Overcoming Engineering Challenges to Enable Commercial-Scale mRNA Vaccine Manufacturing

Increasing production capacity may necessitate the facility to cater for higher hazardous area category (e.g., H-Occupancy) design features, such as specialized building construction and potential blast zones. [...]an assessment should cover: * Quantification of flammable material use for production steps, including buffer preparation and LNP storage * Equipment and facility cleaning strategies that contribute to the facility flammable materials inventory * Impact of HVAC design to avoid hazardous atmospheres (e.g., full fresh air), use of local exhaust ventilation (LEV) or fume hoods * Solvent distribution methods (e.g., closed solvent delivery and waste removal systems) * Location of solvent bulk storage outside of the processing area/ facility, and piping in what is necessary plus removing spent solvent in a timely manner (e.g., piped transfer to a waste tank for removal by a specialist contractor). At present, the process cannot be fully single-use, so thought needs to be put into the cleaning and sterilization processes, plus the analytical support infrastructure needed for reusable product-contact surfaces. [...]it is recommended that for each mRNA project, consideration is given to the following aspects to determine the link between the equipment available and the facility design: * Need for custom/proprietary equipment * Independent production rooms with "through-wall" buffer transfer through iris ports in from logistics corridor (Buffer Prep/Hold) * Room electrical classification needs versus process step. * Equipment selection versus electrical and fire code requirements * Benefits and limitations of implementing single-use technologies, given that the process will be hybrid (with stainless steel). [...]the limited capacity for outsourcing of supporting functions, such as facility environmental monitoring or product sterility testing, should be considered during concept design.

Preparing Pandemic Vaccine Capacity

Among the challenges of a pandemic is the need to scale up to billions of doses, at a larger scale than typically needed for vaccines, from raw materials all the way through to the materials for the containers for fill/finish. Having adequate raw materials, building and staffing the facilities, and tech transfer are all keys to success. [...]we can plug into existing infrastructure, including services (gas, water, waste, etc.) as well as analytics and quality labs." Emergent BioSolutions says that its flexible CDMO capacity deployment model can respond quickly to demand fluctuations. The company's facilities in France, Switzerland, and the US are working on the project;at CordenPharma Colorado, unique high-pressure chromatography systems usually used for manufacturing peptides have been reallocated for purifying lipids.

Impact of Pandemic on Permanent Procedures

Conducting virtual audits, conducting effective virtual training, and enhancing communications with suppliers to ensure an uninterrupted supply chain are among the changes implemented to maintain operations, stay compliant, and continue manufacturing medically necessary products. The necessity for virtual audits was to allow companies and regulators to continue to evaluate the compliance stature of manufacturers while respecting stay-at-home and social distancing requirements that prevented in-person site audits. Some of these venues are free, and some require a registration fee. supply chain quality Enhanced communication with suppliers to ensure an uninterrupted supply chain has also become a priority during the pandemic.

Following Guidelines During a Crisis

The guidance states, "These preventative measures can include steps to prepare personnel such as: * "Educating employees on topics such as, in the case of a pandemic, personal hygiene (hand washing and coughing and sneezing etiquette), social distancing, and appropriate use of sick leave * "Encouraging employees to get immunized as appropriate by providing information on local vaccination services or by offering on-site vaccination services, if reasonable * "Providing information for and encouraging employees to develop family emergency preparedness plans * "Reviewing CGMP [current good manufacturing practice] regulations regarding appropriate sanitation practices and restriction of ill or sick employees from production areas (see 21 CFR [Code of Federal Regulations] 211.28)" (2). Examples include: * "Production equipment routine maintenance * "Utility system performance checks and maintenance (e.g., air temperature, lighting, compressed air) * "Environmental monitoring of facilities such as cell culture, harvesting, and purification rooms during production * "Stability testing for certain drug products and components * "Periodic examinations of data and of reserve samples" (2). EMA, Guidance on the Format of the Risk Management Plan (RMP) in the EU-in Integrated Format, EMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2 Human Medicines Evaluation (EMA, 31 October 2018).

