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Abstract The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Control (CMC) Community hosted a virtual panel discussion on July 15, 2022, to provide a forum to discuss industry and regulator CMC challenges associated with emergency use authorizations.

Abstract Combination products are therapeutic and diagnostic products that include two or more of the following: drug, biologic, and device. These products are needed for enhanced clinical outcomes and have more than one Mode of Action (MOA). Therefore, they require a more complex regulatory pathway and compliance with a minimum of two (2) sets of regulatory standards. In 2013, the 21 Code of Federal Regulations (CFR) Part 4 was published to clarify the applicable GMP regulations when drugs, devices, or biological products are included. The FDA (U.S. Food and Drug Administration) released additional guidance in 2017 to streamline the regulatory framework and provide transparency about demonstrating GMP compliance when multiple regulatory standards overlap. This paper summarizes the Current Good Manufacturing Practice (CGMP) requirements for drug-device combination products (Biologic combinations are not discussed in this paper). Emphasis is placed on considerations for structuring a compliant drug-device stability program, including the use of bracketing and matrixing the test schedule to support the establishment of the product expiry date and how legacy products can be evaluated to meet current standards.

Abstract The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Controls (CMC) Community hosted two virtual panel discussions focusing on several novel regulatory review pathways for innovative oncology products: Real-Time Oncology Review (RTOR), Project Orbis, and the Product Quality Assessment Aid (PQAAid). The panel sessions were held on August 27, 2021, for the discussion of RTOR, and January 21, 2022, for the discussion of Project Orbis and the PQAAid. Both panel sessions included representatives from the US Food and Drug Administration (FDA) and subject matter experts from the pharmaceutical and biotechnology industries, with the aim of facilitating knowledge sharing on CMC-specific advantages, challenges, eligibility criteria for participation, and operational modifications instituted through the utilization of these acceleration initiatives. Key topics included managing cross-regional regulatory CMC requirements, adapting to expedited development timelines, coordinating interactions between health authorities and industry, and potential opportunities for future improvement and expansion of these programs. As RTOR, Project Orbis, and PQAAid are relatively new initiatives, the experiences shared by the panel experts are valuable for providing deeper insight into these new regulatory pathways and processes.

Abstract The Stability Community of the American Association of Pharmaceutical Scientists (AAPS) held a virtual workshop on “Vaccine Stability Considerations to Enable Rapid Development and Deployment”, on March 24-25, 2021. The workshop included distinguished speakers and panelists from across the industry, academia, regulatory agencies, as well as health care leaders. This paper presents a review of the topics covered. Specifically the challenges in accelerating vaccine development and analytical characterization techniques to establish shelf-life were covered. Additionally, vaccine stability modeling using prior knowledge stability models and advanced kinetic analysis played a key in the EUA approaches discussed during the workshop. Finally, the role of stability studies in addressing the challenges of vaccine distribution and deployment during the pandemic were a focus of presentations and panel discussions. Although the workshop did not have any presentation topics directly dedicated to the mRNA vaccines, the techniques discussed are generally applicable. The mRNA vaccine developers were represented in the panel discussions, where experts involved in the EUA approval/deployment stages for this vaccine type could discuss the challenges as applied to their vaccines.

The Bank of Canada commissioned the Bitcoin Omnibus Survey in 2016 to monitor trends in the adoption and use of Bitcoin and other cryptoassets. This report presents findings from the latest iteration of the survey, which was conducted in 2018. We find that between 2016 and 2018 the share of Canadians who were aware of Bitcoin increased from 62 percent to 89 percent and those that owned Bitcoin increased from 3 percent to 5 percent. However, the share of past owners also increased, suggesting an influx of Bitcoin owners who subsequently divested after the steep rise of prices in 2017. The main reason for owning Bitcoin remains speculation, though this share decreased slightly since 2017. On the other hand, the share of Canadians who reported using Bitcoin for transactions a few times a month or more increased. Finally, we discuss how Bitcoin adopters differ from overall Canadians with respect to their financial literacy and cash holdings.

Abstract Brazil, the largest country in South America, has become the second largest pharmaceutical market in the emerging world. The Brazillian Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria - ANVISA) was created in 1999 with the primary goal to protect and promote public health surveillance over products and services in Brazil. The governing body and structure of this new regulatory agency will be the aims of this paper, where the authors hope to share their understanding on the regulatory processes and its significant importance of this agency.

