Upstream Development

Identifying False Metabolite Measurements During Cell-Culture Monitoring Effective Application of the Multivariate Hotelling’s T2 Statistic

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Upstream process scientists and engineers actively monitor bioreactor metabolite levels during cell culture using off-line blood-gas analyzers (BGAs) and related instrumentation. But such tools introduce inherent variability into metabolite measurements. The magnitude of that variability depends on the measurement range. Mammalian cells are sensitive to concentrations of one such metabolite: dissolved CO2. In cell cultures, CO2 levels often are reported as partial pressure (pCO2) in millimeters of mercury (mmHg). Available literature frequently reports that elevated pCO2 concentrations have adverse impacts…

Standard Operating Procedures in a Good Practice Environment: Benefit or Burden?

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I was both excited and curious the day I started a new job in the quality affairs department of a pharmaceutical company. As usual, I attended onboarding meetings and received a training plan that contained a list of standard operating procedures (SOPs). So far, so good. But once I looked into the company’s training documents, my excitement turned to surprise. The SOP training included more than 150 good practice (GxP) SOPs, several of them longer than 50 pages and full…

June 26, 2023

A Case Study in Environmental Monitoring: Reviewing Incubation Times Upon Recovery of Microorganisms

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Environmental monitoring (EM) remains an essential detection tool for cleanrooms within healthcare and pharmaceutical-manufacturing facilities. During monitoring, an agar growth medium is incubated at a specific temperature for a set time. There is no single approach to incubation. Researchers have performed several EM incubation studies, with results reflecting a diversity of practice. Typically, biomanufacturing sites either run selective monitoring sessions using single-incubation regimes with two different culture media, or they leverage a dual-incubation system using two temperature ranges with a…

March 21, 2023

Deciphering Nutritional Needs in Bioprocess Optimization: Targeted and Untargeted Metabolomics with Genome-Scale Modeling

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Microbiology has risen as a major part of global industry over the past three decades. Industrial microbiology, biotechnology, biopharma and now biointelligent production systems (1) embrace a wide range of manufacturing platforms and product areas involving microbes, animal cells, and plant cells — as well as whole organisms. The multibillion-dollar applications of biomanufacturing display great variety. They include microbial-based production of such valuable metabolites as amino acids, vitamins, solvents, and organic acids as well as larger products such as enzymes,…

October 20, 2022

Enabling Next-Generation Biomanufacturing Using Cell-Free Technology

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Weston Kightlinger, director, cell-free protein synthesis, National Resilience. Kightlinger shared his company’s work to enable next-generation biomanufacturing, focusing on biologics and cell-free protein synthesis. Resilience was formed to address the need for robust manufacturing supply chains that remain stable amid times of disruption and enable design of therapeutics in pace with scientific advancements. Resilience is a technology-focused manufacturing company dedicated to democratizing access to complex medicines. It is building a network of high-tech manufacturing facilities: 11 sites, 1,700 employees, and a…

August 24, 2022

Hardware, Software, and Wetware: 20 Years of Advancements in Biopharmaceutical Production, Part 1

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The past couple of decades have witnessed significant advances in upstream bioprocess technologies and approaches. Since its establishment, BPI has been a facilitator of discussion in both print and professional conferences, as well as in webcasts and news online. To mark the 20th anniversary of the publication, we surveyed articles published over the past two decades and found hundreds that highlight significant advances in both emerging and established themes in biopharmaceutical production: • “hardware” and assets (e.g., analytical instrumentation, bioreactors,…

August 22, 2022

Transfection: Past, Present, and Future

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The science behind transfection spans from calcium phosphate precipitation to newer methods that are easier to perform, more efficient, and consistent. Mirus Bio strives to perfect gene delivery to cells in culture and support different applications within the life sciences community. The company’s capabilities include RNA interference (RNAi), clustered regularly interspaced short palindromic repeats (CRISPR), and viral vector development for cell and gene therapies with the launch of TransIT-VirusGEN GMP transfection reagent and kits for supporting clinical and commercial adenoassociated…

August 19, 2022

Navigating New Options for Commercial-Scale Biopharmaceutical Production

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Scalability remains a critically important topic for biopharmaceutical companies. For conventional protein products, the strategy once was straightforward: Drug makers would scale up, beginning with cultures in flasks and roller bottles to grow enough cells to inoculate laboratory-scale (often glass) bioreactors, then again to pilot- and commercial-scale, stainless-steel, stirred-tank bioreactors. At their highest volumes, such reactors can handle tens of thousands of liters of cells and growth media. If a drug developer did not have the requisite equipment to scale…

March 16, 2022

Scaling AAV Production: Easing the Transition from Laboratory Scales to Commercial Manufacturing

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Adenoassociated virus (AAV) has emerged as the leading vector for gene therapy delivery. Compared with options such as lentivirus and adenovirus, AAV exhibits a strong safety profile because it has low pathogenicity and requires a helper virus to replicate. AAV is also capable of long-term gene expression, and it can infect both dividing and nondividing cells (1–5). Developers of advanced therapies have found such advantages to be quite attractive. As of January 2021, two gene therapy products have gained US…

March 16, 2022

Mind the Gap: Managing Relationships Between Upstream and Downstream Intensification

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Process intensification (PI) describes an integrated framework of strategies to maximize the output of a unit operation, a process, or an entire facility. By implementing PI strategies, biomanufacturers can accomplish their productivity goals by increasing production speeds and titers, reducing facility footprints, and cutting costs. Overall, such changes improve production efficiency and flexibility. Collectively, the biotherapeutic industry has made multiple advancements in intensifying upstream processing. PI strategies include using high-density cell banks, implementing seed-train intensification (n – 1 perfusion), and…

March 16, 2022