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.

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-Pass Tangential Flow Filtration (SPTFF) in Continuous Biomanufacturing

The inhibiting effect of the secondary phosphite antioxidant degradation product bis(2,4-di-tert-butylphenyl)phosphate (bDtBPP) on cell growth is well-known. The present study describes structurally related compounds which are likely to be formed from similar widely used phosphite antioxidants used in materials for the manufacturing of single-use (SU) equipment. Two potential candidates of such compounds-3,3',5,5'-tetra-tert-butyl-2,2'-dihydroxybiphenylphosphate (TtBBP) and bis(p-nonylphenyl)phosphate (bNPP)-were identified by chromatography and mass spectrometry followed by synthesis and X-ray structure elucidation. Additionally, the formation of TtBBP was confirmed in an analytical degradation study and its migration from SU bioprocessing material was estimated. The cytotoxicity evaluation by means of cell culture spiking experiments and flow cytometry analysis revealed that' even if cell growth was inhibited by all the compounds to some extent, bDtBPP showed the most severe effect and stoods out from the other two degradants investigated. Graphical abstract.

Identification and evaluation of cell- growth-inhibiting bDtBPP-analogue degradation products from phosphite antioxidants used in polyolefin bioprocessing materials

Using extractables data from single-use components for extrapolation to process equipment-related leachables: The toolbox and justifications.

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

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Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing