Issue link: https://www.e-digitaleditions.com/i/1138630
34 July 2019 Tablets & Capsules Pharmaceutical manufacturers have long recognized that magnesium stearate is a problematic excipient. Can the variability found by Delaney et al. explain at least some of the performance variability seen with magnesium stearate? Applying other spectroscopic methods, such as near infra-red (NIR) and Raman spectroscopy, to excipi- ents on a regular basis may further enhance our knowl- edge of their characteristics and variability. Creation of new grades of existing excipients. As dis- cussed previously, continuous manufacturing puts addi- tional constraints on excipients. It might not be possible to overcome these constraints using existing excipients and grades. Excipient suppliers may be able to develop new excipient grades to meet the needs of continuous or other advanced manufacturing methods, but only so much leeway exists within an excipient's monograph definition and specification. Potential users may be reluctant to use excipients that exceed those bounds, since revising a phar- macopeia monograph takes time. Many companies prefer to use materials that comply with the monograph because the regulatory filing is more straightforward. Development of new co-processed excipients. Co-processing has great potential to solve many prob- lems related to continuous pharmaceutical manufacturing and/or other advanced manufacturing technologies. Co-processed excipients can provide functionalities and performance that non-co-processed excipients most likely won't be able to achieve. Co-processing may also be a means to incorporate excipients at low levels with- out requiring an extra feeder and/or avoiding the prob- lems associated with metering poorly flowing materials. For example, using the co-processed excipient silici- fied microcrystalline cellulose (SMCC) is a convenient way to add colloidal silicon dioxide to the continuous manufacturing train while simultaneously enhancing direct-compression carrying capacity or post-wet-granu- lation compactibility compared to adding the individual components separately. This concept of ease of addition of low-concentration excipients could possibly be extended to other materials, such as lubricants, surfac- tants, and disintegrants, and even to APIs. Other co-processed excipients are available that may find application in continuous manufacturing. Functional- ities and/or performance characteristics for which co-pro- cessing may provide the solution could include improved blend-segregation resistance; improved compaction for both direct-compression and wet-granulation applica- tions; and improved hot-melt processing. • Understanding the variability of the critical mate- rial attributes (CMAs) of the excipients and/or APIs and determining how this variability impacts the drug product's critical quality attributes (CQAs). The CMAs may include some properties in the pharmacopeial monograph specification but will likely also include additional physical or chemical characteristics. As with any drug product development process, whether batch or continuous, you must also address other factors, such as bioavailability, manufacturability, and the chemical and physical stability of both the API and the dosage form, among others. Routinely manufacturing an acceptable finished drug product requires: • Creating segregation resistance in the final blend, even for continuous direct-compression processes. This involves adequately dispersing the API throughout the blend to achieve both content uni- formity and bioavailability—particularly for some poorly water-soluble APIs—and maintaining that dispersion until manufacture of the final unit dose (by forming an ordered mixture, for example, in which the blend components adhere to each other to form ordered units); • Ensuring the flowability of the final powder blend into the tablet die or through the capsule dosing mechanism to achieve acceptable weight and con- tent uniformity; and • Ensuring the compactibility of the final blend for tableting or consolidation during encapsulation. Excipients and continuous manufacturing Excipients will play an important role in the transition to continuous pharma manufacturing, and the industry can facilitate that transition by encouraging progress in the following areas: • Improved understanding of the excipients currently in use; • Creation of new grades of existing excipients; • Development of new co-processed excipients; and • Development of new chemical excipients. Improved understanding of current excipients. For- mulators should consider using excipient-characteriza- tion methods beyond the methods in the pharmacopeia monograph and the traditional functional-assessment methods, such as compaction of powder blends to assess lubricant performance. This may involve using analytical methods not traditionally associated with excipient characterization. For example, Delaney et al. used solid-state 13 C-nuclear magnetic resonance (SS 13 C-nmr) and other characteriza- tion methods to investigate magnesium stearate from dif- ferent commercial sources and were able to show that at least three, and possibly four, types of magnesium stearate were commercially available [2]. The data also suggested that a batch-to-batch variability can exist in magnesium stearate from the same supplier. Co-processed excipients can provide functionalities and performance that non-co-processed excipients most likely won't be able to achieve.