Tag: Drug Delivery

Neurodegenerative conditions|||||
By Karla Sanchez
June 21st 2023
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Karla Sanchez

Karla Sanchez

Senior Consultant Biomedical Engineer

Neurodegenerative conditions: turning a corner to better treatment?

Pace is accelerating for tackling neurodegenerative diseases. Can we unlock better treatment? Can we reach a cure?

Ageing populations face neurodegenerative conditions, such as Alzheimer’s Disease, Parkinson’s Disease, Motor Neurone Disease, Multiple Sclerosis, and others. These impact an estimated 60 million people worldwide, equivalent to the current UK population.

Whilst each condition has different mechanisms of neurodegeneration, they all have something in common: prognosis is bleak, treatment is limited, and there is no cure.

However, after decades of research, there has been a series of breakthroughs. Here, we focus on two areas of progress: how treatments have moved on and hope for the future.

The rise of RNA-based therapeutics 

The effective development of RNA-based vaccines during the COVID-19 outbreak catapulted RNA-based therapeutics into the spotlight. Whilst theoretical knowledge of RNA therapy has existed for over 30 years, the bulk of associated FDA approval for treatments involving the nervous system has occurred in the last decade(1).

A major advantage of RNA-based therapy over conventional small molecule and protein-based approaches is its high specificity and precision, resulting in a more targeted approach to treating disease with specific gene mutations or overexpression.

However, to devise effective RNA-based therapeutics, the genetic hallmarks of the neurodegenerative disease of interest must be known.

Motor Neurone Disease (MND) is one such condition where specific mutations in the SOD1 gene have been identified and in this case, in two per cent of diagnosed cases.

A recent breakthrough in phase three clinical trials targeted this gene using the drug Tofersen. Tofersen, developed by Biogen, directly interferes with the faulty overproduction of SOD1. After six months, patients had a reduction in SOD1 levels, and after 12 months the same patients reported better mobility and lung function(2,3). Although patients with SOD1 mutations only represent two per cent of those living with MND, these trials provide ‘proof of concept’ that similar gene therapy-based approaches may help other forms of the disease.

Another pioneering strategy, developed by Atalanta Therapeutics and Genentech, focuses on a technology called branched siRNA (small interference RNA). This is a type of molecule that helps regulate gene expression by binding to a complementary messenger RNA, which in turn can encode the gene of interest.

Branched siRNA uses novel RNA interference nucleotide technology to suppress the activity of genes that function abnormally, such as mutations. This slows the progression of the disease or stops it altogether.

It is hoped this approach can be applied across multiple neurodegenerative diseases, including Parkinson’s Disease, Huntington’s Disease and Alzheimer’s Disease.

Although testing is still in the pre-clinical stage, the branched siRNA platform aims to enable RNA interference to be deployed as a therapeutic approach throughout the brain and spinal cord. This overcomes the long-standing challenge of achieving adequate distribution within the central nervous system (CNS) to ensure the therapeutic agent reaches the nervous tissue(4,5).

Progress in non-RNA therapeutics 

Non-RNA therapeutics for neurodegenerative conditions also continue to progress. Examples include the monoclonal antibody Donanemab, developed by Eli Lilly. Phase three clinical trials showed it to slow clinical decline by 35% in patients with Alzheimer’s Disease, compared to a placebo(6).

Effective delivery remains a major challenge  

One of the main challenges in developing RNA therapeutics, and therapeutics for the brain in general, remains the efficiency of its delivery to the target tissue.

To treat neurodegenerative conditions, the therapeutic agent aims to reach the CNS. The presence of the blood-brain barrier (BBB), a cell-formed wall separating the bloodstream and the CNS, makes it difficult to deliver drugs. The BBB’s almost impermeable characteristics allow very few molecules to cross and make systemic drug delivery less efficacious.

There are two common approaches to overcome this: re-engineering the therapeutic agent to make it compatible with BBB permeability or bypassing the BBB altogether.

Re-engineering the therapeutic agent

This typically involves chemical modification of the drug (e.g., from water-soluble to lipid-soluble molecules) to enable passive diffusion through the BBB. Another approach is to design drug carriers that mimic the structure of endogenous molecules (e.g., monosaccharides, hormones) to activate carrier-mediated transport or nanocarriers(7,8). Both approaches add complexity to manufacturing.

Another cross-BBB approach is Focused Ultrasound (FUS), where high-intensity sound waves temporarily disrupt the BBB to enable drug-loaded microbubbles to enter the CNS9.

Bypassing the blood-brain barrier 

Bypassing the BBB can save time and effort in formulation by using a range of therapeutic agents not constricted by size or BBB compatibility. Of its three most common types of delivery: intraparenchymal, intranasal, and cerebrospinal fluid (CSF) delivery; the latter is often the favored approach, due to lower clinical complexity10.

 
 

Evaluating CSF delivery routes 

CSF delivery most commonly include intrathecal (IT) or intraventricular (ICV) routes.

IT involves an injection either on the lumbar or a cisterna magna region to deliver the drug and let CSF pulsatile flow support the distribution of the therapeutic agent in the brain and spinal cord.

ICV is more invasive. It involves two surgical interventions, one to place a catheter connecting the cerebral ventricles to the injection port at the top of the skull and one to remove the catheter.

To date, ICV has two approved drugs (Rituxan for CNS Lymphoma, and Brineura for Neuronal Ceroid Lipofuscinoses type two). IT lumbar injection has one (Spiranza for Spinal Muscular Atrophy) and plenty more in clinical and pre-clinical stages across a spectrum of neurodegenerative and neurological diseases(11). Irrespective of the approach, the trend is clear: less invasive, lower dosage, and targeted delivery is the way to go.

