Development of biopharm products is driven by quality, time to market, and cost, and it is these factors that have forced an evolution to state-of-the-art analytical test methods that have gradually replaced old tried-and-tested approaches. There has always been a healthy conflict between the need to progress and improve methods, balanced against the greater certainty of traditional methods. So as time goes by and confidence is gained, the state of the art becomes the next generation of tried and tested. But the progress is not always either continuous or straightforward.
This article illustrates some factors and pitfalls that influence progress from tried-and-tested methods to state-of-the-art ones. After the principle factors of quality assessment are summarized, examples are provided from the author's experiences during the past decade where different driving factors have forced replacement of old methods with new. And as a demonstration that new is not necessarily better, in one example the problems encountered with the new method forced a return to the old.
Biomanufacturing Revolves Around Quality and Testing
Reliable quality data is the focus of all regulatory investigation and licensing. Analytical testing is necessary during biomanufacturing to demonstrate high levels of control and quality, thus providing confidence that the final active product is consistently pure, efficacious, and safe. The scope of analytical testing encompasses every stage of manufacture, from master cell bank to final batch release testing and stability studies. This testing is not limited to actual product testing, as it is also essential to monitor the performance and quality of the manufacturing facility itself.
A potentially huge amount of analytical data is produced during routine biomanufacture, typically generated by numerous orthogonal technologies. Analytical development is, therefore, essential to ensure that the information provided is usable and focused. Fundamentally this involves the application of the most suitable analytical techniques, in terms of sensitivity, specificity, and regulatory acceptability. Many of these techniques are now well-established and have been optimized for their application; however, their development for new applications is continuing.
Figure 1a. Structural Features of Example Biopharmaceuticals.
So What Defines Product Quality
Biological medicinal products form a broad range of product types including nucleic acid, proteins (Figure 1), viruses, and cell therapies. The development of biological materials as therapeutic agents requires the comprehensive assessment of quality with regard to regulatory guidelines such as those of the International Conference on Harmonisation (ICH) (Figure 2). The quality of a biotech product is defined by both the product itself, which should be both characterized and consistent, and the manufacturing process, which must be both validated and reproducible.
Figure 2. ICH Guidelines Applicable to Manufacture of Biotech Products16
The assessment of product quality is determined using several criteria including:
- Physico-chemical properties
- Biological activity
- Immunochemical properties
- Purity, impurities, and contaminants
A well-characterized product1 is critical during development, both to establish batch-to-batch consistency, and to establish analytical tests and specifications for process control and product release (Figure 3). In addition, the assessment of product stability relies on the adequate product characterization prior to and during a stability testing program.
Figure 3. Characterization Testing as the Basis for Choosing Suitable Quality Control Tests