What are Key Performance Indicators in Pharmaceutical Manufacturing?
Key Performance Indicator (KPI) is a metric for the status of each step in a pharmaceutical manufacturing process. KPIs and KPI measurement are related to critical quality attributes and therefore influenced, as well, by the critical process parameters. The KPIs should indicate that each production step proceeded as expected giving confidence that in the end the CQAs will be within the appropriate limits.
Collected process data are used in case of need for root cause analysis or for process characterization studies based on experimental design (e.g. for scale-up and scale-down). PAT will be best fulfilled when CQAs and KPIs can be directly measured with high frequency. Common KPIs in a bioreactor include:
KPI Examples in Manufacturing Biopharmaceuticals
Product Quality and Product Titer
The main goal of bioreactor operation within a manufacturing plant is to produce as much product as possible with the quality needed to make it functional for its therapeutic purpose. Quality and yield are important as the product often requires further purification in downstream processes that may cause additional modifications or losses.
The most important biopharmaceutical products are monoclonal antibodies, recombinant proteins, or other types of therapeutic proteins (like vaccines). Therefore, bioprocess CQAs are often considered attributes specific to the protein’s quality such as the glycosylation patterns or molecular-size distribution. The most commonly used KPI at the bioreactor is the total protein titer and eventually, specific titer for the protein type (e.g. IgG).
The most promising results for in-situ measurement of product titer and quality have been obtained with spectroscopic technologies, which have the same limitations described for nutrient and metabolite measurements. Likewise, HPLC, mass spectrometers, NMR, fluorescence or super-resolution microscopy, capillary electrophoresis or biochemical analyzers installed at-line or off-line are often seen as more reliable solutions to quantify the mentioned CQAs and KPIs at the bioreactor. Again, sterile sampling technologies and procedures make these quality attributes and process indicators limited with respect to PAT control guidelines.
Total and Viable Cell Density
Other Key Performance Indicators successfully used for in-situ control at the bioreactor are Total Cell Density (TCD) and Viable Cell Density (VCD). TCD indicates the total amount of cells in the bioreactor, while VCD is an indicator of the viable cells (alive and still productive). VCD is directly correlated with final product yield and is thus of high importance. Different off-line measurement technologies have been established over the years. For example, total cell density, as well as viable cell density, can be measured via off-line automated cell counter systems. A major disadvantage is that these methods are based on time-consuming sampling procedures which reduce the possibility that the cell growth is monitored in a process-safe way compatible with PAT principles. For this reason, several efforts have been put forth over the years to find technologies suited for accurate and reproducible real-time measurements.
Some efforts for real-time cell density are based on the use of molecular spectroscopy, others on soft sensing techniques (e.g. algorithms based on the evolution of OUR and CER), both requiring MVDA to generate application specific calibrations which are labor intensive to maintain.
The most reliable measurements are obtained using near-infrared light sensors to measure culture turbidity in microbial fermentations (representative of TCD) or by using capacitance sensors to measure viable cell density (especially for mammalian cell cultures). Information from these two measurement types can also be used to determine cell viability. Turbidity and capacitance are currently the most common technologies used in production processes to measure TCD and VCD in real-time. These sensors can withstand autoclavations, CIP, and SIP cycles to meet hygienic standards.
White Paper: How Does PAT Apply to the Bioreactor?
Your All-Inclusive Guide to Quality Attributes, Critical Process Parameters, and Key Performance Indicators at the Bioreactor
This 20-page white paper provides a comprehensive, but accessible, overview of requirements and recommendations related to the FDA’s Process Analytical Technology (PAT) initiative for the biopharmaceutical industry.