Abstract An American Association of Pharmaceutical Scientists (AAPS) workshop on stability challenges for clinical supplies and commercial distribution of drug product that are not addressed in the International Conference on Harmonization (ICH) Quality documents was held from April 3rd – 4th, 2017 in Rockville, MD. Seventeen subject matter experts (SME), from industry and the Food & Drug Administration (FDA) presented and facilitated the round-table discussions. A total of fifty-five participants that included experienced pharmaceutical scientists, both from small and large pharmaceutical companies and service providers, benefited from the opportunity to interact face-to-face with industry partners and regulatory agency SMEs. The two-day meeting was divided into five major sections to ensure face-to-face interactions and round-table discussions between participants and SMEs: 1) statistical approaches to stability, dissolution, and shelf life testing, 2) microbiological quality of drug products, 3) strategies to support distribution, unplanned excursions, and transportation of drug products, 4) regulatory considerations on stability testing of biologics, and 5) in-use stability during clinical and commercial phases. All in all, this interactive workshop focused on challenges and successes of addressing stability concerns that affect pharmaceutical development, manufacturing, distribution, and use of drug substances/products for which no or limited ICH guidance exists. The interactive meeting provided a unique opportunity to industrial scientists and regulatory agency liaisons to facilitate the discourse on how to address stability challenges that are not addressed in harmonized guidelines: this paper summarizes those discussions.

Abstract An AAPS joint face-to-face meeting was held on April 6th, 2016 at MedImmune, Gaithersburg, MD. The meeting was organized by members of the Steering Committees of the Stability Focus Group, the Pharmaceutical Impurities Focus Group and the Chemistry, Manufacturing and Controls (CMC) Statistics Focus Group. Twenty two subject-matter-experts (SME) from the Industry and the Food & Drug Administration (FDA) participated as discussion facilitators or discussion leaders. The total participants reached 65 people representing various sizes of pharmaceutical companies. Four contemporary technical topics on analytical approaches to ensure product quality were selected to be discussed and shared information: (1) Approaches to set release limits and managing method variability; (2) Ensure product quality through lifecycle management; (3) Best practices for predictive stability programs; and (4) ICH Guideline M7 and mutagenic impurities. The purpose of the meeting was to share the best practices in the industry related to the topics; therefore, it is not intended for the participants to reach a consensus on the key issues discussed. This paper summarizes the discussions in the meeting.

CONTEXT: The mandibular canal (MC) is an essential landmark that should be considered before any surgeries. Therefore, accurately assessing the location and characteristics of the MC in cone beam computed tomography (CBCT) imaging is very important. AIMS: To determine the characteristics of the MC in relation to adjacent anatomical structures in CBCT projections. SETTINGS AND DESIGN: The convenience sampling method. METHODS AND MATERIAL: This was a retrospective study of 112 CBCT images of Vietnamese patients aged 18 to 69 years, taken for clinical indications between 2018 and 2023. The evaluation was carried out by comparing and arranging the anatomical structures of different planes in three-dimensional space to assess and measure relevant dimensions. STATISTICAL ANALYSIS USED: Independent samples T-test. RESULTS: The average diameter of the MC from the apex of the second premolar to the distal apex of the second molar, if there were no missing teeth in this segment, was 2.58 ± 0.52 mm (right) and 2.55 ± 0.54 mm (left). If there were a missing tooth in this segment, the measurements were 2.51 ± 0.79 mm (right) and 2.47 ± 0.45 mm (left). The difference between the two sides regarding the presence or absence of a missing tooth was not statistically significant. CONCLUSIONS: The precise localization of the MC related to the tooth apex and the diameter of the MC can vary in each person. CBCT indications should be considered when establishing treatment planning to avoid damaging the inferior alveolar nerve in the MC.

Background: Pseudomyxoma peritonei (PMP) is a rare condition, with no previously described location in the spine. Here is presented a case of PMP extension to the thorax and then the spine, treated with two-level vertebrectomy, laminectomy, and posterior fusion. Case Report: We report here the case of a 64-year-old man presenting pathological fractures of T6 and T7 due to PMP extension to the pleural cavity and thoracic spine. He presented interscapular pain with mild spinal cord compression symptoms. He was treated by achieving T5-T8 laminectomy, T2-T10 pedicle fixation, and T6-T7 vertebrectomy. The postoperative course was uneventful apart from a pulmonary embolism (PE) with favorable evolution under anticoagulants. Conclusion: To achieve spinal cord decompression, kyphosis correction, and spine stabilization, a two-level vertebrectomy, laminectomy, and posterior fusion would be beneficial for a PMP lesion of the thoracic spine. [ABSTRACT FROM AUTHOR]

