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Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.
PATH’s Microarray Patch Center of Excellence aims to accelerate transdermal patch technology for public health needs.
Transdermal drug delivery offers benefits such as needle-free delivery and easier self-administration. Microarray patches are one type of transdermal delivery in which a set of microscopic projections (i.e., microneedles) that contain a dry drug are applied to the skin using a bandage-like patch. PATH is a nonprofit, global health organization that has been investigating transdermal drug delivery patches for more than 10 years. In August 2018, the organization launched the Microarray Patch (MAP) Center of Excellence as a four-year initiative to accelerate development, particularly for global health needs, such as vaccines and essential medicines. Pharmaceutical Technology spoke with Darin Zehrung and Courtney Jarrahian, directors of the MAP Center of Excellence, about the initiative and some of the challenges they have identified for transdermal patch manufacturing. Zehrung is global program leader and Jarrahian is a program advisor, both in Medical Devices and Health Technologies at PATH.
PharmTech: Please explain what the Microarray Patch Center of Excellence initiative is and how it was started. What are your current goals?
Zehrung and Jarrahian (PATH): Microarray patches, or MAPs, are an innovative delivery technology in early-stage development that could be used to administer vaccines and drugs without a needle or a syringe. For the past decade, PATH, in collaboration with developers and global stakeholders, has advanced the design and development of microarray patch technology for a range of public health needs, including measles, HIV, influenza, malaria, neonatal sepsis, and polio (1). We recognized challenges-including siloed information and limited opportunities for platform-wide approaches-that we could address to improve efficiency of product development. As a result, PATH formed the MAP Center of Excellence, with support from UK Department for International Development, to catalyze development of this promising technology.
Through the Center of Excellence, our aim is to mobilize stakeholders and coordinate a strategic effort to identify and accelerate MAP technology for high-priority health needs in low- and middle-income countries. Currently, we are one year into this four-year initiative. PATH is working with the MAP developer community and global health stakeholder organizations on six functional areas-program needs, product development, manufacturing, regulatory, business strategy, and engagement-that are critical to advance this promising innovation.
PharmTech: What are some of the key challenges for manufacturing microneedle patches?
Zehrung and Jarrahian (PATH): Establishing scalable, automated, good manufacturing practice–compliant manufacturing processes for MAPs is a major focus area of this technology class and will be critical for its success. Technologies can be adapted from other fields to address challenges of precise loading of very small quantities of liquid into the MAP projections. Minimizing drying time is necessary to enable high throughput. Developing processes with high production yield and efficiency in use of the drug substance is also important for cost and sustainability, particularly for costly APIs.
For delivering drugs that require larger dosages (more than a couple of milligrams), a major challenge is providing sufficient drug loading and release, which can require alternative array designs and larger patch sizes. Under our MAPs for PrEP (pre-exposure prophylaxis) program, funded by the US Agency for International Development and the President’s Emergency Plan for AIDS Relief (PEPFAR), PATH has been working with partners to address this challenge to enable delivery of long-acting antiretrovirals and hormonal contraceptives by MAP.
PharmTech: What are some of the challenges for developing/manufacturing microneedle patches for vaccines in particular?
Zehrung and Jarrahian (PATH): One key challenge is that vaccines cannot be terminally sterilized. Experts have debated about whether a low-bioburden manufacturing approach will be sufficient from a product quality and risk perspective, or whether vaccine MAPs will have to be produced aseptically, which adds complexity and cost to manufacturing facilities and equipment. In addition, vaccine antigens can lose potency quickly, so formulation optimization to maintain stability is critical, especially if enhanced thermostability is desired.
PharmTech: Have you completed any projects for vaccines patches that have been transferred to commercial use?
Zehrung and Jarrahian (PATH): Commercialization is the moonshot. Currently, vaccine MAP development is at preclinical and early clinical stages and no vaccine products have been commercialized yet. However, to build an evidence base to support future commercialization, we’ve completed studies evaluating factors that will influence cost-effectiveness (2) and stakeholder acceptability (3) of seasonal influenza MAPs, for example. Several developers have published Phase I clinical study results for influenza vaccine MAPs (4–6). To advance the development of MAPs for measles-rubella (MR) and inactivated poliovirus vaccine, PATH worked alongside other organizations such as the World Health Organization (WHO) and the Bill & Melinda Gates Foundation to develop target product profiles and cost analysis. In Ghana, PATH conducted a user study of MAP prototypes with healthcare workers, mothers, and children (7). PATH participates in the WHO MR MAP Product Development Working Group. Under the Center of Excellence, we are assessing the feasibility and value proposition of MAPs for other vaccines, including hepatitis B, human papillomavirus, rabies, and vaccines delivered during disease outbreaks.
