Smart specification setting for dry powder inhalation carriers

Dry powder formulations are generally produced by mixing micronized drug particles with larger carrier particles. Lactose monohydrate is by far the largest commercially utilized excipient as a carrier1. Lactose characteristics, such as particle size distribution, highly affect the aerosol performance of a powder2. Mixing coarse with fine lactose, in combination with influencing other properties, provides formulators a means to optimize the aerodynamic behaviour of a final DPI blend. Studies have shown that the inclusion of fine particles can significantly increase in the respirable fraction of the drug³. Control on the particle size of lactose, and especially the fines content is therefore crucial 4.

All production processes however, including the production processes for inhalation grade lactose monohydrate, have some inevitable degree of variation 5. Production processes can shift amongst others due to equipment getting older, variation in conditions, human intervention and variability of starting materials. The occurrence of variations does not mean that a process is out of control. It refers to the fact that not all batches are exactly the same and that the impact of variations on the final dosage form should be understood. Formulators should ask themselves which ranges of variation are acceptable for their formulation, to maintain efficacy and safety of the final product. Additionally, the impact of variation (e.g. lactose variability) can be minimized and controlled. Such evaluation should include the entire scope of potential variations and their effect on the full set of critical to quality attributes.

One way to control the particle size of the lactose carrier is the application of pre-set particle size distribution specifications. A specification refers to a defined test method with specified acceptance criteria. Most commercially available inhalation lactose grades are supplied with pre-defined specifications. For unique, customized grades of lactose however, specifications should be agreed upon by the supplier and the user. Specifications are proposed and justified by the applicant during registration of a drug product, and they need to be approved by the competent authorities. For changes in the registered specification, applicants must assess the effects of the change through appropriate studies.

For suppliers, particle size specifications indicate which level of variation is acceptable by the users and should therefore be in line with the capability of the production process. For the users, particle size specifications ensure that commercial products can be manufactured robustly over the entire lifecycle of a product. Manufacturing processes should be developed in such a way that starting material variation does not impact the performance outside the acceptable limits.

This paper evaluates two extreme strategies for the agreement of specifications between suppliers and users. The first strategy considered is based on evaluation of the production capabilities of a supplier only. The second strategy focuses on understanding the effect of variability on the final performance, in line with Quality by Design (QbD) principles.