Abstract Background Besides Escherichia coli, Bacillus subtilis is an important bacterial species for the production of recombinant proteins. Recombinant genes are inserted into shuttle expression vectors which replicate in both E. coli and in B. subtilis. The ligation products are first transformed into E. coli cells, analyzed for correct insertions, and the correct recombinant plasmids are then transformed into B. subtilis. A major problem using E. coli cells can be the strong basal level of expression of the recombinant protein which may interfere with the stability of the cells. To minimize this problem, we developed strong expression vectors being repressed in E. coli and inducer-free in B. subtilis. Results In general, induction of IPTG-inducible expression vectors is determined by the regulatory lacI gene encoding the LacI repressor in combination with the lacO operator on the promoter. To investigate the inducer-free properties of the vectors, we constructed inducer-free expression plasmids by removing the lacI gene and characterized their properties. First, we examined the ability to repress a reporter gene in E. coli, which is a prominent property facilitating the construction of the expression vectors carrying a target gene. The β-galactosidase (bgaB gene) basal levels expressed from Pgrac01-bgaB could be repressed at least twice in the E. coli cloning strain. Second, the inducer-free production of BgaB from four different plasmids with the Pgrac01 promoter in B. subtilis was investigated. As expected, BgaB expression levels of inducer-free constructs are at least 37 times higher than that of the inducible constructs in the absence of IPTG, and comparable to those in the presence of the inducer. Third, using efficient IPTG-inducible expression vectors containing the strong promoter Pgrac100, we could convert them into inducer-free expression plasmids. The BgaB production levels from the inducer-free plasmid in the absence of the inducer were at least 4.5 times higher than that of the inducible vector using the same promoter. Finally, we used gfp as a reporter gene in combination with the two promoters Pgrac01 and Pgrac100 to test the new vector types. The GFP expression levels could be repressed at least 1.5 times for the Pgrac01-gfp+ inducer-free construct in E. coli. The inducer-free constructs Pgrac01-gfp+ and Pgrac100-gfp+ allowed GFP expression at high levels from 23 × 104 to 32 × 104 RFU units and 9–13% of total intracellular proteins. We could reconfirm the two major advantages of the new inducer-free expression plasmids: (1) Strong repression of the target gene expression in the E. coli cloning strain, and (2) production of the target protein at high levels in B. subtilis in the absence of the inducer. Conclusions We propose a general strategy to generate inducer-free expression vector by using IPTG-inducible vectors, and more specifically we developed inducer-free expression plasmids using IPTG-inducible promoters in the absence of the LacI repressor. These plasmids could be an excellent choice for high-level production of recombinant proteins in B. subtilis without the addition of inducer and at the same time maintaining a low basal level of the recombinant proteins in E. coli. The repression of the recombinant gene expression would facilitate cloning of genes that potentially inhibit the growth of E. coli cloning strains. The inducer-free expression plasmids will be extended versions of the current available IPTG-inducible expression vectors for B. subtilis, in which all these vectors use the same cognate promoters. These inducer-free and previously developed IPTG-inducible expression plasmids will be a useful cassette to study gene expression at a small scale up to a larger scale up for the production of recombinant proteins.

Introduction: Circulating cell-free RNA (cfRNA) is a potential hallmark for early diagnosis of Alzheimer’s Disease (AD) as it construes the genetic expression level, giving insights into the pathological progress from the outset. Profiles of cfRNA in Caucasian AD patients have been investigated thoroughly, yet there was no report exploring cfRNAs in the ASEAN groups. This study examined the gap, expecting to support the development of point-of-care AD diagnosis. Methods: cfRNA profiles were characterized from 20 Vietnamese plasma samples (10 probable AD and 10 age-matched controls). RNA reads were subjected to dierential expression (DE) analysis. Weighted gene correlation network analysis (WGCNA) was performed to identify gene modules that were significantly co-expressed. These modules’ expression profiles were then correlated with AD status to identify relevant modules. Genes with the highest intramodular connectivity (module membership) were selected as hub genes. Transcript counts of dierentially expressed genes were correlated with key AD measures—MMSE and MTA scores—to identify potential biomarkers. Results: 136 genes were identified as significant AD hallmarks (p < 0.05), with 52 downregulated and 84 upregulated in the AD cohort. 45.6% of these genes are highly expressed in the hippocampus, cerebellum, and cerebral cortex. Notably, all markers related to chronic inflammation were upregulated, and there was a significant shift in all apoptotic markers. Three co-expressed modules were found to be significantly correlated with Alzheimer’s status (p < 0.05; R 2 > 0.5). Functional enrichment analysis on these modules reveals an association with focal adhesion, nucleocytoplasmic transport, and metal ion response leading to apoptosis, suggesting the potential participation of these pathways in AD pathology. 47 significant hub genes were found to be dierentially expressed genes with the highest connectivity. Six significant hub genes (CREB1, YTHDC1, IL1RL1, PHACTR2, ANKRD36B, RNF213) were found to be significantly correla with MTA and MMSE scores. Other significant transcripts (XRN1, UBB, CHP1, THBS1, S100A9) were found to be involved in inflammation and neuronal death. Overall, we have identified candidate transcripts in plasma cf-RNA that are dierentially expressed and are implicated in inflammation and apoptosis, which can jumpstart further investigations into applying cf-RNA as an AD biomarker in Vietnam and ASEAN countries [ABSTRACT FROM AUTHOR]