Vaccine Manufacturing Process Research Articles

An in vitro assay for toxicity testing of Clostridium perfringens type C β-toxin.

Veterinary vaccines against Clostridium perfringens type C need to be tested for absence of toxicity, as mandated by pharmacopoeias worldwide. This toxicity testing is required at multiple manufacturing steps and relies on outdated mouse tests that involve severe animal suffering. Clostridium perfringens type C produces several toxins of which the β-toxin is the primary component responsible for causing disease. Here, we describe the successful development of a new cell-based in vitro assay that can address the specific toxicity of the β-toxin. Development of the cell-based assay followed the principle of in vitro testing developed for Cl. septicum vaccines, which is based on Vero cells. We screened four cell lines and selected the THP-1 cell line, which was shown to be the most specific and sensitive for β-toxin activity, in combination with a commercially available method to determine cell viability (MTS assay) as a readout. The current animal test is estimated to detect 100 - 1000-fold dilutions of the Cl. perfringens type C non-inactivated antigen. When tested with an active Cl. perfringens type C antigen preparation, derived from a commercial vaccine manufacturing process, our THP-1 cell-based assay was able to detect toxin activity from undiluted to over 10000-fold dilution, showing a linear range between approximately 1000- and 10000-fold dilutions. Assay specificity for the β-toxin was confirmed with neutralizing antibodies and lack of reaction to Cl. perfringens culture medium. In addition, assay parameters demonstrated good repeatability. Here, we have shown proof of concept for a THP-1 cell-based assay for toxicity testing of veterinary Cl. perfringens type C vaccines that is suitable for all vaccine production steps. This result represents a significant step towards the replacement of animal-based toxicity testing of this veterinary clostridial antigen. As a next step, assessment of the assay's sensitivity and repeatability and validation of the method will have to be performed in a commercial manufacturing context in order to formally implement the assay in vaccine quality control.

In-process quality control in foot-and-mouth disease vaccine production by detection of viral non-structural proteins using chemiluminescence dot blot assay

Foot-and-mouth disease (FMD) is a contagious viral disease of cloven-footed animals. Immunization with inactivated virus vaccine is effective to control the disease. Six-monthly vaccination regimen in endemic regions has proven to be effective. To enable the differentiation of infected animals from those vaccinated, non-structural proteins (NSPs) are excluded during vaccine production. While the antibodies to structural proteins (SPs) could be observed both in vaccinated and infected animals, NSP antibodies are detectable only in natural infection. Quality control assays that detect NSPs in vaccine antigen preparations, are thus vital in the FMD vaccine manufacturing process. In this study, we designed a chemiluminescence dot blot assay to detect the 3A and 3B NSPs of FMDV. It is sensitive enough to detect up to 20 ng of the NSP, and exhibited specificity as it does not react with the viral SPs. This cost-effective assay holds promise in quality control assessment in FMD vaccine manufacturing.

(RP)UHPLC/UV analytical method to quantify dsRNA during mRNA vaccine manufacturing process

dsRNA is a product related impurity produced during the mRNA manufacturing process. The established immuno-based detection methods lack the flexibility and speed required to be applied throughout the manufacturing process....

Sulfate limitation increases specific plasmid DNA yield and productivity in E. coli fed-batch processes

Plasmid DNA (pDNA) is a key biotechnological product whose importance became apparent in the last years due to its role as a raw material in the messenger ribonucleic acid (mRNA) vaccine manufacturing process. In pharmaceutical production processes, cells need to grow in the defined medium in order to guarantee the highest standards of quality and repeatability. However, often these requirements result in low product titer, productivity, and yield. In this study, we used constraint-based metabolic modeling to optimize the average volumetric productivity of pDNA production in a fed-batch process. We identified a set of 13 nutrients in the growth medium that are essential for cell growth but not for pDNA replication. When these nutrients are depleted in the medium, cell growth is stalled and pDNA production is increased, raising the specific and volumetric yield and productivity. To exploit this effect we designed a three-stage process (1. batch, 2. fed-batch with cell growth, 3. fed-batch without cell growth). The transition between stage 2 and 3 is induced by sulfate starvation. Its onset can be easily controlled via the initial concentration of sulfate in the medium. We validated the decoupling behavior of sulfate and assessed pDNA quality attributes (supercoiled pDNA content) in E. coli with lab-scale bioreactor cultivations. The results showed an increase in supercoiled pDNA to biomass yield by 33% and an increase of supercoiled pDNA volumetric productivity by 13 % upon limitation of sulfate. In conclusion, even for routinely manufactured biotechnological products such as pDNA, simple changes in the growth medium can significantly improve the yield and quality.Graphical

Rapid determination of influenza vaccine potency by an SPR-based method using subtype or lineage-specific monoclonal antibodies.

Potency testing and release of annual influenza vaccines require preparation, calibration, and distribution of reference antigens (RAs) and antisera every year, which takes an average of 8 to 12 weeks, and can be a major limiting factor in pandemic situations. Here we describe for the first time a robust Surface Plasmon Resonance (SPR)-based method that employs influenza subtype or lineage hemagglutinin (HA) specific monoclonal antibodies (mAbs) to measure the HA concentration in influenza multivalent vaccines. Implementing such an advanced test method will at the very least eliminate the rate-limiting and laborious efforts of making antisera reagents annually, and thus expedite the influenza vaccine delivery to the public by at least 6 weeks. Results demonstrate that the SPR-based method, developed using Biacore, is robust and not influenced by the type of RAs (inactivated whole virus, split, or subunit vaccine-derived materials), whether they are used as monovalent or multivalent preparations. HA concentrations obtained for monovalent drug substances (DS) or quadrivalent drug products (DP) of inactivated influenza split vaccine showed a tight correlation (the best fit value for the slope is 1.001 with R2 of 0.9815 and P-value <0.0001) with the corresponding values obtained by the current potency assay, Single Radial Immunodiffusion (SRID). Supplementary analysis of the results by the Bland-Altman plot demonstrated good agreement between the SPR and SRID methods, with no consistent bias of the SPR versus SRID method. We further demonstrate that the SPR-based method can be used to estimate HA concentrations in intermediates of the influenza vaccine manufacturing process containing varying matrices and impurity levels. Further, the results demonstrate that the method is sensitive to detecting degradation of HA caused by elevated temperature, low pH, and freezing. It is evident from this report and other published work that the advancement of analytical techniques and the early findings are encouraging for the implementation of alternate potency assays with far-reaching benefits covering both seasonal and pandemic influenza.

Unsupervised Fault Detection of Pharmaceutical Processes Using Long Short-Term Memory Autoencoders

Unsupervised multilayer long short-term memory autoencoder (LSTM-AE) models are proposed for monitoring nonlinear batch processes. The methodology is demonstrated for a simulation-based study of an industrial-scale penicillin process and for an industrial vaccine manufacturing process, using production data. The LSTM-AE model was trained with two different loss functions: minimizing mean square error (MSE) between the input and reconstructed data and maximizing the average fault detection rate (FDR¯) in the training data set. Two algorithms are also proposed for obtaining contribution plots for the diagnosis of faults. For the industrial case study, where the faults are not known a priori, the contribution plots are found to be a valuable tool for identifying possible sources of faults. Furthermore, a semisupervised procedure has been proposed to select the normal process region for training the model. Two metrics are also presented to evaluate the performance of the proposed methodology: one for the simulator case study in which fault knowledge is available and one for the industrial case study in which fault knowledge is not available a priori. The proposed unsupervised algorithms exhibit a clear improvement in accuracy over linear methods or nonlinear techniques that do not explicitly account for dynamic behavior.

Deep longitudinal multi-omics analysis of Bordetella pertussis cultivated in bioreactors highlights medium starvations and transitory metabolisms, associated to vaccine antigen biosynthesis variations and global virulence regulation.

Bordetella pertussis is the bacterial causative agent of whooping cough, a serious respiratory illness. An extensive knowledge on its virulence regulation and metabolism is a key factor to ensure pertussis vaccine manufacturing process robustness. The aim of this study was to refine our comprehension of B. pertussis physiology during in vitro cultures in bioreactors. A longitudinal multi-omics analysis was carried out over 26 h small-scale cultures of B. pertussis. Cultures were performed in batch mode and under culture conditions intending to mimic industrial processes. Putative cysteine and proline starvations were, respectively, observed at the beginning of the exponential phase (from 4 to 8 h) and during the exponential phase (18 h 45 min). As revealed by multi-omics analyses, the proline starvation induced major molecular changes, including a transient metabolism with internal stock consumption. In the meantime, growth and specific total PT, PRN, and Fim2 antigen productions were negatively affected. Interestingly, the master virulence-regulating two-component system of B. pertussis (BvgASR) was not evidenced as the sole virulence regulator in this in vitro growth condition. Indeed, novel intermediate regulators were identified as putatively involved in the expression of some virulence-activated genes (vags). Such longitudinal multi-omics analysis applied to B. pertussis culture process emerges as a powerful tool for characterization and incremental optimization of vaccine antigen production.

