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.

RHEUMATOID ARTHRITIS FLARE FOLLOWING COVID-19 VACCINATION IN MALAYSIAN POPULATION AND ITS ASSOCIATED RISK FACTORS

BackgroundFlare of Rheumatoid Arthritis (RA) following COVID-19 vaccination has been reported with a low occurrence observed in those patients with disease remission. However, no local data is available in our multi-ethnic Malaysian population.ObjectivesTo evaluate the prevalence of RA flare in Malaysian patients following COVID-19 vaccination and its associated risk factors.MethodsThis was a cross-sectional study assessing RA flare based on patient-reported disease flare through self-administered questionnaires and physician-reported flare. Patient self-reported disease flare was defined as ‘a sudden worsening of rheumatology condition or arthritis within 1 month post-vaccination' while physician-reported flare was defined as ‘an increment of disease activity score 28-joint documented within 3 months post-vaccination‘ from either a scheduled or unscheduled clinic visit. A total of 186 RA patients attended the rheumatology clinic in Hospital Putrajaya from May to July 2022 who completed the primary COVID-19 vaccination under the Malaysian National Vaccination Programme were recruited. Demographic data, disease parameters including serology for rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA), cessation of disease modifying anti-rheumatic drugs (DMARDs) around vaccination, type of vaccines and adverse events were examined using descriptive and univariate analyses.ResultsMajority (93%) of RA patients enrolled were female with a mean age of 58 years old (standard deviation, SD 12.2) and mean disease duration was 12 years (SD 7.7). More than half were seropositive (66% RF, 63% ACPA) with 47.4% had double seropositivity (RF and ACPA positive). All patients received DMARDs with the majority (71%) were on methotrexate (MTX), 21.5% were on leflunomide, 17.7% on other DMARDs, with a small proportion (14%) of patients were receiving prednisolone. Only 4.8% of patients were on biologics or targeted synthetic disease modifying anti-rheumatic drugs. Half of the patients were in remission prior to vaccination. 62% of patients received Pfizer-BioNTech vaccine as the primary vaccine, followed by Sinovac-CoronaVac (24.6%) and Oxford-AstraZeneca (13.4%) vaccines. A booster dose had been administered to 80% of patients, of which 88.7% was Pfizer-BioNTech vaccine. MTX therapy were discontinued in 39.4% of patients (n=52) post-vaccination for a week duration. The prevalence of RA flare was only 12.9% (n=24) in which 14 were self-reported and 10 were physician-reported flares (4 severe flare, 6 mild-moderate flare). Flare rates were higher during the first and second dose of vaccination with 29.2% respectively, and only 12.5% were reported after booster vaccination. Common vaccine adverse effects were fever (16.8%), myalgia (8.6%) and arthralgia (6.4%). There were no significant differences in the occurrence of flare post-vaccination between age, gender, disease activity prior to vaccination, types of vaccine, usage of MTX and prednisolone, and discontinuation of MTX post-vaccination. Although seropositivity did not exhibit statistically significant flare rate post vaccination, sub-analysis revealed four times higher rate of flare in those who has double positivity compared to seronegative RA patients (12% vs 4%).ConclusionPrevelance of RA flare post-COVID-19 vaccination in Malaysian RA population is low. No significant associated risk factors were identified although double seropositivity appeared to have higher number of flares.References[1]Bixio, R., Bertelle, D., Masia, M., Pistillo, F., Carletto, A. and Rossini, M. (2021), Incidence of Disease Flare After BNT162b2 Coronavirus Disease 2019 Vaccination in Patients With Rheumatoid Arthritis in Remission. ACR Open Rheumatology, 3: 832-833.[2]Li X, Tong X, Yeung WWY, Kuan P, Yum SHH, Chui CSL, Lai FTT, Wan EYF, Wong CKH, Chan EWY, Lau CS, Wong ICK. Two-dose COVID-19 vaccination and possible arthritis flare among patients with rheumatoid arthritis in Hong Kong. Ann Rheum Dis. 2022 Apr;81(4):564-568.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

THE KINETICS OF HUMORAL AND CELLULAR RESPONSES AFTER THE BOOSTER DOSE OF COVID-19 VACCINE IN INFLAMMATORY ARTHRITIS PATIENTS

