QA/QC

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…

Viral Risk Evaluation of Raw Materials Used in Biopharmaceutical Production

Ensuring a continuous supply of safe medicines to patients is a key objective for both health authorities and the pharmaceutical industry. A critical component to that end is maintaining a reliable supply of qualified raw materials (RMs). Manufacturers must ensure not only the suitability of RMs for their intended use in a manufacturing process, but also their highest attainable safety with regards to viruses and other adventitious agents. The need to apply a risk-based RM control strategy is in line…

Investigation of Foreign-Particle Contamination: Practical Application of FT-IR, Raman, and SEM-EDS Technologies

The presence of visible foreign particulate matter is considered a critical defect in parenteral products and one of the main reasons they can be recalled (1). Foreign particles present during any stage of manufacturing are considered to be contaminants and can impose a risk to the control of the manufacturing processes (2). For those reasons, particle contamination arising in any manufacturing step initiates a nonconformance or out-of-specification observation. That requires an investigation to identify root cause so as to mitigate…

Science, Risks, and Regulations: Current Perspectives on Host Cell Protein Analysis and Control

State-of-the-art analytics guide process development by providing companies with thorough understanding, effective removal, suitable control, and comparability assessment after process changes of host cell proteins (HCPs) in recombinant biotechnology products. An array of analytical techniques and approaches can be used to establish control strategies for host cell proteins. Techniques used for HCP characterization and comparability include two-dimensional (2D) gel electrophoresis with a range of stains, 2D immunoblotting, 2D high-performance liquid chromatography (HPLC), 2D difference gel electrophoresis (DIGE), and increasingly mass…

Regulating Quality in Continuous Processing

Regardless of the industry and product being manufactured, continuous processing has demonstrated numerous benefits. In addition to smaller manufacturing footprints, reduced material consumption and waste generation, increased efficiencies, and lower capital and operating costs continuous manufacturing typically leads to more consistent processes and product quality. In the pharmaceutical industry, the latter two attributes align perfectly with FDA’s Quality by Design (QbD) and process analytical technology (PAT) initiatives. The challenge is determining how to apply these concepts in practice. Applying the…

Using Technology to Overcome Bioprocessing Complexity: Advanced Concentration and Analytical Technologies Accelerate Development and Manufacture of mAbs, Vaccines, and Biosimilars

Unlike chemically synthesized drugs, whose structure is known and reproducible, biological drugs are derived from living cells and are sensitive, complex mixtures requiring cutting-edge biological technologies for their production. The growing importance of biosimilars in recent years is reflected in a corresponding rise in market value. The value of the global biologic therapeutic drug market reached approximately US$230 billion in 2014 and, according to BCC Research, will increase to nearly $390 billion by the end of 2019. This corresponds to…

Critical Factors for Fill–Finish Manufacturing of Biologics

Over recent decades, protein-based therapeutics have emerged as key drivers of growth in the pharmaceutical industry. Drug development pipelines have filled with biologics, and a handful of monoclonal antibody (MAb) products have become some of the best-selling drugs around the world. Production of biotherapeutics is often challenging because of the inherent instability of these large, complex molecules. Their fragile nature has forced manufacturers to change how bulk drug substances (BDSs) are handled and final drug product is formulated, sterile filtered,…

Clearance of Persistent Small-Molecule Impurities: Alternative Strategies

Small-molecule impurities that bind to and copurify with protein biopharmaceuticals traditionally have been removed using bind-and-elute (BE) chromatography. However, that approach may be undesirable for a number of reasons. For instance, it may present a facility-fit challenge or provide a lower process yield than what is acceptable. A common scenario in which BE chromatography may be undesirable is in removal of unreacted conjugation reagents. Bioconjugates represent an important and growing class of pharmaceuticals that include PEGylated proteins, vaccines, and antibody–drug…

Best Practices for Critical Sterile Filter Operation: A Case Study

A number of regulatory guidelines recommend preuse integrity testing of critical sterilizing liquid filters for aseptic processing (1–3). Before sterilization, a preuse test will confirm that a filter is installed properly and was not damaged during shipment or handling. Performing a preuse test after sterilization detects damage that may have occurred during the sterilization cycle. Testing after sterilization limits risk, so it is a practice applied based on risk assessment. Because it is perceived to reduce business loss risk, preuse…

Fucosylation of a Therapeutic Antibody: Effects on Antibody-Dependent, Cell-Mediated Cytotoxicity (ADCC) Potency and Efficacy

Product quality attributes are critical for the functionality and manufacturability of therapeutic antibodies. They can be significantly influenced by a number of production process parameters, such as cell culture media. The composition of growth and feed media can influence antibody glycosylation, including the concentration of ammonia, glutamine, glucose, and metal ions (1, 2). Thus, it is critical during media development and optimization to monitor and consider a culture medium’s impact on glycosylation. For therapeutic antibodies whose mechanism of action includes…