Genomic Diversity of a Globally Used, Live Attenuated Mycoplasma Vaccine.

The Mycoplasma synoviae live attenuated vaccine strain MS-H (Vaxsafe MS; Bioproperties Pty., Ltd., Australia) is commonly used around the world to prevent chronic infections caused by M. synoviae in birds and to minimize economic losses in the poultry industry. MS-H is a temperature-sensitive strain that is generated via the chemical mutagenesis of a virulent M. synoviae isolate, 86079/7NS. 32 single nucleotide polymorphisms have been found in the genome of MS-H compared to that of 86079/7NS, including 25 in predicted coding sequences (CDSs). There is limited information on the stability of these mutations in MS-H in vitro during the propagation of the vaccine manufacturing process or in vivo after the vaccination of chickens. Here, we performed a comparative analysis of MS-H genomes after in vitro and in vivo passages under different circumstances. Studying the dynamics of the MS-H population can provide insights into the factors that potentially affect the health of vaccinated birds. The genomes of 11 in vitro laboratory passages and 138 MS-H bird reisolates contained a total of 254 sequence variations. Of these, 39 variations associated with CDSs were detected in more than one genome (range = 2 to 62, median = 2.5), suggesting that these sequences are particularly prone to mutations. From the 25 CDSs containing previously characterized variations between MS-H and 86079/7NS, 7 were identified in the MS-H reisolates and progenies examined here. In conclusion, the MS-H genome contains individual regions that are prone to mutations that enable the restoration of the genotype or the phenotype of wild-type 86079/7NS in those regions. However, accumulated mutations in these regions are rare. IMPORTANCE Preventative measures, such as vaccination, are commonly used for the control of mycoplasmal infections in poultry. A live attenuated vaccine strain (Vaxsafe MS; MS-H; Bioproperties Pty. Ltd., Australia) is used for the prevention of disease caused by M. synoviae in many countries. However, information on the stability of previously characterized mutations in the MS-H genome is limited. In this study, we performed a comparative analysis of the whole-genome sequences of MS-H seeds used for vaccine manufacturing, commercial batches of the vaccine, cultures minimally passaged under small-scale laboratory and large-scale manufacturing conditions, MS-H reisolated from specific-pathogen-free (SPF) chickens that were vaccinated under controlled conditions, and MS-H reisolated from vaccinated commercial poultry flocks around the world. This study provides a comprehensive assessment of genome stability in MS-H after in vitro and in vivo passages under different circumstances and suggests that most of the mutations in the attenuated MS-H vaccine strain are stable.

Understanding and Addressing COVID-19 Vaccine Hesitancy Among Healthcare Providers in Bexar County, Texas

IntroductionCOVID-19 challenged our healthcare systems and unsurprisingly, so did its vaccine. Chief among these were the uniquely politicized nature and logistical difficulties surrounding its deployment. Understanding provider attitudes toward the COVID-19 vaccines and their willingness/ability to deliver them is essential to developing an ideal vaccine distribution plan for Bexar County, Texas.MethodsAn electronic survey was sent to providers serving adult patients across Bexar County. Membership includes representation from local hospitals, Bexar County Medical Society, and the San Antonio Metropolitan Health District's vaccination program. The survey measured provider attitudes toward the vaccines and asked logistical questions regarding patient hesitancy and clinic infrastructure.ResultsResponses were collected from 66 ZIP codes (90% of ZIP codes in the county), and 377 providers answered the survey. Respondents who were unlikely to recommend the vaccine (3%) shared concerns involving distrust of the vaccine manufacturing process. Recommendations made by physicians to support their vaccine administration efforts included broadening the reporting timeframe (n=35), providing trained support staff (n=18), and improving logistical support (n=14). Furthermore, responses showed that only 14.44% of provider facilities were able to meet originally published refrigeration requirements to store Pfizer's vaccines compared with 87.47% for Moderna's vaccines.ConclusionsSurvey results were used to improve the efficiency of vaccination programs and address vaccine hesitancy through various avenues of information delivery. It is recommended to replicate the outcomes and applications of this study in other populations to improve the efficiency of vaccination programs and reduce vaccine hesitancy.