In the race to show safety and efficacy with either invasive or non-invasive approaches, all solutions will have to be patient-centered.

A new dawn for the treatment of neurodegenerative diseases  

The complexities of neurodegeneration have long frustrated scientists and clinicians alike, despite decades dedicated to studying its diseases, aetiologies, and treatments. However, we are making more rapid and more significant progress.

We have some way to go, but we mustn’t overlook the magnitude of these milestones. New therapeutics and delivery techniques are paving the way to more effective and efficient treatment.

By increasing our understanding of genetic hallmarks of the diseases, and using tools such as AI in drug discovery, we can unlock faster pathways to RNA-based treatments. Similarly, by finding innovative ways of demonstrating the safety and efficacy of delivery methods, such as modeling, we can edge closer to less invasive procedures and lower dosages to minimize potential side effects.

We need more research, more awareness, earlier diagnosis, and a better understanding of risk factors to enable prevention and earlier intervention.

But we are now getting closer to better treatment and one day finding a cure.

 

References 
  1. http://nectar.northampton.ac.uk/16015/1/Anthony_Karen_RNAB_2022_RNA_based_therapeutics_for_neurological_diseases.pdf
  2. https://www.sheffield.ac.uk/neuroscience-institute/news/promising-mnd-drug-helps-slow-disease-progression-and-benefits-patients-physically
  3. https://www.nejm.org/doi/full/10.1056/NEJMoa2204705
  4. https://www.gene.com/stories/pioneering-novel-therapeutics-in-neuroscience
  5. https://www.nature.com/articles/s41587-019-0205-0
  6. https://clinicaltrials.gov/ct2/show/NCT04437511?term=TRAILBLAZER-ALZ&cond=Alzheimer+Disease&draw=2&rank=3
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905930/
  8. https://ijponline.biomedcentral.com/articles/10.1186/s13052-018-0563-0#:~:text=Modification%20of%20the%20drug%20to,capable%20of%20crossing%20the%20BBB.
  9. https://clinicaltrials.gov/ct2/show/NCT03321487
  10. https://www.frontiersin.org/articles/10.3389/fnagi.2019.00373/full
  11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305158/

 

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For more on how to advance RNA therapeutics and targeted CNS drug delivery for neurodegenerative diseases, contact Cambridge Design Partnership.

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Could oligonucleotide manufacturing advances redefine therapy
By Alejandra Sanchez and Carla Greig
June 20th 2023
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Alejandra Sanchez

Consultant Biomedical Engineer

Carla Greig

Consultant Biomedical Scientist

Could oligonucleotide manufacturing advances redefine therapy? 

Oligonucleotides have the potential to address some of the most devastating diseases that remain stubbornly resistant to treatment. These include neurodegenerative, vascular, respiratory, and oncological illnesses. As exciting as this branch of science is, the oligo industry is still in its commercial infancy. Large-scale oligonucleotide manufacturing is not straightforward, and various challenges need addressing.

To understand these, Alejandra and Carla, two Consultant biomedical engineers at Cambridge Design Partnership (CDP), were invited to take part in the Innovation in Oligonucleotide Manufacturing Symposium hosted by CPI at their new facilities in Glasgow. After an intensive day of discussion between key stakeholders from industry, academia, government, and the regulatory sector, we present the main takeaways. For this to make sense, let’s start from the beginning.

How do oligonucleotides work?

Oligonucleotides are short DNA or RNA molecules, typically around 20  nucleotides (basic building blocks of nucleic acids) in length. They can modulate gene expression, the process by which information included in a gene informs the assembly of a protein molecule. They do this by binding to pre-mRNA and mRNA, the carriers of genetic information before the mature mRNA is translated into proteins. Because mRNAs carry code for all cellular proteins, oligonucleotides could be effective for targets and diseases not treatable by current drugs1.

What is their importance as therapeutic agents?

Oligonucleotide therapeutics prevent or modulate the expression of almost any gene as part of highly targeted treatment. They aim to target the genetic basis of the disease rather than the symptoms. Compared to conventional therapies, oligonucleotides have a higher specificity with reduced side effects. They can target specific molecules that are currently difficult to target, such as RNA. Several oligonucleotide therapeutics are already on the market, with Novartis Pharmaceutical’s Vitravene, for treating cytomegalovirus retinitis in immunocompromised patients, being the first to be approved by the FDA in 1998.

The list of diseases that oligonucleotides can target is ever-growing, with the market valued at USD 5.19 billion in 2020 and expected to rise to USD 26.09 billion by 20302.

How are oligonucleotides manufactured?

Oligonucleotides are synthesized chemically, where nucleotides are added stepwise, resulting in a growing chain. Each nucleotide is subjected to a series of chemical reactions to create a stable component allowing the chain to grow.

The two different types of oligonucleotide manufacturing are solid-phase and liquid-phase synthesis. Solid-phase oligonucleotide synthesis is carried out on a solid insoluble object, such as polystyrene beads, placed in columns that enable all reagents and solvents to pass through freely.

In liquid-phase synthesis, the oligonucleotides are grown on soluble polymeric support within a homogeneous media; the polymer-bound product is commonly recovered from the reaction mixture by precipitation, thus allowing the rapid elimination of excess reagent and soluble by-products.

Solid phase allows high throughput synthesis and purification, with liquid phase taking longer to synthesize the oligonucleotides. However, liquid-phase has the advantage of being performed on a larger scale and typically being less expensive than solid-phase synthesis. Once the desired oligonucleotide has been synthesized, the material can be passed to the next processing steps, including purification, concentration and, commonly, lyophilization.

