use and the improper disposal of drugs. The third is from pharmaceutical waste from manufacturing facilities. An efficient, sustainable bioprocessing workflow is crucial for the timely production of biologics and therapies to both the manufacturer and patients, for years to come.

EMA’s vision of a single source of truth for clinical trial information forces a major shift in how companies collect and store trial data and documents.

The Clinical Trials Regulation represents a milestone on the journey to a more competitive European R&D environment, particularly for multinational studies. Improved trial transparency - and EMA has recently opened a public consultation in this area - will make it easier for patients to participate in research. A harmonised approach to clinical trial applications across Europe should lead to faster approvals.

However, companies have been facing challenges in several areas since EU CTR became mandatory three months ago. Sponsors and contract research organisations (CROs) find it difficult to coordinate submissions cross-functionally and meet tight deadlines, partly due to fragmented and time-consuming data collection. Redactions are another sticking point. Disclosures must be fully integrated within the standard clinical trial process yet occur more frequently across the trial lifecycle than before.

Some issues are outside companies’ control and will only ease once the Clinical Trials Information System (CTIS) reaches a steady state. Still, companies don’t need to wait for the next phase of CTIS to improve their oversight of the complete submission file. Changing the resourcing of their regulatory and clinical teams and adapting their data collection, request for information (RFI), and redaction processes will provide muchneeded visibility sooner. The benefits are not limited to EU CTR. Clarifying ownership and

EU CTR Challenges Sponsors and CROs To Get Their Houses

in Order

creating a single source of trial information would also make rest-of-world studies more efficient.

ONE TEAM IN THE DRIVER’S SEAT

Small single-country studies are usually good candidates for a pilot submission to CTIS and have been used to uncover the limitations of existing processes and systems. Insights from these first submissions have helped sponsors decide on an effective resourcing model for subsequent studies, including whether or not to outsource to CROs.

Sponsors that insource have improved alignment by creating a single EU CTR cross-functional process and team structure, spanning from regulatory and clinical to quality, safety, and trial disclosure. In the past, these teams had independent responsibilities. Regulatory managed the submission of health authority approvals while clinical teams handled ethics committee approvals at the site or country level. Condensing regulatory and ethics committee approvals into a single process requires adjustments to team structure and responsibilities.

Companies have set up their centralised submission teams for success by clarifying ownership of the end-to-end process and confirming new responsibilities. Among Veeva customers, there isn’t a consensus on which team should be in the driver’s seat: roughly half point to regulatory while the remainder opts for clinical operations. Irrespective of which team leads, its submission responsibilities are broader than before, extending to regulatory, ethics, and disclosures.

As the nominated team is pivotal in collecting trial-related information, its remit should be clearly communicated to the broader organisation. Understanding who is accountable for gathering information from different stakeholders (e.g., quality, regulatory affairs, clinical) is critical, particularly during RFIs from EMA, which require a response within 14 days. A tracker specifying ownership for each task can make it easier to collect RFI answers across the organisation.

STEPHAN OHNMACHT, Vice President, R&D Business Consulting and WERNER ENGELBRECHT, Senior Director, Strategy, Veeva Vault Clinical Operations.

Companies are also exploring new ways of working to counter the challenges of fragmented data collection and dynamic redactions. Some sponsors have delegated data entry into CTIS to CROs for outsourced studies, eliminating a few extraneous steps. Similarly, centralising responsibility (whether internally or outsourced) for redactions helps to manage this process more effectively because training, guidelines, and SOPs can be implemented in just one dedicated team.

SINGLE SOURCE OF TRIAL INFORMATION

Some companies are now sufficiently well-versed with the regulation to submit Parts I and II together. Leading companies go further during the initial submission by including many countries under Part II. Submitting multi-country studies in parallel decreases the number of evaluation cycles, reduces the risk to patient recruitment, and shortens the overall approval timeline. But it’s a heavier upfront lift, for which easy access to trial-related information is essential.

While it may be tempting to navigate a submission with pre-existing data collection processes, this could prove shortsighted. Currently, CTIS lacks an API capable of receiving data and documents from either sponsor systems or technology partners (including Veeva). However, the next phase of CTIS will probably involve API capabilities, which could make company integrations more straightforward. Doing the hard work now to create a robust data foundation will pay dividends if (and when) the API is introduced by EMA.

Sponsors and CROs that have centralised data entry into one team (resourced with up to 10 people in enterprise biopharma) are already seeing the benefits of the new model. Having one part of the organisation accountable for data entry and upload to

CTIS streamlines user access management and reduces the training effort required. However, data entry teams often need external support to create a repository of all the data points for each CTIS submission and then scale this structured approach across the company. This CTIS data collection tracker2 should be a single source of truth of all reportable data from different systems.

It can also be helpful to reflect on the spirit of the regulation when setting up a process to manage redactions. Companies need to balance disclosure risk with the benefits to patients of greater trial transparency. Usually, the two main types of data anonymisation activities (commercially confidential information and protected personal data) take place using a hybrid approach. Redactions of company information are often centralised because they require legal knowledge (e.g., information relating to patents), and personal data redactions are decentralised so local teams can apply their national legal understanding.

Modifying redactions can quickly become messy in a hybrid model. Information that is confidential today might not

be in a few months when the trial ends. Nor do all redactions involve obscuring text. Some content may need to change or be rephrased. The complexity of managing redactions could hinder patients and sites from enjoying easy access to studyrelated information envisioned in the regulation. To address these areas, sponsors should work in a system that maintains a close relationship between source and redacted documents so that teams can easily manage changes to content before public disclosure.