BackgroundImpaired immunogenicity of COVID-19 vaccinations in inflammatory arthritis (IA) patients results in diminished immunity. However, optimal booster vaccination regimens are still unknown, due to unstudied kinetics of the immune response after booster vaccinations.ObjectivesThis study aimed to assess the kinetics of humoral and cellular responses in IA patients after the COVID-19 booster.MethodsIn 29 IA patients and 16 healthy controls (HC) humoral responses (level of IgG antibodies) and cellular responses (IFN-γ production) were assessed before (T0), after 4 weeks (T1), and after more than 6 months (T2) from the booster vaccination with BNT162b2.ResultsIA patients, but not HC, showed lower anti-S-IgG concentration and IGRA fold change at T2 compared to T1 (p=0.026 and p=0.031). Furthermore, in IA patients the level of cellular response at T2 returned to the pre-booster level (T0). All immunomodulatory drugs, except IL-6 and IL-17 inhibitors for the humoral and IL-17 inhibitors for the cellular response, impaired the immunogenicity of the booster dose at T2. However, none of the immunomodulatory drugs affected the kinetics of both humoral and cellular responses (measured as the difference between response rates at T1 and T2).ConclusionOur study showed impaired kinetics of both humoral and cellular responses after the booster dose of the COVID-19 vaccine in IA patients, which, in the case of cellular response, did not allow the vaccination effect to be maintained for more than 6 months. Repetitive vaccination with subsequent booster doses seems to be necessary for IA patients.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Taking an Alternative Approach to Drug Delivery

Increased awareness of the carbon footprint associated with pharmaceutical products and the replacement of high global warming potential (GWP) constituents used in the final product, or within the manufacturing process, may drive further diversification of formulation approaches in the future. [...]the nose offers an opportunity to deliver drugs directly to the brain or central nervous system (CNS) via the olfactory pathway. Two relatively recent commercializations for intranasal delivery are naloxone nasal spray to treat suspected opioid overdose emergencies and diazepam nasal spray for short term rescue treatment of seizure clusters. [...]in cystic fibrosis, the overproduction of mucus and alteration of mucus properties, represents a challenge for effective drug delivery by inhalation alone.

EFFECTS OF DMARD TREATMENT ON SARS-CoV-2 mRNA VACCINATION IN PATIENTS WITH SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASE: A MATCHED, PROSPECTIVE COHORT STUDY

BackgroundPatients suffering from systemic autoimmune rheumatic disease (SARD) display poor antibody development after two doses of mRNA vaccinations leaving these patients with only limited humoral protection against severe SARS-CoV-2 disease courses. Of key interest is the effect of conventional synthetic (csDMARD) and biological/ targeted drugs (b/tsDMARDs) disease modifying antirheumatic drugs on the time of protection.ObjectivesTo compare antibody titer development in patients with vasculitis and connective tissue disease (CTD) with healthy controls 6 months after two mRNA vaccinations and after third immunization. To analyze factors, that affect the velocity of titer decline, well as qualitative humoral response.MethodsPatients with SARD were enrolled and matched for gender and age with healthy control subjects (HC) and the humoral response after 6 months to two doses of mRNA vaccine BNT162b2 in terms of SARS-COV-2 antibody titer was assessed. In addition to binding antibody units (BAU) we also analyzed neutralizing antibodies. Patients receiving B-cell depleting therapy and those with prior SARS-CoV-2 infection (via detection of nucleocapsid antibodies) were excluded. Differences