A US manufacturer of a generic solid oral dosage form had multiple lot dissolution failures of a primary product in a highly competitive market. These lot failures caused a drug supply shortage with the client's marketing partners and under supply agreements could have led to financial penalties and potential loss of market share to competitors for the client. Pharmatech experts joined the client's own technical personnel in a cooperative team effort to identify and correct the root cause of the problem.


Identify root cause and implement process changes within regulatory constraints

Pharmatech will analyze mechanistic drivers of lot failures and design experiments (DOE) to identify root cause of lot failures. Relevant analytical methods will be assessed by Pharmatech for suitability by Measurement System Analysis (MSA). Pharmatech will propose solutions within the constraints of the regulatory environment (CBE 30 or better). Pharmatech will demonstrate the process changes are robust and reproducible.


Application of process variation analysis, DOE, and MSA

Pharmatech personnel integrated directly with the client’s engineering team. Twice weekly updates were provided by the team to maintain communication with the client’s senior management due to the criticality of the project. Pharmatech identified potential mechanisms for dissolution failures as due to a) coating thickness, b) coating surface area or c) permeability of the coating. Pharmatech implemented improved particle size measurement systems (static image analysis and cross-sectional SEM) to evaluate coating thickness and surface area mechanisms. Pharmatech designed experiments to explore factors, which could impact coating permeability. Process changes were implemented and multiple lots were produced under protocol to show that the process remained robust and reproducible.


Identified raw material and process water impact as root cause

Pharmatech implemented a new particle size measurement system to replace sieve analysis. The root cause as lot variation of coating polymer and process water content leading to variability of the coating permeability. Per Pharmatech recommendations, new coating polymer evaluation procedures were implemented by the client to screen out unsuitable lots. Quantitative Karl Fisher moisture analysis was introduced to replace qualitative method used to determine moisture content of solvents. Pharmatech recommended further process changes to reduce overall variation of dissolution results. Process remains robust and reproducible as further client work continues to improve raw material specifications and performance screening methods for the coating polymer.