biologics – BioProcessing Journal

Standardized and GMP-Ready, Closed-System Processing of Expanded Adipose-Derived Stem Cells Using the Gibco CTS Rotea System Across 2D and 3D Bioreactor Expansions

The manufacturing of cell-based therapies requires harmonized processing protocols to ensure consistent quality. Expanded adipose-derived mesenchymal stromal cells (ASC) are among the most promising candidates for such therapies due to their regenerative and immunomodulatory properties. However, transitioning these therapies to large-scale production presents challenges related to cell recovery, formulation, and in-process cell counting (IPC). The Gibco CTS™ Rotea™ multipurpose Counterflow Centrifugation System enables multiple workflow operations—including cell separation, concentration, washing, and buffer exchange—and is designed to operate within a GMP environment. From a cell concentration perspective, the Rotea system can also formulate concentrated cells in different types of media, including fetal bovine serum…

Biologics Production

2D 3D Adipose Derived Mesenchymal Stromal adipose stem cell adipose-derived mesenchymal ASC automation biologics bioreactor cell expansion cell therapy cellular therapies centrifugation closed system downstream purification GMP manufacturing Mesenchymal Stromal Cells msc rotea Wash Volume Reduction xeno-free media

Five Insurance Tips for Biotechnology Companies Facing Product Recalls or Liability Claims

Biotechnology companies — those that research and manufacture products through the use of biological techniques such as genetic engineering and the development of specialized strains of biological substances — constitute an increasing segment of the US economy. These companies might: (a) create a new type of insect- or drought-resistant corn by the modification of genes; (b) alter naturally occurring enzymes to aid in manufacturing or to help produce foods; (c) use recombinant DNA to create medicines that are remarkably effective in curing or treating disease; or (d) use any of a number of other techniques to create beneficial and potentially lucrative products. Just like other industries, biotechnology groups can be faced with recalls of their products, either voluntary or government-mandated, or claims that their products have caused bodily injury or property damage to their customers. Because biopharmaceuticals are produced by — or extracted from — a biological source, the chances of a product recall are higher than that of a synthesized drug. In April 2012, a report by GBI Research, an independent research firm, concluded that biologics were involved in more recalls, voluntary or mandatory, than drugs from other sources for the four-year period from 2007 through 2010…

Biologics Production

biological product recall biological substances biologics biopharmaceutical recall biotechnology biotechnology insurance DNA gene engineering liability issues recombinant dna therapeutics

Bovine Serum Albumin Partitioning in Aqueous Two-Phase Systems: Effects of Variables and Optimization

The objective of this study was to optimize process conditions for the effective partitioning of bovine serum albumin (BSA) using response surface methodology (RSM). Initially, four different salts (tripotassium citrate, tripotassium phosphate, sodium carbonate, and sodium sulphate) were tested for the ability to partition BSA. Among the salts chosen, tripotassium citrate was observed to yield a high partition coefficient. The effect of phase forming components: concentration, PEG molecular weight, and pH were studied for a PEG/tripotassium citrate system and the information obtained was utilized to fix the ranges in RSM studies. Four different independent variables (PEG 2000, tripotassium citrate, NaCl concentrations, and pH) were considered for RSM studies and the responses generated were partition coefficient (k) and percentage yield. A statistical model was developed and the values obtained were 99% within the confidence level. Optimal conditions of the system were found as: 0.25 M sodium chloride, 32% PEG 2000 (w/w), 16% tripotassium citrate (w/w), pH 6.0, a partition coefficient of 6.03, a recovery of 91.76%, and a controlled operating temperature of 303.15 K…

Biologics Production

biologics bioprocess bovine serum albumin bsa partitioning phase forming components response surface methodology rsm salts for partitioning

A Comparative Bioreactor Vessel Study: Conventional Reusable Glass and Single-Use Disposables for the Production of Alkaline Phosphatase

