COVER

AN INCREASINGLY COMPLEX LANDSCAPE FOR COMBINATION PRODUCTS

The complexities involved in selecting or developing the correct device for a combination product have never been more challenging. A convergence of trends, including signifi cant growth in the global drugdevelopment pipeline, the need for more complex delivery devices to address targeted applications and drug attributes, and increased migration of care from clinical to self-administration in home settings have driven demand for a wide range of solutions. This is coupled with a crowded competitive landscape in the biologics, biosimilars and generics segments, in which multiple competitors may be pursuing the same applications. Pharma companies are under increased pressure to driven patient centricity, increase speed to market, reduce their risk, and create value for patients and other stakeholders across the landscape. Beyond the patient, this includes an ecosystem of stakeholders including providers, namely healthcare professionals, but also health systems; payers, to consider factors such as value-based care; and regulators, as the market for product introduction and the intended fi ling approach can impact device selection and development strategies. These factors then need to be considered within the available or emerging technology landscape. All these factors lead to a need for developers to adopt a holistic approach to developing a device strategy, which is focused on the entire combination product that spans development stages and requires specialised expertise at every step of the process and balancing a variety of factors and infl uences that need to be considered. This leads to better near- and long-term decision MARK TUNKEL, GLOBAL CATEGORY DIRECTOR, SERVICES AT NEMERA, EXPLORES THE FACTORS THAT SHOULD BE CONSIDERED WHEN DEVELOPING A DEVICE STRATEGY IN THE CURRENT TECHNOLOGY LANDSCAPE, AND HOW A HOLISTIC APPROACH CAN LEAD TO BETTER AND MORE LONG-TERM DECISION MAKING.

A HOLISTIC APPROACH TO DEVELOPING A DELIVERY DEVICE STRATEGY

making across the life cycle of drug products.

INTEGRATING THE VOICE OF THE PATIENT INTO DEVELOPMENT

We believe at the earliest stages of establishing the functional requirements and user needs for a new device application, it is critical to fully understand the patient journey as well any related clinical processes.

Our team of design research utilises a method called applied ethnography to achieve this goal. This relies on interviews and in-context observations of practices, processes and experiences within the patient’s home or use environment. Potential use cases are looked at broadly beyond the administration event or complying with instructions for use. This starts from when a patient is diagnosed, to receiving their device, through the entire process of preparing, administering, and disposal and the times in between treatment to understand how the process changes over time and how frequency of administration may impact the patient experience. It is equally important to gain an understanding of the experience of healthcare professionals to consider relevant settings in clinical environments. This is important in applications where care is being provided in both in home and clinical environments as well as a migration of care, such as an oncology ward, with signifi cant support systems to an environment of selfadministration where clinical personnel are not present and the burden of support falls to a family member or caregiver.

The outputs include patient journey maps, clinical process maps, an understanding of prioritised user needs and values, and pain points that can be leveraged toward improving the patient and provider experience.

This supports meeting needs holistically while making decisions around assessing the technology landscape to identify existing IP or platforms that may be fi t for the intended purposes related to function and drug product attributes. This includes decisions around modality and variations within if considering existing IP platforms. This may also lead to the development of a novel delivery system in which this foundation can be utilised to establish user needs and functional device requirements.

SURROUNDING THE DEVICE FOR SAFE, EFFECTIVE AND DIFFERENTIATED COMBINATION PRODUCTS

Once a technology or development project has been initiated its human factors and patient experience, activities must be integrated to ensure an effi cient development process. The selected device, in combination with the drug, is appropriate, safe and eff ective for the target population. This also extends to optimising the patient experience to create competitive diff erentiation, and to ensure adherence and engagement with patients and clinical stakeholders. A good example of this approach might be the consideration of a biosimilar application where competitors are targeting the same reference drug and devices. Alternately, for NDAs and new device development programmes, the company needs to project what a future use case might look like and anticipate areas of risk to ensure that development is tailored to mitigate them. In both instances, the company needs to be sure that it is addressing the defi ned user groups populations and early use-related risk analysis activities to defi ne the human factors and usability program. At the earliest stages of establishing the nctional requirements and user needs for a new device application, it is critical to lly understand the patient journey as well any related clinical processes.

Clinical risks must be identifi ed through conducting formative and summative usability testing for all aspects of the device and supporting assets in alignment with the human factors programme defi nition, including the production of human factors engineering report documentation for use in for regulatory submissions. This process is linked to developing instructions for use, valueadded packaging, as well as leveraging digital health related add-ons to support patient engagement/ adherence, as well as extend the value of a device platform. This can also be augmented by fi t for purpose pre-clinical, clinical, and small series device supply to accelerate development timelines and defer capital expenses. It is crucial this is all completed holistically.

BENEFITS OF PARTNERING WITH AN INTEGRATED SERVICE PROVIDER

Nemera’s integrated development, consulting, and manufacturing services allows customers to achieve the outcome of a successful regulatory submission and commercial launch of safe, eff ective, and diff erentiated combination products with a single partner applying an agile process across the device and combination product value chain. This will drive patient centricity, reduction of risk, and increased speed of market access. This approach can be applied to our IP platforms or with organic development and allow customers to focus on their core business.

INTRODUCING AIDAPTUS:

THE PLATFORM AUTO-INJECTOR THAT ANTICIPATES FUTURE TRENDS IN DRUG DEVELOPMENT

Michael Earl, director, Pharmaceutical Services at Owen Mumford, explains how Owen Mumford’s Covidcompliant study design and careful planning allowed them to fi nalise their product design and present this innovative product, Aidaptus, to the market.

FACILITATING THE INJECTION PROCESS The aim of platform devices is to accommodate a broad range of possible drug delivery options, and allow use with a variety of formulations from the clinical trial phase through the product lifecycle. This minimises the level of validation testing and regulatory requirements when selecting a device for each drug and formulation. However, this means that during device development, the needs of multiple potential patient groups must be considered – as the fi nal therapy area is not yet determined – and any identifi ed risk factors related to use of the product need to be addressed. These considerations need to cover the whole injection process, from use to disposal. The Aidaptus disposable auto-injector introduces a consistent injection process for users. The injection process has two phases, where needle insertion and dose delivery are controlled by two separate springs. The needle is automatically activated with pressure on the injection site, followed by delivery of the drug. This two-step delivery makes it less likely that patients will experience drug wastage or ‘wet injections’ before completing their injection. They can also check dose progression and that they’ve administered the full dose with the help of the bright yellow plunger rod clearly visible in the viewing window, and audible clicks at the start and end of dose delivery. The window also allows users to clearly inspect the drug before injection, and check drug clarity injection, and check drug clarity and colour. Injecting medication can Injecting medication can cause anxiety for many patients, and some may patients, and some may suff er from needle phobia. suff er from needle phobia. Aidaptus’ design keeps the needle hidden before, during and after use; this feature can help to make injection less intimidating and injection less intimidating and may encourage treatment adherence as a result. To protect patients from needlestick injury, the safety shroud locks in place once injection is complete, so that the needle is not exposed to the user before disposal into a sharps container.

CREATING A VERSATILE PRODUCT Timescales from drug development to clinical trials and fi nal regulatory approval have shortened in recent years. This places some pressure on drug delivery devices, as they should ideally be able to accommodate modifi cations to the drug during the formulation, development and life-cycle management process – without signifi cantly impacting the fi nal product timelines. Aidaptus’ design aims to provide pharma manufacturers the option to modify drug volumes and viscosities, without needing to change their selected delivery device. The self-adjusting plunger with its patented design adapts to a range of syringe fi ll volumes without any changes to the device and with no change in parts. The auto-injector is also compatible with either a 1mL or 2.25mL prefi lled syringe, with a minimal number of change parts and without aff ecting the product’s small, discreet size (162mm x 18mm). For further fl exibility, both vented and vacuum fi lling are possible, allowing for a choice of contract fi lling partners. As the market for drug delivery devices develops, Aidaptus’ over wrap can be tailored to integrate additions or Near Field Communication (NFC) to enable connectivity. With this level of versatility, drug developers can focus on optimising their products for patients, with minimal concern about selecting a device that is both suitable for the drug formulation and user-friendly.

LEARNING TO MANAGE THE RISKS INVOLVED IN HIGH POTENCY DRUGS MANUFACTURING

The increasing use of high potent active pharmaceutical ingredients (HPAPIs) in cancer treatment drugs is proving highly eff ective in saving lives, but they can pose a severe risk to process technicians and process engineers during production – and if mistakes are made the results could be fatal.

For example, Dolastatin 10 and Ansamitocin are amazing drugs. One is harvested from a marine mollusc and the other from an African shrub – and while they have two very diff erent backstories, what they have in common is that they are both cytotoxic. Used in microscopic doses, this quality enables a targeted approach to modern treatments that are transforming oncology.

