Talecris Biotherapeutics (Research Triangle Park, N.C.) manufactures treatments for rare genetic conditions, including primary immune deficiency diseases and hemophilia. The raw material for these products is nothing less than human plasma, itself potentially at risk from infection by viruses or organisms such as pathogenic prions.
At the front end, a strict blood-donor screening process and in-house plasma sample testing ensure that starting materials are safe, says Todd Gierman, Ph.D., assistant director for nucleic acid technology (NAT) testing. Barcoded containers of samples are transferred from donor sites to the company’s manufacturing facility in Clayton, N.C., where they are pooled. There, they undergo further testing using a combinatorial process that was developed in-house, which allows 96 test samples to be evaluated as one. Talecris as been the first plasma fractionator so far to test all plasma in-house, says Gierman.
Raw material then undergoes rigorous pathogen safety testing to determine that pathogens — critical as well as emerging concerns — are not present, says Nathan Roth, Ph.D., a leader of the company’s Pathogen Safety Team. The tests are followed by virus removal or inactivation steps that ensure the safety of final product.
Using a milliliter-scale version of the actual manufacturing process, clearance tests are then performed. "We identify critical process parameters and then test at the extremes of these parameters, and use them to establish control setpoints," says Roth. "Testing robustness at process extremes provides a large safety envelope for any process parameter."
During testing, the starting material is first spiked with pathogen, and the amount of infectious agent in the material is measured before and after processing. Even material that meets all specs is then subjected to viral inactivation or removal, depending on the pathogen of greatest potential risk. Inactivation methods include use of dry heat, low pH, caprylate, solvent or detergent, supercritical fluids or irradiation, while removal is accomplished via some combination of polyethylene glycol (PEG) precipitation, chromatography, depth filtration or nanofiltration. The bioproteins are extremely delicate, so the process must be conducted carefully.
Only after all material has undergone all these steps does it reach the actual manufacturing plant. After manufacturing, careful cold chain management ensures product safety once the medication leaves the plant. We interviewed SVP of operations Mary Kuhn to learn how the company ensures quality during production.
PM – How do you determine which parameters are critical to product quality within the manufacturing plant?
MK – It’s important to monitor key parameters during critical process steps. One must also analyze data trends so that you catch problems before they become issues. Even a slight change may indicate a problem. For Talecris, bioburden trending and environmental monitoring are extremely important; we also monitor process steps that could damage the protein, impact purity or viral clearance if done incorrectly.
PM – Can any of this be done in real time?
MK – Due to their nature, the microbiological monitoring tests are done off-line. For monitoring process steps, we are starting to look at where we can utilize Process Analytical Technology (PAT) to obtain real-time results.
PM – Are you using interdisciplinary teams to accomplish this?
MK – We have a strong interdisciplinary culture within our Talecris operations, and a process in place, which starts with the management team. I’m the Chair of that team, which includes representatives from engineering, quality, manufacturing, supply chain and support functions such as HR, finance and technology. We meet weekly to rapidly identify key issues that our operations are facing.
Our team strives to set an example for the rest of our organization. Within each processing facility, we have also established multi-functional teams called business units, in which different functional areas are represented. These teams meet to discuss the issues that their specific area is facing. For instance, filling and freeze drying has a business unit team.
By meeting frequently with all cross-functional partners, issues can be communicated and addressed quickly. For instance, by reviewing environmental monitoring data almost on a daily basis, the business unit team can detect a trend early on and isolate it down to a specific piece of equipment or area of room and take action before it has a quality impact to the product.
PM – You’re not using electronic batch recordkeeping technology at the facility. How do you make the data and the process transparent?
MK – All process data is collected in a system called “BioMan.” Most of the data is trended manually and summary reports issued. We’re in the process of implementing software to automate the data mining process for even more sophisticated analysis.
PM – Talecris has an active PAT program in place. What role is PAT playing in this overall quality program?
MK – PAT is a very important initiative for Talecris to further enhance monitoring and control of critical parameters. By linking PAT with automation, we can achieve real-time quality assurance as well as integrated data management and analysis ability across the entire process.
PM – Can you give any specific examples of how you are applying PAT right now?
MK – We’ve been using PAT very successfully to monitor pH, a critical parameter for bioprocessing. It also has been implemented in our WFI [Water for Injection] system for monitoring quality of the water.
PM – Does Six Sigma play a part in your overall quality programs?
MK – We’ve had continuous improvement teams in place for three years, tied back to each business unit, but now we’re getting people trained as [Six Sigma] Green Belts.
PM – Are you using any other methodologies? How about FMEA?
MK – We started using FMEA late last year, and find it extremely useful. Identifying what could fail in your process from any aspect — i.e., equipment failure, human error, how you would know it had failed and in what time frame — gives you a good road map to risk mitigation strategies.
PM – Optimizing patient safety is critical, but have all these quality and continuous improvement efforts shown any bottom-line impact to date?
MK – We’ve had a “gross margin improvement program” in place for about a year, targeted to overall margin improvement. It’s focused on improving yield, overall efficiency, equipment and raw material utilization, and reducing reject batches. This year, the project has focused on processes, systems and tools, as well as cultural issues, and has achieved a 10% improvement in gross margin.