Single-use, stirred-tank bioreactor systems have been used in large-scale production for a number of years. Bench-scale, stirred-tank bioreactors have not been commercially-available for single-use until recently. The New Brunswick™ CelliGen® BLU pitched-blade bioreactor was introduced in 2009, and the CelliGen BLU packed-bed bioreactor, in 2012. Little information is currently available on the utility of these bioreactors for bench-scale production of recombinant products. Thus, we designed this study to perform multiple comparisons with these single-use bioreactors and their traditional glass vessel counterparts. The data comparisons included: (1) CelliGen BLU pitched-blade vs. glass pitched-blade; and (2) CelliGen BLU pitched blade in batch mode vs. CelliGen BLU packed-bed in perfusion mode. Chinese hamster ovary (CHO) cells were used to measure alkaline phosphatase (ALKP) production in each bioreactor. The final measured concentration of ALKP, after eight days of batch-mode culture in the single-use, pitched-blade bioreactor, was 1.6 U/mL compared to 2.1 U/mL in the reusable bioreactor. After six perfusion harvests in the single-use, packed-bed bioreactor, the combined ALKP production was 16.2 U/mL compared to 17.4 U/mL in the reusable bioreactor in batch mode. Multiple batch culture runs in the pitched-blade bioreactor would be required to match the output of a single run in the packed-bed bioreactor in perfusion mode. Results demonstrate that there are no significant differences between the reusable and single-use systems for bench-scale production of recombinant proteins. Our results also suggest that the CelliGen BLU packed-bed bioreactor, when operated in perfusion mode, is superior to the CelliGen BLU pitched-blade bioreactor when operated in batch mode, confirming our studies from 2012…

Biologics Production

alkaline phosphatase alkp production batch mode batch production bench-scale bioproduction biologics celligen blu cho cells glass bioreactors glass vessels perfusion mode single-use single-use bioreactor stirred-tank bioreactor

The Pervasiveness of Bovine Viral Diarrhea Virus in Commercial Bovine Serum

The procurement of lots of bovine serum that are free of infectious bovine viral diarrhea virus (BVDV) and of neutralizing antibodies to BVDV can still be problematic for manufacturers of biologics. For cell-culture based applications requiring the use of bovine serum as a cell culture medium supplement, the BVDV issue has plagued the industry for decades. Has there been any improvement over the years? The literature from the past four decades has been reviewed to answer this question. There is some evidence that the frequency of detection of infectious BVDV in commercial bovine serum lots has decreased in recent years. There are, however, insufficient data for making conclusions in the case for neutralizing antibodies to BVDV. There are several complementary approaches for mitigating the risk of introducing infectious BVDV into a manufacturing process. These include eliminating the use of serum, pre-treatment of the serum by the vendor or end-user, or treatment of media formulated with the serum to inactivate any BVDV that might be present.

Biologics Production

animal-derived materials biologics bovine serum bvdv cell culture media medium supplement viral inactivation

Process Intensification of Protein A Affinity Step for Monoclonal Antibody Purification Using Membrane and Multi-Column Chromatography

With growing interest in process intensification in the biopharmaceutical industry, implementing cost-effective purification strategies has become increasingly important, particularly for the expensive protein A affinity capture step in monoclonal antibody production. This study compares traditional resin-based batch chromatography (rbBC), multi-column chromatography (MCC), and membrane chromatography (MC) using small-scale experiments with commercially available formats. Performance metrics including yield, elution volume, and impurity reduction were evaluated. The best-performing conditions for MC and MCC were used to project cost and productivity for mAb purification at the 1,000 L bioreactor scale. Both MC and MCC demonstrated significant advantages over rbBC. MC achieved the highest productivity (234–236 g/L/h, 19–20-fold higher than rbBC) and the lowest media costs, resulting in up to 91% reduction in cost-of-goods (CoG) per batch. MCC also showed notable improvements, with 4.6–5.1-fold higher productivity than rbBC, and up to 72% CoG savings. Due to its operational similarity to rbBC and compatibility with existing infrastructure, MC was selected for further evaluation. Optimization was performed using a 3.5 mL membrane over 50 cycles, followed by scale-up to a 58 mL membrane tested on a pilot-scale skid representative of clinical or commercial manufacturing. The process was successfully run for 55 cycles, demonstrating comparable yield, impurity reduction, and elution profiles to rbBC. These results support the feasibility of membrane chromatography as a scalable and economical alternative for protein A capture in intensified downstream processing.

Biologics Production

biologics downstream purification membrane chromatography multi-column chromatography process intensification protein a removal

Maximizing Performance of pH Measurements for Inline Conditioning Buffer Preparation for Chromatography

In biopharmaceutical manufacturing, buffer preparation is traditionally performed manually by dissolving solid salts in water for injection (WFI) followed by offline mixing and specification testing. This method requires large buffer volumes, extensive infrastructure, and significant labor, often creating bottlenecks in production. To address these limitations and support process intensification, inline buffer preparation technologies have emerged…

Biologics Production

biologics cell therapy cleaning-in-place continuous buffer release downstream purification dynamic flow in-line conditioning in-line dilution inline conditioning inline dilution inline ph monitoring ion traps on-demand buffer formulation ph probes ph sensor designs process analytical technology salt memory sensor drift sodium hydroxide cip wfi

