Module 3 - Strategic case studies in practice

Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)

10.3 Example 3: Presentation of a Design Space for a Biotechnological Drug Substance Unit Operation This example is based on a design space for a drug substance purification unit operation (Q-anion exchange column run for a monoclonal antibody in flow-through mode), determined from the common region of successful operating ranges for multiple CQAs. This figure illustrates a potential depiction of a design space based on successful operating ranges for three CQAs and the use of prior knowledge (platform manufacturing) in developing a design space. The ranges represented here indicate areas of successful operation. Operation beyond these ranges does not necessarily mean that drug substance of unacceptable quality will be produced, simply that these operating conditions have not been studied and therefore the quality of the drug substance is unknown. Viral clearance and Host Cell Proteins (HCP) ranges were derived from multivariate experimentation (see ICH Q8). The successful operating range for DNA was derived from prior knowledge (platform manufacturing) which in turn was derived from results of multivariate studies performed on related products. The successful operating range for HCP lies within the viral clearance and DNA successful operating ranges. In this example, the diagrams below show how HCP limits the unit operation design space compared to viral safety and DNA. Consideration of additional input variables, process parameters, or CQAs could limit design space further.

The design space is applicable only within specified conditions, including

1. Appropriately defined quality criteria for input materials;

2. Appropriately selected CQAs and process parameters.

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