between two groups were calculated with Wilcoxon signed-rank test.ResultsA total of 53 patients with SARD (42 patients suffering from connective tissue disease and 11 with vasculitis respectively) and 73 HC were analysed. Interestingly only patients receiving a combination therapy of different csDMARDs/ b/tsDMARDs demonstrated diminished antibody titers 6 months after two doses of mRNA vaccine (p-value p-value<0,001), whereas patients receiving only csDMARD as monotherapy displayed comparable antibody levels to healthy controls. This effect was equalized after a third booster vaccination (p-value=0,13). Concerning disease entities, patients with vasculitis seemed to have lower BAU than HC (p-value<0,05) and patients suffering from CTD. After third vaccination both patient groups had lower antibody levels than HC (vasculitis: p-value <0,0001;CTD: p-value p-value<0,01). Lower antibody levels before third vaccination correlated with lower antibodies after third immunization.ConclusionPatients with autoimmune rheumatic diseases undergoing combination therapy may be more vulnerable to SARS-CoV-2 infection, due to reduced antibody levels 6 months following two doses of mRNA vaccine. Our data strongly recommends antibody measurements in patients receiving combination therapy and individualized earlier booster vaccination.Figure 1.Anti-SARS-Cov-2 S antibody titers. A: Antibody titers measured 6 months after two doses of mRNA vaccination in patients with connective tissue disease, vasculitis and healthy controls. B, Antibody levels according to disease entity. AB: antibody;BAU: binding antibody unit;CTD: connective tissue disease;HC: healthy control;mono: disease modifying anti-rheumatic drug monotherapy;combination: combination therapy of disease modifying anti-rheumatic drugs;RBD: receptor binding domain;[Figure omitted. See PDF]Table 1.Demographic parameters and therapy of study participants.SARD (n=53)HC (n=73)Age, mean (standard deviation)53.55 (±14.04)51.27 (±14.07)Female45 (84.9%)47 (64.4%)Connective tissue disease42 (79%)Vasculitis11 (21%)csDMARD or b/tsDMARD monotherapy22 (41%)csDMARD and/or b/tsDMARD combination therapy13 (25%)No therapy18 (34%)Methotrexate8 (15%)Mycophenolate mofetil10 (19%)Hydroxychloroquine17 (32%)Azathioprine8 (15%)Belimumab3 (6%)Tocilizumab3 (6%)Glucocorticoid dose 1. vaccination, mean (standard deviation)2.8 (±10.8)Glucocorticoid dose 2. vaccination, mean (standard deviation)2.6 (±10.7)SARD: Systemic autoimmune rheumatic disease, HC: Healthy controls, csDMARD: conventional synthetic disease modifying antirheumatic drugs and b/tsDMARD: biological/ targeted drugs disease modifying antirheumatic drugsREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsElisabeth Simader Speakers bureau: Lilly, Thomas Deimel: None declared, Felix Kartnig: None declared, Selma Tobudic: None declared, Helmuth Hasla her Grant/research support from: Glock Health, BlueSky Immunotherapies and Neutrolis, Thomas Maria Karonitsch: None declared, Daniel Mrak: None declared, Thomas Nothnagl: None declared, Thomas Perkmann: None declared, Helga Lechner-Radner: None declared, Judith Sautner: None declared, Florian Winkler: None declared, Heinz Burgmann Speakers bureau: speaker fees from Shionogi, Pfizer, MSD, Paid instructor for: advisory boards for Valneva, MSD, Gilead, Consultant of: consulting fees from MSD, Pfizer, Takeda, Gilead, Daniel Aletaha Speakers bureau: other from Abbvie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Grant/research support from: grants from Abbvie, Amgen, Lilly, Novartis, Roche, SoBi, Sanofi, Stefan Winkler: None declared, Stephan Blüml Speakers bureau: personal fees from Abbvie, personal fees from Novartis, Peter Mandl Speakers bureau: reports speaker fees from AbbVie, Janssen and Novartis, Grant/research support from: research grants from AbbVie, BMS, Novartis, Janssen, MSD and UCB.

