Downstream Validation

Degradation of Biopharmaceuticals During Cleaning Processes: Comparing Two Different Analytical Methods for Assessment with Bispecific Antibodies

Before June 2015, pharmaceutical manufacturing of certain types of drugs required dedicated facilities. The European good manufacturing practice (GMP) guidelines state that to minimize the risk of cross-contamination, “dedicated and self-contained facilities must be available for the production of particular medicinal products, such as highly sensitizing materials (e.g., penicillin) or biological preparations (e.g., from live microorganisms). The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs, and nonmedicinal products should not be…

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Process Validation: Calculating the Necessary Number of Process Performance Qualification Runs

The 2011 process validation (PV) guidance document from the US Food and Drug Administration (FDA) states that the number of samples used for PV “should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches. The confidence level selected can be based on risk analysis as it relates to the particular attribute under examination” (1). In alignment with those expectations, I present herein two statistical methodologies for calculating the necessary number of process performance…

Investigation of HCP Enrichment During CGMP Scale-Up

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…

Host-Cell Protein Analytics: History and Future Trends

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…

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

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…

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

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.…

Multivariate Data-Driven Modeling for Continued Process Verification

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,…

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

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…

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

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…

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

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.…