BIRS Course: RNA Vaccine Manufacture and Assessment of Regulatory Documents for RNA Vaccines

This paper is in three segments: (A) Segment on Vaccine Manufacture; (B) Segment on Ready to Use (RTU) Fluid Path for Compounded Sterile Preparations, mRNA Vaccines, and Phage Therapy, (C) Segment on Competency Framework for Addressing Regulatory Review These segments can be used separately or in combination. Additionally, they can be presented in any order. The time devoted to each segment depends on the depth of the course coverage. These segments are interrelated and describe how to make vaccines, how to manufacture vaccines with a point-of-care system built from ready-to-use parts; and how to regulate vaccines. This is a timely review because of the importance of vaccines for the treatment of diseases. It is hoped that it will lead to new approaches to vaccine manufacture and regulation

Medical Devices Regulation in West Africa – A Situation Analysis

Harmonization of medical devices regulation is receiving strong global attention through the International Medical Devices Regulator’s Forum, an offshoot of the Global Harmonization Task Force on medical devices. Other current trends include the Global Medical Devices Nomenclature and the Medical Devices Single Audit Program. The medical devices regulatory field is in a state of constant innovations; technologies and new regulations and guidelines are evolving to meet the changing needs and trends. This is a veritable development because medical devices and technologies are assuming significant strategic roles in the healthcare value chain – prevention, diagnostics, treatment and cure of diseases – in which they act as “force multipliers,” affecting the economics of healthcare. The questions then are – what is the situation of medical devices regulations in Africa? Is Africa trending along with the global harmonization of medical devices regulation? This research focuses on the state of medical devices regulations in West Africa. The research question is – what is the current state of medical devices regulations in West Africa. To answer this question, a review of publicly available data was conducted. First, the World Health Organization’s website was reviewed for the most current data on the status of West African countries’ medical devices regulations. Then, all the available websites of National Medicines Regulatory Authorities in West Africa were reviewed to ascertain their current medical devices regulatory status. The results show that West African countries are lagging behind in the regulation of medical devices. Only 28% and 17% of the countries have regulations and guidelines respectively. It is recommended that the international partners sensitize, educate and support the national medicines regulatory authorities in West Africa to build their regulatory framework for medical devices using the World Health Organization’s model

Structural Properties, Order-Disorder Phenomena and Phase Stability of Orotic Acid Crystal Forms

Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1) and dimethylsulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135°C and loses only a small part of the water when stored over desiccants (25°C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen-bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a non-layer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions different levels of order-disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration

Human Capacity Building in Africa – The BIRS Model

Human capacity sufficiency and sustenance in regulatory science is a key factor for harmonization and an identified issue in the harmonization process specifically in Africa. The human factor is the linchpin for progress----there can be no working system without human capacity. Harmonization depends upon education that motivates and prepares individuals for leadership that subsequently fuels the profession. This paper proposes that one of the root causes is lack of sufficient institutions in Africa providing education in regulatory sciences and introduces the Biotechnology Innovation and Regulatory Sciences (BIRS) program model. This education model began with the IPAT program and evolved into the BIRS program of Purdue University. The goal of this program is to enable the manufacture of quality medicines in Africa for Africans by equipping leaders in Africa through higher education aligned with building industrial capacity. The program awards an MS degree from Purdue University in BIRS. These programs established a global professional community of regulatory scientists composed of Industrial Pharmacy Advanced Training (IPAT) graduates in Africa, Purdue MS graduates (from the US and Africa), PhD graduates, faculty, industry, and regulatory leaders. The community is diverse, including about 30% women and 50% Africans, and focuses on technical skills, leadership, regulatory science, and innovation. Currently, this community numbers over 350 members including about 200 graduates of Purdue’s certificate and master’s programs in the US, about 140 graduates of the IPAT certificate and Purdue’s master’s program in Africa, and professors, industry and regulatory leaders who have taught in the program over the years. In 10 years, the program has educated over 100 African scientists at the certificate level and over 40 African scientists at the MS level. Sponsorship of the program with funds and in kind has come from UNIDO, the Merck Foundation, and the Bill and Melinda Gates foundation

An Efficient, Green Chemical Synthesis of the Malaria\ud Drug, Piperaquine

To provide a robust, efficient synthesis of the malaria drug piperaquine for potential use in resource-poor settings. We used in-process analytical technologies (IPAT; HPLC) and a program of experiments to develop a synthesis of piperaquine that avoids the presence of a toxic impurity in the API and is optimized for overall yield and operational simplicity. A green-chemical synthesis of piperaquine is described that proceeds in 92 – 93 % overall yield. The chemistry is robust and provides very pure piperaquine tetraphosphate salt (> 99.5 %). The overall process utilizes modest amounts (about 8 kg/kg) of 2-propanol and ethyl acetate as the only organic materials not incorporated into the API; roughly 60 % of this waste can be recycled into the production process. This process also completely avoids the formation of a toxic impurity commonly seen in piperaquine that is otherwise difficult to remove. An efficient synthesis of piperaquine is described that may be useful for application in resource-poor settings as a means of expanding access to and reducing the cost of ACTs

Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline

Bedaquiline has been approved as a combination therapy to treat multi-drug-resistant tuberculosis in adults ≥ 18 years old. The citrate, fumarate, phosphate, and tartrate salts have obtained patents, but the structures for these moieties have not been extensively described in the literature; only the powder X-ray patterns have been published. To expand the knowledge of the bedaquiline structure, this study provides detailed information for the synthesis, elucidation, characterization, and stability of four additional new potential molecular entities, namely, benzoate, hydrochloride (HCl), nicotinate, and malonate salts. The salts were formed using a 1:1 ratio of the counter ions (acids) to a 30 mg equivalent of the bedaquiline free base. The principles of the International Conference on Harmonization Q6 were used to characterize the new salts and their stability-indicating parameters were evaluated at 0, 3, and 6 months under accelerated conditions of 40 °C and 75% relative humidity. The benzoate salt exhibited the lowest tendency to lose its chemical potency. Aside from the HCl salt, the others retained their chemical structure, displaying long-term stability. All salts were non-hygroscopic and the hydrated benzoate and nicotinate salts were stable to dehydration. Regarding their chemical potencies, thermal analysis, chemical stability, and water sorption potential, the salts were ranked as follows: benzoate > malonate > nicotinate > HCl