Vaccine Administration: The Growing Role of Prefilled Syringes

(Note: The MIDAS database reflects vaccine doses that are dispensed with a prescription in retail or hospital settings, so the COVID-19 vaccines and other public-health-administered vaccines are not fully reflected in that data set.) Stamoran adds, "However, across the rest of the world, vial-based vaccines still make up the majority of the volume dispensed." [...]there is plenty of room for growth for this newer administration device. [...]PFS are now widely used for annual flu shots, heparin injections, and a growing list of injectable therapies across multiple disease states. According to a 2021 article authored byGuillaume Lehee, R&D Innovation Leader for BD Medical-Pharmaceutical Systems, the use of PFS to vaccinate 300 million individuals in the United States in the event of a future pandemic could save more than three million hours of healthcare practitioners' time (1). [...]today's PFS are not yet proven to be compatible with ultrafrozen temperatures as the existing glass materials and other components may not stand up to the extremely low required temperatures," explains Stamoran.

Track-and-Trace Progress Benefits Supply-Chain Security Efforts

COVID-19 vaccines, approved under emergency use authorization, were not required to meet serialization requirements, but they have been properly labelled to meet US Food and Drug Administration (FDA) requirements, he says, complete with 2D barcodes with GTIN, lot, and expiry date. The company decided to serialize its Diprovan anesthetic, a workhorse generic product, using radio frequency identification tags containing the four identifiers (2). "If an agent is handling your product on your behalf, they need to leverage GS1 Standards including GTINs for products [and] global location numbers (GLNs) for physical locations, and share data electronically using electronic product code information services (EPCIS) to capture events from manufacturing to serialization [and] capping to shipping.

COVlD-19 vaccine Distribution: Preparing for the Unexpected

In December 2020, two shipments of the vaccine experienced temperature excursions in which product was actually kept at overly cold temperatures (3). Urgent need to protect data One problem that vaccine developers and regulatory agencies need to address is the urgent need to protect data, says Nigel Thorpe, technology director with Secure Age, which specializes in enterprise data encryption using a public key infrastructure platform. For operators on the plant floor, the efforts required are fraught with potential error, especially during shift changes, says Jim Evans, director of Verista, Inc.'s vision, connectivity, and automation division. Raw materials The speed with which vaccines have been developed and are being distributed pose important questions centred around variability. If we're having a raw materials shortage when the vaccines haven't even been scaled up, what will happen when they get full approval?" he asks.

Improving Agility Through Scalability

Miniaturized, modular, and continuous manufacturing processes will help speed scale-up, address supply chain complexity, and prevent shortages of important medications, Janet Woodcock, director of the United States Food and Drug Administration's (FDA's) Centre for Drug Evaluation and Research (CDER), noted during a meeting of the US National Academy of Sciences (NAS) in late February 2020. Describing the research at the NAS meeting (2), Rao said his team has conducted a demonstration project involving Neupogen (filgrastim) and is working with GE on development of remote bioreactor sensors to monitor analytes, oxygen, and carbon dioxide in smallscale systems in real time (2). [...]since research results were first published, he notes, robotics have been improved, and now include integrated online measurement systems using infrared (IR), FourierTransform IR, and high-pressure liquid chromatography and mass spectrometry so that key parameters can be measured in real-time, permitting online process monitoring as well as process optimization. Use of Raman and nuclear magnetic resonance (NMR) spectroscopy, refractive index, excipient identification, metabolite monitoring, and cell counts has now become routine, in both process development and manufacturing, says Christy.