What are the main challenges in the process?

Oligonucleotide manufacturing is a complex process with many limitations, especially in scalability. The major problems researchers face are currently due to high expenses regarding the raw materials for oligonucleotide synthesis, a lack of funding for oligonucleotide therapies, and a shortage of skilled resources in the oligonucleotide synthesis field. These problems create substantial bottlenecks in the research required for therapeutic oligonucleotides and, ultimately, the clinical use of these therapies.

Key takeaways on the manufacturing of oligonucleotides 

  • Moving towards liquid-phase oligonucleotide synthesis. Solid-phase oligonucleotide synthesis is a great tool for rapidly making lots of oligos in the lab. However, it has drawbacks when manufacturing hundreds of kg or even multi-ton quantities per year, which might be the case for emergent nucleotide products targeting more common diseases3.

    The major problems include:

    • As the oligo grows, the space for the fresh nucleotides to diffuse and react gets tight, leading to incomplete couplings. This results in an altered sequence of monomers and incorrect genetic information in the final product, which must be removed by extensive and expensive processes.
    • It is hard to scale up the solid beds (insoluble particles to which the oligonucleotide is bound during synthesis).
    • The synthesis and purification steps generate large amounts of organic and aqueous waste.

 

  • Liquid-phase synthesis stands as a promising approach to increase the yield of the overall process while allowing the production of large amounts of oligonucleotides in, potentially, a more sustainable manner4.

 

  • New alternatives to current purification methods are under investigation. Promising approaches to simplifying the purification steps show good results in the investigational phase5. Examples are membrane-sieving technology and biocatalytic processes used for phase separation. In the biocatalytic process, oligonucleotides are synthesized in a single operation, with fewer impurities and by-product production, and in aqueous media. All these are promising features that target the current limitations of existing synthesis methods3.

 

  • New approaches come with new challenges: The development of novel and alternative technologies offers opportunities to address some of the limitations of solid-phase synthesis while also creating new challenges. For instance, using nanofiltration membranes to support the synthesis of oligonucleotides in liquid phase can present issues such as membrane stability and fouling. Another concern regarding the enzymatic approach is the availability of raw material with the right purity.
    If we consider the bigger picture, another novel approach in the pharmaceutical industry is the adoption of digital manufacturing technologies. However, this up-and-coming tool may come with its own challenges due to lack of pharmaceutical manufacturing expertise and the high cost of initial funds.

 

  • Raw materials suppliers are already working towards reducing the gap. Strategies to reduce the prices of chemicals and deliver sustainable solutions are already underway. For instance, Honeywell US, a major supplier of the raw material required for oligonucleotide production, recycles solvents and assigns dedicated chemical drums to individual businesses to avoid cross-contamination.

Big wins for early pioneers

At CDP, we see every challenge as an opportunity, and we are pleased to know that governments and large industries have already recognized these problems.  Major efforts to accelerate research in the UK have been launched, not only as funding from governmental innovation agencies but also from pharmaceutical companies. In addition, the 18 oligonucleotide therapies already approved by the US Food and Drug Administration (FDA) for clinical use are leading the way6.

There is a need for rapid adoption of next-generation processes that reduce risk, cut costs and save time while enabling on-demand therapies for every patient. However, regulatory-wise, standards in this industry are yet to be established. The risk around safety and efficacy remains a significant concern: How do we ensure we have the right sequence in each molecule? How do these molecules behave for a specific treatment? And what is the risk for the patient? These are just a few questions that still need to be addressed.

The event at CPI highlighted the importance of bringing experts together to shape the path and accelerate innovation. Understanding the challenges in the oligonucleotide space and planning around them will allow us to drive successful manufacturing at scale. The moment to build the future is now!

References
  1. Kole R, Krainer AR, Altman S. Nat Rev Drug Discov. 2012 Jan 20;11(2):125-40. doi: 10.1038/nrd3625.
  2. Allied Market Research, Oligonucleotide Synthesis Market report, Code A08356, July 2021
  3. Sarah Lovelock, “Biocatalytic approaches to therapeutic oligonucleotide manufacture” in “Enzyme Engineering XXVI”, Andy Bommarius, Georgia Institute of Technology, USA; Vesna Mitchell, Codexis, USA; Doug Fuerst, GSK, USA Eds, ECI Symposium Series, (2022). https://dc.engconfintl.org/enzyme_xxvi/37. Abstract: https://dc.engconfintl.org/cgi/viewcontent.cgi?filename=0&article=1034&context=enzyme_xxvi&type=additional
  4. J. Org. Chem. 2021, 86, 1, 49–61 Publication Date: November 30, 2020 https://doi.org/10.1021/acs.joc.0c02291
  5. Dousis A, Ravichandran K, Hobert EM, Moore MJ, Rabideau AE. Nat Biotechnol. 2023 Apr;41(4):560-568. doi: 10.1038/s41587-022-01525-6.
  6. Martin Egli, Muthiah Manoharan, Nucleic Acids Research, Volume 51, Issue 6, 11 April 2023, Pages 2529–2573.
WHITE PAPER

Developing future drug delivery systems

BY CLARE BEDDOES, AMY KING & JAMES HARMER
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“This document explores the future of drug delivery systems, specifically at-home self-injection, and the way in which drugs will be packaged in the future to enhance patient experience and ensure successful clinical outcomes.”