PharmTech: One of the benefits of patch delivery for vaccines is greater stability for storage and transportation, which reduces the need for a cold chain. Can you share some of your findings from your work in this area?
Zehrung and Jarrahian (PATH): If MAPs are sufficiently thermostable to not require storage in the traditional cold chain (in which vaccines must be stored between 2 and 8 °C) for part of their storage life, that could facilitate new delivery strategies that have the potential to increase access to vaccination. This access is especially important in countries where the cold chain infrastructure is weak. WHO’s minimum standard for a vaccine to be eligible for licensure for use in a controlled temperature chain (CTC) is stability for a minimum of three days at a temperature greater than or equal to 40 °C (8). MAPs could simplify storage and transport, and ultimately improve vaccine access. CTC storage won’t be feasible for all vaccine MAPs due to inherent stability limitations of some antigens.
PATH has developed the Vaccine Technology Impact Assessment (VTIA) model, which compares the total cost of delivery of different vaccine presentations, including the costs of transportation and storage in the cold chain. Our analyses have found that MAPs eligible for CTC storage can reduce vaccine transportation and storage costs. However, the total impact on the cold chain will depend on the storage volume of the MAP compared to the currently used vaccine presentation and the length of time the vaccine can be stored in a CTC. Many vaccines used in low- and middle-income countries are packaged in 10-dose vials, so MAPs are likely to require more storage space on a per-dose basis, particularly those with an integrated applicator device. But compared to the single-dose vials and prefilled syringes commonly used in high-income countries, MAPs could have a packaged volume advantage.
PATH is also supporting the Vaccine Innovation Prioritization Strategy (VIPS) launched by Gavi, WHO, the Bill & Melinda Gates Foundation, PATH, and UNICEF in 2017. This global initiative aims to drive vaccine product innovation to better meet country needs and to improve immunization coverage and equity. MAPs are among the vaccine product innovations being assessed. Insufficient cold chain capacity has also been identified as a key immunization challenge through VIPS that could be addressed through the use of innovations.
PharmTech: What are some of the considerations for packaging of patches (in vaccines or otherwise)? Do you have any research projects in this area?
Zehrung and Jarrahian (PATH): Maintaining low moisture content over the shelf life of the product is generally critical for MAPs, as the microneedles can lose their sharpness and mechanical strength if exposed to moisture. This will require careful consideration of materials and seals for MAP packaging, and potentially incorporation of desiccant into the packaging system. In addition, it is important to consider physical protection of the microstructures if the product is dropped or crushed during storage or prior to use, so a rigid package format may be needed. Human factors design is also a critical consideration, as well-designed packaging can improve usability and prevent some types of user errors. Requirements for labeling, extractables/leachables, and biocompatibility are important as well. PATH is currently reviewing materials and designs for MAP packaging.
PharmTech: What are the next steps for the Center of Excellence initiative?
Zehrung and Jarrahian (PATH): We’re initially focusing on the regulatory and manufacturing pathways for MAP technology as a platform. In partnership with Cardiff University, Wales [UK] we’ve launched an initiative working with industry, regulators, and academia to harmonize MAP definitions, critical quality attributes, and key test methods and will aim to produce a white paper documenting these considerations. We’re assessing manufacturing readiness across the technology class, and we plan to host a workshop in early 2020 to delve into key manufacturing challenges and potential solutions.
Related to advancing MAPs specifically for global health impact, we’ll be conducting user needs assessments in low-resource countries and using the information to inform target product profiles for prioritized MAP products. User feedback will help ensure that the product meets the needs of health care workers, patients, and health systems to optimize uptake and impact of MAPs in the future.
1. N. Peyraud et al., Vaccine 37 (32) 4427–4434 (2019).
2. B.Y. Lee et al., Vaccine 33 (37) 4727–4736 (2015).
3. E. Jacoby et al., Vaccine 33 (37) 4699–4704 (2015).
4. S. Hirobe et al., Biomaterials 57, 50–58 (2015).
5. N.G. Rouphael et al., The Lancet 390 (10095) 649–658 (2017).
6. G.J.P. Fernando et al., Vaccine 36 (26) 3779–3788 (2018).
7. PATH, “Evaluation of Microarray Patches for Human Factors-Considerations and Program Feasibility” PATH.org (August 2017).
8. World Health Organization, “Immunization, Vaccines and Biologicals, Controlled Temperature Chain (CTC),” accessed Sept. 23, 2019.
Vol. 43, No. 11
Pages: 48–49, 54
When referring to this article, please cite it as J. Markarian, “Advancing Transdermal Drug Delivery,” Pharmaceutical Technology 43 (11) 2019.