Part 2 of a 2 part series
For the previous blog in this series, raw material testing programs were outlined, and common considerations for Contract Development and Manufacturing Organizations (CDMO) were discussed. In this section, the focus will be a specific example and highlight some of the thought processes behind raw material program development. Captisol®, a common formulation excipient for injectables, will serve as said example.
Captisol, or Betadex Sulfobutyl Ether Sodium, is a beta-cyclodextrin that is specially engineered to sequester active pharmaceutical ingredients (APIs) and increase their solubility, stability, and bioavailability. At least 11 commercial products (e.g. Abilify™, Celenia™, Kyprolis™) use Captisol as an excipient, and these formulations have seen 4-fold to 150,000-fold increases in solubility. These products belong to global pharmaceutical companies such as Pfizer, Amgen, Baxter, Merck, and Spectrum, amongst others. Needless to say, the demand for Captisol as a raw material is increasing.
When dealing with an excipient that sees use around the globe, a smart way to begin is by determining in which parts of the world the product will be marketed. For Captisol, let’s assume the product will be distributed in the USA and in Europe. Regulatory professionals and scientists should collaborate to determine which tests from the United States Pharmacopeia (USP) monograph and the, newly established, European Pharmacopoeia (EP) monograph will be necessary to confirm that the quality and identity of sourced Captisol meet the corresponding federal guidelines for its use as a raw material.
A brief survey over the two Captisol monographs (USP and EP) will reveal that, although the formatting is significantly different, the required tests and information needed for raw material confirmation is similar. Both monographs dictate that the excipient concentration is confirmed by liquid chromatography, the appearance and pH is evaluated for a defined solution, water content is determined by Karl Fischer moisture analysis, impurity B (1,4-Butane sultone) is quantified by gas chromatography, etc. Other than solution preparation and specifications, the two monographs agree strongly on which critical factors need to be evaluated for Captisol; however, there are some major differences.
Look closely and it is noticed that EP requires that the percentage of reducing sugars be enumerated by wet chemistry and absorbance spectroscopy. Also, the USP suggests capillary electrophoresis (CE) for determining the degree of substitution in Captisol, while EP puts forward nuclear magnetic resonance (NMR). Both tests aim to quantify the number of 1,4-Butane sultone chains that have replaced hydrogens on the anhydroglucose units of the beta-dextrose ring, but the USP method requires each possible substitution species (I-X) to meet specified percentage ranges whereas the EP method only requires the average degree of substitution to be reported.
Additionally, USP has impurity C, impurity D, and sodium chloride being quantified by ion-exchange chromatography, whereas the EP has those two impurities lumped into the liquid chromatography for impurity A and sodium chloride being measured by wet chemistry techniques. Lastly, both compendia require microbial enumeration/contamination and specified organism testing, but the specifications and required organisms differ. Only the USP requires bacterial endotoxin testing.
In short, aside from endotoxin testing and reducing sugar content, the two monographs agree on which factors are critical to the quality of Captisol. In this example; however, special care and planning would be crucial for establishing a thorough raw material testing program that is efficient and respects the major differences between the monographs. Attention to detail would be paramount to avoid unnecessary errors caused by minor differences between the monographs (Don’t forget to run a Nitrogen overlay if you plan to perform EP pH testing!). Communicating clearly with your analytical testing lab and putting energy into planning upfront will save time, money, and frustration in the long run.
Singota has been certified as a qualified analytical testing facility by Ligand, the owner of Captisol and its unique technology. Contact us at email@example.com if interested in a quote or if you have inquiries regarding Captisol or other raw material testing.