Clare Beddoes – Principal Consultant, Drug Delivery

Here at CDP, we don’t think of the packaging as simply the container for the drug. We consider the whole delivery experience, from the device itself through to the accompanying materials such, as the instructions for use (IFU). While several factors must be considered in the selection of the right device and packaging materials for injectable drugs, including the drug rheology, how the drug is administered, and by whom and where, this document takes a high-level view of how specific consumer trends may impact the experience of self-injection devices.

In this paper, we explore:

  • The futuring methodologies needed to stretch strategic thinking
  • How consumer needs – and packaging – are changing
  • The consumerization of healthcare
  • Improving drug delivery systems that benefit the patient, the planet and the manufacturer
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respiratory drug delivery|
By Mark Allen
January 25th 2023
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Mark Allen

Consultant Mechanical Engineer

Key trends in respiratory drug delivery

It was great to be back in person for the Drug Delivery to the Lungs conference in Edinburgh recently. Here, we share insights on three major themes from the event and a trend we think will reshape the future of respiratory drug delivery in the next 10-20 years.

Sustainable pMDIs

The shift in pMDIs from using HFC propellants towards less polluting gases has gained momentum with California imposing a ban on the sale and distribution of R227ea from the end of 2030 and R134a from the end of 2032, including medical use. This provides an end-of-the-line for the sale of all current pMDI products in California.

The transition needs formulators, device designers, scientists, and other disciplines to collaborate to solve the challenges presented by the different physical properties of the new gases. The assessment of all types of inhalers from a sustainability perspective has advanced, too, with life cycle analysis (LCA) and carbon credits schemes being discussed – our sustainability team provides reviews and recommendations for a range of medical devices to help our clients improve their devices and provide evidence to back up their green credentials.

Usability for adherence

Time and again, studies show that it’s challenging to measure asthma and COPD patients’ adherence to their medication. Medication adherence appears much lower than for other diseases – estimates range from 22-78% adherence, compared to 70% for diabetes.

Low adherence needs to be addressed by making devices easier to use and tailoring them to the patient’s needs. Reducing user steps is key to make using the device easier, but patient feedback and tailoring to specific needs are necessary, too – something connected inhalers could help solve through digital reminders appropriate to the patient’s needs. Independently verifying that increased adherence is due to connected or smart inhalers is difficult to prove – something the industry is investigating.

Modelling of drug delivery

Several talks at this year’s event covered modelling, with in-silico methods advancing in capability and popularity over the last 10 years. Topics covered included constructing a full airway model to assess drug deposition under different breathing profiles and using maths with physiological signals to detect disease and drug-induced changes. Posters demonstrated an even wider range of possible models, including our own.

Our modelling and simulation teams produce models for clients that highlight potential robustness issues with mechanical components and digital sensing techniques at early stages to determine suitable technologies for medical devices.

Learning from the past, looking to the future

Federico Lavorini, Professor and Consultant in Respiratory Medicine at the Department of Clinical and Experimental Medicine, Careggi University Hospital, Florence, Italy, gave an excellent summary of drug delivery over the last 100 years, including innovations where design has reduced user error.

Further talks considered what pharma could learn from other markets, especially as we move from ‘sick care’ to ‘health care’ – where technology identifies and treats conditions before they become symptomatic. Our Drug Delivery and Insight & Strategy teams work closely together to understand upcoming trends and draw on insights into consumer expectations from the consumer and digital markets for our clients.

Biologic treatments are coming to respiratory drug delivery and are likely to use Soft Mist Inhalers (SMIs) and Dry Powder Inhalers (DPIs) for delivery, with current trends looking to lean heavily on DPIs. This is likely to lead to the development of new, higher-performance DPIs to provide the best efficiency delivering these high-cost treatments to the patient. We have dramatically increased the performance of DPI engines for our clients through our science-based approach to increase fine particle fraction for their devices.

How we can help

Our team are experienced in all stages of the development of drug delivery devices for a wide range of scenarios and applications in the medical industry, with a dedicated team working in these areas. Here at CDP, we have these specialists all under one roof to partner with you to bring your device to market and can also draw on the learnings of our colleagues in consumer markets to guide on relevant future consumer expectations.

Mastering fluid flow to enhance user experience|
March 22nd 2022
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Mastering fluid flow to enhance user experience

Ice cream and blood are two things you probably don’t want to think about simultaneously. But both are full of organic proteins and fats and behave differently from a fluid like water when they’re pumped through tubes. Innovators sometimes think about these similarities when creating, for example, a novel ice cream dispenser or device that filters out platelets from donor blood .

How a substance flows is a vitally important consideration for many products, from foods to skincare to medical devices to household paints. Development teams need to keep in mind a wide range of flow behaviors (for example, flow through nozzles, non-Newtonian flow, and foaming) to hit the sweet spot: a positive user experience that makes a product stand out in a crowded market. This means thinking about the science of how liquids and gases behave (fluid dynamics), as well as how the product responds to user interaction.

Look at how the squeezable plastic ketchup bottle differs from the glass bottles that were standard before 1983. The new design completely changed the user experience – no more digging down into the bottle with a knife to get the ketchup flowing again. Things became even easier for ketchup lovers with the debut of the upside-down squeezable bottle – no more awkwardly storing ‘regular’ bottles upside down in the fridge.

Or think about how the experience of washing your hands changed after the arrival of the liquid soap dispenser. Instead of having to share the same bar of soap with others, people can now wash “without the soapy mess”, as Robert R Taylor, who introduced SoftSoap liquid soap, put it, and can take only as much soap as they need.