MEETING THE NEW STANDARD FOR AMBITION

A single source of truth for European clinical trial information will benefit patients, who will soon find it easier to participate in ongoing trials. Mandatory use of the same system should enhance stakeholder access to trial information without compromising robust data privacy standards. However, EU CTR also challenges sponsors and CROs to reconsider how they collect and store trial data and documents for EU and non-EU studies. The European Medicines Agency has thrown down the gauntlet — and for some companies, this provides a welcome opportunity to get their houses in order.

Changing the resourcing of their regulatory and clinical teams and adapting their data collection, request for information (RFI), and redaction processes will provide much-needed visibility sooner.

The Covid-19 Update

WITH Covid-19 MAKING AN UNWELCOME REAPPEARANCE IN GLOBAL NEWS OVER THE PAST MONTH, WE AT EPM HEADQUARTERS HAVE COLLECTED SOME OF THE KEY STORIES TO KEEP YOU AS UPDATED AS POSSIBLE.

Covid-19 Variants

Detected in UK

On August 18th, the UK Health Security Agency (UKHSA) published an initial risk assessment of the SARSCoV-2 variant BA.2.86. This variant was detected in the UK on Friday 18 August, and has also been identified in Israel, Denmark and the US. It has been designated as V-23AUG-01 for the purpose of UKHSA monitoring.

The newly identified variant has a high number of mutations and is genomically distant from both its likely ancestor, BA.2, and from currently circulating XBB-derived variants. There is currently one confirmed case in the UK of an individual with no recent travel history, which suggests a degree of community transmission within the UK. Identifying the extent of this transmission will require further investigation.

Dr Meera Chand, Deputy Director, UKHSA said: “V-23AUG-01 was designated as a variant on 18 August 2023 on the basis of international transmission and significant mutation of the viral genome. This designation allows us to monitor it through our routine surveillance processes. We are aware of one confirmed case in the UK. UKHSA is currently undertaking detailed assessment and will provide further information in due course.”

There is currently insufficient data to assess the relative severity or degree of immune escape compared to other currently-circulating variants.

Moderna Clinical Trial Confirms Updated Covid-19 Vaccine Generates Robust Immune Response

Moderna, Inc announced on the 17th of August that preliminary clinical trial data confirming its updated Covid-19 vaccine for the fall 2023 vaccination season showed a significant boost in neutralising antibodies against EG.5 and FL.1.5.1 variants. These results suggest that Moderna’s updated Covid-19 vaccine may effectively target the expected circulating variants of Covid-19 during the upcoming vaccination season.

The World Health Organization (WHO) recently classified the EG.5, or “Eris,” strain as a variant of interest. EG.5 is now the dominant

variant in the U.S. according to the Centers for Disease Control and Prevention (CDC), while also accounting for a growing proportion of cases across the globe. The FL 1.5.1, or “Fornax,” variant is also beginning to surge in parts of the U.S.

“These new results, which show that our updated Covid-19 vaccine generates a robust immune response against the rapidly spreading EG.5 and FL 1.5.1 strains and reflects our updated vaccine’s ability to address emerging Covid-19 threats,” said Stephen Hoge, M.D., President of Moderna. “Moderna is

committed to leveraging our mRNA technology to provide health security around the world.”

In addition to demonstrating a human immune response against the EG.5 and FL 1.5.1 strains, Moderna previously presented the only clinical trial data confirming that its updated Covid-19 vaccine showed robust human immune responses across the key circulating XBB strains at the June 2023 FDA VRBPAC. With this new trial data, Moderna has now confirmed an antibody response against current strains of concern.

Moderna has submitted its updated Covid-19 vaccine to the U.S. Food and Drug Administration, the European Medicines Agency (EMA) and other regulators around the world. Pending authorisation, it will be ready for fall vaccination with sufficient global supply.

Regeneron and BARDA Collaborate on Next Generation Covid-19 Vaccines

Regeneron Pharmaceuticals have entered into an agreement with the Biomedical Advanced Research and Development Authority (BARDA) to support clinical development, clinical manufacturing and the regulatory licensure process of a next-generation Covid-19 monoclonal antibody therapy for the prevention of SARS-CoV-2 infection. The agreement is part of ‘Project NextGen,’ an initiative by the U.S. Department of Health and Human Services (HHS) to advance a pipeline of new, innovative vaccines and therapeutics for Covid-19.

BARDA, part of the

Administration for Strategic Preparedness and Response at HHS, and Regeneron have previously worked together to deliver novel medicines for Ebola and Covid-19 at unprecedented speed and under urgent circumstances. The new program announced falls under Regeneron and BARDA’s ongoing Other

Transactions Agreement initiated in 2017 to develop a portfolio of antibodies targeting up to 10 pathogens that pose significant risk to public health. For the new Covid-19 program, HHS will fund up to 70 percent of Regeneron’s costs for certain clinical development activities for a next-generation monoclonal antibody therapy with broad neutralising activity against SARS-CoV-2, the virus that causes Covid-19. The new contract has an estimated value of up to approximately $326 million of government funding.

“We’re pleased to expand our longstanding BARDA relationship, which is predicated on Regeneron’s decades of investment in deep scientific research and enabling technologies,” said Leonard S. Schleifer, M.D., Ph.D., Board

Co-Chair, President and Chief Executive Officer of Regeneron.