Application and mechanism of histamine receptor antagonists in treatment of coronavirus disease 2019: research progress.

The coronavirus disease 2019 (COVID-19) has become a global pandemic. It is urgent to find treatments to control the infection and improve symptoms. Homologous modeling and clinical analyses suggest that histamine receptor antagonists have broad prospects in the treatment of COVID-19. This article introduces the research progress of histamine H1 receptor antagonist combined with azithromycin, histamine H2 receptor antagonist famotidine alone or combined with aspirin, and histamine H1 and H2 receptor antagonists used in combination in the treatment of COVID-19. Finally, the possible mechanism of histamine receptor antagonists in the treatment of COVID-19 was introduced and the application prospect of histamine receptor antagonists in the treatment of COVID-19 was analyzed.Copyright © 2022, Second Military Medical University Press. All rights reserved.

The SARS-CoV-2 Antibody and Drug Research Based on the Structure of the Spike Protein and the Mechanism of Cell Entry.

COVID-19 is a severe acute respiratory syndrome caused by a novel coronavirus, SARS-CoV- 2.COVID-19 is now a pandemic, and is not yet fully under control.As the surface spike protein (S) mediates the recognition between the virus and cell membrane and the process of cell entry, it plays an important role in the course of disease transmission.The study on the S protein not only elucidates the structure and function of virus-related proteins and explains their cellular entry mechanism, but also provides valuable information for the prevention, diagnosis and treatment of COVII)-19.Concentrated on the S protein of SARS-CoV-2, this review covers four aspects: (1 ) The structure of the S protein and its binding with angiotensin converting enzyme II (ACE2) , the specific receptor of SARS-CoV-2, is introduced in detail.Compared with SARS-CoV, the receptor binding domain (RBD) of the SARS-CoV- 2 S protein has a higher affinity with ACE2, while the affinity of the entire S protein is on the contrary.(2) Currently, the cell entry mechanism of SARS-CoV-2 meditated by the S protein is proposed to include endosomal and non-endosomal pathways.With the recognition and binding between the S protein and ACE2 or after cell entry, transmembrane protease serine 2(TMPRSS2) , lysosomal cathepsin or the furin enzyme can cleave S protein at S1/S2 cleavage site, facilitating the fusion between the virus and target membrane.(3) For the progress in SARS-CoV-2 S protein antibodies, a collection of significant antibodies are introduced and compared in the fields of the target, source and type.(4) Mechanisms of therapeutic treatments for SARS-CoV-2 varied.Though the antibody and medicine treatments related to the SARS-CoV-2 S protein are of high specificity and great efficacy, the mechanism, safety, applicability and stability of some agents are still unclear and need further assessment.Therefore, to curb the pandemic, researchers in all fields need more cooperation in the development of SARS-CoV-2 antibodies and medicines to face the great challenge.Copyright © Palaeogeography (Chinese Edition).All right reserved.

Biodegradable Polyester Nanoparticle Vaccines Deliver Self-Amplifying mRNA in Mice at Low Doses

Delivery of self-amplifying mRNA (SAM) has high potential for infectious disease vaccination due to its self-adjuvanting and dose-sparing properties. Yet a challenge is the susceptibility of SAM to degradation and the need for SAM to reach the cytosol fully intact to enable self-amplification. Lipid nanoparticles are successfully deployed at incredible speed for mRNA vaccination, but aspects such as cold storage, manufacturing, efficiency of delivery, and the therapeutic window can benefit from further improvement. To investigate alternatives to lipid nanoparticles, a class of >200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs) that enable efficient delivery of SAM in vitro and in vivo as assessed by measuring expression of SAM encoding reporter proteins is developed. The ability of these polymers to deliver SAM intramuscularly in mice is evaluated, and a polymer-based formulation that yields up to 37-fold higher intramuscular (IM) expression of SAM compared to injected naked SAM is identified. Using the same nanoparticle formulation to deliver a SAM encoding rabies virus glycoprotein, the vaccine elicits superior immunogenicity compared to naked SAM delivery, leading to seroconversion in mice at low RNA injection doses. These biodegradable nanomaterials may be useful in the development of next-generation RNA vaccines for infectious diseases.Copyright © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-kappaB signaling pathway.

