Biomanufacturing Operations

While the drug-device combination product industry is always investing in technology that could better meet the needs of patients, governments and sponsors, the COVID-19 pandemic has accelerated the process, bringing in more outside investment and a broader range of organisations in active development

Andrew Riso at Kindeva Drug Delivery

With supply chain limitations and storage difficulties still part of our collective memory, we currently operate within a unique moment in time geared toward innovation – promising more investment and advancements in next-generation drug delivery, including microneedle technology, which ‘might be a big step forward in increasing vaccine equity’ globally.1

To clarify the potential benefit of prevention over treatment, the Global Preparedness Monitoring Board (GPMB) estimated in its 2020 Annual Report that ‘it would take 500 years to spend as much on investing in preparedness as the world is losing due to COVID-19.’2 This has led to a great deal of innovative work in vaccination and therapeutic delivery, which is largely driven by government organisations responsible for medical stockpiles and nationwide health.

It is against this backdrop that microneedle technology has become a cornerstone of ongoing development. Given the potential benefits it offers, there is a great deal of opportunity ripe for exploration.

The point of microneedle patches

Microneedle patches deliver a drug intradermally using an adhesive patch containing an array of microscopic needles that penetrate the skin to an optimal depth. There are currently three main categories of microneedle patches in development:

1. Solid-coated microneedles that use an array of solid needles coated with the drug formulation, which then enters the patient’s system
2. Dissolvable microneedles that utilise a drug formulation that is moulded into an array of needles, which then dissolve in the patient’s skin
3. Liquid microneedle delivery that provides a stream of a liquid drug formulation that enters the patient via an array of hollow needles.

While there is more work being done in the microneedle space, no technology has yet been approved by the US Food and Drug Administration (FDA). However, solid-coated and dissolvable microneedles have recently garnered greater progress with regards to research, development and clinical advancement.

Microneedles and macro challenges

The lack of regulatory approval is one of the major challenges in the development of microneedles. As of August 2023, there has only been one microneedle technology to submit a New Drug Application (NDA) to the FDA, which was subsequently rejected. A deficiency exists and further guidance could help smooth the development pathway. That being said, the relatively small number of specific regulatory requirements offered from the FDA, European Medicines Agency (EMA) and other regulatory bodies also ensures developers are not pigeonholed, leaving more opportunities for innovation and creativity within the space. Even with this greater developmental leeway, it is vital that communication with applicable regulatory agencies is started early and maintained throughout to inform the process and avoid surprises down the road.

However, when it comes to the challenges driving microneedle research, there are clear needs that must be addressed with current vaccines and therapeutics. As brought to light during the COVID-19 pandemic, supply chain limitations and cold chain needs may have a devastating impact on the availability of drugs and vaccines meant to safeguard global health. In the case of the former, issues with high-touch resources − such as glass − can bring the manufacturing of drug-device combination products to a standstill, offering no satisfactory workaround by which products can still reach patients. The issue of cold chain storage can add even more challenges. COVID-19 vaccines need to be kept at extremely cold temperatures (-15°C and lower) to maintain efficacy. This makes drug storage and shipment both complex and costly while introducing hurdles that might require entire batches of a drug to be discarded. These challenges are a large part of the current investment in microneedle technology, which shows promise in overcoming a host of potential pitfalls. This is particularly true for government investment, as strategic stockpiles may suffer when drugs have strict shipment and storage requirements.

An array of opportunities

Microneedle patches address a number of the overarching challenges directly, which opens up possibilities for governments around the globe. Among the potential benefits for vaccines, as discussed in Pharmaceutics, are ‘dose savings, elimination of the cold chain, improved safety and potential self-administration.’ 33The ongoing increased interest is a boon for in-house developers and contract development and manufacturing organisations (CDMOs) alike, as it can seriously reduce the amount of investment required from a sponsor. This is helping break down barriers in the development process, allowing more organisations to bring their innovative ideas to this space. At this stage of the process, even competitors are rooting for one another, knowing that the first approval brings the entire industry closer to realising the overall promise of this delivery technology.

Among the most prominent reasons for the ongoing investment in this technology is the long shelf life of microneedle patches. It is in this aspect that the scientists busily developing just-right formulations for these products take centre stage as the driving force behind their success. A vaccine that is stable at room temperature fully eliminates the issue of cold chain storage and transportation, cutting costs and complexity. Additionally, these patches may require less vaccine, which could provide dose sparing benefits. Altogether, these benefits aid stockpiling by countries, regardless of wealth, providing fast dissemination of the products and aiding global health initiatives.