“Although Covid-19 has moved to an pandemic stage, many people – including those with immunocompromising conditions – continue to face exposure that impacts their everyday life and could cause serious health consequences. We believe Regeneron can once again apply our drug discovery and development expertise to help prevent disease in vulnerable populations. American biopharmaceutical companies developed remarkable Covid-19 therapeutics and vaccines in record time, successfully changing the course of the pandemic, and we’re gratified that the U.S. Government continues to support early research from this uniquely innovative industry.”

Follow us: Organized by: Ipack Ima

An event by: pharmintech.it

HARNESSING STRUCTURED DATA TO TRANSFORM PHARMA PROCESSES

Remco Munnik is a Director at Iperion and a respected subject matter expert in RIM, eCTD, xEVMPD and ISO IDMP, Chair of Medicines for Europe Telematics group; and President of the IRISS Forum.

Regulatory change is driving data-driven processes and there is increasing recognition that these data-based requirements are creating opportunities to transform processes along the pharma lifecycle. And the structured data that is at the heart of these transformations is the key to eliminating product shortages, and managing labelling change. At Amplexor’s recent BE THE EXPERT 2023 global conference, Remco Munnik of Iperion - a Deloitte business, discussed how good-quality data can be put to work to enhance internal and external processes, identifying new markets and reducing time to market.

The fact that Life Sciences is now adopting and seeing value in structured data is a huge turning point for the industry, and this acceptance is becoming increasingly palpable. Once companies are able to see beyond the mandatory detail of the regulations that are helping to drive data-oriented process change, their opportunities for transformation of entire functions and their approaches to product tracking and management will broaden and multiply.

Certainly, harnessing structured data and using this for strategic advantage is about so much more than adhering to the specific requirements of IDMP, ePI, CTIS, ESMP, PQ/CMC and associated global implementation projects for their own sake. Access to goodquality data can help to significantly improve internal and external processes - with a view to identifying new market openings, optimising clinical trials, shortening time to market, eliminating product shortages, and managing labelling changes seamlessly and without fuss.

At a recent conference – Amplexor’s annual global BE THE EXPERT forum, in June, in Split, Croatia – participants were more acutely aware and enthusiastic about the potential than in previous years. Although there remained a clear appetite to learn and interpret the latest updates on EU IDMP and other data-based requirements with a bearing on key aspects of the R&D and marketing authorisation/ post-marketing product lifecycle (including safety surveillance and licence maintenance), event participants were even keener to appreciate the broader opportunities that exist for companies to transform the way they operate. This includes the way they track products, tap new market potential, and connect with and add value for clinicians, caregivers, prescribers, payers, and - of course - patients.

DOING MORE WITH DATA

Taken individually, the various mandates and required data capabilities and systems, can seem daunting. Take the new European Shortages Monitoring Platform, expected to go live within two years. This has been conceived by the European Medicines Agency (EMA) in the wake of Covid-19 related supply chain disruption and shortages - not just of immediate vaccines and treatments, but of other critical medicines as entire countries and regions went into lockdown.

The new data-driven platform is EMA’s response to the situation, intended to pre-empt and curb unexpected

supply issues – whether these involve paracetamol, antibiotics, flu vaccines, or hormone replacement therapy products – through prompt reporting of emerging issues. (In the US, the FDA has even more granular guidance around supply precautions and contingencies.)

While functional managers and IT teams might baulk at the additional reporting requirements, once companies are generating regulatory data - as captured currently in documents - they have the opportunity to do so much more with it.

It makes sense, then, to make the best possible job of capturing and maintaining that data, to a consistently high standard.

GATHERING INSIGHTS

Once companies have captured all of the data they want and need, the next step is to structure it in such a way that it can be exchanged reliably with other systems, both internally and externally. Instead of requiring that new manual processes are invoked to enter the latest relevant data into a new system or portal, that information should pre-exist and be readily redirectable to fulfil each additional emerging need – fulfilling a range of new use cases relatively easily. That is, once companies have reliable, consistent,

good-quality, structured data organised and ready to go.

Take the shortage management use case. Ultimately, gaining visibility of potential product shortages requires simply that product data and supply chain information can be combined to provide, compile and report the relevant insight. In other words, once all of the contributing insights have been released from static PDFs (e.g. CMC manufacturing process and control information as submitted to regulators

in Module 3) and exist as live intelligence that can inform other teams and fulfil new reporting demands. For instance, visibility of how many products have a certain excipient, and where a product is manufactured, could

automatically flag up emerging supply issues out of China, India or any other country, if that country is in lockdown.

TIME TO START THE GROUNDWORK

Whether in Europe or not, there is a need for Life Sciences companies to move forward with their data preparation plans with new intent. Certainly, given the broad opportunity for process transformation and the potential for crucial new actionable insights, it makes no sense for companies to wait

for Regulators to issue final data formatting instructions, or for software vendors to have exactly the right fields defined, before teams start doing the real work.

There is a lot of groundwork regulatory, quality and safety functions could be doing today to get their data in shape, while the Is are still being dotted and Ts being crossed at a regulatory level. In other words, getting control of internal data is paramount, and relying on regulators or the software industry to trigger next internal data-related preparations is a passive and risky way to approach this.

It’s a bit like starting to get financial book-keeping in order only once the Tax Office has asked for an annual tax declaration – when really everything should have been recorded continuously throughout the year. In this case, there is a chance to avoid the 11th-hour panic of databased regulatory compliance, given that reliable on-demand reporting is possible and holds great benefit today (assuming appropriate attention has been given to data capture and management.

