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18 Pharmaceutical Technology ® Trends in Formulation eBook September 2024 PharmTech.com E XCIPIENTS FIGURE PROVIDED BY THE AUTHORS. performance. Given the limitations of material intro- duction into the continuous process, excipient per- formance then assumes greater importance in CM. Inherent risk mitigation in CM processes CM provides the ability to isolate non-conforming ma- terial without compromising the batch in its entirety. CM also mitigates much of the tech transfer risk asso- ciated with traditional batch manufacturing, primarily through elimination of scale-up. However, CM by itself does not mitigate raw material risk. Formulation design should be guided by the finished product CQAs regard- less of whether the product is manufactured continu- ously or batch-wise. CM reduces the process degrees of freedom relative to batch manufacturing, but not the impact of raw material variations. The output from a continuous manufacturing run is variable, dependent on run time, in contrast to the fixed output from a batch process, which is dependent on equipment size. The ICH Q13 guideline includes an example of a CM tablet noting that "the continuous process verification approach, coupled with appropriate regulatory action for reporting manufacturing changes, was used to validate run time extensions beyond cur- rent experience" (2). Excipient selection should consider potential risks from extended running, such as fouling of tooling. Excipients should not need tighter specifications in CM than in batch processing. The process should be de- signed such that any transient disturbances associated with raw material variability are averaged out according to the residence time distribution of the CM process. Ex- cipient variability may be more visible due to PAT, as the smaller working volumes in CM allow better temporal and spatial correlation with excipient variability. In CM, the significance of a disturbance is a func- tion of its magnitude and duration. The robustness of CM is demonstrated by the example in the ICH Q13 guideline where a disturbance of ±20% lasting less than 90 seconds would not cause the drug concentra- tion in the blend to exceed the 90–110% label claim. Similarly, for a ±5% disturbance of 300 seconds or 5 minutes, the product would still meet label claim. It is likely that CM will provide more insight into excipient impact especially if the greater amount of PAT data associated with CM can be subjected to multivariate analysis. The IPEC QbD guideline (3) provides methods for the categorization and control of excipients. Excipient traceability in drug product batches manufactured by CM In CM, traceability is defined as "the ability to track the distribution of materials throughout the manu- facturing process" (2). Traceability is required so that non-conforming material can be diver ted. Under- standing of the residence time distribution is required for traceability to control material diversion. Traceability is also required to determine where individual batches of an excipient occur in the out- put f inished product stream. If a second batch of an excipient is introduced into a CM run, there will be finished product initially containing excipient batch 1 on ly, then product containing increasing propor t ions of batch 2, a nd f i na l ly product w it h batch 2 only. Products may be conforming but the lo- cation of the transition material needs to be known in the event of a subsequent investigation or recall associated with an excipient batch. For this reason, it is advisable to time slice long runs into sequential smaller batches. The need for excipients designed for purpose The need for new excipients has never been greater nor the benefits clearer. Novel excipients with im- proved proper t ies ca n enable A PI solubi lizat ion, consistent product mass f low, more precise PAT measurements, and in some cases, better pharmaco- kinetic profiles with improved dosing regimens and higher product efficacy. In CM, co-processed excipi- ents (CPEs) have emerged as a fit-for-use alternative to simplify formulations. CPEs are multi-functional and have many of the desired functionalities required to develop CM drug products. The formulation approach is simple: combine the API with the CPEs via blending, and compress. The CM process approach with CPEs is also rather simple, as the manufacturer would only require a minimum of two feeders, when appropriate, greatly reducing the complexity of the control strat- egy compared to traditional five- to six-component drug products. FIGURE . Example of a funnel plot for the feeding of a drug substance. FIGURE COURTESY OF INTERNATIONAL COUNCIL FOR HARMONISATION [ICH]. COPYRIGHT: ICH, USED UNDER PUBLIC LICENSE.