Many of these patches will utilise an applicator that ensures proper needle depth, and the simple press-and-apply process may accommodate in-home self-application, which would pair with simpler storage and shipping requirements to allow for mailing of the products to a civilian population. This would reduce three major burdens to vaccination and treatment:

1. The need for a trained healthcare professional to administer the drug

2. The need for reliable transportation on the part of patients

3. Scheduling difficulties on both sides of the provider-patient equation.

Beyond shelf stability and ease-of-use, microneedle patches have the potential to provide more efficient delivery with fewer side effects. These devices are developed ‘to deliver the drug molecules to the bloodstream by controlling diffusion through the skin,’ as described in Polymers.4 By applying a vaccine directly to the skin, it is being delivered where antigen-presenting cells reside. This could reduce or eliminate adjuvants − and given their role in causing side effects, this may eliminate or reduce the frequency and severity of those effects. Thanks in part to these factors, microneedle patches could elicit a potent immune response − potentially even with poor immunogenicity.5

Given that these devices ‘are capable of penetrating directly through the skin to the deeper layers of the dermis,’ as noted in Pharmaceuticals, they may be able ‘to deliver drug molecules across the skin and maintain the local drug concentration for a long time at minimal invasive drug delivery.’ 6 Among the benefits of this delivery, the drug is not subject to the delays encountered in other administration methods, such as the lengthier process for an oral drug that must digest in the gut. Microneedle patches may provide a faster method for getting a drug into the body outside of an IV, which can be of vital importance in acute treatment of pain and life-threatening emergencies.

The sticky subject of manufacturing

As with most drug-device combination products, microneedle patches are complex, particularly in manufacturing, but as a Materials Letters study discusses, ‘developing a simple and cost-effective manufacturing method with proper precision is crucial for the mass production of microneedles.’ 7 Along with the high equipment costs required for this technology platform, there are two major elements to consider with regard to manufacturing challenges.

1. Content uniformity

It is not enough to develop a single patch with perfectly coated microneedles or dissolvable needles that all reliably dissolve. That same level of perfection must then be replicated across all subsequent patches. The efficacy of the product for patients relies on the ability of the manufacturer to consistently recreate a patch with identical needle coating or dissolvability over and over again. If this is not achieved, there is no guarantee that an accurate dose of the drug is being delivered.

2. Capacity

Given the intended application for many microneedle patch products, it is vital that a manufacturer is able to scale to meet demand while maintaining content uniformity. If a commercial quantity of patches, potentially numbering in the millions or billions, cannot be manufactured, then all of the benefits previously discussed mean little as the product will be unavailable for both government stockpiles and patients in sufficient numbers.

The in-house impediment

For the most part, companies are busy developing their own drug formulations and technology, but there is little room at present for pharmaceutical companies hoping to partner with a CDMO. Part of the issue is that every microneedle patch must be purpose-built, considering the complex formulation science that enables delivery and how that affects the specifics of coating the needles or accurately forming dissolvable needles.

While many organisations are developing preclinical, clinical and regulatory strategies, most do not also manufacture the product themselves. This means that there is a divide between the formulation side and the manufacturing side, which can introduce uncertainty with regard to the efficacy of the final product.

Unlike many other drug-device combination products, microneedles are not simply offering a method for administering a drug. They are actively coated in the drug or made of the drug, so these two parts of the product are inextricably linked in a more intimate manner than in other devices.

With a qualified CDMO partner, organisations can accelerate the process while maintaining line-of-sight into how development and manufacturing are working together to create a unique, effective product. CDMOs can help sponsors who do not have direct access to commercial manufacturing capabilities ensure that their product is efficiently developed through an always-informed process that spans the entirety of the organisation, offering time savings with regard to tech transfer and proof-of-concept.

Injecting promise into the process

While microneedle patches are still a technology platform in search of approval, they could bring about a true paradigm shift in the intradermal delivery space. For governments across the globe, there is hope that these products will provide opportunity for getting more people vaccinated and enable cheaper stockpiling. As investment continues to flow into their development, microneedle technology appears to be on a steady track forward, but the vast complexity in formulation and manufacturing requires a high degree of expertise − without which efficacious products stand little chance of ever hitting the market. With an extensive influx of government investment, present circumstances offer real potential for organisations with the right blend of know-how and capabilities to realise true innovation and bring microneedles to a market currently clamouring for them.

References

1. Thomasy H (2023) Tiny needles make a big impact for vaccine delivery, Drug Discovery News, 19.2
2. A World in Disorder (2020) Global Preparedness Monitoring Board Annual Report Executive Summary, 5
3. Feng Y X et al (2023) Microneedles: An Emerging Vaccine Delivery Tool and a Prospective Solution to the Challenges of SARS-CoV-2 Mass Vaccination, Pharmaceutics, 15
4. Aldawood F K et al (2021) A Comprehensive Review of Microneedles: Typles, Materials, Processes, Characterizations and Applications, Polymers 13.16
5. Mahmoud A et al (2021) Immunogenicity and safety of inactivated Influenza Split-Virion vaccine administered via a Transdermal Microneedle System, J Vaccines Immunol 7.1, 41-48
6. Damiri F et al (2022) Microneedle-Based Natural Polysaccharide for Drug Delivery Systems (DDS): Progress and Challenges, Pharmaceuticals 15.2, 190
7. Atefeh M K et al (2023) Development of dissolvable microneedle patches by CNC matching and micromolding for drug delivery, Materials Letters 330