In the pharma sector, underpinned by EMA’s agile approach, there is already clear buy-in to working towards a structure enabling data and documents to be exchanged seamlessly. Pharma companies that are well on the way to being able to connect and exchange information effortlessly are reaping the benefits of being able to address supply issues effectively and efficiently, keeping their product pipelines flowing.

Q: With lung cancer accounting for 25% of total cancer deaths in the US and worldwide, what benefits does spray drying for inhaled delivery offer for lung cancer treatments?

A. Lung cancer remains a significant unmet medical need. One way in which treatment might be improved could be to deliver anticancer drugs directly to the surface of the lungs. Local delivery that targets therapy to the site of action would reduce the dosage burden in comparison with systemic delivery, while also bypassing the first pass metabolism of the liver.

In order to create inhaled formulations delivered via a dry powder inhaler, particles with consistent shape and size need to be created. By using spray drying with careful tailoring of the process conditions, both particle size and morphology can be controlled to achieve targeted delivery to various levels of the lung – including the deep lung. The formulation of inhalable

EXECUTIVE Q&A: LONZA

Michael Shultz, Group Lead, Inhalation, Lonza.

powders for spray drying is not limited to small molecules, but can be achieved for complex biologics such as monoclonal antibodies that are frequently used as cancer treatments.

Other advantages of formulating as a dry powder include the possibility of a longer shelf life, and it could, potentially, eliminate the need for cold chain storage and distribution (which is particularly limiting for many biologics). This would facilitate access to lifesaving therapies. Additionally, DPIs are small, portable, and the treatments are simple for most patients to self-administer. Therefore, formulating as a dry powder can offer significant advantages over liquid formulations that require a nebuliser, and all the limitations associated with these devices. Spray drying is a powerful technology that can make a DPI formulation a reality for both small molecule therapies and biotherapeutics for the treatment of lung cancer.

Q: How efficient is inhaled drug delivery of dry powder in reaching the lungs?

A. If the shape and size of the particles fall within the correct parameters, then it can be extremely efficient to deliver drugs to targeted regions within the lung – the bronchi, bronchioles and alveoli – via a dry powder inhaler. Particles can be engineered to have a narrow, targeted aerodynamic size for deposition in the deep lung – minimising the number of fine particles that are so small that they are simply exhaled, and particles so large that they do not reach the target tissue.

Inhalable powders are generally contained within a capsule or blister, and once pierced within the inhaler device are dispersed by the patient’s breath upon inhalation. An important consideration is the potential of the powder to agglomerate, which would significantly impact delivery to the desired target in the lung. Cohesive or poorly dispersible powders may remain within the device, or catch on the patient’s throat. Spray-dried powders can be engineered to have good dispersibility properties, ensuring minimal particle aggregation, and resulting in efficient powder delivery.

Q: What challenges would you encounter within the spray drying process?

A. The parameters employed during a spray drying process will have a direct impact on the behaviour of the powders that are made. The challenges faced can vary, depending on the nature of the API and excipients required for the formulation. Important parameters include how the solution to be spray dried is prepared,

its atomisation, the kinetics of the drying process, and the collection of particles. A number of variables are involved, such as inlet and outlet temperatures, both gas and liquid flow rates, liquid pressure, the liquid-to-gas ratio, solids loading, and even the selection of the nozzle. All of these parameters are carefully tuned during process development to achieve the desired powder properties.

The solubility of the API and excipients are key parameters that need to be considered, and if solubility is low this can cause problems that will need to be overcome. Another challenge comes when scaling up the manufacturing process, and this needs to be considered early on during development. If processing times are prolonged, there will be inevitable cost implications. A number of methods can be employed to overcome these challenges, such as using temperature shift processes or including volatile processing aids to improve solubility and shorten

processing times. Biologics, in particular, can pose significant challenges because of the inherent sensitivity of these complex molecules to the physical stresses of the spray drying process. A careful and thorough risk assessment, and mitigation strategies to address any risks, are key for successful process development.

Q: Along with L-leucine are there other promising excipients that are helping to improve inhalation efficiency?

A. The number of excipients with FDA approval for inclusion in inhaled formulations is decidedly limited. However, as amorphous powders have a tendency to be cohesive, it is important to incorporate dispersibility enhancers to help reduce the adhesion between particles. While L-leucine is not yet on the approved list, it is expected that it will be added in the near future.

There are, however, a number of excipients that are already

on the approved list that can improve properties such as flowability (and thus give better aerosolisation), as well as potentially acting as stabilisers, binders and enhancing bioadhesion. These include magnesium stearate, which can also act as a dispersant, plus carrageenan, HPMC, gelatin and glycine. The carriers lactose and mannitol can also improve aerosolisation. And including ingredients such as trisodium citrate, sodium lauryl sulfate and silicon dioxide in the spray dried solution may also have an impact on delivery efficiency.

Trehalose is another ingredient that, like leucine, is yet to be included in the approved list for respiratory dosage forms. This sugar – a disaccharide comprising two glucose units – is commonly used in injectable drug formulations where it confers stabilising properties, and has shown promise for biologics during formulation development for inhalable dry powders.

Q: What alternative approaches to spray drying are available, and what are their benefits/drawbacks?

A. When developing a new inhalable dry powder, it is important to assess the many possible manufacturing methods that are available. Of course, compatibility of the API with the manufacturing process is paramount in that decision. Additionally, factors such as development and manufacturing costs, reproducibility, and scalability need to be considered if the product is to be both robust and economically viable.

