Manufacturing technologies for biologics rely on large, centralized, good-manufacturing-practice (GMP) production facilities and on a cumbersome product-distribution network. Here, we report the development of an automated and portable medicines-on-demand device that enables consistent, small-scale GMP manufacturing of therapeutic-grade biologics on a timescale of hours. The device couples the in vitro translation of target proteins from ribosomal DNA, using extracts from reconstituted lyophilized Chinese hamster ovary cells, with the continuous purification of the proteins. We used the device to reproducibly manufacture His-tagged granulocyte-colony stimulating factor, erythropoietin, glucose-binding protein and diphtheria toxoid DT5. Medicines-on-demand technology may enable the rapid manufacturing of biologics at the point of care.

Point-of-care production of therapeutic proteins of good-manufacturing-practice quality.

G eneral requirements for Extractables and Leachables (E&L) are already mandated by regulatory agencies. Biopharmaceutical companies must meet these requirements in demonstrating equipment suitability and GMP compliance whether the equipment is of traditional design or single-use. However, because of the absence of specific regulatory requirements for extractables testing of SingleUse Systems (SUS) components, companies have needed to generate SUS extractables testing methods by extrapolating from their interpretation of regulatory requirements for existing container closure testing methods. Extractables testing studies conducted by suppliers of SUS for biomanufacturing comprise filling or soaking SUS components in model solvents, and testing the resultant extracts for compounds that were released to the solvent by the treatment. Exposure times and temperature ranges are extended to exaggerate the chemical conditions of actual use. However, there are currently no industry standards for such studies, and while solvents used are often more aggressive than what is typical in biomanufacturing, the full range of conditions encountered by SUS components in actual use is not always represented. In addition, this lack of standardization in extractables testing creates difficulties for end-users in interpreting and comparing test data from different SUS suppliers. Extractables testing study data provided by SUS suppliers must be well documented, reproducible, and readily interpretable in order for biopharmaceutical companies to use a scientific and risk-based approach in determining the readiness of various submissions to regulatory agencies. Current regulatory guidance requires that biopharmaceutical manufacturers ensure the manufacturing systems do not adulterate the final drug product. The end users have used SUS extractables testing data and leachables evaluation to assess potential risks to patients of the use of these components in product manufacturing. If extractables testing data provided by an SUS supplier are not sufficient to perform adequate assessment of risks, it is the time-consuming process for the biopharmaceutical company to conduct their own studies to generate sufficient extractables testing data. This results in the same components being tested multiple times and delay in applications of SUS in biomanufacturing. For a biopharmaceutical company to move a new drug molecule candidate through the clinical development process, the company first develops a position on the drug candidate that will be presented to regulatory agencies for concurrence. This position is applied to successive stages of the clinical development process, culminating in final process validation for commercial manufacturing and licensure. Regulatory guidance for Process Validation outlines three distinct stages: process design, process qualification, and process verification. Equipment design data for bioprocessing components, whether of traditional or single-use design, is required at each stage. Extractables testing is a key Reprinted from PHARMACEUTICAL ENGINEERING THE OFFICIAL TECHNICAL MAGAZINE OF ISPE

/pdf/standardized-extractables-testing-protocol-for-single-use-lny7wwbkj3.pdf

Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing

Quantifying the clearance of extractables and leachables (E/L) throughout ultrafiltration/diafiltration (UFDF) operations allows for greater flexibility in the implementation of single-use technologies in steps upstream of the UFDF process. A proof-of-concept study was completed in which the clearance of 7 E/L from single-use technologies (trimethylsilanol, hexanoic acid, butyrolactone, t-butyl alcohol, caprolactam, acetonitrile, and benzyl alcohol) in four representative proteins were measured and monitored during the UFDF process using quantitative NMR. This study demonstrated that the defined E/L spiked into a variety of protein solutions can be cleared to 1 ppm, which is explained in detail. The overall clearance trend observed for both buffer control and protein-containing solutions resembled the ideal clearance trend where no apparent interactions were observed between E/L with the protein, UFDF system, or with other defined E/L which may be present in the system. Additionally, the UFDF system is capable of clearing these potential E/L from single-use technologies below 1 ppm irrespective of initial concentrations in the load (1,000 or 100 ppm), independently from the type of protein. In general, mass recoveries were within ±15% of each spiked compound in protein solutions and their respective buffer controls, suggesting spiked E/L do not interact strongly with protein. By demonstrating the product independent clearance trends of the spiked E/L across UFDF, these results will contribute to the simplification of the E/L toxicology assessment and allow modular manufacturing approach for single-use technologies in biopharmaceutical manufacturing. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:718-724, 2016.

Clearance of extractables and leachables from single-use technologies via ultrafiltration/diafiltration operations.

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.

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

In addition to degradation products, impurities, and exogenous contaminants, industries such as pharmaceutical, food, and others must concern themselves with leachables. These chemicals can derive from containers and closures or migrate from labels or secondary containers and packaging to make their way into products. Identification and quantification of extractables (potential leachables) and leachables, typically trace level analytes, is a regulatory expectation intended to ensure consumer safety and product fidelity. Mass spectrometry and related techniques have played a significant role in the analysis of extractables and leachables (E&L). This review provides an overview of how mass spectrometry is used for E&L studies, primarily in the context of the pharmaceutical industry. This review includes work flows, examples of how identification and quantification is done, and the importance of orthogonal data from several different detectors. E&L analyses are driven by the need for consumer safety. These studies are expected to expand in existing areas (e.g., food, textiles, toys, etc.) and into new, currently unregulated product areas. Thus, this topic is of interest to audiences beyond just the pharmaceutical and health care industries. Finally, the potential of universal detector approaches used in other areas is suggested as an opportunity to drive E&L research progress in this arguably understudied, under-published realm.

The role of mass spectrometry and related techniques in the analysis of extractable and leachable chemicals

Single-use systems have been increasingly used in biopharmaceutical manufacturing processes. Despite their multitude of advantages, these plastic and elastomeric assemblies also draw concerns about chemical compounds that may migrate to finished products and impact product quality or safety. Evaluation of such extractables/leachables and their potential impact remains a challenge to many suppliers and end users. Based on extensive experience on filter extractables study, a practical and science-based approach for determination of extractables/leachables from single-use systems used in biomanufacturing has been developed. The general procedure is presented through a case study.

Determination of Extractables and Leachables from Single-Use Systems

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Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing

Determination of Extractables and Leachables from Single-Use Systems