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg.kg-1), and positive control sildenafil group (100 mg.kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% +/- 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF- kappaB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF- kappaB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-kappaB and signal transducer and activator of transcription 3 (STAT3) by DYY.Copyright © 2023, Chinese Pharmaceutical Association. All rights reserved.

Study on potential common action and mechanism of Reduning Injection against SARS, MERS and COVID-19 based on network pharmacology and molecular docking technology.

Objective To explore the potential common mechanism and active ingredients of Reduning Injection against SARS, MERS and COVID-19 through network pharmacology and molecular docking technology. Methods The TCMSP database was used to retrieve the chemical components and targets of Artemisiae Annuae Herba, Lonicerae Japonicae Flos and Gardeniae Fructus in Reduning Injection. The gene corresponding to the target was searched by UniProt database, and Cytoscape 3.8.2 was used to build a medicinal material-compound-target (gene) network. Three coronavirus-related targets were collected in the Gene Cards database with the key words of "SARS""MERS" and "COVID-19", and common target of three coronavirus infection diseases were screened out through Venny 2.1.0 database. The common targets of SARS, MERS and COVID-19 were intersected with the targets of Reduning Injection, and the common targets were selected as research targets. Protein-protein interaction (PPI) network map were constructed by Cytoscape3.8.2 software after importing the common targets into the STRING database to obtain data. R language was used to carry out GO biological function enrichment analysis and KEGG signaling pathway enrichment analysis, histograms and bubble charts were drew, and component-target-pathway network diagrams was constructed. The key compounds in the component-target-pathway network were selected for molecular docking with important target proteins, novel coronavirus (SARS-CoV-2) 3CL hydrolase, and angiotensin-converting enzyme II (ACE2). Results 31 active compounds and 207 corresponding targets were obtained from Reduning Injection. 2 453 SARS-related targets, 805 MERS-related targets, 2 571 COVID-19-related targets, and 786 targets for the three diseases. 11 common targets with Reduning Injection: HSPA5, CRP, MAPK1, HMOX1, TGFB1, HSP90AA1, TP53, DPP4, CXCL10, PLAT, PRKACA. GO function enrichment analysis revealed 995 biological processes (BP), 71 molecular functions (MF), and 31 cellular components (CC). KEGG pathway enrichment analysis screened 99 signal pathways (P < 0.05), mainly related to prostate cancer, fluid shear stress and atherosclerosis, hepatocellular carcinoma, proteoglycans in cancer, lipid and atherosclerosis, human T-cell leukemia virus 1 infection, MAPK signaling pathway, etc. The molecular docking results showed that the three core active flavonoids of quercetin, luteolin, and kaempferol in Reduning Injection had good affinity with key targets MAPK1, PRKACA, and HSP90AA1, and the combination of the three active compounds with SARS-CoV-2 3CL hydrolase and ACE2 was less than the recommended chemical drugs. Conclusion Reduning Injection has potential common effects on the three diseases of SARS, MERS and COVID-19. This effect may be related to those active compounds such as quercetin, luteolin, and kaempferol acting on targets such as MAPK1, PRKACA, HSP90AA1 to regulate multiple signal pathways and exert anti-virus, suppression of inflammatory storm, and regulation of immune function.Copyright © 2022 Drug Evaluation Research. All rights reserved.

