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20 Pharmaceutical Technology ® Trends in Formulation eBook September 2024 PharmTech.com E xcipiEnts Excipients have always played a critical role in drug product processing, and there is a need for material innovation to enable further adoption of CM from tra- ditional batch manufacturing. Challenges and opportunities The information provided above has demonstrated how important excipient properties are to the success of CM. However, there are some challenges and op- portunities with the use of current excipients in CM processes such as the following: • Ultra-low-density materials, such as fumed silica, cannot be fed unless preblended. • High regulatory uncertainties related to CPEs. • Excipients need stronger PAT signals to distin- guish more easily from API spectra. • Excipients could help mitigate fouling of CM lines and enable more efficient clean in place (CIP). • There are few incentives for excipient innova- tion (e.g., FDA Pilot Program for the Review of Innovation and Modernization of Excipients [PRIME] [4]). Regulatory and industry perspective on how to mitigate risks Excipient attributes of ten var y between suppliers, even for the same grade. They may have differences in properties such as particle size and f lowability which can affect process variability in CM runs. As such, sourcing excipients for CM will likely lead to detailed negotiations in supplier quality agreements wherein compliance with the pharmacopeia monograph tests will not be sufficient and customer-specific tests and specifications will become more important. Considering that formulations with more excip- ients can potentially have more variabilit y when raw materials are sourced from different suppliers, co-processed excipients (CPEs, combinations of two of more excipients into one) can benefit both batch and CM processes. Particularly for CM, formulating with CPEs has the advantage of reducing the number of process feeders and simplifying the control strategy. Although advantageous for accelerating formulation design and maximizing process robustness, the use of CPEs present a supply chain risk as they are sourced from a single supplier. This risk needs to be discussed during supply agreement negotiations, in addition to the compliance / testing topics described earlier. For both batch and CM products, there is an expec- tation on the part of regulatory agency review staff that risks to finished product quality (CQAs) will be assessed and understood, critical material attributes (CMAs) identified, and risk mitigation strategies, in- cluding extra testing as needed, will need to be put in place. There is also an expectation that such informa- tion will be included in regulatory filings. The imple- mentation of risk mitigation strategies to reduce the impact of the risks identified in the risk assessment, including supply chain, will likely influence the final choice of excipients. Conclusion As CM becomes more common, excipients that tradi- tionally have been used may not provide optimal CM formulations. There will be a greater need for inno- vation and the use of new excipient technologies to provide enhanced properties designed for purpose in CM applications. It will be more important than ever to develop improved regulatory strategies to provide the incentives needed for this innovation. It is hoped that the development of FDA's PRIME program which allows for an independent safety as- sessment of different novel excipient types will open the door to the innovation needed to support success- ful implementation of CM going forward. References 1. PQRI. "Managing Excipient and API Impact on Continuous Manufacturing". PQRI Workshop May 17–18, 2022. 2. ICH. Q13 Continuous Manufactur ing of Dr ug Sub- stances and Drug Products, Step 4 (ICH, Nov. 16 2022). 3. IPEC. Incorporation of Pharmaceutical Excipients into Product Development Using QbD Guide (IPEC, 2020). 4. F DA. P i lot P rog ra m for t he Rev iew of I n nova- tion and Modern ization of Excipients (PRIME). FDA.gov. ■ Krizia M. Karry, PhD, is head of Global Technical Marketing, Pharma Solutions, BASF. Brian Carlin is president and owner of Carlin Pharma Consulting LLC. Nigel Langley, PhD, MBA, is global technical director at Gaylord Life Sciences and Immediate Past Chair, IPEC- Americas. R. Christian Moreton, PhD, is partner, FinnBrit Consulting. David R. Schoneker is president and owner of Black Diamond Regulatory Consulting. Katherine L. Ulman is owner and president of KLU Consulting LLC. Joseph Zeleznik is technical director North America at IMCD.