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14 October 2020 Tablets & Capsules Excipient standards This leads to the next question of how we should control excipient quality. What standards and specifi- cations should we apply on a routine basis for our application? When we think about excipient standards, the pharmacopeia monograph is an obvi- ous starting point, as the monograph is concerned with confirmation of the excipient's identity and fitness for purpose. Even in the absence of a pharmacopeia monograph, there is an expectation that the excipient will comply with a specification akin to a pharmacopeia monograph. In addi- tion, the FDA expects that the excip- ient will have been manufactured to an appropriate standard of cGMP. Since there is no single universal test to assess excipient performance and each formulation will have subtle differ- ences in an excipient's performance requirements (func- tionality), the pharmacopeia monograph cannot possibly cover all the performance nuances across an excipient's entire spectrum of applications. Performance specifica- tions are properly the joint responsibility of the excipient user (pharmaceutical manufacturer) and the excipient sup- plier. This is in line with the current thinking on QbD [4]. Quality by Design In QbD, a product developer is required to demon- strate an enhanced understanding of the product's com- ponents and manufacturing process, as they affect the quality of the finished product. The development orga- nization assesses the risk factors (material attributes and processing parameters) that have the potential to impact the finished product's critical quality attributes (CQAs). The organization then undertakes a series of studies (design of experiments (DoE)) to evaluate how these fac- tors will impact the product's CQAs and note those that can have an impact. Based on the DoE results, the orga- nization establishes a design space and control strategy incorporating the critical material attributes (CMAs) and critical process parameters (CPPs) identified as having the potential to impact finished-product quality. Excipient specifications Often, an excipient CMA for a particular applica- tion will be outside the monograph specification, so the excipient user and supplier must negotiate and agree to a control for that excipient characteristic. For an excip- ient user to unilaterally impose a non-monograph spec- ification on an excipient is a recipe for disaster. If the excipient supplier is not made aware, how can they be expected to control for a parameter that is not in their specification? The same is true for excipients where no Note that the variance (σ2) has been used because variances are additive. The "interactions" term is deliberately plural and may contain many different components relating to factors such as how the operator loads the blender, material cohe- siveness, material adhesiveness, and others. To have the best chance of developing a robust product, we need to reduce all the variability contributions to below an accept- able maximum, including the excip- ient variability. Excipient composition For bulk APIs, the purity of the material is linked to efficacy and pos- sibly the reduction of side- effects. The mantra "safety, purity, and effi- cacy" applies. Excipients, by contrast, are very often mix- tures of materials with major and minor components, and the minor components may contribute to the overall per- formance of the excipient in a particular application. For example, the compactibility of coarse-grade dibasic cal- cium phosphate dihydrate is influenced by the presence of foreign ions in the crystal lattice, which cause dislo- cations and weakness, allowing brittle fracture to take place. Very pure coarse-grade dibasic calcium phosphate dihydrate does not compact as well. However, in general, the exact relationship between excipient composition and excipient performance is not well understood and will vary with each application. Excipient monographs are evolving, and there is an effort to develop more specific tests that can better determine the excipient's composition. However, there is still a lot of work to be done, and we do not have methods to determine the composition of all excipients. Excipient performance Before we examine the standards to be applied to excipients, it is necessary to examine how excipient per- formance arises. How an excipient performs in a given application must be some function of the excipient's chemical structure, chemical composition, chemical prop- erties, physical properties, physical state, and morphol- ogy (if it is a solid). The impact of these different factors will vary with the particular formulation. We can begin to see how the interaction term in the product variability equation can be very complex, since there is the possibil- ity of both chemical and physical interactions between the API and excipients, between excipients, and also between the API, excipients, and process. The interac- tions may involve a minor component of the excipient rather than the major component, since excipient per- formance is frequently dependent to some extent on the presence of minor components. To have the best chance of developing a robust product, we need to reduce all the variability contributions to below an acceptable maximum, including the excipient variability.