Unique Considerations for Process Development for Biopharmaceuticals

Process development and characterization studies are primarily performed at laboratory scale to make them cheaper and faster. Therefore, developing a representative scaled-down model is crucial to meaningful process characterization and successful process-fit analysis. For example, scale-down of a fermentation step may involve keeping the scale-independent parameters (such as process temperature, pH, inoculation percentages for each step, and times of feed media additions) at the same control set point as the large-scale process, assuming similar vessel geometries, and changing the mixing and air flow rate to mimic the conditions at large scale. Qualifying such scale-down models before their use in process characterization studies is key to establishing a representative design space.

Before defining a cell culture process, the manufacturer may perform a clone selection (in the case of mammalian or microbial expression systems). A suitable clone must be selected from a number of available clones for establishment of the master cell bank. The clone selection should be based on the quality target product profile (QTPP) and a risk assessment. Parameters determining the selection will be a combination of product quality attributes (e.g., impurity profile) and process performance (e.g., specific productivity per cell, consistent yield), usually assessed at small scale. Prior knowledge of process parameter ranges, existing cell culture platforms, and literature data will play a significant role in clone selection. This could be combined with a mechanistic approach. Alternatively, DOE could be applied for a multivariate approach if a larger number of parameters are investigated.

For cell culture unit operations, a risk assessment should be performed to select the process parameters and the drug substance or drug product quality attributes to be investigated in a systematic approach (e.g., DOE). The risk assessment will take into account the type of host cell and expression system, prior knowledge, platform technologies, and knowledge from the clone selection and literature data, and should include raw materials and their impact on CQAs. Process parameters selected are those that may have an effect on quality attributes that are linked to the identity, strength, quality, purity, or potency of the product and may ultimately relate to the safety and efficacy of the product. In addition, those process parameters are commonly investigated that affect various aspects of process performance, such as product yield. There may be cases when CQAs cannot be measured in the cell culture broth because of interference from other components present in the sample matrix or other limitations associated with the analytical assay. To evaluate the influence of cell culture process parameters on quality attributes for such cases, it may be necessary to process the output from some of these small-scale experiments over the subsequent process steps until adequate product quality determinations can be made.

The process steps are tightly linked, with the output of the previous step serving as the input to the next step. The focus in cell culture is on consistency, productivity, product integrity, and freedom from contamination. The focus of purification is on purity and freedom from process and related materials.

For drug substance purification and drug product formulation steps, the same principles, as outlined for cell culture, apply for the establishment of a design space. Whereas in cell culture, the individual steps of the process differ mainly in terms of scale, container type, and culture media, each purification unit operation may comprise a distinct technology. This situation provides the opportunity to establish a design space for each unit operation, as well as to combine several different unit operations in a certain order to ensure the desired quality of the product.