Assessment of a New Automatic, Water-Free Thawing Device Specially Designed for the Context of the Cell Therapy Industry

The number of cellular therapies in clinical trials and on the market has continued to rise significantly in recent years—and so does the need to maintain strict control over all manufacturing steps in order to reduce batch-to-batch variability. One potential source of product variability is the manual thawing of cryopreserved cells in a water bath, which can differ between operators. Additionally, water baths pose a significant contamination risk, making them less suitable for GMP environments. To overcome these challenges, several companies have developed water-free thawing devices that offer better control of the thawing process. However, these devices either accommodate only one vial at a time or lack U.S.
FDA 21 CFR 11 compliance in producing a computer-generated audit trail. Hence, we have developed a novel, water-free and dry-heat-based, fully programmable thawing device that is capable of thawing up to ten vials simultaneously and complies with 21 CFR11 requirements…

Biologics Production

adipose-derived MSC adipose-derived stem ASC biologics cell thawing cell therapy cellular therapies novel thawing device water-free thawing

Recent Statutes, Regulations, and Court Cases Affecting Intellectual Property Rights of Life Sciences Institutions: Key Provisions of the Leahy-Smith America Invents Act and the Biologics Price Competition and Innovation Act; Part III: Analysis of the BPCIA: FDA Guidelines Concerning the Characterization of Reference and Follow-On Macromolecules

The Leahy-Smith America Invents Act (AIA) and the Biologics Price Competition and Innovation Act (BPCIA) are dramatically reshaping business strategies designed to protect intellectual property and regulatory exclusivity rights granted by the United States Patent and Trademark Office (PTO) and the Federal Drug Administration (FDA) to the sponsors of new and follow-on versions of many biopharmaceutical products. The AIA alters many provisions in the U.S. patent statutes, most notably long-standing policies and practices relating to the conditions for patentability of an invention, particularly 35 USC §§ 102 and 103 relating to novelty and non-obviousness, respectively, and introduces new provisions relating to post-grant review proceedings and prioritized examination that will affect the business plans of academic and corporate institutions seeking to discover and develop health care products that serve unmet medical needs or provide consumers with safe sources of drug products at a low cost. The BPCIA implements many new provisions relating to the abbreviated review and approval of follow-on biopharmaceutical products. Important aspects of the BPCIA, particularly issues identified in draft guidance documents that were released by the FDA in February 2012 concerning the characterization, comparison, and evaluation of reference and follow-on macromolecules, will be discussed in this article. Political issues that may jeopardize the BPCIA, economic considerations faced by drug product sponsors, and public reaction to the guidance documents are also discussed in this final article of a three-part series describing key provisions of the AIA and the BPCIA that affect intellectual property and regulatory exclusivity rights of institutions having an interest in developing novel or follow-on versions of biopharmaceutical drug products…

Biologics Production

35 USC 102 35 usc 103 biologics biopharmaceuticals biosimilar patentability biosimilars bpcia follow-on biologics intellectual property life sciences IP patent resolution process patent terms ppaca regulatory exclusivity

Intellectual Property Rights of Life Sciences Institutions: Key Provisions of the Leahy-Smith America Invents Act and the Biologics Price Competition and Innovation Act; Part II: Analysis of the BPCIA, the Pre-Approval Patent Resolution Process, Regulatory Exclusivity Periods, and Complementary Rules Affecting Patent Terms

The Patient Protection and Affordable Care Act (PPACA), which was passed in 2010, included the Biologics Price Competition and Innovation Act (BPCIA) authorizing the United States Food and Drug Administration (FDA) to establish an abbreviated regulatory approval pathway for complex macromolecules produced in living cells or organisms. The BPCIA implements many new provisions relating to the abbreviated review and approval of follow-on biopharmaceutical products. These include: (1) evaluating the biochemical properties of reference and follow-on macromolecules; (2) establishing procedures for the exchange of information between product sponsors, regulatory agencies, and the federal court system; and (3) establishing periods of regulatory exclusivity which complement patent rights typically awarded to the sponsor of a reference molecule. Important aspects of the BPCIA, particularly issues relating to the exchange of information between product sponsors and the establishment of periods of regulatory exclusivity protecting a novel or follow-on macromolecule are discussed in this article. This is the second in a series of three articles describing key provisions of the Leahy-Smith America Invents Act (AIA) and the BPCIA that affect intellectual property rights of academic and corporate institutions having an interest in the life sciences…

Biologics Production

biologics biopharmaceuticals bpcia intellectual property life sciences IP patent resolution process patent terms ppaca regulatory exclusivity

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