Downstream Validation

Investigation of HCP Enrichment During CGMP Scale-Up

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On paper, scaling a bioprocess from a 10-L to a 100-L to a 2,000-L bioreactor may seem like a straightforward math problem that could be solved by software. In practice, however, the exercise relies on a complex set of biological, chemical, and engineering assumptions; on maintenance of healthy cell cultures; and on management of equipment and analytics while adjusting to each increase in scale (1). Process development and quality control groups need to monitor how scale-up might affect critical quality…

October 20, 2022

Host-Cell Protein Analytics: History and Future Trends

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Different analytical methods have been developed to detect host-cell proteins (HCPs) in bioprocess streams. Advancements in such methods are enabling biomanufacturers to optimize their purification processes and ensure that their products are safe and efficacious. To celebrate the 20th anniversary of BioProcess International, Ken Hoffman (founder of Cygnus Technologies) provides insights into the history, trends, and future of HCP analytics. History: 1990s to 2022 The recombinant therapeutic protein industry was in its infancy in the early 1990s. HCPs were recognized…

August 22, 2022

Managing Host-Cell Proteins: Robust Risk-Assessment Frameworks for Process-Related Impurities in Biological Products

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Although biomanufacturing processes are designed to generate highly pure drug substances, some host-cell proteins (HCPs) copurify with target proteins and thus remain in finished drug products. Biopharmaceutical developers are keenly aware that such impurities must be minimized to protect patients. HCPs can activate several kinds of immune responses in treated patients, including production of antidrug antibodies and induction of cross-reactivity with therapeutic proteins (1–5). HCPs also can diminish drug efficacy, potency, and/or stability (6, 7). Thus, regulatory guidances such as…

May 20, 2022

Mycotoxin Risk Determination: Measuring the Potential for Patient Exposure with Antithrombin Alfa Sourced from Transgenic Goat Milk

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Antithrombin alfa is a recombinant human antithrombin developed as an anticoagulant treatment for people with hereditary antithrombin deficiency who are undergoing surgical or childbirth procedures (1). Marketed under the ATryn brand name by LFB SA (Les Ulis, France), antithrombin alfa was approved for use in adults by the US Food and Drug Administration (FDA) in February 2009 (2). Antithrombin alfa is expressed in the milk of transgenic goats and purified through a multistep downstream process encompassing both filtration and chromatography.…

March 16, 2022

Multivariate Data-Driven Modeling for Continued Process Verification

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Continued process verification (CPV) is an integral part of process validation for the manufacture of human and animal drugs and biological products (1). It is designed to meet three primary goals: maintain a validated state of products, their processes, and related systems; enable continuous process improvements; and meet regulatory requirements for life-cycle validation. A CPV program for a biologic product entails regular collection of data related to critical process parameters (CPPs) and critical quality attributes (CQAs) and the preprocessing, analysis,…

October 28, 2021

Risk Determination of Potential Mycotoxin Exposure to Patients: Testing Recombinant Human Factor VII from Transgenic Rabbits

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Sevenfact eptacog beta is a new recombinant human factor VIIa (rFVIIa) developed by LFB SA in Les Ulis, France, as a bypassing agent (BPA) for treatment and control of bleeding in people with hemophilia A and B and inhibitors (1, 2). The product was approved for use in adults and adolescents by the US Food and Drug Administration (FDA) in April 2020 (3). It is expressed in the milk of transgenic rabbits and purified through a multistep process using both…

October 28, 2021

eBook: Process-Related Impurities — Emerging Strategies for Detection, Identification, and Management of Host-Cell Proteins

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Host-cell proteins (HCPs) represent a major class of process-related impurities (PRIs) that are generated during biopharmaceutical manufacture. Although the vast majority of such proteins are removed from a drug substance during downstream purification, residual HCPs can remain in a finished drug product. Even in minimal concentrations, copurifying HCPs can pose safety risks and compromise protein-product yield, efficacy, and stability. Thus, regulatory agencies consider the presence of HCPs to be a critical quality attribute (CQA). Sufficient clearance of these impurities helps…

July 28, 2021

Virus Assay Variation Is the Main Source of Variation in Viral Clearance Studies: Retrospective Analysis of a Large Data Set

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Biopharmaceuticals produced from mammalian cell cultures are susceptible to viral contamination. That risk is mitigated by applying complementary approaches. Those include extensive testing of cell banks, selecting low-risk raw materials, testing cultivations for viruses, and documenting the capacity of a purification process to inactivate and remove viral contaminants. The latter commonly is referred to as viral clearance and usually expressed as a log reduction value (LRV). Novo Nordisk has performed several viral clearance studies for different processes and process steps.…

April 16, 2021

HCP Assay Development: Managing Risks with Evolving Technologies

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Host-cell proteins (HCPs) are major impurities of concern in biomanufacturing. When present in drug formulations, they can reduce efficacy (by compromising product stability), introduce toxicity, and increase a recipient’s risk for long-term immunogenicity. Understanding HCP profiles and integrating effective removal strategies are important parts of developing new biological drugs — to fulfill regulatory guidelines and to ensure patient safety through product quality. HCP populations can be both complex and structurally diverse, and some changes in upstream culture conditions can affect…

March 9, 2021

Emerging Strategies for Drug Product Comparability and Process Validation: Part 1 — Analytical Tools and Drug Product Comparability

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Process validation is a key part of the development and manufacture of all approved drug products, but its completion can be a daunting task. At a two-day CASSS CMC Strategy Forum held in July 2016 in Gaithersburg, MD, speakers and attendees addressed the many technical, practical, and regulatory facets of drug product process validation and comparability. In part 1 of this report, we summarize the key discussion points of the first day, which focused on analytics and comparability. Session One:…

March 9, 2021