In addition to spray drying, there are various well-established methods that can be used to manufacture dry powders for inhalation, including milling, spray-freeze drying, and supercritical fluid drying. Additionally, there are emerging technologies such as particle replication in non-wetting templates, inkjet printing, and thin-film freezing. All technologies have their benefits and drawbacks, and these can vary depending on the individual API or the API class. Milling, for example, is a simple and inexpensive method for producing dry powders for inhalation. It can, however, produce particles with poor flow characteristics as a result of high surface energy and the irregular size and shape of the particles. It is also unsuitable for most biotherapeutics, as their fragile nature is not compatible with the high force required.

In contrast, spray-freeze drying and thin-film freezing can produce inhalable low-density, porous powders under conditions that are suitable for heat-sensitive formulations such as biotherapeutics. But while they are compatible with many such molecules, the techniques are complex, time intensive, and comparatively costly. And formulations sensitive to cryogenic stress would not be compatible with these methods. Another technique, supercritical fluid drying, can produce uniform spherical powders in a relatively rapid manufacturing process, and is suitable for many APIs, including biological formulations. Significant drawbacks can arise, though, from solubility issues in supercritical CO2, as well as the high cost of implementing this technology.

Q: What are the main considerations when formulating an inhaled dry powder product?

A. When considering whether to formulate and deliver a drug as a dry powder, patient need is first and foremost. Would a DPI improve their treatment in some way, whether because of faster onset of action, reduced side effects, ease of use, or even improved compliance? An additional consideration is whether it is feasible to make the appropriate powders reliably, reproducibly, and at scale, as this is key for developing a practical and costeffective manufacturing process. This can be assessed during process and formulation development, considering factors such as the desired particle aerodynamic properties, the desired deployment strategy for the final product, API and excipient solubility, and stability during processing and storage. The development process can be complex, and is highly dependent on the chemical properties of each individual API, and also the desired properties of the final powder. In addition, for more complex biologic APIs, functional activity of the molecule must be retained, and special attention must be placed on controlling parameters that affect the physical three-dimensional conformation of the API during the manufacturing process, and after delivery to the lung.

FORGING COLLABORATIONS FOR A PROMISING FUTURE IN THE PHARMACEUTICAL SECTOR

EVENT OVERVIEW

Place yourself at the ‘heart of pharma’ as CPHI Barcelona returns in person to Fira Barcelona, Gran Via, Spain from 24 - 26 October ’23. With over 2500 exhibitors from across the entire pharma supply chain and visitors from over 70 countries the show offers networking, learning and partnership opportunities like never before.

Following the remarkable success of the 2023 event in Frankfurt, the world’s largest pharmaceutical event is making its return to Barcelona, offering even more avenues to foster essential new connections and provide valuable content within the pharma industry. Encompassing various sectors, the event spans ingredients, finished dose, contract services, and fine chemicals, along with biologics, packaging, and machinery.

EXCITING NEW FEATURE

The Start-Up Market CPHI Barcelona introduces The StartUp Market, a dedicated space in Fira Barcelona’s Hall 3 for industry Start-Ups, innovators, and small enterprises to showcase new products and solutions. This hub offers a chance to explore innovations and connect with pharma’s forefront. Eligible Start-Ups from pharma, biopharma, digital,

or medical device sectors can exhibit, enjoying benefits like feature promotion, Start-Up mentors, and a networking lounge.

CONFERENCE AGENDA HIGHLIGHTS

CPHI Barcelona boasts a comprehensive conference agenda spanning topics like biomanufacturing, partnering success, future therapies, and sustainability, shaping the industry’s future. Find more information by visiting their online agenda.

A UNIQUE BLEND OF INPERSON AND ONLINE EXPERIENCES

The goal for CPHI is not just to empower its audiences at

events but to become an integral part of their 365 new business drives – to help stimulate deeper connections year-round through online communities, learnings and networking. A good example is the constantly improving digital and matchmaking tools, which allow registered users to build completely unique networks and connections that match to individual needs and business goals.

“The rapid growth of the global industry necessitates the adoption of integrated digital and in-person solutions, to aid in the acquisition of new contacts and the fulfilment of evolving needs,” states Sherma Ellis Daal, Brand Director at CPHI Barcelona. She adds “we have seen that

industry professionals seek partnerships with organisations that share their environmental and social values. At CPHI, our focus will be on providing more tools to facilitate partnering and nurturing of relationships for continuous innovation, healthcare advancements, and overall business growth.”

One such tool is the Event Planner, a digital app attendees can utilise to form connections and make their time at CPHI more productive. Through this app, attendees can plan meetings with exhibitors ahead of time and begin their networking early. Then while at the event, the app provides a personalised schedule with the pre-planned meetings and any exhibits of interest.

PASS OPTIONS

There are three kinds of passes that attendees can choose from: VIP, Standard, and Explorer. All passes grant access to online and in-person events, with additional benefits such as early entry and other amenities added to the VIP and explorer passes.

SUANFARMA AT CPHI BARCELONA

HALL:7 STAND:M30

SUANFARMA CDMO

(Contract Development & Manufacturing Organization) provides integrated, end-to-end solutions for development and commercialisation services of Intermediates and Drug Substances for Small Molecules. We specialise helping pharmaceutical, biotech and healthcare companies delivering full integrated services that compress timelines to market maximising success. Our TT&GO platform offers the highest degree of technological

ALMAC GROUP

HALL:3 STAND:L30

Almac Group is a global leader in providing a range of expert services and support across the drug development lifecycle to the life sciences sector. The international company is privately owned and has grown organically, now employing over 7,000 highly skilled personnel across 18 facilities including Europe, the USA and Asia.

