Transformation of Biopharmaceutical Manufacturing Through Single-Use Technologies: Current State, Remaining Challenges, and Future Development.

Single-use technologies have transformed conventional biopharmaceutical manufacturing, and their adoption is increasing rapidly for emerging applications like antibody-drug conjugates and cell and gene therapy products. These disruptive technologies have also had a significant impact during the coronavirus disease 2019 pandemic, helping to advance process development to enable the manufacturing of new monoclonal antibody therapies and vaccines. Single-use systems provide closed plug-and-play solutions and enable process intensification and continuous processing. Several challenges remain, providing opportunities to advance single-use sensors and their integration with single-use systems, to develop novel plastic materials, and to standardize design for interchangeability. Because the industry is changing rapidly, a holistic analysis of the current single-use technologies is required, with a summary of the latest advancements in materials science and the implementation of these technologies in end-to-end bioprocesses.

Design of Improved Flow-Focusing Microchannel with Constricted Continuous Phase Inlet and Study of Fluid Flow Characteristics.

This paper proposed an improved flow-focusing microchannel with a constricted continuous phase inlet to increase microbubble generation frequency and reduce microbubbles' diameter. The design variables were obtained by Latin hypercube sampling, and the radial basis function (RBF) surrogate model was used to establish the relationship between the objective function (microbubble diameter and generation frequency) and the design variables. Moreover, the optimized design of the nondominated sorting genetic algorithm II (NSGA-II) algorithm was carried out. Finally, the optimization results were verified by numerical simulations and compared with those of traditional microchannels. The results showed that dripping and squeezing regimes existed in the two microchannels. The constricted continuous phase inlet enhanced the flow-focusing effect of the improved microchannel. The diameter of microbubbles obtained from the improved microchannel was reduced from 2.8141 to 1.6949 µm, and the generation frequency was increased from 64.077 to 175.438 kHz at the same capillary numbers (Ca) compared with the traditional microchannel. According to the fitted linear function, it is known that the slope of decreasing microbubble diameter with increasing Ca number and the slope of increasing generation frequency with increasing Ca number are greater in the improved microchannel compared with those in the traditional microchannel.

Extractables from integrated single-use systems in biopharmaceutical manufacturing. Part I. Study on components (Pall Kleenpak connector and Kleenpak filter capsule).

Single-use systems for manufacturing biopharmaceuticals can include filter capsules, connectors, tubing, and polymeric film biocontainers. In order to tackle the variety of extractable compounds from these fairly complex systems, we first studied such systems' representative components, and then examined an entire single-use system comprised of filtesr, connectors, tubing, and biocontainers. This approach greatly simplifies the identification of the extractable compounds from the whole system. The test design was based on common, actual processes conducted under worst-case conditions. Part 1 of this series of papers describes a systematic study of extractables from two components, a sterile connector and a capsule filter, in water and ethanol as model solvent extractants. The complete extractables results were obtained using a combination of qualified analytical methods. The results indicated that the potential for the connector and the capsule filter to release leachable materials in significant amounts into the chemically compatible drug product is very low, taking into account the less vigorous conditions in most processes and dilution effects when compared to the water and ethanol extraction conditions reported here. Application of study results is discussed.

Risk-based scientific approach for determination of extractables/leachables from biomanufacturing of antibody-drug conjugates (ADCs).

Recent developments in biopharmaceutical processes twined with a desire to remove cleaning and cross-contamination issues from drug production have led to the widespread introduction of single-use technologies and systems within operations. One key area that end users need to address with the advent of these single-use solutions is the potential for increased levels of extractables and leachables within a process, which need to be evaluated and understood as part of any regulatory submission. A science-based and practical method for characterization of extractables and leachables from single-use systems used in manufacturing antibody-drug conjugates has been developed and described in detail. This risk-based approach minimizes the amount of test work while meeting the regulatory requirements to ensure the drug safety and quality. The test design is optimized and the analytical methods (gas chromatography/mass spectrometry, liquid chromatography/mass spectrometry, and inductively coupled plasma/mass spectrometry) are shown to be suitable for quantifying and identifying the extracted chemical compounds. Application of this characterization method speeds up the filing process for qualification and validation of single-use systems used in bioprocesses.