QbD and PAT in Upstream and Downstream Processing - BioPharm International talks to industry experts about the implementation of QbD and PAT tools in biopharmaceutical manufacturing - BioPharm

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QbD and PAT in Upstream and Downstream Processing
BioPharm International talks to industry experts about the implementation of QbD and PAT tools in biopharmaceutical manufacturing


BioPharm International
pp. 28-37

DOWNSTREAM PROCESSING
BioPharm: In implementing QbD, what would you identify as the CQAs in a typical downstream bioprocess in which the product was produced using cell culture?

Weber (CMC Biologics): This is probably the most difficult question to answer. We have found the CQAs for downstream are very product dependent. Glycosylation and sialylation are definitely two outputs that require product and product quality understanding and are the most common across different cell-culture processes. After that, variation in the product profile begins to manifest itself too much, preventing universal CQAs to be established.

McKnight (Genentech): Some CQAs are generated in, or substantially changed by, certain downstream unit operations. Size variants or charge variants, for example, may be generated during hold times, and product quality attributes such as host-cell proteins and size variants are typically reduced through the purification process and controlled to an acceptable level by consistent purification process performance.

Rathore (IIT Delhi): The downstream process attributes would be similar to those mentioned earlier for upstream processing. These include process-related impurities (e.g., antifoam, additives added during the processing, Protein A leachate), host-cell impurities (e.g., host-cell proteins), and product-related impurities (e.g., aggregate, basic variants, acidic variants, glycoxylation pattern). The big difference is that the ease of measurement of these attributes improves significantly in downstream processing as the samples are relatively cleaner.

BioPharm: In implementing QbD, what would you identify as the CPPs in a typical downstream bioprocess in which the product was produced using cell culture? What are the most difficult parameters to control and why?

McKnight (Genentech): Chromato-graphy unit operations are typically most sensitive to the pH and ionic strength of wash and elution conditions. Control of these critical buffers is managed through batch preparation and release prior to use based on acceptable pH and conductivity ranges. Process capability is sufficient to reproducibly prepare buffers within narrow pH and conductivity ranges, such that only a subset of the most sensitive buffers are typically determined to be CPPs.

Rathore (IIT Delhi): Typical CPPs in downstream processing would include parameters such as pH, conductivity, temperature, and gradient for chromatography steps; temperature, agitation rate, and sparge rate for refolding steps; and pH and hold time for the viral inactivation step. The challenge in downstream processing mainly comes from the fact that the steps are relatively short in duration. For example, a typical elution in chromatography column may be 3060 minutes. Our ability to measure and then take action, therefore, is quite challenged if the assay is not a real-time assay (such as HPLC).

Johanning (QAtor): CPPs in a typical downstream process involving cell culture include holding time, pH control, temperature control, and UV control. UV control/cutting is the most difficult parameter to control because UV cutting techniques/equipment are still an area for further development. They relatively often challenge batch release (out of specification).

Vanden Boom (Hospira): Originator and biosimilar products have similar downstream CPPs. For chromatography steps, these may include protein load, pH (load or elution depending on step), temperature, flow rate, and conductivity for ion-exchange steps. Viral inactivation steps may have temperature, pH, or detergent concentration as a CPP depending on the modality of inactivation. Pressure and filter volume represent CPPs for viral filtration steps. Again, if engineering controls permit tight control of these parameters, some may be downgraded to a lower parameter designation.

Weber (CMC Biologics): Using a QbD approach, downstream CPPs would be proposed only through using risk assessments of the possible impact to pre-identified CQAs. Downstream CPPs will vary greatly depending on the nature of the molecule, the purification strategy, and the order and timing of unit operations. Nevertheless, there are certain potential CPPs common to many downstream processes. The following list of operations/parameters is potentially responsible for affecting product quality/CQAs, particularly toward the end of a purification process. Not all of these would necessarily end up as CPPs:

  • Viral inactivation: pH of inactivation, time of inactivation, and concentration of inactivation solution
  • Viral filtration: filter load density (mg/mL membrane) and filtration pressure
  • Chromatography operations: load density, pH and/or conductivity of buffers, residence time, volumes, and eluent concentration
  • Filtration operations: load density, transmembrane pressure, crossflow rate, and diafiltration diavolumes.

The most difficult parameters to control are those with narrow allowed ranges. Using QbD, well-designed DOEs are intended to grant maximum flexibility in defining allowed ranges.

BioPharm: What tools are typically used to measure CPPs and the resultant process inputs and outputs in a downstream process, including PAT tools?

McKnight (Genentech): CPPs for chromatography operations frequently include pH and conductivity of the most sensitive wash or elution buffers. Control of these critical buffers is managed through batch preparation and release prior to use based on acceptable pH and conductivity ranges. This practice predates the PAT initiative, but serves the intended purpose of PAT.

Rathore (IIT Delhi): The same aforementioned tools would be applicable here as well as we are measuring the same attributes. As mentioned previously, the difference lies in the fact that the samples are much cleaner and hence easier to analyze. However, the time for decision is significantly less, thus making PAT implementation more of a challenge.

Weber (CMC Biologics): Put simply, the right downstream equipment for chromatography and filtration should have built-in monitoring of all potential CPP parameters and should cover a wide range of operational values. This can either transmit out for a PAT approach, or can allow for well-designed process monitoring.


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