While the flow of some liquids is analogous to water, whose behavior is well understood, other substances behave in much more complicated ways, requiring in-depth analysis work to understand when designing new products. For example, the air bubbles in ice cream make it behave as a liquid foam. Ice cream’s flow will change depending on how you’re dispensing it: Push it at high pressure through a narrow channel or nozzle, and the air bubbles will be compressed, allowing more ice cream to flow through the nozzle at once. When the ice cream is returned to normal pressure, the air bubbles re-expand, and the ice cream returns to its original size. Because of this complex and variable behavior, designing a product to dispense ice cream relies on hands-on experiments… which can mean going through gallons of ice cream before you can create a design that works as intended. Only by conducting these experiments to understand ice cream’s behavior can you build the mathematical model required to effectively develop a high-performance machine.

While it’s a shame to use gallons of ice cream in the quest for a better product, it’s not an environmental disaster. But shipping water-based products around the world does contribute to fossil fuel consumption and climate change. Removing water from laundry detergent helps cut shipping emissions by reducing bulk and making shipping more efficient. But it also dramatically changes how detergent flows and gets used by consumers. For example, measuring out 10 ml more detergent than recommended likely wouldn’t have an impact if you’re using a product that’s mostly water. But being off by 10 ml when detergent is concentrated could make a big difference for your laundry. So, it’s vital to ensure that dispensing is accurate, which requires an understanding of flow.

There are so many flow behaviors that can affect a product’s design. For example, should a container for insecticide include a mechanism to avoid skin contact and spillage? How could a medical device for freezing tumors be redesigned to eliminate vapor locks without the use of heavy and bulky high-pressure gas cylinders? Is there a way to dispense foaming hand soap in a decorative pattern for a premium experience?

Getting the design right for a flowing substance can differentiate between a product that fails and one that creates an experience that shifts category norms and delivers breakthrough consumer delight.

References

Pilot manufacture for drug delivery devices||
By Jon Powell
January 18th 2022
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Jon Powell

Head of Manufacturing

Prepare the way: Pilot manufacture for drug delivery devices

Bringing a drug delivery device to a clinical trial is a complex endeavor. You need to keep a handle on multiple moving parts, for example, the active pharmaceutical ingredient (API) development, the regulatory pathway, establishing the supply chain, and labeling. Developing a novel drug delivery device takes things to another level.

Many manufacturers shy away from the challenge, relying instead on proven technologies, so patients and clinicians don’t benefit from the most advanced user-centered design, and pharma companies can’t leverage the competitive advantage new technology delivers.

Here, I share some of the obstacles encountered conducting pilot builds in-house to help our clients bring devices to market – and give four pointers for ideal pilot manufacturing for clinical trials.

Develop your manufacturing process and architecture in tandem

3D CAD makes it all too easy to lose touch with reality and forget that the model on the screen is only an idealized representation. Zoom in 4,000%, and everything lines up beautifully. There’s no gravity, and parts have infinite stiffness, no tolerance, and perfect alignment. But, when you get natural variation in the manufacturing process, results can be disastrous. Components may not even fit together.

Once a design is frozen, making changes is expensive. After it’s passed to a high-volume manufacturer, costs become exponentially higher. Understanding manufacturing processes – and how changes can impact a project’s timeline – is critical for successful delivery. You need to prepare for the supply-chain ‘whiplash effect’: a tiny change at the top of the chain can mean seismic shifts at the end of it. That knock-on is the reason your product development strategy should incorporate pilot manufacture. Pilot manufacture keeps this effect in check by minimizing the volumes involved.

It’s vital to consider the whole supply chain, not just the component manufacturer, but the process equipment partners, filling, packaging, sterilization, and logistics. Each step has requirements to be understood and communicated to relevant parties. By developing manufacturing and assembly processes in tandem with device design, we can be flexible to insights arriving from either direction.

Pick the right partners for success

One of my first jobs was for a major automotive company. In their heyday, they ran the foundries that made the ball bearings for their vehicles. Today, they wouldn’t dream of it. No company does everything anymore. Few organizations would claim to be experts in all areas of drug delivery. Even those that manufacture and fill their own devices rely on external partners to produce the plastic resin and packaging materials and often outsource activities such as sterilization.

Partnering with experts to contribute specific knowledge is a time-efficient way to overcome obstacles in the development pathway. It also unlocks access to cutting-edge equipment and facilities that are expensive to maintain. While developing a breath-actuated inhaler, we engaged an external test house to conduct bio-compatibility evaluations on the device. We may have the skills in-house to perform this testing but maintaining accreditation for an activity that isn’t core to our business doesn’t make financial sense.

Know the limits

When developing a device, it’s essential to explore sources of potential variation. The same goes for the manufacturing process. You can use various tools to do this, but we frequently return to the humble ‘process failure modes and effects analysis’ (pFMEA). The pFMEA is a structured way to consider all the process steps – and how they could go awry. Developing a robust pFMEA ensures the team focuses on the highest risk areas and starts thinking about implementing mitigations.

A key checkbox for each manufacturing process step is if the results can be verified or validated. The US Food & Drug Administration Code of Federal Regulations Title 21 defines verification as “confirmation by examination and provision of objective evidence that specified requirements have been fulfilled.” Many processes can be verified using in-process measurement systems. But several can’t, for example, the joining of two plastic parts by ultrasonic welding. You can’t determine the strength of this weld without destructive testing. The ultrasonic welding process needs to go through process validation to determine the limits within which the process should be operated.

When communicating with stakeholders, it’s crucial to know the volume limits and have a realistic plan for producing parts representative of the final production process. For example, how many parts can the mold tools make? There’s a trade-off between tool production speed, tool cost, and tool life. Low-cost soft aluminum tools might be ready in two weeks but only suitable for 2,000 shots, whereas a more expensive hardened steel version might take 16 weeks (without validation) but last for over 100,000 shots.

