Therapeutic protein formulation is no easy task. Biological drugs may be destined for prefilled syringes or glass vials, or they may be made into lyophilized powders that will be reconstituted in a clinical setting. No matter what their final state will be, recombinant proteins must remain potent and efficacious during storage. In recent years, pharmaceutical companies have turned increasingly to high-concentration protein formulations. Such drug formulations can offer patients the convenience of self-injection — instead of a trip to the hospital for an intravenous infusion treatment.
But these new formulations present a problem. Higher concentrations can exacerbate already existing tendencies for proteins to behave poorly. Such formulations are more likely to form aggregates that can reduce potency or even, perhaps, incite an immune-system responses. High-concentration formulations also tend to be more viscous, which can interfere with the plunging action of prefilled syringes. These principles apply to ...
Sponsors developing and manufacturing protein therapeutic products use a number of analytical tests (e.g., cell-based potency and chromatographic assays) to assess quality attributes of their active ingredients and drug products. Tests are conducted for a number of purposes, including characterization, comparability, lot release, and confirmation of stability.
This two-part article includes the findings of the California Separation Science Society (CASSS) Chemistry, Manufacturing, and Controls (CMC) Strategy Forum titled “Reference Standards for Therapeutic Proteins: Current Regulatory and Scientific Best Practices and Remaining Needs,” held in Gaithersburg, MD, on 15–16 July 2013. The discussion also is based on findings of previous CASSS reference standard meetings, two workshops held during the WCBP conferences in 2012 and 2013, and the conference “Reference Standards for Therapeutic Proteins: Their Relevance, Development, Qualification and Replacement” (
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,
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,
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,
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,
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). The latter was coorganized...
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Implementing continuous process improvements is increasing in priority for the biopharmaceutical industry. Such implementation can be driven by product safety, purity, and stability enhancement opportunities as well as by cost-reduction pressures. Companies invest in projects to improve product quality assurance, safety, and yield as well as production efficiency (
1
). Such changes may come at any process stage, from early cell-growth methods through final-product packaging improvements. Examples include growth medium optimization, purification column operation optimization, and enhanced recovery during final filling (
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). Continuous improvement and innovation projects often call for changes to licensed processes that require validation, but not necessarily animal or clinical studies.
PRODUCT FOCUS:
RECOMBINANT PROTEINS
PROCESS FOCUS:
PRODUCTION
WHO SHOULD READ:
PROCESS DEVELOPMENT, ANALYTICAL,...
+2Single-use components such as tubing, connectors, and filters have been widely used for many decades in bioprocess unit operations. Users have been able to identify and quantify the specific benefits of single-use over cleanable systems. In more recent years, many other process components have been designed for disposability such as bioreactors, mixers, and chromatography and ultrafiltration systems. Those and other advances have made it possible to incorporate multicomponent, presterilized manifolds into both existing and new processes, realizing benefits such as reduced cleaning, shortened set-up times, increased production throughput, and enhanced sterility assurance.
Although such developments have raised the possibility of developing fully disposable multistage processes, some unit operations have not been easy to convert to single-use because of limitations on scalability, costs, performance, and/or the unavailability of single-use options. One operation in which single-use technology is becoming mo...
Risk assessment is used as a vetting tool to determine areas of influence and uncertainty regarding key factors for critical responses. It helps biopharmaceutical companies build both product and process knowledge during development. Every formulation, unit-operation characterization, and design optimization should begin with risk assessment and ends with an understanding of sensitivity, the quantified influence of key factors, improved control logic, edge-of-failure determination, and a qualified design space.
Quality risk management (QRM) is an essential element in every aspect of drug product and substance development and manufacturing throughout a product's life cycle. According to ICH Q9, QRM is designed to ensure that each drug's critical quality attributes (CQAs) are defined and maintained from phase to phase during product and process development and manufacturing (
1
). Regarding changes in drug-product formulation, definition, analytical methods, and manufacturing process operations, companies u...
The concept of “lean thinking” is applied with increasing frequency in a number of industries, including biopharmaceutical manufacturing, to eliminate waste and optimize workflow.
Lean thinking
refers to focusing on standardizing processes within workplaces to minimize redundancies and improve value. Safety also is important to every workplace, especially in biopharmaceutical manufacturing because it uses process chemical ingredients. By embedding attention to safety into the practice of lean manufacturing, companies can improve employee buy-in of lean initiatives while reinforcing the importance of safe practices. This combined philosophy allows companies to improve both workplace safety and efficiency.
Although safety and lean programs may seem to have disparate goals, the two are more intertwined than many people may think. The eight wastes targeted by lean initiatives are commonly identified as underused talent, waiting, defects, unnecessary movement, excessive product transportation, extra inventor...
Recently I spoke with editorial advisor Hazel Aranha (manager of viral clearance and safety at Catalent Pharma Solutions) about viral contaminants and risk management. A recognized expert in the field, Aranha contributed “Current Issues in Assuring Virological Safety of Biopharmaceuticals” to BPI's March 2012 issue and was interviewed by Ellen Martin for her September 2012 article, “Legacies in Bioprocessing.”
BPI:
Have there been any recent viral transmission incidents that you can share to highlight the concern over this issue?
Aranha:
Fortunately, to date, biopharmaceutical products have had an excellent safety record, and we have not had any virus transmission of pathogenic virus — and I stress the word
pathogenic
— associated with their administration. That said, there have been instances of contaminated manufacturing batches and environments. There have been reports of batch contamination with mouse minute virus (MMV) and other adventitious virus contamination of manufacturing environments. Even...
In 1982, authentic human insulin produced in genetically engineered
Escherichia coli
(under the trade name Humulin, from Genentech) was the first recombinant protein to be licensed by regulatory authorities for therapeutic use. That licensure and the subsequent production of human growth hormone heralded a new era of biopharmaceuticals and were the first examples of the industry's future potential. Both proteins are produced as fully active biologicals in
E. coli.
Insulin and human growth hormone are fairly simple small proteins, without complexities such as posttranslational modifications, which are required for many bioactive glycoproteins.
E. coli
bacteria are ideally suited for producing small proteins, primarily because of their extensive genetic and metabolic characterization, fast growth rate, fermentation ability at very high cell densities, and relatively low costs associated with large-scale production. However, bacteria lack the genetic, metabolic, and posttranslational mechanisms required...