IMPROVING PATIENT SAFETY THROUGH THE ESTABLISHMENT OF A PHARMACIST-LED BLOOD MONITORING CLINIC FOR JAK INHIBITORS IN RHEUMATOLOGY

BackgroundJanus kinase inhibitors drugs (JAKi) are novel small molecule medications known to cause abnormalities such as elevations in hepatic transaminases, decreases in neutrophil and lymphocyte counts and elevations in cholesterol and creatinine kinase. Blood monitoring is recommended and dose adjustments are advised if abnormalities arise. Recent warnings by the EMA and MHRA have highlighted the importance of monitoring these medications.Timely review and management of patients on JAKi drugs is difficult to maintain with increasing workload amongst the rheumatology team. A baseline audit (2020) demonstrated that hospital blood monitoring guidelines for JAKi drugs were not being followed. The rheumatology multidisciplinary team met and utilised Quality Improvement methodology including fish and driver diagrams to address this. This led to the creation of a pharmacist-led JAKi blood monitoring clinic.ObjectivesTo establish a pharmacist-led rheumatology blood monitoring clinic for the JAKi drug class in order to: increase patient safety with increased compliance to blood monitoring, save consultant/nurse time, improve communication with primary care on the frequency of blood testing required, increase patient understanding of the importance of blood monitoring with JAKi drugs, reinforce counselling advice such as risk of infections, shingles and thrombosis and promote medication adherence.MethodsThe clinic was established in March 2021. Patients commencing JAKi drugs are referred to the pharmacist-led clinic by the medical team. The pharmacist contacts the patient by phone following delivery of their medication. The patient is counselled on their new medication and dates for blood checks are agreed. A letter is sent to the patient and their GP providing this information. The patient is booked into virtual telephone appointments and bloods are monitored every month for the first 3 months and every 3 months thereafter. Any change or abnormality in blood results are flagged early in the patient's treatment and if necessary, discussed with the consultant. Adjustments are made to the patient's dose if appropriate.ResultsIn order to evaluate the benefit of the pharmacist clinic a re-audit of compliance with blood monitoring (March 2021- September 2022) was carried out alongside a patient satisfaction postal survey (August 2022).A total of 58 patients were sampled in the re-audit. The re-audit found an increase in compliance in blood monitoring since the introduction of the pharmacist clinic. 98% of patients had their full blood count performed at 3 months compared to 56% in audit 1 and 95% of patients had their lipid profile completed at 3 months compared to 15% in audit 1 (Table 1).A patient satisfaction survey (N=62, response rate 48%) found that 28 (93%) patients either agreed or strongly agreed that they were more aware of the importance of attending for regular blood monitoring when prescribed JAKi therapy as a result of the clinic.The pharmacy team made several significant interventions (self-graded Eadon grade 4 and 5). For example by improving medication adherence, detecting haematological abnormalities that required JAKi dose reduction, identifying patients suffering from infection requiring intervention including shingles and Covid-19.Table 1.Comparison of audit results pre (Audit 1) and post (Audit 2) clinic establishmentAudit 1 (N=48)Audit 2 (N=58)Number of patients with full blood count completed at weeks 4, 8 & 1227 (56%)57 (98%)Number of patients with lipid profile completed at week 127 (15%)55 (95%)Number of patients LFTs completed at weeks 4, 8 & 1226 (54%)54 (93%)ConclusionIntroduction of the pharmacist-led clinic has increased patient safety by ensuring compliance with blood monitoring as per hospital guidelines. The clinic has paved the way for improved communication with primary care teams and has provided patients with extra support during their first months on treatment with their JAKi. It has also expanded the role of the rheumatology pharmacy team and saved nursing and medical time.Acknowled ementsI wish to thank the SHSCT Rheumatology team for all their help, support and guidance with this project.Disclosure of InterestsNone Declared.

New Biotherapies Push Tecmological Innovation Forward

[...]on the positive side, innovations in the use of synthetic raw materials and disposable equipment are expected to enhance manufacturing process development, she says. "The AttenuBlock platform incorporates 10 years of research and development at Emory University, where researchers employed rational and precise codon deoptimization and other genetic strategies to produce hundreds of targeted mutations into the RSV genome, providing exquisite control over viral protein expression," Moore explains. [...]the dose of a live attenuated vaccine is typically much lower than all the other non-replicating vaccine types, including genetic (RNA/DNA), viral vectors, protein subunit, inactivated, and virus-like particles (VLPs). [...]to meet global supply and demand, Meissa is implementing straightforward, economical, and scalable vaccine manufacturing technologies, Moore says. [...]licensed VLP vaccines are extremely effective.