Addressing the pressure to bring clinical candidates through the pipeline more efficiently and at a lower cost, Almac provides an integrated CMC service, bridging the gap between drug substance and product development.

An established provider

innovation throughout our acquired knowledge and experience in transfer processes. We have the best know-how and technologies to carry out fermentation, purification, and chemical synthesis processes in our CDMO plants including Regulatory support.

At SUANFARMA CDMO, we are more than just a CDMO company; we are your strategic partner to success. This is made possible by combining our scientific expertise, and strong track

record in development and commercial manufacturing, with flexible mindset and full transparency. Our dedicated team of experts is committed to focusing on your success, providing tailored solutions to meet your specific needs.

SUANFARMA exists to foster healthier lives in a sustainable world. Let's work together to bring your innovative products and therapies and build The Core of a Better Life.

of both drug substance (advanced intermediates and API – small molecules and peptides) and drug product development services, our clients are assured of scientific continuity from a dedicated project team, resulting in significant time and cost savings. Integrated teams within Chemical and Pharmaceutical Development work closely to understand the physicochemical properties of the API to ensure the optimum chemical entity for clinical supply manufacture. By routinely applying innovative technology solutions, we provide alternative synthesis options which are scalable, safe and economic.

For First-in-Human or later phase development, manufacture or registration batches, Almac have access to a wide range of innovative technologies for both potent and non-potent solid oral dose products.

Having chemical and pharmaceutical operations at the same campus allows for optimal communication and knowledge transfer, exploiting the Almac advantage of a single-partner approach. Smoothing transition through the drug development process and commercialisation reduces the uncertainties inherent in a multi-supplier multi-site process. Through our continued investment in the expansion of our stateof-the-art services, Almac ensures continued support across the product development lifecycle.

ENHANCING SPEED AND ACCURACY IN DRUG DELIVERY AND PACKAGING –THE IMPORTANCE OF THE LABEL

Laura Johnson, Loftware Senior Director of Sales, Life Sciences.

Recent years have shed light on the importance of acting with speed and agility when developing and delivering pharmaceutical products. The expedited trial procedures for the Covid-19 vaccine underscored the necessity for proactivity and collaboration throughout the supply chain. The urgency of the pandemic prompted regulatory agencies, pharmaceutical companies, research institutions, and manufacturers to work collaboratively and often in ways that hadn’t been previously explored. Medical trials were streamlined whilst rigorous safety and scientific standards were maintained.

In this way, the pandemic highlighted the importance of maintaining communication and information throughout the pharmaceutical supply chain. From raw material suppliers to manufacturers, down to distribution networks, each aspect of the supply chain had to adapt rapidly to meet demand for the Covid-19 vaccine rollout. In fact, the pandemic expedited the progression of trends already underway in the pharmaceutical industry, notably the implementation of critical digital methods such as the cloud.

Often overlooked, a drug’s packaging and label are essential for the seamless transportation of any product. Cloud-based labelling solutions

provide crucial delivery information, enable greater visibility, ensure regulatory compliance, and reduce the likelihood of costly recalls. For the pharmaceutical sector, where patient wellbeing and treatment efficacy are core

priorities, packaging and the label assume an even greater level of importance, safeguarding handlers as well as the end consumer.

NAVIGATING A COMPLEX REGULATORY LANDSCAPE

The accuracy and clarity of pharmaceutical products rightly faces much attention. The sector, already heavily regulated, has recently seen a raft of changes across the globe, including the EU’s False Medicines Directive, Brazil’s implementation of the National

Medicine Control System, and the FDA’s updated Code of Federal Regulation.

Looking ahead, the sector can anticipate further regulations. For example, the US Drug Supply Chain Security Act, which aims to create an electronic traceable supply chain to prevent the entrance of counterfeit and fake medication, is set to be implemented in November 2023. Earlier this year, the European Parliament granted an extension to the European Union’s Medical Device Regulation (EU MDR), now set to be implemented in 2027. These evolving

regulations can be burdensome for manufacturers, presenting additional risks and costs.

Unsurprisingly, Loftware’s recent ‘2023 Top 5 Trends in Labelling and Packaging Artwork’ report revealed that 84% of business leaders consider today’s regulatory demands to be more complex than ever before.

The label assumes a pivotal role for pharmaceutical companies who must adhere to current and future regulations. By adopting a centralised cloud-based labelling solution,

pharmaceutical companies can manage and update labels, collaborate with stakeholders, and access real-time data from anywhere and at any time. This not only improves the speed, accuracy, and efficiency of drug delivery and packaging processes, but also gives manufacturers access to the necessary data to meet the diverse set of regulations across jurisdictions. The realtime monitoring, next-level security measures, seamless scalability, and enhanced collaboration capabilities enabled by cloudbased systems further simplifies and automates the process, thereby enabling manufacturers to focus on other core operations.

IMPORTANCE OF TRACEABILITY

Visibility throughout the supply chain is vital and for the pharmaceutical industry, the stakes are high. Technological advancements now mean it’s possible to trace products both upstream and downstream with greater ease. The label, which carries important product information such as serial numbers, certificates of origin, and batch information, establishes a vital link between the digital and physical aspects of the product. In essence the label enables a complete audit trail from raw ingredients to manufacturing and distribution

to the end-user, thereby helping to remove counterfeit drugs from the supply chain, ensure patient safety, and safeguard brand reputation. By enhancing their label management with cloud technology, pharmaceutical companies can improve quality control, better mitigate risk, and avoid unnecessary recalls resulting from label and print errors.

FUTURE-PROOFING PHARMACEUTICAL MANUFACTURING

The pharmaceutical industry’s response to recent challenges underscores the vital importance of agility, collaboration, and adherence to evolving regulations. The expedited development of the COVID-19 vaccine highlighted the critical role of effective supply chain communication and adaptation, with cloudbased labelling solutions emerging as a key driver of streamlined processes and enhanced compliance. The integration of this technology not only ensures regulatory adherence but also strengthens efficiency, patient safety, and brand reputation. As the industry continues to navigate a complex regulatory landscape, embracing innovative solutions like cloud-based labelling will become paramount, allowing pharmaceutical companies to forge a resilient path toward a secure and successful future.

e label assumes a pivotal role for pharmaceutical companies who must adhere to current and ture regulations.

SAFEGUARDING BRANDS AND PATIENTS: Layered Anti-Counterfeiting Measures in Packaging Design

David Gonzalez, Technical Account Manager, MM Packaging.

Packaging security is a serious concern for the healthcare market. As the 10th most counterfeited product in the world, fake pharmaceuticals are recognised by authorities as a substantial threat to public health.

The prevalence of counterfeit pharmaceuticals in the market varies by region, on average ranging between 1-30%. This trade’s exact value is by nature difficult to quantify but is estimated at US $65 billion-$200 billion per year. These fakes do not just endanger consumers; any health incident caused by counterfeit medicines can damage customer trust in the supplier and undermine their credibility in the public eye.

With pharmaceutical packaging serving as the primary safeguard for medicines and other treatments, technologies that can combat counterfeiting are of the utmost importance. To protect their brands and customers, packaging manufacturers have a duty to integrate the latest anticounterfeiting features into their designs, adopting a layered approach that provides multiple points of security.

WORKING IN TANDEM

Effective pharmaceutical packaging needs to be both secure and accessible to consumers. As experts in secondary packaging for the pharmaceutical sector, MM Packaging has a wealth of

experience in creating new technical solutions to prevent counterfeiting or tampering, without sacrificing ease of use.

MM Packaging broadly classifies anti-counterfeiting measures into two groups: ‘non-visible’ forensic and covert features; and ‘visible’ overt and brand enhancement features. While hidden features (e.g., reactive and non-visible inks, encrypted information, and hidden images) require specialist equipment to detect, overt measures allow customers to prove authentication at the point of purchase. This latter category can encompass everything from holograms to pearlescent and thermochromic inks – all of which are designed to be visually distinctive and difficult to replicate.

None of these features in isolation can provide a ‘silver bullet’ in terms of protecting products from fraud. Building truly secure pharmaceutical packaging means layering different features to create a unique solution bespoke to each customer’s needs.

SERIALISATION

Serialisation technology has made it easier than ever to track products across the pharmaceutical supply chain. The process is one of the easiest anti-counterfeiting tools to implement, and since the introduction of the European Falsified Medicines Directive (EU FMD) in 2019, it is now required practice in many parts of the world.

Under regulations like this, companies are required to

authenticate pharmaceutical folding cartons in a unified manner by including Data Matrix codes and their inscription in national databases. Serialisation provides information on everything from product origin to expiration dates and conditions of use, with unique serial numbers meaning the data is simple to trace, store, monitor, and optimise.

This measure facilitates monitoring products as they move through the supply chain, providing enhanced visibility and a clear chain of custody that makes it far harder for counterfeits to move through undetected. It also has the added benefit of allowing batches to be quickly traced should a product recall be required.

For the most part, serialisation is conducted using inkjet printing, thermal transfer, or laser etching. However, next-generation coding technology, such as MM Packaging’s Clear Code, has been developed offering a wide array of benefits. By using CO2, fibre, or UV lasers combined with colour-change technology, manufacturers can produce high-contrast imaging on robust coatings that delivers quality images tailored for optical character recognition systems.

The advantages of using such methods include enhanced rub resistance, high contrast and clarity of the image code, higher line speed, and reduced waste due to vision system errors during coding. This process can also be specially formulated for specific customer applications and is fully compatible with other printing methods like thermal transfer or hot stamping, providing versatility in packaging design.

In many cases, serialisation can be carried out during the

packaging design stage. This can lead to significant time savings for manufacturers and optimises the packaging process later on.

TRACKING AND TAMPERPROOFING

Like many sectors, pharmaceutical supply chains can struggle with poor transparency and product oversight. Control of traceability is critically important for identifying irregularities in this network, and as a result, advanced tracking systems such as radio frequency identification (RFID) seals are an exciting innovation for the industry.

RFID seals can be integrated into pharmaceutical packaging, letting companies track the products’ journey throughout the supply chain from warehouse to pharmacy. These solutions make it simple to trace products back to the manufacturer and reject any that cannot be reliably sourced back as counterfeits.

Blockchain technology provides even greater oversight, with the additional benefit of making products difficult to tamper with. This means it is perfect to combine with other tamperevident solutions, such as carton dust flap locks, glued thumb tabs, and re-close tear tops, to render pharmaceuticals unalterable, enabling pharmaceutical companies and consumers alike to easily monitor if the contents have been manipulated.

With the EU FMD also requiring businesses to employ tamper evident labels and closures in secondary pharmaceutical containers, technologies like these can work together to provide effective compliance and security.

