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Equipment and process optimization must be considered for scaling up these developmental technologies to commercial production.
Microneedle array patches (MAPs) have been in development as an alternative to injections for delivering vaccines and other drugs. Microneedle patches differ from transdermal patches that deliver medicine through the outermost layer of the skin (the stratum corneum), because the microneedles pierce the stratum corneum and deliver the drug into the epidermis or upper part of the dermis, but not deep enough to cause pain. Microneedle technologies include solid microneedles coated with the drug, hollow microneedles filled with a liquid drug, and dissolvable microneedles with the drug embedded in a soluble material.
Microneedle patches have been studied in a clinical trial for delivering a flu vaccine (1) and in preclinical trials for delivering inactivated rotavirus vaccine (IRV) and co-administration of IRV and inactivated poliovirus vaccine (2). Recently, MAPs are being investigated for a vaccine to fight COVID-19 (3). The University of Pittsburgh Medical Center (UPMC) announced in an April 2, 2020 press release that its scientists had developed a potential vaccine against SARS-CoV-2 that would be delivered through a MAP (3). The fingertip-sized patch uses 400 microneedles that deliver the spike protein pieces into the skin, where the needles, which are made of sugar and the protein pieces, dissolve. Noting that scalability is crucial for vaccines intended for protection from pandemics, UPMC said that the process to make and purify the protein for the vaccine is scalable, and that mass-producing the microneedle array involves spinning the protein-sugar mixture into a mold using a centrifuge. Advantages of the vaccine, dubbed PittCoVacc, are that (like other MAPs) it does not require a cold chain for storage and that it maintains its potency after being sterilized with gamma radiation. The researchers are in the processing of submitting an investigational new drug application to FDA.
PATH, a nonprofit, global health organization has been investigating transdermal drug delivery patches for more than 10 years and is in the middle of a four-year initiative, through its Microarray Patch (MAP) Center of Excellence, to accelerate development for global health needs, such as vaccines and essential medicines, in low- and middle-income countries. The group says that developing scalable, automated, good manufacturing practice (GMP) processes is crucial for success (4).
“Although microneedle arrays are being used commercially in some cosmetic applications in Asia, the technology is not yet commercial for vaccines. Optimization of equipment and manufacturing processes is crucial for producing these systems in the large quantities and reasonable costs needed for clinical studies and vaccination campaigns,” adds Stefan Bernsau, sales director for Needle Technology at Harro Höfliger (HH), which develops and manufactures various types of production and packaging equipment for pharmaceutical companies, the medical device industry, and other industries. The company is working with various organizations and partners to develop microneedle array patch (MAP) technology, and in January 2020, Harro Höfliger and PATH hosted a workshop on MAP manufacturing attended by MAP developers and representatives from the World Health Organization, UNICEF, the Bill & Melinda Gates Foundation, and the Gavi Vaccine Alliance. Pharmaceutical Technology spoke with Bernsau about some of the considerations for MAP manufacturing.
PharmTech: What are some of the advantages of using MAPs for vaccines?
Bernsau (HH): Vaccine delivery faces several challenges that can be addressed with MAP technology. A significant issue is that low- and middle-income countries often do not have a clear cold chain, which is necessary for transport and storage of liquid, injectable vaccines. MAPs do not require a cold chain. Another concern is that a significant number of people have a fear of regular injection needles and the associated pain. Microneedles in a patch form eliminate the pain. In addition, MAPs can be administered without skilled healthcare workers, by trained workers or potentially by self-administration. This advantage is beneficial for developing countries that lack skilled healthcare providers. Recently, it is also being thought of as a benefit for all countries for use in pandemics, where patients could potentially have the vaccine delivered for self-administration, thus avoiding the need for people to go to doctors’ offices or hospitals.
PharmTech: What are the biggest challenges in microneedle patch manufacturing and what are some best practices for addressing these challenges?
Bernsau (HH): Companies developing products at the laboratory scale are looking at issues such as dosing (either by coating or filling) and drying. At the commercial scale, however, automation is crucial for obtaining output at an appropriate cost, with a reasonable total cost of ownership. As a machine manufacturer, we want to join in the development process as early as possible so that we can provide input to developers for how to optimize the process for commercial automation.
One of the constraints for vaccine manufacturing is that most cannot be terminally sterilized, therefore they must be produced in a sterile environment. One of the keys for sterile production is material flow through the processing line: raw materials must be brought into the machine; various automated steps are performed; then the product must be taken out of machine. Sterile environments can include isolators or various types of barrier technology, depending on the cleanroom setup.
Dosing of the API, either into the hollow mold or as a coating, must be done in a combination of high precision and with high output. These are very small doses, and different dosing technologies are used to obtain the specific tolerances needed for a particular process. There are some new developments in the market for dosing. VAXXAS, for example, has developed their own high-speed and high-precision dosing technology that is similar to ink-jet printing technology. As another example, scraper technology can be a solution for dissolvable microneedles, depending on the viscosity and the physical characteristics of the liquid or the vaccine.
For the automation of the lines, we use dedicated servo-driven units because the parts being handled are so small-the whole array may be about the size of a penny, for example. Robotic arms can cause turbulence in the airflow, which can be a problem regarding the aseptic requirements of such small, precise units. Another proven technology is a so-called ‘walking beam,’ which uses pick-and-place handling for small and delicate parts inside an isolator.
PharmTech: What are some best practices for inspection of MAPs after manufacturing?
Bernsau (HH): Several quality attributes need to be inspected, particularly that the required amount of drug is there (either coated or filled). Inspection of microneedles is more difficult than syringe inspection because of the small size of the microneedles. Cameras are used to view the top and side. Other critical pieces are the light source, appropriate software, and hardware for fast computing speed. A best practice is 100% inspection of each part, but a challenge is the speed and an eventual reflectance of image acquisition to accomplish this.
PharmTech: What are the requirements for packaging of microneedle patches?
Bernsau (HH): To a large degree the microneedles are fragile; they are typically packaged in an applicator, with a rigid container to protect the needles. The patch must also be packaged in a sterile environment. After primary packaging, it must also be packaged for transportation. An advantage of MAPs is that temperature is not as much of an issue, compared to traditional liquid vaccines, because the MAPs vaccine is dry.
PharmTech: Do you foresee in-country, for-country production with MAP technology?
Bernsau (HH): It is far too early to know whether production in developing countries is feasible, because the initial investment in these lines is high and a lot of technical knowledge and skill are needed to run these lines. However, some organizations are looking at this possibility, and the current pandemic may cause more governments globally to think about in-country production.
1. NIH, “Researchers Develop Microneedle Patch for Flu Vaccination,” Press Release, June 27, 2017.
2. Micron Biomedical, “Micron Receives Additional Funding from the CDC for Collaboration on the Development of a Microneedle Patch for IRV-IPV Co-administration,” Press Release, Aug. 27, 2018
3. UPMC, “COVID-19 Vaccine Candidate Shows Promise,” Press Release, April 2, 2020.
4. J. Markarian, Pharm. Tech. 43 (11) 48–49, 54 (2019).
Vol. 44, No. 5
When referring to this article, please cite it as J. Markarian, “Manufacturing Microneedle Array Patches for Vaccine Delivery,” Pharmaceutical Technology 44 (5) 2020.