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Active Pharmaceutical Ingredients (API) raw material variability is not always thoroughly considered during pharmaceutical process development, mainly due to low quantities of drug substance available. However, synthesis, crystallization routes and production sites evolve during product development and product life cycle leading to changes in physical material attributes which can potentially affect their processability. Recent literature highlights the need for a global approach to understand the link between material synthesis, material variability, process and product quality. The study described in this article aims at explaining the raw material variability of an API using extensive material characterization on a restricted number of representative batches using multivariate data analysis. It is part of a larger investigation trying to link the API drug substance manufacturing process, the resulting physical API raw material attributes and the drug product continuous manufacturing process. Eight API batches produced using different synthetic routes, crystallization, drying, delumping processes and processing equipment were characterized, extensively. Seventeen properties from seven characterization techniques were retained for further analysis using Principal Component Analysis (PCA). Three principal components (PCs) were sufficient to explain 92.9% of the API raw material variability. The first PC was related to crystal length, agglomerate size and fraction, flowability and electrostatic charging. The second PC was driven by the span of the particle size distribution and the agglomerates strength. The third PC was related to surface energy. Additionally, the PCA allowed to summarize the API batch-to-batch variability in only three PCs which can be used in future drug product development studies to quantitatively evaluate the impact of the API raw material variability upon the drug product process. The approach described in this article could be applied to any other compound which is prone to batch-to-batch variability.

Whether producing biologic or small-molecule drugs, pharmaceutical manufacturers (sponsors and contract service organizations) must manage a complex network of raw material suppliers, which provide chemical and biological materials; including starting compounds, intermediates, solvents, cell lines, yeast, bacteria, cell-culture media and feeds, excipients, production materials such as tubing, single-use manufacturing equipment and packaging materials, among others. Ensuring that the correct materials have been received and that they meet quality and other specifications (such as manufacture under GMP conditions) can be a daunting task. Extensive collaboration with preferred suppliers and reliance on third-party vendors that can handle some of the workload are two strategies that can help simplify the issue and reduce supply chain risk.

Growing Complexity

The overall pharmaceutical supply chain is complex due to the nature of the drug development and commercialization process, which can extend for several years. Extensive and ever-changing regulatory requirements for not only manufacturing processes, but also the transportation and import/export of materials from basic starting ingredients to pharmaceutical intermediates, APIs and drug products further complicate the situation given the increasing globalization of the industry.

For fine chemicals in particular, the growing complexity of the compounds being developed as drug candidates has resulted in more complex production routes requiring more steps (that might be performed at different facilities) and greater numbers of raw materials, including specialized compounds. An increasing percentage of drug candidates are highly potent and/or niche products for the treatment of smaller patient populations and require smaller volumes, leading to an increase in the use of multi-product manufacturing facilities.