THE PREVALENCE AND INCIDENCE OF PSORIASIS AND PSORIATIC ARTHRITIS IN ENGLAND FROM 2009-2019: AN OBSERVATIONAL STUDY USING PRIMARY CARE DATA

BackgroundPsoriasis (PsO) and psoriatic arthritis (PsA) can greatly impact quality of life and result in substantial personal and societal costs. Complete and up to date data on the prevalence and incidence of these conditions and whether these change over time and vary by age is important for healthcare service planning so that specialist care and funding can be appropriately allocated.ObjectivesTo determine the prevalence and incidence of PsO and PsA in males and females from 2009-2019 across all age groups in England.MethodsWe used Clinical Practice Research Datalink AURUM, a primary care electronic health record database, including 20% of the English population. The codes used to identify patients with PsO and PsA were selected by rheumatologists and dermatologists and cross-checked with published code lists from other studies to ensure inclusion of all relevant codes. All included patients must have data for at least 1 year before their diagnosis. The annual incidence and point prevalence were calculated from 2009-2019 and stratified by age/sex. The study period ended in 2019 to avoid COVID-19 pandemic affecting results.ResultsThe prevalence of PsO and PsA in males and females increased annually, peaking in 2019 (PsO males 2.41% [95% confidence interval (CI) 2.40, 2.42];PsO females 2.60% [95% CI 2.59-2.61];PsA males 0.20% [95% CI 0.20-0.20];PsA females 0.21% [95% CI 0.21- 0.22]), as illustrated in Table 1. In 2019, the prevalence of PsO and PsA was highest in the over 65 years age group;PsO 4.25% [95% CI 4.22-4.28] and PsA 0.38% [95% CI 0.37-0.38]. The annual incidence (per 100,000 person years) of PsO has gradually decreased in males (from 168 (164-171) in 2009 to 148 (145-151) in 2019) but in females it has been stable with a slight annual decrease (from 180 (177-184) in 2009 to 173 (170-176) in 2019). The annual incidence for PsA has increased in both males and females (13 (12-14) in 2009 and 15 (14-16) in 2019 for males and 12 (11-13) in 2009 and 18 (17-19) in 2019 for females).ConclusionThe increasing prevalence of PsO and PsA highlights the importance of organising healthcare services to meet this need, particularly in the elderly population.ReferencesNIL.Table 1.Prevalence of PsO and PsA from 2009-2019 in EnglandYear20092010201120122013201420152016201720182019Population (n)1073383110910802110318501118036711343299112249341137842211657996119336261223432512420998PsO (n)216841229106239819250667259988268032276804286499295712304568311104PsO prevalence (%, 95%CI)-Male1.98 (1.96-1.99)2.06 (2.05- 2.07)2.13 (2.12-2.14)2.19 (2.18-2.20)2.24 (2.23- 2.25)2.33 (2.32- 2.34)2.37 (2.36- 2.38)2.39 (2.38- 2.40)2.40 (2.39- 2.41)2.40 (2.39- 2.42)2.41 (2.40- 2.42)-Female2.07 (2.05- 2.08)2.14 (2.13- 2.16)2.22 (2.21- 2.23)2.29 (2.28- 2.31)2.35 (2.33- 2.36)2.45 (2.43- 2.46)2.50 (2.49- 2.51)2.53 (2.52- 2.54)2.56 (2.54- 2.57)2.58 (2.56- 2.59)2.60 (2.59- 2.61)PsO incidence (100,000 person years)-Male168 (164-171)158 (155- 162)161 (158-165)153 (150-157)161 (157- 164)156 (153- 159)155 (152- 159)154 (151- 157)153 (150-156)150 (147-153)148 (145-151)-Female180 (177-184)176 (172-179)181 (177-184)171 (167-174)175 (171-178)176 (172-180)179 (176-183)178 (174-181)177 (174-181)174 (170-177)173 (170-176)PsA (n)1444515443164681752218545196182072021994232572451425683PsA prevalence (%, 95%CI)-Male0.14 (0.14- 0.14)0.15 (0.14- 0.15)0.15 (0.15- 0.16)0.16 (0.16- 0.16)0.17 (0.16- 0.17)0.18 (0.17- 0.18)0.18 (0.18- 0.19)0.19 (0.18- 0.19)0.19 (0.19- 0.20)0.20 (0.19- 0.20)0.20 (0.20- 0.20)-Female0.13 (0.13- 0.13)0.14 (0.13- 0.14)0.15 (0.14- 0.15)0.15 (0.15- 0.16)0.16 (0.16- 0.16)0.17 (0.17- 0.18)0.18 (0.18- 0.18)0.19 (0.19- 0.19)0.20 (0.19- 0.20)0.20 (0.20- 0.21)0.21 (0.21- 0.22)PsA incidence (100,000 person years)-Male13 (12- 14)12 (11- 13)13 (12- 14)12 (11- 13)13 (12-14)14 (13- 15)14 (13- 15)14 (13-15)1514-16)14(13- 15)15 (14-16)-Female12 (11- 13)13 (12- 14)13 (12- 14)14 (13-15)14 (13-15)15 (14-16)17 (16- 18)16 (15- 17)17 (16- 18)18 (17-19)18 (17-19)Acknowledgements:NIL.Disclosure of InterestsArani Vivekanantham: None declared, Edward Burn: None dec ared, Marta Pineda-Moncusí: None declared, Sara Khalid Grant/research support from: SK has received research grant funding from the UKRI and Alan Turing Institute outside this work. SK's research group has received grant support from Amgen and UCB Biopharma., Daniel Prieto-Alhambra Grant/research support from: DPA's department has received grant/s from Amgen, Chiesi-Taylor, Lilly, Janssen, Novartis, and UCB Biopharma. His research group has received consultancy fees from Astra Zeneca and UCB Biopharma. Amgen, Astellas, Janssen, Synapse Management Partners and UCB Biopharma have funded or supported training programmes organised by DPA's department., Laura Coates Speakers bureau: LC has been paid as a speaker for AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Medac, Novartis, Pfizer and UCB., Consultant of: LC has worked as a paid consultant for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer and UCB., Grant/research support from: LC has received grants/research support from AbbVie, Amgen, Celgene, Eli Lilly, Novartis and Pfizer.