EFFICACY AND SAFETY OF ABBV-599 HIGH DOSE (ELSUBRUTINIB 60 MG AND UPADACITINIB 30 MG) AND UPADACITINIB MONOTHERAPY FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS: A PHASE 2, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

BackgroundABBV-599 is a novel combination of elsubrutinib (ELS;a selective BTK inhibitor) and upadacitinib (UPA;a JAK inhibitor) that targets non-overlapping signaling pathways associated with systemic lupus erythematosus (SLE).ObjectivesTo report results from SLEek, a phase 2, randomized, placebo (PBO)-controlled, parallel-group, multicenter study evaluating efficacy and safety of ABBV-599 and UPA monotherapy in adults with moderately to severely active SLE (NCT03978520).MethodsPatients (pts) were randomized 1:1:1:1:1 to once daily (QD) ABBV-599 high dose (HD;ELS 60 mg + UPA 30 mg), ABBV-599 low dose (LD;ELS 60 mg + UPA 15 mg), ELS 60 mg, UPA 30 mg, or PBO. The primary endpoint was the proportion of patients at W24 achieving SLE Responder Index-4 (SRI-4) and steroid dose ≤ 10 mg QD;additional efficacy and safety endpoints through W48 are also reported. The pre-specified 2-sided alpha level was 0.1.Results341 patients were enrolled. After a planned interim analysis when 50% of pts reached W24, the ABBV-599LD and ELS 60 mg arms were discontinued for lack of efficacy (no safety concerns). Of 205 continuing pts (ABBV-599HD n = 68, UPA 30 mg n = 62, PBO n = 75), baseline characteristics were well balanced. The primary endpoint (proportion achieving SRI-4 and steroid dose ≤ 10 mg QD at W24 vs PBO) was met by ABBV-599HD and UPA 30 mg. Key secondary endpoints were also achieved at W48 in both groups (Table 1). Overall flares and time to first flare were substantially reduced in the ABBV-599HD and UPA 30 mg groups through W48 (Figure 1). Anti-double stranded DNA antibodies were significantly decreased with both treatments. TEAEs considered related to study drug were 42.6% ABBV-599HD, 32.3% UPA 30 mg, and 33.3% PBO. There were no malignancies or VTE. There were 3 non-fatal CV events (1 MI on PBO and 2 ruptured cerebral aneurysms [1 each on ABBV-599HD and UPA 30 mg]);all were assessed as unrelated to study drug by investigators. No new safety signals were observed beyond previously known data for UPA or ELS.ConclusionABBV-599HD (ELS 60 mg + UPA 30 mg) and UPA 30 mg demonstrated significant improvements in SLE disease activity and flares with acceptable safety through 48 weeks.Table 1.Key Endpoints at Week 48PBO (n = 75)ABBV-599HD (n = 68)UPA 30 mg (n = 62)SRI-4 and steroid dose ≤ 10 mg QD, n (%) [95% CI]a24 (32.0) [21.4, 42.6]33 (48.5) [36.7, 60.4]*27 (43.5) [31.2, 55.9]SRI-4, n (%) [95% CI]a24 (32.0) [21.4, 42.6]35 (51.5) [39.6, 63.3]*28 (45.2) [32.8, 57.5]+BICLA, n (%) [95% CI]a19 (25.3) [15.5, 35.2]33 (48.5) [36.7, 60.4]***33 (53.2) [40.8, 65.6]***LLDAS, n (%) [95% CI]a18 (24.0) [14.3, 33.7]27 (39.7) [28.1, 51.3]*31 (50.0) [37.6, 62.4]***Joint-Count 50 in patients with ≥ 6 affected joints at baseline, n/n (%) [95% CI]a26/59 (44.1) [31.4, 56.7]37/58 (63.8) [51.4, 76.2]*34/59 (57.6) [45.0, 70.2] +CLASI-50 in patients with baseline CLASI ≥ 10, n/n (%) [95% CI]a5/14 (35.7) [10.6, 60.8]6/12 (50.0) [21.7, 78.3]5/8 (62.5) [29.0, 96.0]*Change from baseline in steroid dose, mg, LS mean (SE)b−1.5 (0.5)−1.5 (0.5)−1.2 (0.5)SFI, events/patient-years (95% CI)c Overall flares2.8 (2.4, 3.3)1.5 (1.2, 1.9)***2.0 (1.6, 2.4)** Mild/moderate flares2.5 (2.1, 2.9)1.3 (1.0, 1.6)***1.9 (1.5, 2.3)* Severe flares0.3 (0.2, 0.5)0.2 (0.1, 0.3)0.2 (0.1, 0.3) +Time to first flare by SFI, days, median (Q1, Q3)c141 (57, NE)312 (114, NE)*311 (99, NE)**BILAG-based flare rate, estimated incidence ratec0.570.19*0.26Data are presented for the full analysis set.aMissing data imputed using NRI incorporating multiple imputation to handle missing data due to COVID 19.bMissing data imputed using MMRM.cObserved data w/o imputation.+P <.1;*P <.05;**P <.01, ***P <.001 vs PBO.ABBV-599HD, elsubrutinib 60 mg QD and UPA 30 mg QD;CLASI-50, ≥ 50% reduction in CLASI activity score;Joint-Count 50, ≥ 50% improvement in tender or swollen lupus joints;LLDAS, Lupus Low Disease Activity State;NE, not estimated;PBO, placebo;SFI, SELENA SLEDAI Flare Index;UPA, upadacitinib.AcknowledgementsAbbVie and the authors thank the patients who particip ted in the study and all study investigators for their contributions. Medical writing assistance, funded by AbbVie, was provided by Callie A S Corsa, PhD, of JB Ashtin.Disclosure of InterestsJoan T Merrill Consultant of: AbbVie, Alexion, Alumis, Amgen, Astra Zeneca, Aurinia, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, GlaxoSmithKline, Lilly, Merck, Pfizer, Provention, Remegen, Sanofi, UCB, and Zenas, Grant/research support from: Astra Zeneca, Bristol Myers Squibb, and GlaxoSmithKline, Yoshiya Tanaka Speakers bureau: AbbVie, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Gilead, Lilly, Mitsubishi-Tanabe, and Pfizer, Grant/research support from: AbbVie, Asahi-Kasei, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, and Takeda., David d'cruz Consultant of: GlaxoSmithKline, Lilly, and UCB., Karina Vila Consultant of: AbbVie, Daniel Siri Grant/research support from: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Gilead, Hoffman Laroche, Jansen, Lilly, and Sanofi, Xiaofeng Zeng: None declared, Kristin D'Silva Shareholder of: AbbVie, Employee of: AbbVie, Ling Cheng Shareholder of: AbbVie, Employee of: AbbVie, Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, Thao Doan Shareholder of: AbbVie, Employee of: AbbVie, Denise Kruzikas Shareholder of: AbbVie, Employee of: AbbVie, Alan Friedman Shareholder of: AbbVie, Employee of: AbbVie.

