QA/QC

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Response to the Publication of USP ‹1207›

The BioPhorum Operation Group’s (BPOG’s) Container Closure Integrity Testing (CCIT) workstream would like to congratulate the United States Pharmacopeia’s committee for its latest revision to USP chapter <1207> Package Integrity Evaluation: Sterile Products. Generally, we believe it provides a comprehensive overview of the available methods for container–closure testing and outlines many important elements for consideration in establishing a successful CCIT strategy. We first responded to the USP <1207> draft when it was released for comment in 2014. And from our…

Microsoft Word - CHO HCP for BioProcess Sep2016.docx

HCP Antigens and Antibodies from Different CHO Cell Lines

Cell lines derived from Chinese hamster ovary (CHO) cells are widely used in therapeutic protein production because they can perform human-compatible posttranslational modifications, they are easy to use for manufacturing, and they do not propagate most human pathogenic viruses (1, 2). Expressed therapeutic proteins are secreted into CHO culture supernatant along with impurities originating from the host cells themselves. Such host cell proteins (HCPs) are important contaminants for monitoring because they directly affect drug quality, safety, and efficacy. HCPs are…

Figure 1: Proposed mechanism for the formation of the drug substance degradation product (2)

Setting Raw-Material Specifications Using Prediction Models: Determination of a Specification Limit for a Raw-Material Impurity in mPEG-Aldehyde

Impurities related to raw materials used for bioproduction can be inadvertently introduced into a manufacturing process, causing potential failure to meet in-process controls or release specifications. Unexpected impurities also can reduce yield and affect the quality, safety, and effectiveness of a final product (1). Raw-material impurities can originate from starting components or reagents used in manufacture. They can be generated in situ during synthesis or as degradation products. Impurities also can result from improper handling, packaging, and storage. Identification and…

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Special Report on Process- and Product-Related Impurities (A CMC Strategy Forum Special Focus Series): Extractables, Leachables, Particles, and Aggregates

The CMC Strategy Forums focus on relevant chemistry, manufacturing, and controls (CMC) issues throughout the life cycle of a therapeutic and thereby foster collaborative technical and regulatory interaction. Forum chairs share information with regulatory agencies to help them merge good scientific and regulatory practices. Outcomes of forum meetings are published in BioProcess International and on the CASSS website (www.casss.org). This process is meant to help ensure that biopharmaceutical products manufactured with advancing technologies in a regulated environment will continue to…

Figure 1: Immunoglobulin G (IgG) structure consists of four polypeptide chains, including two identical light chains (~25 kDa) and two identical heavy chains (~50 kDa). Each light chain consists of one constant domain (CL) and one variable domain (VL), and each heavy chain consists of three constant domains (CH1, CH2, and CH3) and one variable domain (VH). The Fab is the antigenbinding region containing hypervariable or complementarity-determining regions (CDRs), whereas the Fc region is highly conserved across molecular species. The hinge region contains two disulfide bonds and glycosylation (shown as red dots) at CH2 domain of Fc fragment.

Biosimilar Therapeutic Monoclonal Antibodies: Gaps in Science Limit Development of an Industry Standard for Their Regulatory Approval, Part 2

Last month, Part 1 of this discussion briefly described the regulatory landscape for developing biosimilar therapeutic monoclonal antibodies (TMAbs). We identified certain specific structural components of TMAb drug substances that warrant particular attention because alterations to them are likely to affect therapeutic safety and effectiveness. Now we conclude by considering whether studies of reference materials can further the development of analytical industry standards to ensure comparability of putative biosimilar TMAbs with innovator TMAbs. We suggest that the time is right…

Figure 2: Intact ESI-MS spectra of both nonsuccinylated and succinylated proteins; upper figures represent the full charge envelope of the two proteins, and lower figures illustrate a narrower m/z charge range. Each m/z charge state of the nonsuccinylated protein was observed to be a primary species, whereas significant heterogeneity was seen for the charge states of the succinylated protein.

Mass Spectrometric Conjugate Characterization: Process Qualification of Recombinant Protein–Hapten Conjugation

Conjugated protein biotherapeutics such as PEGylated proteins (with polyethylene glycol), antibody–drug conjugates (ADCs), and protein–haptens often present unique analytical challenges related to characterizing the conjugation aspect of their manufacturing processes. Analytical characterization of this class of proteins requires knowledge of the sites of conjugation, the degree of conjugation, and the drug-to-protein ratio. Here we present case studies in development of reliable methods based on mass spectrometry (MS) to characterize a protein–hapten drug substance during late-phase process validation. This protein is…

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Providing Lipids Boosts Protein Productivity: Testing a Feed Supplement with Multiple Cell Clones and Media Formulations

As the biologics (and now biosimilar) markets continue to grow, pressure increases on biomanufacturers to reduce cost of goods sold (CoGS). One way they can reduce cost is by increasing protein productivity in terms of protein titer per volume of culture. Media optimization is a key strategy for increasing protein productivity. In the past few decades, average titers across the industry have increased greatly — from <0.5 g/L in the 1980s to >3 g/L today, and it is not uncommon…

Figure 1: Core protein engineering technology; scaffold protein is shown in yellow, and the fused protein of interest (e.g., cell-adhesion protein, enzyme, or single-chain antibody molecule) is shown in blue.

Advanced Protein Engineering Enhances Biopharmaceutical Manufacturing and Analytics

Production of proteins for pharmaceutical use is a complex, multistep process that requires technologies for purifying such molecules from highly complex biological mixtures. It also calls for reliable, cost-effective, high-throughput analytical techniques to determine protein quality and functionality to ensure the safety and efficacy of end-products. Mistakes in product development and manufacturing not only are immensely costly, but they can also put patients at risk. Many well-established processes and analytical tools are available for use in manufacturing antibody drugs (e.g.,…

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Special Report: A Strategy for Cost-Effective Capture Using Agarose-Based Protein A Resins

It is well recognized that the cost of Protein A resins is substantial. If a developmental monoclonal antibody (MAb) makes it to marketing approval and manufacturing, the high cost of purification using a Protein A resin is amortized over a large number of purification cycles, and the contribution to cost of goods is reduced to acceptable levels. However, a high percentage of clinical projects will fail, and the Protein A resin will be used only for a small number of…

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Progress Toward Commercial Scale and Efficiency in Cell Therapy Bioprocessing

Regenerative medicine includes both cell and gene therapies. Currently 672 regenerative medicine companies operate around the world, and 20 products have been approved by the US Food and Drug Administration (FDA). Of 631 ongoing clinical trials by the end of 2015 (1), over 40% are in oncology, followed in prominence by cardiovascular and infectious diseases. Here I focus on gene and cell therapy bioprocessing in which the final products delivered to patients are cells. Cell therapies are either autologous (derived…