They form part of the HPAPI section of the pharmaceutical industry, which now accounts for 25% of all drugs produced. It’s a sector that is projected to be worth $40 billion by 2027.

POTENTIAL DANGERS The challenge with HPAPIs, however, lies in their effi cacy. Intended to be toxic to cells, they have a typical occupational exposure limit that is under 10 micrograms per cubic metre, and this requires tight manufacturing controls – as their high potency means the consequences of even a small mistake can lead to a range of life-threatening side eff ects and even death to the operator.

Mistakes would also leave drug manufacturers exposed fi nancially if something goes wrong as the penalties can be huge. The potential implication of such a mistake was illustrated by the record $500 million a global leading

drug manufacturer had to pay in 2013 when safety violations were found to have occurred while manufacturing generic drugs at its plant.

With the pharmaceutical industry relying on a network of specialist contract manufacturers, it’s conceivable that such an incident could force these companies out of business if a violation or contaminated batch was traced back to their sites.

MANAGING TOXICITY With HPAPIs, manufacturers need to be particularly wary of the dangers, as their physical nature heightens the risks involved during production. Some are dense compounds, but others are highly micronised and exist almost as a gas. This makes the risk of cross-contamination signifi cantly worse since standard cleaning procedures, used after the manufacturing of conventional drugs, may not be eff ective, and visible checks would not be enough to validate the process.

This can add major costs to manufacturing as facilities require more intensive cleaning before any further work can take place on site. It also means companies are paying for a facility to stand idle while these processes are carried out. While the competitive nature of the market means that businesses will want to minimise the cost of production, they need to be careful how they do this when it comes to HPAPIs. Fundamentally, ensuring that engineering controls are in place that properly contain manufacturing lines – and they are not placing unrealistic faith in personal protective equipment (PPE).

Where operators are dealing with microscopic amounts of toxic, gaseous compounds, PPE is only the last line of defence. In some cases, failure to provide proper containment systems has led to deaths of workers – despite the fact they were wearing PPE.

CONTAINMENT SOLUTIONS In contrast to PPE, containment solutions safely separate workers from the production process and remove the risk of exposure. Traditionally this would involve rigid isolators – but, while these units are still popular, they can be costly and they still require intense cleaning and validation after every use.

This is a key reason why many manufacturers are increasingly turning their attention to fl exible alternatives, such as polymer glove bag isolators, that are more cost eff ective. These fl exible solutions use specialist protective fi lms made of polyurethane, polyethylene and PVC, to prevent any harmful ingredients reaching the operators. This fi lm typically fi ts on an ergonomically sound rigid structural stainless steel frame, with other necessary equipment installed around it.

One of the big benefi ts of this is that when production is complete, the fl exible fi lm isolator glove bag can be removed and safely disposed of until a new containment enclosure is installed. The cleaning process is greatly reduced and often not required, meaning downtime validation is minimised. All that needs to be replaced is the protective fi lm itself, and this keeps costs to an absolute minimum.

INCREASING SPEED TO MARKET Flexible solutions also provide huge advantages in that they can be quickly installed in diff erent spaces and contexts. Broadly speaking, any pharmaceutical manufacturing environment where a support structure can be installed is suitable for these containment systems.

Many operators are surprised these fl exible solutions can deliver the necessary protection, but this type of high containment has been proven to achieve less than 1 µg/ m3 (OEB 5). This technology can also support products with OELs in the nanogram range.

This approach, along with the reduced cleaning validation, is helping manufacturers overcome a broad range of problems that would otherwise be preventing the pharmaceutical industry from manufacturing life-saving HPAPI compounds and getting them to patients faster.

In an industry where getting to market quickly can make a big diff erence to a company’s prospects, this is providing manufacturers with an alternative solution that helps them to be more competitive – without risking the health or safety of their workers, and eff ecting the quality of their products, in the process.

Author: MARK

ARNOLD, MD of ONFAB, part of Envair Technology

e HPAPI section of the pharmaceutical industry now accounts for 25% of all drugs produced and is projected to be worth $40 billion by 2027.

A FLEXIBLE PLATFORM DEVICE

TO STREAMLINE MARKET LAUNCHES

Chronic diseases are one of the world’s major challenges, causing staggering human and economic costs. As well as affecting quality of life for patients and their families, they place a huge burden on overstretched healthcare systems and global economies, while also presenting an important challenge to pharma companies.

