Use Of Liquids And Soft Foods As Vehicles For Enteric Coated Bead Drug Product

By Amanda Connor

Client profile

This client is a global biopharmaceutical company, with a pipeline that primarily consists of treatments for rare and rheumatic diseases. Their mission focuses on overlooked or forgotten diseases, with a concentrated effort on improving the lives of the patients these marginalized diseases affect.

Product background

The client’s product of interest was a delayed-release capsule containing delayed-release enteric-coated microbeads used to treat a rare, genetic condition in adults and children. The design of this drug product is critical in ensuring the medicine releases in the small intestine instead of the acidic stomach and the coating of the beads is how this is controlled. The genetic condition for which this drug product treats usually presents symptoms within a child’s first year of life. Therefore, it was critical that the product be safe and effective in children and adults beginning at one year of age and older.

Partnering with Alcami

Alcami began its partnership with this client in 2013. Alcami’s vast experience in drug product formulation and development as well as analytical method development led the client to pursue the establishment of Alcami as their leading CDMO for all drug product manufacturing and analytical development and testing. The small molecule analytical development teams executed numerous in-use studies intended to support drug product formulation and optimization for this extremely complex drug product. As part of this growing partnership, when the client required an extensive in-use study to test the suitability of various liquids and soft foods as vehicles for administering this drug product to children, they looked to Alcami for their expertise in designing and performing unique compatibility studies.

At the time this study was initiated, the regulatory guidance was not yet fully established so the client and Alcami had to collaborate to determine how best to execute the testing. The purpose of these food studies is to determine suitable soft foods or liquids that can safely and effectively administer the drug product while maintaining patient compliance to the approved dosing. In order to test the viability of any food products the client wished to indicate as an option for administration, the following parameters were tested on the drug products before and after exposure to each food:

• Potency Drug product shows no significant change in assay
• Stability No formation of new degradants or change to release profile
• Dissolution Understand the effect of the vehicle on drug product release

Therefore, a method needed to be developed to expose the drug product to various foods and liquids then analyze the exposed drug products using validated methods for assay, related substances, and dissolution. If the food-exposed drug products were not significantly altered from a control drug product which was not exposed to the foods, then the food was considered a suitable vehicle for administration.

The client requested a total of 20 foods to be tested as potential vehicles in four groups of five foods. The diverse selection of foods was intended to provide multiple options for children worldwide to ensure patient compliance. Additionally, expedited testing was needed to support regulatory filing in multiple countries. With the extensive history and knowledge on this drug product and the associated analytical methods, as well as the widespread laboratory capabilities, Alcami was able to successfully test all 20 foods for suitability in the requested timeline.

Challenges and solutions

In order to accurately determine the impact of the foods on the drug product, a method had to be developed to first expose the drug product to the food then extract the product back out of the food before testing for potency, stability, and dissolution. For the purposes of determining the impact the food had on the drug product on potency and stability, an accurate assay result had to be obtained on the product after exposure. Additionally, because the drug product was intended to absorb in the intestines, testing had to be designed to ensure the enteric coating remained intact during exposure to the foods. The analytical dissolution method for routine Quality Control testing involves two stages: the acid stage is to ensure the enteric coating remains intact and the active does not dissolve in acid conditions (to mimic the stomach) and the buffer stage is to ensure the product released appropriately once it reached the pH in the intestines.

The method developed for the food exposure and extraction involved allowing the drug product to sit in the food being tested for the specified duration of time. Once the exposure was complete and the drug product beads were filtered out of the food, they could be tested for assay or dissolution. In order for the beads to be tested for potency using the assay method, they had to be completely dry which required additional steps after being extracted from the food and rinsed with the acid medium. During development, the food-exposed drug product beads were all dried to constant weight then a portion was prepared for assay testing and a portion for dissolution testing. The assay testing was successful and provided acceptable results for the dried beads. However, the dissolution testing, specifically the acid stage, of the dried product indicated that the enteric coating on the beads had been compromised as the percent of the active released in the acid stage was more than considered acceptable per product specifications (>10%). Therefore, additional development was performed in order to determine if the coating had been compromised by the food or by any of the other preparations. It was eventually determined that the drying step had compromised the coating, so the final study was performed with a separate food preparation for the dissolution testing which did not include a drying step.

Where are they now?

Alcami performed these studies on 20 total foods, and only three foods were determined to be unsuitable for the administration of this particular drug product. The data generated during this study provided multiple options for patients worldwide to more easily ingest this life-saving drug. The study was published by the client and referenced when the client filed their new dosage form for the drug product beads which were approved by the FDA in February 2020.

Alcami continues to support routine release and stability testing for both dosage forms as well as the drug substance. The partnership between the client and Alcami is and is expected to remain very strong for this product.

Key to success

The key to the most successful food effect studies is knowing the important details behind food selection

• Region – The region(s) where patients will use the product is critical to selecting foods that are available to the patient population
• Patient Group – The age and tolerance to various food substances as well as variety of food that should be studied is different for different age groups and conditions
• Solubility Profile – the solubility of the drug substance at various pHs is important for selecting appropriate food substance vehicles
• Physical Traits – the particle size distribution and knowledge of all potential polymorphs (if more than one) of the drug substance are critical for food selection and development of the experimental approach