MICRO-OPTICS

Micro-optics are another anti-counterfeiting tool that has seen significant advances in recent years. These small lenses, ranging from a few micrometres to millimetres in size, focus on even smaller customised icons beneath them to provide high-quality authentication.

Through a strategic partnership with Crane Currency (‘Crane’), MM Packaging has successfully implemented world-leading micro-optics into pharmaceutical packaging. This collaboration has led to an integrated, secure solution that is having a realworld impact on patients’ safety.

As a pioneer in overt security features, Crane provides microoptics that are used on some of the world’s most valuable banknotes, including the US $100 bill. Its specialist PROFOUND technology offers three-dimensional depth and movement for easy authentication and is unique in the market in that it can be integrated with customers’ designs, enabling them to select everything from the colours to the icons used.

The production methods that go into Crane’s micro-optics are a closely guarded secret, requiring secure proprietary tooling and software that only Crane can access, with effects unmatched elsewhere in the world. This technology also uses unique raw materials and production equipment, meaning it is easy to authenticate but difficult to replicate.

Working in conjunction with MM Packaging’s expertise in secondary packaging, and a strong multi-layered portfolio of overt and covert security technologies, PROFOUND microoptic solutions provide the capstone of a thorough approach to pharmaceutical packaging security.

The growth of counterfeiting will continue to challenge the pharmaceutical sector for years to come. It is a problem without a single easy solution; instead, addressing this will require a multilayered approach, incorporating multiple security technologies to protect both consumers and pharmaceutical company reputations. The result of such work will be packaging that is beyond the scope of counterfeiting, putting replication out of reach.

With pharmaceutical packaging serving as the primary safeguard for medicines and other treatments, technologies that can combat counterfeiting are of the utmost importance.

Serca Pharmaceuticals Present Strategy for Game-Changing Post Heart Attack Cardioprotection

Serca Pharmaceuticals recently presented exciting preclinical data showcasing its novel therapeutic strategy targeting the SERCA2 complex to protect heart tissue from ischemia-reperfusion injury at the European Society of Cardiology Congress 2023, the world’s largest cardiology congress, in Amsterdam, The Netherlands, 25-28 August 2023.

The findings presented suggest that specifically blocking the adrenergic regulation of SERCA2-activity is beneficial and provides evidence that small molecular protein to protein interaction (PPI) disruptors with this mechanism, such as Serca’s lead product 13-M, reduce infarct size and preserve cardiac function.

13-M, is a small, first in class NCE shown to have important protein to protein interaction (PPI) characteristics with the capacity to modulate the SERCA2 Ca2+ pump and is the first small molecule to target the AKAP18d-PLB interaction. The compound could be

Talking points

transformative in treating cardiology patients who are impacted by MI and stenting and is currently in preclinical drug development.

Without treatment, 30% of MI patients will go on to develop heart failure. Infarct size is the biggest predictor of post-MI heart failure. Supported by over a decade of research in signalling pathways and SERCA2, 13-M has shown a 30% reduction in infarct size in preclinical models; in the clinic >10% infarct reduction is considered meaningful.

Kjetil Hestdal, Chief Executive Officer said: “This marks yet another important step forward in development of muchneeded novel treatments for acute myocardial infarction and associated heart failure. Our findings presented at the ESC Congress show that by targeting regulation of the SERCA2 complex, we can potentially protect against myocardial ischemia-reperfusion injury. We are aiming to develop 13-M as a breakthrough treatment for patients impacted by MI and stenting, that we anticipate will fulfil the significant unmet need of preserving heart tissue and function.”

BENEVOLENTAI DOSES FIRST PARTICIPANTS IN CLINICAL TRIAL

serves as the leading asset in our clinical development portfolio. BEN-8744 exemplifies our innovative approach targeting a novel pathway with the potential for meaningful differentiation from existing standard-of-care treatments.”

Joanna Shields, Chief Executive Officer of BenevolentAI, added: “Our AI powered drug-discovery platform identified PDE10 as a novel target for UC, with no prior direct associations linking it in scientific literature. BEN-8744 demonstrates the capacity of our technology platform to uncover novel avenues in the treatment of disease.”

Late last month, BenevolentAI announced that the first participants have been dosed in Phase I first-in-human studies of its oral phosphodiesterase 10 (PDE10) inhibitor, BEN-8744, intended for the treatment of Ulcerative Colitis (UC). The topline data readout from this study is expected in Q1 2024.

Dr. Anne Phelan, Chief Scientific Officer of BenevolentAI, said: “UC is a disease with significant unmet patient needs, as rates of sustained remission remain disappointingly low. Initiation of this Phase I study marks a significant milestone in treating this complex disease and

BEN-8744 is a peripherally restricted small molecule PDE10 inhibitor in development as a potential first-in-class treatment for Ulcerative Colitis (UC). Administered orally, it also has the potential for addressing other indications within inflammatory bowel disease. BEN-8744 constitutes a different mechanism of action for the treatment of UC, providing an opportunity for further differentiation based on safety and efficacy. PDE10 reduces intracellular levels of the signalling molecule cGMP. Restoration of cGMP levels by PDE10 inhibition is anticipated to have a direct anti-inflammatory and diseasemodifying benefit. BEN-8744 is a wholly owned asset in the BenevolentAI drug programme pipeline.

The latest episode of The MedTalk Podcast featuring Konrad Brodaczewski and Dr Andrzej Decewicz of Grena.

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