Early-Stage Considerations for the Manufacture and Delivery of Vaccines

Vials are versatile;in addition to liquids, they can be used to package lyophilized and cryogenic products, as well as those in powder form. If there are stability issues, reformulation will be required;this decision will be influenced by the nature of the vaccine, preferred shipping methods, and the container options. In-house manufacture may require investment in new capacity for a dedicated line for mass production of a single product or a flexible filling operation that can handle multiple products and different size vials. Depending on the future global needs for vaccinations, prefilled syringes may gain a significant market share.

Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data

ObjectiveTo assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen.DesignComparative observational study using data collected from routine care.SettingFour French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020.Participants181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care.InterventionsHydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group).Main outcome measuresThe primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting.ResultsIn the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment.ConclusionsHydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.

FREQUENCY OF DISEASE FLARE AND ITS RISK FACTORS FOLLOWING TWO-DOSE OF COVID-19 VACCINATION IN PATIENTS WITH RHEUMATOID ARTHRITIS

BackgroundAmid the coronavirus disease 2019 (COVID-19) crisis, two messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have benefitted most people worldwide. However, the safety of vaccine has not been established in patients with rheumatic arthritis (RA). Previous studies reported that flares of underlying RA following SARS–CoV-2 vaccination were not so frequent, and there was no report of severe flare. However, those reports did not assess patients' disease activity with validated disease activity measures and described only simple self-reported questionnaires. Hence, the effect of vaccination on disease activity in patients with RA is still unclear. Understanding the association between arthritis flare in patients in RA and vaccination is important to overcome vaccine hesitancy.ObjectivesTo clarify the effect of SARS-CoV-2 vaccination on disease activity in patients with RA and identify risk factors associated with RA flares following the vaccination.MethodsThis is a prospective cohort study in patients with rheumatic musculoskeletal disease including RA who received the SARS-CoV-2 mRNA vaccines BNT162b2 or mRNA-1273 from March 16, 2021, at Keio University Hospital. The disease activity was evaluated with disease activity score for 28 joints using C-reactive protein (DAS28), simplified disease activity index (SDAI), and clinical disease activity index (CDAI) before vaccination and after second vaccination (within two months). RA flare was defined as ΔDAS28-CRP>0.6with requirement of treatment intensification. All analysis in this study was carried out with JMP.ResultsWe enrolled 318 patients with RA in this analysis. The mean age was 61 years old, and 283 (89%) were female. The mean DAS28-CRP before vaccination and after 2nd dose of vaccination were 1.70±0.71 and 1.78±0.81, respectively (p=0.84). The increase in DAS28-CPR after vaccination > 0.6 was observed in 53 patients (16.7%), and among them, 23 patients (8.2%) needed treatment intensification. The types of SARS-CoV-2 vaccine, humoral immunogenicity including neutralizing antibody titer and its adverse effects including systemic reaction (fever or general fatigue) were not different between the flare and non-flare groups (9.8 vs 9.1 IU/mL, p=0.88;31.2% vs 18.7%, p=0.32, respectively). In the flare group, swollen joint counts (SJC), hourly erythrocyte sedimentation rates, DAS28-CRP, and SDAI were significantly higher than those in the non-flare group (0.5 vs 0.0, p<0.000;13 vs 11 mm/h, p=0.01;1.57 vs 1.45, p<0.001;3.9 vs 2.4, p=0.02, respectively). Multivariable logistic regression analysis revealed that the number of swollen joints before vaccination contributed RA exacerbation after SARS-CoV-2 vaccination significantly (odds ratio 1.3, 95% confidence interval 1.06-1.65, p=0.01). The receiver operating curve analysis identified that having two or more swollen joint counts predicts RA flares after vaccination with an area under the curve of 0.64, a sensitivity of 42.3%, and a specificity of 86.9%.ConclusionDisease flare with requirement of treatment intensification is observed in 8.2% of patients with RA. Patients with higher disease activity, especially having two or more swollen joint counts are at high risk of flare following mRNA SARS-CoV-2 vaccination.Reference[1]Connolly CM, Ruddy JA, Boyarsky BJ, et al. Disease Flare and Reactogenicity in Patients With Rheumatic and Musculoskeletal Diseases Following Two-Dose SARS-CoV-2 Messenger RNA Vaccination. Arthritis Rheumatol. 2022;74(1):28-32. doi: 10.1002/art.41924. Epub 2021 Dec 3.Figure 1.Risk factors associated with RA flares after vaccination[Figure omitted. See PDF]Acknowledgements:NIL.Disclosure of InterestsNone Declared.

EDQM Combats COVID-19 and Makes Plans for Future

Developers can take them into account to help build appropriate analytical control strategies for their COVID-19 candidate vaccines and ensure the quality and safety of the final product," says Keitel. For USP, building trust in the effectiveness of COVID19 vaccines and treatments, ensuring global access to these treatments, and combating falsified and substandard medicines are the focus, according to Fouad Atouf, PhD, vice president, USP Global Biologics. [...]for existing and new therapies, USP compendial tests and methods address common issues shared by all drug manufacturers, such as suitability, validation, contamination control, stability testing, and qualification of raw materials," Atouf adds. -

DETECTION OF SARS COV-2 ANTIBODIES FOLLOWING VACCINATION IN PATIENTS WITH RHEUMATIC MUSCULOSKELETAL DISEASE (DECODIR) – A REPORT FROM A DANISH PROSPECTIVE COHORT STUDY