Validating injection mold tools can be a lengthy process. Exploring the process window needs planning and performing multiple molding and measurement runs and subsequent analysis. Companies only want to bear this cost once, so experienced development teams need to hold firm when encountering adverse test results. I know of an auto-injector that showed promise early on, albeit with an infrequent failure observed in testing during development, that was allowed to pass into design freeze. More thorough testing during design verification revealed results that triggered the regulatory application to be rejected. Cue months of tooling validation needing to be reassessed.

Combination products require the delivery devices to be filled or co-packaged with primary containers of the API. Clinical trials complicate this because they need devices filled with the API or safe and sterile placebo. The filling process can be complex, especially when the API is highly viscous or uses technologies such as microspheres to sustain the release of active components over time. You need to factor in time to explore the filling and develop the process settings. Thought needs to be given to the amount of API and placebo available and the lead times for new batches as this can limit the amount of filled and finished devices.

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Digital tooling to reduce time to market

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Not documented? You’re not done.

Understanding the controls needed to manage risk is essential for a manufacturer delivering high-quality, safe, and reliable products. ISO 14971 sets out a best practice framework for managing risk in the context of medical devices. We advise creating a quality control plan that summarizes the production risk mitigation controls identified through risk assessment in a clear, concise format. This control plan also blueprints the actions needed if a specific limit or check is breached.

Anyone who has experienced an audit by a notified body or regulatory agency will recognize their love of records. The mature management systems used by large manufacturers often aren’t available for the short-run low volumes involved at the scale-up stage. Building a bespoke database compliant with 21 CFR part 11 to handle records can be a lengthy activity, particularly when compared with the pace of setting up paper-based systems.

Managing paper records generated by the manufacturing process can be challenging, putting storage and recall burdens on a manufacturer. Companies scan these documents soon after completion to reduce this burden. But the destruction of originals is risky, and the recall and integrity of e-records must be checked before destruction.

Pilot manufacturing helps optimize the journey of a drug delivery device to clinical trial. It’s not without its own challenges, but synchronizing manufacturing process and device design development, partnering with experts, having a plan for producing components that’s representative of the final production process, and keeping a handle on records puts you in a position to maximize pilot manufacturing’s potential.

References

Connect with CDP

For more on how to navigate pilot manufacture and bring drug delivery devices to clinical trial with confidence, contact Cambridge Design Partnership.

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ISO 11608 applies to needle-based injection systems||
By Steve Augustyn
April 1st 2021
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Steve Augustyn

Senior Consultant Mechanical Engineer

ISO 11608: All change for injector standards

Anyone who works with injection devices will be familiar with the ISO 11608 series of standards. The standards cover requirements, test methods, and design guidance for needle-based injection systems, and they are currently nearing the end of the most comprehensive review and update since 2012.

This review of ISO 11608 aims to better align the various parts of the standard and define a new class of device coming to the market, on-body delivery systems (OBDS), which the current revision of the standards doesn’t adequately describe. CDP develops and verifies many needle-based injection systems on behalf of our clients. Our manufacturing capability also gives us insight into the challenge of moving from building a handful of devices to building thousands of products. The Final Draft International Standard will be published soon, and I’d like to share some of the proposed changes.

It’s important to note that the current status of these standard parts is “draft”. The details of these documents may well change before publication, assuming that the various international bodies approve the publication of these standards. That said, let’s get into some detail.

ISO 11608 – update history in brief

Since the publication of ISO 11608-1: Pen Injectors for Medical Use – Requirements and Test Methods in 2000, the standard has expanded to cover many aspects of needle-based injection systems (NIS). The various parts of the published standards now cover:

  • General Requirements (11608-1 since 2012)
  • Needles (11608-2)
  • Finished Containers (11608-3)
  • Electronic and Electromechanical Injectors (11608-4)
  • Automated Functions (11608-5)

These standards were then joined by 11608-7 (Accessibility for persons with visual impairment) in 2016, which covers design guidance for improving accessibility to NIS for visually impaired users. These parts of the standard come under the remit of ISO Technical Committee 84 (ISO TC84), a committee focused on defining the requirements and test methods to ensure safe and effective devices are made available to the widest number of people.

I’ve had the privilege of being one of the UK’s representatives to this committee since 2013, so I’ve had a front-row seat for many of these discussions. So, what changes should device manufacturers and designers anticipate?

ISO 11608-1 – Needle-based Injection Systems

In this revision of the 11608 family, TC84 has worked to align the various parts, ensuring every potential NIS is addressed in the collection of parts, that they integrate well, and topics aren’t duplicated. ISO 11608-1 is the ‘parent’ part – the fundamental section of the standard that establishes the requirements and test methods for all NIS devices covered by the whole standard.

The revision to part one includes the introduction of OBDS (more fully described in ISO 11608-6) and several new concepts. These concepts include primary function, the functions of the device that allow it to be used safely and effectively. Functional stability, which expands testing regimens to simulate whole-life testing for reusable devices, is also introduced in this revision. In addition, the design specification for the NIS must consider the impact and requirements of the medicinal product, and the guidance on risk-based design approaches has been expanded.

There are also several smaller modifications to ISO 11608, including moving all requirements for electronics and EMC testing to ISO 11608-4, the addition of a choking hazard warning for small components, and the associated test fixture. A section has also been added to the document giving guidance on design verification with reference to ISO 13485.

ISO 11608-2 – Double-ended Pen Needles

The changes to ISO 11608-2 (Double-Ended Pen Needles) are more subtle. The determination of flow rate has been expanded to include suggested flow ranges and the sample sizes have been brought in line with the requirements in ISO 11608-1. The testing requirements to confirm compatibility between a needle and a specific NIS have been revised to include dose delivery and needle hub removal force. In addition, the samples required for functional compatibility have been reduced and guidance has been added regarding the requirements for the inner needle shield.

ISO 11608-3 – Containers and Integrated Fluid Paths

The scope of ISO11608-3 has now been expanded beyond defining cartridge geometry and performance to cover NIS Containers and Integrated Fluid Paths. Again, this change has been prompted by the development of OBDS. The requirement for resealing the cartridge has been reduced from 1.5x the intended use to a minimum of 1.0x the intended life. At the same time, the particle size for coring characterization has increased from 50um to 150um or larger. General requirements for soft cannulas and fluid line connections have also been added – another feature of the standard that can be traced back to introducing the OBDS class of device. Cartridge geometry definition has also been moved to an informative annex, meaning it’s no longer mandatory.

ISO 11608-4 – Needle-based Injection Systems Containing Electronics

I’ve had no direct visibility of the updates to ISO 11608-4. However, colleagues from the dedicated work group have summarized the two high-level changes as:

an expansion of the scope to include all electronics on a NIS (not just those concerned with the delivery of the drug product)
medicinal product delivery while connected to mains power (for recharging the battery) will be permitted

The challenge for part 4 has been to reference the parts of IEC 60601 which are appropriate for NIS. Part 4 references IEC 60601 explicitly, adopting the general requirements, means of patient protection, and power input requirements from the relevant components of the standard. The minimum ingress protection has been increased from IP22 to IP52, allowable temperatures for skin contact are defined, failure obvious to the user after free fall preconditioning is permitted, and the use of NIS in oxygen-rich environments has been defined.

ISO 11608-5 – Automated Functions

The revised text for ISO 11608-5 now explicitly directs the reader to ISO 11608-1 for general requirements and focuses on automated needle insertion and dose delivery. Requirements for fenestrated needles (needles with holes in the side) have been defined and the implications of non-perpendicular needle and cannula insertion are explored. The dose accuracy test has been modified for needles with automated insertion, and defining and measuring automated dose delivery time is now a requirement.

ISO 11608-6 – On-body Delivery Systems

This review includes the introduction of ISO 11608-6 defining the requirements for OBDS. This part of the standard initially expanded quickly as new terms and definitions were added but many of the new concepts have been adopted into the following component documents: 11608-1 (General Requirements), 11608-3 (Container and Integrated Fluid Paths), and 11608-5 (Automated Functions).

The crucial difference between an OBDS and an infusion pump is that the OBDS’s performance is defined by dose accuracy for a fixed volume; an infusion pump is defined by the rate at which the medicinal product is delivered. OBDS are also distinct from other NIS types in that they are attached to the body, whereas traditional NIS are held by the user for the duration of the delivery. The requirements and design guidance reflect this difference in use and the concept of a delivery profile (as a characterization tool, not a performance requirement) has been included to help device builders better understand their products.

This summary only scratches the surface of the comprehensive review of ISO 11608, and on the current timeline, these changes will not be published until late 2022, but if your development program extends beyond that date, I hope you found this summary helpful. The draft standards can be purchased from the ISO web store if you’d like to better understand the scope of the changes and the implications for your device development and verification program. If you’re a device developer and struggling with device performance, CDP has expert teams to help overcome these problems.

I’d like to thank my colleagues from ISO for their assistance in drafting this summary. In particular, Robert Nesbitt, Director of Portfolio Strategy at Abbvie and project leader for the ISO 11608-1 review, and Bibi Nellemose and Lars Brogaard from Danish Standards, whose tireless efforts as TC84’s secretariat keep the whole process running smoothly.

Connect with CDP

For more on how to navigate ISO 11608 changes and develop injection devices that meet evolving standards, contact Cambridge Design Partnership.

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December 17th 2020
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CDP on inhalation trends and what we learned at DDL2020

We’re living in an ever more virtual world. The rate of adoption and adaptation of technologies enabling remote connections and interactions has surpassed even the most optimistic predictions. An example of this is the annual Drug Delivery to the Lungs (DDL) conference, hosted by The Aerosol Society, that a group of CDP colleagues attended last week. Usually held in Edinburgh, this year it was a virtual event. With the content available as a live stream and on demand and virtual booths providing instant access to downloadable material, this approach facilitated a wider reach and more flexibility for attendees seeking to learn about advances in the industry.

The first day highlighted the move to more sustainable lifecycles of products and how this must be balanced with effective drug delivery. With 630 million pressurised metered-dose inhalers (pMDIs) being produced each year and low rates of recycling, even small changes could have a big impact; whether by moving towards biobased polyolefin materials, inclusion of foaming agents to reduce the mass of plastic, or changes to another dosage form. This mirrors the trends that CDP has seen from our clients and the complex nature of plastic sustainability, discussed here by our colleague Dan. It was great to see the different approaches and how we are tackling this as an industry, making many small improvements that can add up to a significant change.

The second day went deep into specific formulations for targeted therapies. It’s always great to hear so many passionate scientists talk about their work and the benefit that it can have for patients. The biggest insight for us is how a deep and seemingly narrow investigation into a specific area can provide inspiration for unrelated therapies; the pharmacodynamic challenges of formulating an inhaled form of a parenterally administered product, engineering of particle sizes through spray drying, and the visualisation of drug particle distribution. Working across different sectors, this is the approach taken by CDP’s science team in projects such as determining the factors influencing vapour droplet size and technology scouting for novel delivery therapies. We were particularly excited to hear how advances in X-ray microscopy (XRM) are enabling the visualisation of active pharmaceutical ingredient distribution in pharmaceutical blends, giving real-life validation to predictive models of distribution and behaviour.