Vaccines and Therapeutics: Quality System Approach to Clinical Applications

Molecular bio-science developments involve applications of mRNA vaccines focused on diagnostic, prophylactic, and therapeutic aspects of COVID-19 related infectious diseases. These applications offer potential solutions for many of the current challenges in treating virus related infectious diseases. The goal of vaccine design and development is to manufacture and consistently produce a vaccine that is safe and effective. The vaccine discovery starts with design input in terms of identification of etiologic agent, immunogenicity, adjuvant, basic scientific concepts, non-clinical and clinical studies, and finally vaccine licensure (FDA approvals). The Lipid Nanoparticle Technology (LNT) for messenger RNA is being used for COVID-19 vaccines. This technology comprises of identifying and mapping signature features of the virus which encompasses the readability of the virus’s blueprint, its neutralization and activation processes in order to deliver antibody proteins to protect the vaccine recipients’ bodies from encounters with the virus. The administering regimens are studied in clinical research laboratory and study materials are tested in suitable bench testing and biological models projecting vaccine candidate’s prophylactic immune response that is safe and effective. The vaccine manufacturing process requires critical quality control points (CQCPs) monitoring in order to maintain the steriochemical and immunological characteristics of the vaccine molecules and enable production of the vaccine in increasingly dosage quantities for ultimate human use. These aspects of vaccine development are well integrated into the total vaccinology life cycle (TVLC) regulatory requirements. The ultimate regulatory safety and efficacy requirements of the vaccine are proven through phases of clinical trials (class I, II, and III studies). The final process for human use to produce safe vaccine is part of pivotal clinical trials and data under the US FDA’s premarket approval process for full-scale production and availability of safe vaccines for clinical use.&#x0D; Keywords: mRNA Vaccines, Diagnosis, Prophylaxis, Therapy, COVID-19

Determinants of Vaccine R&amp;D in the Pharmaceutical Sector

The aim of this paper is to analyse the economic and financial assets that influence vaccine research investments by pharmaceutical companies. Starting from vaccine manufacturing process, the first part describes European Union (EU) and United States (US) regulatory systems and the relative Intellectual Property Rights (IPRs). Then, the main obstacles to vaccine research and the main strategies suitable to enhance it are discussed. The second part introduces an empirical analysis of 10 pharmaceutical companies’ corporate Research and Development (R&amp;D) from the 2008-2015 period by using STATA 12, through a Fixed Effect estimation of two models. The three hypotheses considered regard the main assets that influence vaccine research and why, the relevance of properties acquisition as a substitute for R&amp;D as whether regulatory framework does obstruct investments choices or not. The results confirm that liquidity and size have a positive impact on vaccine research, whereas leverage influences it negatively. In addition, more acquisitions lead to fewer R&amp;D investments since companies find less expensive to acquire knowledge rather than investing on it. Finally, a Chow Test that considers 2010 as a breaking point, led to no structural breaks for panel data, which implies that the new European Regulatory Directive on pharmacovigilance has no influence on the pharmaceutical companies’ behaviour. Keywords: vaccines, health economics, research &amp; development

Multi angle light scattering as a process analytical technology tool for real-time monitoring of molar mass of protein-polysaccharide conjugate fractions

Current polysaccharide conjugate vaccine manufacturing process involves conjugation of polysaccharide with protein followed by separation/purification of the conjugate from reaction components and free polysaccharide/protein, by preparative Size-Exclusion Chromatography (SEC). Each SEC fraction is analyzed and pooled the conjugate based on its molar mass and absence of free polysaccharide. In the present work, we have evaluated in-line Multi Angle Light Scattering (MALS) as a Process Analytical Technology (PAT) tool to eliminate the need for offline analysis of individual fractions after purification. The preparatory SEC unit is coupled to a MALS detector, i.e. preparatory SEC-MALS. In SEC, the molecules are separated based on size, where polysaccharide-protein conjugate elutes first followed by free polysaccharide and then free protein. The MALS detector monitors in-line weight-average molar mass (Mw) during SEC-fractionation. Except the first fraction, the molar mass distribution data from in-line MALS enables decision on preparative SEC fractions to be pooled. We found that offline analysis of preparative fractions using analytical SEC-MALS was in good agreement with the >2000 kDa cutoff criterion. Thus in-line process analysis is effective, time-saving, and simple to implement in manufacturing processes of conjugate vaccines.

