Practical Considerations for Demonstrating Drug Substance Uniformity

The authors describe considerations and best practices for meeting drug substance uniformity.
Apr 01, 2011


Drug-substance uniformity is an important consideration for the final step in the manufacture of drug substance/active pharmaceutical ingredient. Uniformity studies are necessary to ensure that the entire contents of the batch are homogenous and that the drug substance specification sample is representative of the batch. This paper describes considerations for drug-substance uniformity, such as selection of appropriate test parameters and sample points, and approaches to establishing acceptance criteria. Additionally, operational considerations and best practices to ensure robust and consistent drug substance filtration and uniformity are described.

The final step in drug-substance (active pharmaceutical ingredient, API) manufacture is typically a 0.2 µm filtration step. This filtration step serves as a final clarification of the process pool and also as a bioburden control measure prior to the storage and further processing of drug substance (DS) to drug product (DP). There are many technical considerations to ensure a consistent and robust bulk filtration step, for example:

  • Selection and sizing of the filter
  • Materials of construction for the DS containers and tubing for transfers
  • Filtration equipment procedures
  • Filter preparation to reduce extractable and leachable components
  • Container–closure integrity.

One aspect that must not be overlooked is the DS uniformity (or homogeneity) which is discussed in this article. When designing validation studies, it is important to consider the stringent regulatory expectations for ensuring batch uniformity and integrity of drug products (1).

The DS may be filtered into single or multiple vessels. In the former case (single agitated vessel), uniformity considerations are mixing speed and mixing time prior to taking a sample that is representative of the entire contents of the vessel. In the latter case, it is necessary to demonstrate uniformity between the DS containers. The initial concentration of product effluent from the filter may be expected to be slightly lower than the rest of the pool due to dilution with residual flush solutions in the filter pores and housing assembly, as well as due to non-specific protein or excipient adsorption to the filter. Thus, uniformity acceptance criteria should take into consideration an asymptotic increase in concentration during a reasonable initial product volume. This paper describes risk-based approaches to establish rigorous acceptance criteria and define operational parameters to ensure consistent DS uniformity.