Opening Up Opportunities in 2023

"The ongoing journey to standardization on more aspects of submission and data exchange will continue to have an impact," he notes. lan Crone, business unit director Europe-fme Life Sciences, which provides business and technology services, points out that the web-based human variations electronic application form (eAF) for centrally authorized products (CAPs) has been available for use since 4 Nov. 2022 on the European Medicines Agency's (EMA's) new product lifecycle management (PLM) portal. Renato Rjavec, Amplexor Life Sciences "Many biopharmaceutical functions have spent the last decade modernizing their base technologies, most often in a cloud/software as a service environment platform that brings foundational benefit to individual functions," states Steve Gens managing partner. Internal productivity and external regulatory requirements are both driving this data connectivity within industry, he adds, which "requires a clear cross functional digitization strategy and focus on cross-functional data governance, master data management, and ensuring all data from these various authoritative systems [are] at the same high level. " "Many biopharmaceutical functions have spent the last decade modernizing their base technologies, most often in a cloud/ software as a service environment platform that brings foundational benefit to individual functions." -

Keeping Europe's Medicines Stocked

[...]best-in-class pharma companies are focusing on reliability and resilience in the supply chain-if they can't make a product or deliver a product on time, a patient is not served, and no sale is made. People can scale to a certain degree but scaling by a factor of 100 is not possible with people in a short period of time and does not deliver on economies of scale. Pharma companies are also issuing 'green bonds' where investors can expect the contribution of capital to improve the company's sustainability.