Vaccinology: Design, Development and Approvals

The goal of vaccine design and development is to manufacture and consistently produce a vaccine that is safe and effective. The vaccine discovery starts with design input in terms of identification of etiologic agent, immunogenicity, adjuvant, basic scientific concepts, non-clinical and clinical studies, and finally vaccine licensure (FDA approvals). The administering regimens are studied in clinical research laboratory and study materials are tested in suitable bench testing and biological models projecting vaccine candidate’s prophylactic immune response that is safe and effective. The vaccine manufacturing process requires critical quality control points (CQCPs) monitoring in order to maintain the steriochemical and immunological characteristics of the vaccine molecules and enable production of the vaccine in increasingly dosage quantities for ultimate human use. These aspects of vaccine development are well integrated into the total vaccinology life cycle (TVLC) regulatory requirements. The ultimate regulatory safety and efficacy requirements of the vaccine are proven through phases of clinical trials (class I, II, and III studies). The final process for human use to produce safe vaccine is part of pivotal clinical trials and data under the US FDA’s premarket approval process for full-scale production and availability of safe vaccines for clinical use.&#x0D; Keywords: vaccine design and development, etiologic agent, immunogenicity

Annual trends in adverse events following mumps vaccination in Japan: A retrospective study

BackgroundIn Japan, a monovalent mumps vaccine is provided on a voluntary basis. Due to public concerns over post-vaccination aseptic meningitis, the vaccination coverage is not high enough. The present study investigated the incidence of adverse events, including aseptic meningitis, after Torii strain–derived mumps vaccination. MethodsThis retrospective, observational study used data collected by a vaccine manufacturer regarding adverse events following mumps vaccinations at medical institutions between 1992 and 2018. In addition, the number of Torii strain–derived mumps vaccines shipped each year was obtained. The incidence (per 100,000 doses) and 95% confidence intervals (CIs) were calculated for all adverse events and each adverse event, categorized as aseptic meningitis, encephalitis, mumps, mumps complications, and others. ResultsDuring the study period, 8,262,121 mumps vaccine doses were shipped, and 688 subjects reported adverse events. The incidence for all adverse events (per 100,000 doses) was 8.33, and the incidence was 4.19 for aseptic meningitis, 0.33 for encephalitis, 0.80 for mumps, 0.25 for mumps complications, and 3.78 for others. The incidence of aseptic meningitis (per 100,000 doses) was 7.90 (95% CI: 5.61–10.18) between 1998 and 2000 but declined by half, to 3.91 (2.46–5.36), between 2001 and 2003. The most recent incidence (per 100,000 doses) of aseptic meningitis, for the period 2016 to 2018, was 2.78 (1.94–3.62). ConclusionThe incidence of post-vaccination aseptic meningitis has declined significantly since 2001, and the incidence has remained stable at fewer than 3 cases per 100,000 doses since 2010. Multiple factors might have contributed to the decline in aseptic meningitis incidence, including (i) lowered misclassification of aseptic meningitis resulting from echovirus infection; (ii) changes in the vaccine manufacturing process in 2000; and (iii) publication in 2008 of the recommendation for vaccination of children at 1 year of age.

The Epidemiological and Economic Impact of a Cell-Based Quadrivalent Influenza Vaccine in Adults in the US: A Dynamic Modeling Approach.

Mutations of the H3N2 vaccine strain during the egg-based vaccine manufacturing process partly explain the suboptimal effectiveness of traditional seasonal influenza vaccines. Cell-based influenza vaccines improve antigenic match and vaccine effectiveness by avoiding such egg-adaptation. This study evaluated the public health and economic impact of a cell-based quadrivalent influenza vaccine (QIVc) in adults (18–64 years) compared to the standard egg-based quadrivalent influenza vaccine (QIVe) in the US. The impact of QIVc over QIVe in public health and cost outcomes was estimated using a dynamic age-structured SEIR transmission model, which accounted for four circulating influenza strains [A/H1N1pdm9, A/H3N2, B(Victoria), and B(Yamagata)] and was calibrated on the 2013–2018 influenza seasons. The robustness of the results was assessed in univariate and probabilistic sensitivity analyses. Switching from QIVe to QIVc in 18- to 64-year-olds may prevent 5.7 million symptomatic cases, 1.8 million outpatient visits, 50,000 hospitalizations, and 5453 deaths annually. The switch could save 128,000 Quality-Adjusted Life Years (QALYs) and US $ 845 M in direct costs, resulting in cost-savings in a three-year time horizon analysis. Probabilistic sensitivity analyses confirmed the robustness of the cost-saving result. The analysis shows that QIVc is expected to prevent hospitalizations and deaths, and result in substantial savings in healthcare costs.

