By Peter Hagwall, Strategy Manager for Process Development Tools

The need for deeper process understanding grows with the increased molecular diversity in the pipeline. For instance, new critical quality attributes (CQAs) associated with these novel formats means more attention must be paid to sources of variability. Many factors can give rise to process variability, such as variation in different process parameters or raw materials. This article focuses on process robustness and the impact of chromatography resin attributes as well as how to identify which parameters and interactions to focus on in your process characterization studies.

Literature covering impact of resin attributes

The effect of resin attributes on chromatographic performance is well known from the basic theory. However, most of the published examples relate to ranges of attributes that are typically broader than the specification ranges for commercially available resins.

From a process robustness perspective, it is more relevant to examine the effect of variations within a tighter range corresponding to the actual variation of the resin manufacturing process. Published examples of such studies are less common simply because most purification processes are robust enough to accommodate small variations in resin attributes.

A recent white paper on understanding sources of process variability lists examples of publications that indicate that resin attributes can impact the outcome of biopharmaceutical processes. It also shares a summary of observed process-specific impacts in some of our resin development projects.

Risk assessment support for quality by design (QbD)

One of the central concepts of QbD, as well as stated in ICH Q8 guideline (1), is the focus on a risk-based approach. The efforts to reduce variability should be based on an assessment of the potential impact on the quality of the drug substance.

There is a lot of focus placed on establishing best practices and tools for such risk assessment procedures. The output of this assessment will guide you on what parameters, attributes, and interactions to include or focus on in the process characterization studies.

The general steps in a QbD-aligned risk assessment procedure

The first step of a risk assessment procedure focuses on gathering existing knowledge of the unit operation. This includes, for example, information about the purpose of the unit operation, the protein properties, and critical process parameters (CPPs).

In the second step you identify factors that might impact the process outcome. This article discusses only resin attributes and interaction effects with process parameters, but there are many other factors that could potentially affect product quality and process performance (Fig 1).

It is important to remember that process parameters like load ratio and, pH, and conductivity are more likely to have an impact than resin attributes in any given process. This fact is reflected in the current practice of focusing on the process parameters first during process characterization.

Fishbone diagram showing chromatography resin as one of the multiple factors that might affect purity in biomanufacturing downstream processes.

Fig 1. Fishbone diagram (Ishikawa diagram) showing chromatography resin as one of the multiple factors that might affect purity.

The final step in the risk assessment is process- and potentially product-specific. It must therefore be performed by the process development team. It is, nevertheless, valuable to include existing experience from chromatography resin manufacturers in this step.

Our recommendations for when to study resin variability

As a resin manufacturer, we can provide risk assessment support based on the experience we’ve collected from our resin development DoE studies and interactions with biopharmaceutical companies.

Table 1 outlines a risk assessment support matrix for chromatography process characterization studies. In this table, we have assessed the different chromatography techniques on a graded scale from “Considered robust” to “Characterization recommended”. Even though this is a much simplified view that does not include CQAs, it can add basic insights.

The typical process parameters studied in process characterization (e.g., load ratio, pH, and conductivity) are also graded for comparison. It is important to acknowledge that interactions between process parameters and resin attributes are possible.

The impact of elution conductivity can, for example, have interaction effects with ligand density in cation exchange chromatography. It can also have interaction effects with salt level and resin hydrophobicity in hydrophobic interaction chromatography (HIC).

Table 1. Risk assessment support matrix for chromatography process characterization studies

Chromatography technique Mode Process parameters Resin ligand density1 Resin based matrix properties
AIEX B/E
 
 
 
FT
 
 
 
CIEX B/E
 
 
 
FT

Not applicable / not assessed

HIC B/E
 
 
 
FT
 
 
 
Multimodal CIEX B/E
 
 
 
FT

Not applicable / not assessed

Multimodal AIEX B/E
 
 
 
FT
 
 
 
Protein A affinity B/E
 
 
 
FT

Not applicable / not assessed

1Ligand density is typically represented by model protein retention for HIC resins

B/E = Bind/elute, FT = Flowthrough


 
Considered robust
 
Characterization to be considered
 
Characterization recommended

To get the full details and more recommendations, download the white paper on understanding and addressing sources of process variability.

DOWNLOAD NOW

References

  1. ICH Q8(R2), Pharmaceutical Development, International Council for Harmonisation (2009). [Online.] www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf. Accessed 01 July 2019.

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