Balancing Change and Certainty in Manufacturing

According to research, for example, the bio/pharmaceutical manufacturing market should witness compound annual growth in the region of 11% between 2022 and 2027 (2), thanks in part to advancing manufacturing technologies. "Most recently, biopharmaceutical manufacturing has been impacted by pressures on supply chain," specifies Antonio Crincoli, vice president of Engineering, Pharma and Consumer Health, Catalent. [...]there is a focus on quality management systems that ensure data integrity and governance, and that digitization occurs with appropriate validation, also, where necessary, that there is segregation of operating systems to eliminate risk of corruption." Antonio Crincoli, Catalent "PAT and an emphasis on process understanding have been embraced by the majority of pharmaceutical manufacturers, and there are several case studies where both artificial intelligence (Al) and machine learning (ML) have led to improved quality or increased yield, even in good manufacturing practice (GMP) facilities," adds Byrd.

Trial Decline

According to the Association of the British Pharmaceutical Industry (ABPI) there has been a significant decline in the number of industry clinical trials nitiated in the UK. "The COVID-19 pandemic has accelerated the decline in ate-stage industry clinical research in the UK, compared to its global peers," said Richard Torbett, chief executive of the ABPI in a press release (3). Findings from an ABPI report into the state of clinical trials in the UK has shown that consistently slow and variable set up times for clinical trials encountered in the NHS are causing some pharmaceutical companies to look elsewhere for clinical research (4). [...]a close relationship is needed between government and the life sciences sector now more than ever to ensure the country does not fall too far behind its global competitors.

Getting Proactive with Pharma Packaging

According to market research, the pharmaceutical packaging sector is expected to grow at a compound annual rate of 7.4% between 2022 and 2031, reaching an estimated USS178.8 billion (€171.8 billion) by the end of the forecast period (1). "Pharmaceutical waste continues to be a huge problem, so to eliminate non-biodegradable and single-use plastics from the supply chain, more research is taking place around bio-based PET [polyethylene terephthalate]. "By designing a product's primary and secondary packaging well from the outset (including investing ample resources into the process), manufacturers can reduce the amount of materials used and wasted, test new eco materials, ensure safety compliance and efficacy, and benefit from cheaper transportation costs," Quelch surmises. [...]pharma companies can benefit from a packaging supplier with a true global footprint," he says.

Connecting the Dots for Pharma

A major driver for innovation within the bio/pharma sector has been the COVID-19 pandemic, which propelled advances such as the approval of messenger RNA (mRNA) vaccines at record-breaking speeds and led to many companies pivoting to deal with the urgent requirements for capacity and supply chain flexibility needed to overcome pandemic challenges. "Before deciding on a location, we conducted extensive market research, and it quickly became clear, just by the sheer proximity of so many biopharmaceutical companies, associations, and research centres, that the event had to be in Geneva. Organized as four half-days, they will each address a theme related to the four main areas of the supply chain present in the exhibition area: pharmaceutical packaging (primary and secondary), medical devices, pharmaceutical sub-contracting, and pharmaceutical equipment. The dream scenario, the real measure of success, is when a product comes to market that happened as a result of a meeting or discussion that took place at our event.

Cold Comfort for Bio/Pharma

The COVID-19 pandemic highlighted how vital cold chain is for the pharmaceutical industry, particularly as some vaccines needed to be produced, transported, and stored at -70 °C. Market projections for cold chain logistics of pharmaceuticals are projected to grow at a compound annual growth rate of 9.03% by 2025, which is reported to be driven by greater global demand for pharmaceuticals, increasing initiatives to promote cold chain, and more demand for reefer containers from the pharma industry (1). Gilmore (Tower Cold Chain): Putting the European success of the COVID-19 vaccine rollout to one side, the demand for effective temperature-controlled packaging solutions in the pharmaceutical supply chain has increased significantly in recent years. Today, the cold chain is grappling with additional challenges: serving a global market, driving out costs and waste, addressing capacity and resource constraints, and dealing with continually mounting regulations-all whilst handling valuable pharmaceutical cargo. Cold chain logistics providers must invest in the latest on-board equipment built into containers to track temperature and location, and to make data available to partners and customers in real time, to prevent or mitigate loss.