One such example is diabetes. Worldwide, around 537 million adults are living with diabetes, and that figure is expected to rise to 643 million by 2030 and 783 million by 2045 [1]. It is a disease that accounted for more than $966 billion of health expenditure in 2021 – 9% of total spending on adults – although it is understood that half of people with diabetes do not meet treatment goals for glucose lowering, which is key to managing their condition. One of the major drivers behind the growing number of diabetic patients is rising rates of obesity, a factor that is known to put patients at greater risk of developing diabetes. Currently, more than 650 million people around the world are living with obesity and this figure is expected to reach more than one billion people by 2030 [2]. The condition accounts for 8% of global healthcare budgets and in the US alone the economic impact associated with obesity is more than $1 trillion. Despite these startling statistics, however, fewer than 3% of people with obesity are pharmacologically treated for it.

Pharma innovation continues to play a key role in addressing the human and financial burden of managing chronic conditions such as diabetes and obesity. The growing emphasis on selfadministration of medication,

for example, provides the means to ease the pressure on health services, improve compliance and make everyday life more convenient for patients. And with the Covid-19 pandemic accelerating this trend as routine patient visits to healthcare facilities plummeted, pharma companies have intensified their focus on drug delivery devices that patients can use in their own homes.

Key to the success of any drug delivery device are factors such as proven technology, low development costs, fast time-to-market and a strong intellectual property (IP) position for the pharma company. Against this background, platform drug delivery devices have become more important than ever, providing an ‘off-the-shelf’ choice that minimises project risk and avoids the requirement for an up-front investment of millions of dollars to fund the development of new bespoke devices. Instead, the availability of customisation options to suit a variety of different drugs and primary packaging with minimal change in components keeps costs down and offers faster timeto-market, enabling patients to benefit from new therapies sooner rather than later.

Stevanato Group’s Alina pen-injector is an example of a platform device for variable and multi-dose treatments for conditions such as diabetes and obesity. The device has a user-friendly design to improve the patient experience. It is intuitive for patients, with minimal user steps, and is designed to give confidence and reassurance.

To help patients select the right dose, Alina has only one number visible in the dosing window at any given time and the dose can be corrected with a simple dial back. Patients receive visual, audible and tactile feedback for dose setting, correction and injection, and the injection force is optimised for patient comfort.

For pharma companies choosing Alina, there are many advantages. The device can be used for different applications as it can deliver a range of different maximum doses – 0.30mL, 0.50mL and 0.6mL – in one shot. In addition, the availability of a range of branding and customisation options means that individual colours can be selected for each market segment.

Design for manufacturing and ease of final assembly have also been taken into account to optimise the production process. The device is manufactured at Stevanato Group’s FDAinspected facility in Germany, where access to tooling and sub-assembly equipment is available to clients aiming to maximise the return on investment in their device programmes and reduce time to market. Dedicated production tooling and lines are available on request for customisation or to support overall risk mitigation strategies.

Alina is fully compatible with Stevanato Group’s range of glass cartridges – such as bulk and ready-to-use EZ-fill cartridges – as well as the company’s final assembly equipment. Moreover, Alina is compatible with a variety of fill-and-finish systems.

Alina can be provided as a flexible device platform because, as a full solution provider, Stevanato Group has a deep understanding of how pharmaceutical products, containers, closures and drug delivery devices interact with each other and work together to form a cohesive system. This holistic approach means pharma companies looking for customised drug delivery and containment solutions can benefit from tailored solutions that combine products and technologies into a coherent, integrated offering.

Stevanato Group’s scalable approach allows for straightforward technology transfer from low volumes – typical in the clinical phase – to mass production on high-volume equipment, enabling pharma companies to anticipate challenges, mitigate risk and reduce investment costs. By working closely with a supplier who can provide a holistic strategy – offering optimised glass containment and device services as well as the appropriate equipment and analytical testing – companies can simplify their commercial journey.

Indeed, Alina was developed to address the need to reduce the complexity of the supply chain, and this philosophy of efficiency is applied to all processes relevant to the development of a combination product, from initial concept through to its launch on the market.

Through the combined support of a platform such as Alina and the complementary Stevanato Group’s expertise as full-solution provider, therefore, pharma companies have the flexibility and capability to streamline the market launch of new drug delivery devices, and patients are ultimately given greater flexibility in managing their chronic conditions.

1. “Diabetes facts & figures”. International Diabetes Federation, Dec 2021. 2. “World Obesity Atlas 2022”. World Obesity, Mar 2022.