During the final day, the focus shifted to advances in delivery devices and challenges to the limits of their operation. Despite being widely used for over 60 years, studies show that over 70% of MDI users do not use the device as intended – so clearly there’s room for improvement. Whether the resolution is an adaption of the current MDI devices or switching to dry powder inhalers (DPIs) remains to be seen. With a step change in technology adoption this year, there is certainly a place for digital and connected solutions but as the final discussion group highlighted, in order to provide value from the digital advances the underlying technology needs to be robust.

CDP’s multidisciplinary, cross functional teams are here to help with your project needs. For more information, contact drug.delivery@cambridge-design.com

|Jessica Platt & Martha Hodgson discussing FemTech|||Clare Beddoes|
June 8th 2020
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Improving drug delivery systems for self-administration

WEBINAR

Improving drug delivery systems for self-administration

With Bastiaan deLeeuw, Uri Baruch, Clare Beddoes and Chris Houghton
8 JUN 2020

As self-administration in the home setting grows in importance, our panel of experts discuss the continuous drive to design and improve drug delivery systems for self-administration and home-use.

Enjoy the full debate where Bastiaan deLeeuw chairs the panel, gathering insights from Uri Baruch (Head of drug delivery), Clare Beddoes (Medical innovation and research consultant) and Chris Houghton (Head of FMCG).

 

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Bastiaan deLeeuw

FemTech Lead and Associate Insights Researcher

Uri Baruch

Senior Insights & Strategy Consultant

Clare Beddoes

FemTech Lead and Associate Insights Researcher

Chris Houghton

Chris Houghton

Senior Insights & Strategy Consultant

pen-injector technology
By Uri Baruch
April 28th 2020
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Uri Baruch

Partner

CDP collaboration on pen-injector technology with the Stevanato Group

Cambridge Design Partnership (CDP), a UK and US based leading technology and product design partner, and the Stevanato Group, a leading producer of glass primary packaging and provider of integrated capabilities for combination products, today announced a collaboration agreement for the development of a new pen-injector based on the Axis-D technology and intellectual property (IP) licensed exclusively from Haselmeier in 2019.

The collaboration between CDP and the Stevanato Group strongly supports the expansion of the Stevanato group’s portfolio of devices for patients suffering from diabetes.

The agreement leverages the mutual strengths: on one side, CDP’s leading design and development expertise in drug delivery and on the other, the Stevanato Group’s extensive experience in glass containers, tooling, injection moulding, device assembly, and its global commercial network.

CDP and the Stevanato Group will be able to offer innovative drug delivery solutions to pharmaceutical customers working together from the first concept right through design development, scale-up, regulatory submission, and commercial-scale production in all global markets.

“We are delighted to be announcing this partnership,” says Uri Baruch, CDP’s Head of Drug Delivery. “The Stevanato Group is well established in the device field as a leading supplier of cartridges and assembly equipment for pen-injectors. It is a pleasure to extend our existing working relationship with them for their pen-injector and to address the needs of patients.”

“Our R&D team – with the active support of CDP, an established player in the design and development of drug delivery devices – will offer a competitive pen-injector platform and some customization options,” comments Paolo Patri, Chief Technology Officer at the Stevanato Group. “With the resources and experience of both companies, we will provide diabetic patients with a product that is easy-to-use, aesthetically appealing, and cost-effective.”

This new collaboration is one of the programmes behind the recent, substantial growth of CDP’s team of healthcare-focused designers and engineers in both Cambridge (UK) and Raleigh, NC (USA) facilities. “This is another strong vote of confidence in CDP. We look forward to this being the first of many end-to-end projects that we can collaborate on in this new partnership”, says Uri Baruch.

About Cambridge Design Partnership: Cambridge Design Partnership is an employee-owned technology and product design partner, located in Cambridge (UK) and Raleigh, North Carolina (US), focused on helping clients grow their business. Over more than 20 years, some of the world’s largest and most innovative companies have trusted CDP with their most important product development programs. CDP provide an integrated and holistic product development capability through a highly qualified team, well equipped development labs and ISO 13485/9001 approved methods. This encompasses research and strategy, design, technology and digital innovation, product development and regulatory and manufacturing support. CDP experts are able to take combination products through a full design cycle and submission, enabling customers to launch products that are user-centric and commercially effective. For more information, please visit our site.

For further information and media enquiries, please contact: media@cambridge-design.com or call 01223 264428

About the Stevanato Group: Established in 1949, the Stevanato Group is the world’s largest, privately-owned designer and producer of glass primary packaging for the pharmaceutical industry. From its outset, the Group has developed its own glass converting technology to ensure the highest standards of quality. The Group comprises a wide set of capabilities dedicated to serving the biopharmaceutical and diagnostic industries: from glass containers with its historical brand Ompi, to high-precision plastic diagnostic and medical components, to contract manufacturing for drug delivery devices, to vision inspection systems, assembly, and packaging equipment. The Group also provides analytical and testing services to study container closure integrity and integration into drug delivery devices, streamlining the drug development process. Thanks to its unique approach as a one-stop-shop, the Stevanato Group can offer an unprecedented set of solutions to biopharma companies for a faster time to market and a reduced total cost of ownership. For more information, please visit Stevanato Group.

For all enquiries, please contact Steven Kaufman