Bo Kara, Ph.D., head, expression and cell sciences, at Avecia Biologics (www.avecia.com), discussed the application of PAT to biopharmaceutical production. “Adopting PAT is particularly appropriate for biopharmaceuticals. With small molecules, testing the product is easier because the structure is known and there are a lot of analytical tools. With biopharmaceuticals, testing is more complex, and you cannot test for everything. PAT is more about understanding your process and how you actually operate.”
Quality by Design (QbD) is a key element of PAT, which Dr. Kara defined as a process that ensures you achieve quality by careful, methodical scrutiny of all the attributes that go into the product and the process.
The PAT approach gives the biotech industry freedom to think more about analytical tools for process development and manufacturing, leading to more information about the product. It gives more assurance and more real-time data. It can involve technologies that lead to a greater knowledge of a protein’s properties such as its secondary structure and glycosylation patterns. It can also be about technologies that make measurements during, rather than at the end of, a process to get more information about the process and whether it is being carried out correctly.
Dr. Kara reported that at Avecia, they have been looking at the use of advanced chemometric tools, in collaboration with an academic group, within the PAT framework as well as at more conventional technologies, applying these to both products and raw materials. “The heart of PAT is to design a robust and reproducible process that works every time,” he explained.
According to Dr. Kara, PAT could have a big impact if the data it produces is used to correct for deviations. “At present, you have an operating window and you have to decide whether to carry on or not if there is a deviation, but PAT may allow for it to be corrected, which you can’t do now because of process validation. We are a long way from this at the moment though.”
PAT has great potential for helping the biotech and pharma industries improve key metrics such as On Time in Full (OTIF, a measure of the capability of the process to produce product when required), Right First Time (RFT, relating variability in product to specification limits), and CpK (a measure of process capability). A recent study reports that today’s pharma has an average of 60–80% for OTIF, 85–95% for RFT, and 1–2 for CpK, with biotech being on the low side of these figures and pharma plants somewhat higher. PAT could lead to near 100% for OTIF and RFT and around 3.2 on CpK, the study surmises.
Another measure that is much discussed in terms of PAT is Sigma level, which is a measure of failure rate and has been related to the cost of poor quality to an industry. Currently, a range of Sigma levels is found throughout industry—in semiconductors it is at level 8, with a vanishingly small failure rate; in the aircraft and automotive industries, it is at level 6 with a failure rate of around three per million (also expressed as a yield of 99.9997%); average pharma today is at 3 Sigma but aspires to 6 Sigma.
Research by IBM has highlighted the gains to be made through improving two different aspects of Sigma, which Dr. Kara noted, could be important for biotech manufacturing.
Process Sigma (PS) is derived from internal failure rates and is a measure of process robustness and understanding. Quality Sigma (QS) is derived from the ability of a quality system to prevent internal failures created by the production process “escaping” into the environment. According to an IBM analysis, pharma has far more to gain by investing in improving PS than QS. In other words, a focus on process understanding rather than improving QC is the way forward.
“PAT is not as new as people may think. Elements of PAT have already been applied in biotech, where the process is always the product,” concluded Dr. Kara. “PAT is not about one-off fixes, it is far more of a systems approach. There will be new tools, but PAT needs QbD and chemometrics and must be built into the whole system, from process development to manufacturing.”