An Overview of Influenza Viruses and Vaccines.

Influenza remains one of the major public health concerns because it causes annual epidemics and can potentially instigate a global pandemic. Numerous countermeasures, including vaccines and antiviral treatments, are in use against seasonal influenza infection; however, their effectiveness has always been discussed due to the ongoing resistance to antivirals and relatively low and unpredictable efficiency of influenza vaccines compared to other vaccines. The growing interest in vaccines as a promising approach to prevent and control influenza may provide alternative vaccine development options with potentially increased efficiency. In addition to currently available inactivated, live-attenuated, and recombinant influenza vaccines on the market, novel platforms such as virus-like particles (VLPs) and nanoparticles, and new vaccine formulations are presently being explored. These platforms provide the opportunity to design influenza vaccines with improved properties to maximize quality, efficacy, and safety. The influenza vaccine manufacturing process is also moving forward with advancements relating to egg- and cell-based production, purification processes, and studies into the physicochemical attributes and vaccine degradation pathways. These will contribute to the design of more stable, optimized vaccine formulations guided by contemporary analytical testing methods and via the implementation of the latest advances in the field.

Vaccines against SARS-COV-2

Vaccines against Covid-19 were developed on the basis of protein S, before it had the mutations identified in these variants. Although research conducted so far is less effective against variants and continues to offer protection against severe forms of Covid-19, further research is ongoing. WHO is working with every country in the world to help coordinate the key stages of this vaccine manufacturing and development process. In particular, to facilitate equitable access for all countries to vaccines against Covid-19 and that they are safe and effective for the billions of people who need them.

An innovative method for accelerating vaccine formulation development and manufacturing process: Using prefabricated vaccine base (standardized mixtures of vaccine excipients)

An innovative method for accelerating vaccine formulation development and manufacturing process: Using prefabricated vaccine base (standardized mixtures of vaccine excipients)

An innovative method for accelerating vaccine formulation development and manufacturing process: Using prefabricated vaccine base (standardized mixtures of vaccine excipients)

An innovative method for accelerating vaccine formulation development and manufacturing process: Using prefabricated vaccine base (standardized mixtures of vaccine excipients)

Enhancement of Cell-Based Vaccine Manufacturing through Process Intensification.

There are many drivers to intensify the manufacturing of vaccines. The emergence of SARS-CoV-2 has only added to them. Since the pandemic began, we have been seeing an acceleration of vaccine development and approval, including application of novel prophylactic vaccine modalities. We have also seen an increase in the appreciation and general understanding of what had been a somewhat obscure discipline. Concurrently, there has been great interest in the application of new understandings and technology to the intensification of biopharmaceutical processes in general. The marriage of these developments defines the field of vaccine manufacturing process intensification Difficulties in its implementation include the many disparate vaccine types-from conjugate to hybrid to nucleic acid based. Then, there are the respective and developing manufacturing methods, modes, and platforms-from fermentation of transformed bacteria to the bioreactor culture of recombinant animal cells to production of virus-like particles in transgenic plants. Advances are occurring throughout the biomanufacturing arena, from process development (PD) techniques to manufacturing platforms, materials, equipment, and facilities. Bioprocess intensification refers to systems for producing more product per cell, time, volume, footprint, or cost. The need for vaccine manufacturing process intensification is being driven by desires for cost control, process efficiency, and the heightened pressures of pandemic response. We are seeing great interest in the power of such disciplines as synthetic biology, process simplification, continuous bioprocessing, and digital techniques in the optimization of vaccine PD and manufacturing. Other powerful disciplines here include process automation, improved monitoring, optimized culture materials, and facility design. The intent of this short commentary is to provide a brief review and a few examples of the exciting advances in the equipment, technology, and processes supporting this activity.