BackgroundThe COVID-19 pandemic caused concerns whether patients with rheumatic musculoskeletal disease (RMD) treated with conventional (cs) or biologic (b) disease modifying drugs (DMARDs) and/or prednisolone exhibit an adequate immune response to the applied SARS-CoV2 vaccines.ObjectivesWe established the DECODIR study to assess and compare the efficacy of the SARS-CoV2 vaccines administered as part of the national vaccine roll-out: BNT162b2 vaccine (Pfizer/BioNTech) and mRNA-1273 vaccine (Moderna). The vaccines were offered as two doses four weeks apart;followed by a booster vaccination six months later. This national regimen included inflammatory rheumatic patients regardless of their respective anti-inflammatory treatment. We used patients' SARS-CoV2 IgG serum level as proxy for vaccination response (1).MethodsThe study was conducted as a longitudinal prospective cohort study. Patients with rheumatoid arthritis (RA), spondyloarthropathies (SpA) or psoriatic arthritis (PsA) receiving their outpatient treatment at the Danish Hospital for Rheumatic Diseases, Sonderborg, and monitored in the Danish DANBIO registry, were included.Blood samples, Disease activity and treatment information (cs/bDMARD, prednisolone) were collected at baseline (i.e. prior to vaccination), after six weeks, six and twelve months. SARS-CoV-2 IgG levels in serum were assessed by ELISA (Thermo-Fischer), and manufacturer's cut-off (>=10 EliA U/mL) selected as definition of sufficient IgG response. Antibody response was measured and compared at all four time points.Associations between antibody response, age, gender, disease (RA/PsA/SpA), treatment (none, cs/bDMARD or prednisolone) and disease activity were tested using proportional odds regression and bootstrapped tests of medians. Results were reported using mean, median (IqR) and bootstrapped 95% confidence interval (CI) of the median.ResultsA total of 243 patients were included at baseline and all were followed-up after six weeks;data from 233 patients were available at six months and for 229 patients at twelve months' follow-up. Those 229 patients had completed the national vaccination programme.The measurements performed 6 months after baseline demonstrated a per se decrease of IgG levels for the whole study population (median of 2.08 EliA U/mL at 6 months vs. 16 EliA U/mL at 6 weeks). The final measurements performed after twelve months demonstrated a significant increase of IgG levels. Thus, the completed vaccination programme, was followed by a significant increase in IgG levels (median of 100 EliA U/mL at twelve months vs. 16.5 EliA U/mL at six months, p < 0.001).Sufficient response rates were now recorded in all treatment scenarios, also in patients treated with prednisolone or combination of csDMARD and bDMARD. These two groups were at 6 months characterized by significant lower response rates, when compared with patients without any DMARD treatment.ConclusionCompleted vaccination programme defined as two doses plus booster vaccination resulted in a sufficient vaccination response as measured by IgG levels regardless of RA treatment.It is noteworthy that IgG levels increased markedly in patients treated with a combination of cs/bDMARD or oral prednisolone, who had low IgG levels (below manufacturer's cut-off >=10 EliA U/mL) after 6 months. Our results strongly support the efficacy of the complete vaccination programme including the 3rd booster vaccine in patients with inflammatory rheumatic diseases.Figure 1.Serum IgG-levels at baseline, 6 weeks, 6 months and 12 months;stratified by antirheumatic treatment. (Box plot showing median and interquartile range).[Figure omitted. See PDF]Reference[1]Schreiber K. et al. Reduced Humoral Response of SARS-CoV-2 Antibodies following Vaccination in Patients with Inflammatory Rheumatic Diseases— an Interim Report from a Danish Prospective Cohort Study. Vaccines 2022, 10(1), 35;https://doi.org/10.3390/vaccines10010035AcknowledgementsWe acknowledge all patients contributing to the DANBIO registry.The Danish Rheumatologic Biobank is a knowledged for handling and storage of biological material.Lab chieftechnician Charlotte Drachmann is acknowledged for her assistance.Disclosure of InterestsChristine Graversgaard: None declared, Karen Schreiber Speakers bureau: Lilly, UCB, Henning Jakobsen: None declared, Randi Petersen: None declared, Anders Bo Bojesen: None declared, Niels Steen Krogh: None declared, Bente Glintborg Grant/research support from: Pfizer, AbbVie, BMS, Sandoz, Merete Lund Hetland: None declared, Oliver Hendricks Speakers bureau: Pfizer, Lilly, Novartis.

Current Evidence of Cannabidiol's Potential as an Anxiolytic Agent

This article will summarize the current knowledge and scientific evidence regarding cannabidiol as a possible pharmacological tool for anxiety disorders. Although the use of this substance in medical practice is gaining momentum, gaps can still be found in the current knowledge regarding its molecular targets, drug-to-drug interactions, efficacy in different populations, adequate dosage, duration of treatment, and correct formulation. Moreover, current evidence is still preliminary, lacking robust, blinded, and placebo-controlled clinical trials in many areas of investigation. After reading this article, readers should have a thorough understanding of the current scientific evidence regarding the use of CBD as an anxiolytic drug. [Psychiatr Ann. 2023;53(6):242–246.]

Pharmacological Properties and Safe Use of 12 Medicinal Plant Species and Their Bioactive Compounds Affecting the Immune System

This paper presents raw plant materials and their characteristic compounds which may affect the immune system. Plant-derived agents in specific doses affect the body's non-specific, antigen-independent defense system. They have immunostimulatory effects on the entire immune regulatory system. They can enhance the immune response through various factors such as macrophages, leukocytes, and granulocytes, as well as through mediators released by the cellular immune system. This paper was inspired by the threats caused by the COVID-19 pandemic. The proper functioning of the immune system is important in limiting the effects of viral infection and restoring the normal functioning of the body. This paper also emphasizes the importance of the skillful use of plant immunostimulants by potential patients, but also by those who prescribe drugs. It is important not only to choose the right plant drug but above all to choose the correct dose and duration of treatment.

Innovations Meet Growing Demand for Prefilled Syringes

Syringe innovations also increase patient and caregiver safety and efficiency and reduce waste of product and packaging materials. "Since it is already packaged ready for the injection, the prefilled syringe saves time and avoids unneeded handling prior to the actual application, minimizing the risk of the injection errors, dilution errors, or non-sterility issues [that are a risk in] multi-dose containers," explains Wenzel Novak, global senior director of business development at Gerresheimer Medical Systems. [...]the advent of a silicone-free design, "Pharmaceutical manufacturers seeking to avoid silicone-induced aggregation and sub-visible particles have had to choose vials even when they wanted to offer other delivery options," said Christiane Gumera, product specialist at W.L. Gore & Associates. [...]automation decreases labour requirements, diminishes the difficulties of working in a cleanroom with full personal protective equipment, and reduces the likelihood of repetitive motion injuries." [...]information technology systems supporting serialization can communicate with the customer's system to ensure that the serial numbers applied are unique and traceable across the network of product manufacturing sites the customer may be using."