Libervant™ - Diazepam buccal film for the treatment of acute seizures

On April 29, 2024 Aquestive Therapeutics, Inc. (NASDAQ: AQST) announced the FDA has approved Libervant™ (diazepam) Buccal Film for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy between 2 to 5 years of age. According to the news release, the film is placed onto the buccal mucosa inside the cheek where it adheres firmly and dissolves quickly, delivering a consistent dose of diazepam. (1)

On March 28 2023, Aquestive Therapeutics, Inc. announced it expanded its exclusive license and supply agreement with Atnahs Pharma UK Limited (“Pharmanovia”), a global pharmaceutical company that revitalizes, extends and expands the lifecycle of established medicines, for Libervant™ (diazepam) Buccal Film to cover the rest of the world, excluding the United States, Canada, and China. The original licensing agreement with Pharmanovia announced in September 2022 covered the European Union, United Kingdom, Sweden, Switzerland, and Norway, as well as countries in the Middle East and North Africa (MENA).

Libervant™ has several favorable characteristics and overcomes many of the disadvantages of other nonparenteral dosage forms used for acute seizure treatments. The thin film, which is less than the size of a postage stamp, is affixed to the buccal mucosa inside the cheek. Placement can be either by the patient or by a caregiver. Diazepam is absorbed transbucally and is also swallowed, so that a portion of the dose is transported to the stomach and absorbed by the small intestine. The polymer hydroxypropyl methylcellulose is used to hold diazepam and excipients in a uniform distribution throughout the film. Because of the uniform distribution, the dose can easily be adjusted by cutting the film. The film has a mucoadhesive surface so that it adheres to the buccal mucosa. It begins to dissolve immediately on application to the mucosa releasing diazepam. In studies with fasted healthy male volunteers, DBF doses of 5 mg to 15 mg exhibited rapid absorption and linear dose-proportional pharmacokinetics.

REFERENCES

(1) Aquestive Therapeutics Receives U.S. FDA Approval and Market Access for Libervant™ (diazepam) Buccal Film in Pediatric Patients Ages 2 to 5 and Provides Update on Anaphylm™ (epinephrine) Sublingual Film, Globe Newswire, Aquestive Therapeutics, Inc., Mon, Apr 29, 2024, 4:00 AM PDT.

(2) Aquestive Therapeutics Expands License and Supply Agreement with Pharmanovia for Libervant™ (diazepam) Buccal Film to Additional Global Markets Globe Newswire, Aquestive Therapeutics, Inc., Wed, Mar 29, 2023

(3) Michael A. Rogawski et al, Diazepam buccal film for the treatment of acute seizures, Epilepsy and Behavior, 101(2019) 106537.

Outline of CMC for vaccines

Here's a breakdown of CMC specifically for vaccines:

Chemistry:

• Drug substance - the antigen component itself, which can be:
  • Inactivated or attenuated viruses or bacteria
  • Purified proteins or carbohydrates derived from pathogens.
  • Recombinant proteins expressed in cell cultures.
  • Nucleic acids (DNA or RNA) encoding antigens.
  • Conjugates of antigens with carrier molecules.
• Drug product - the final, injectable form of the vaccine, containing the drug substance formulated with:
  • Adjuvants: Enhance immune response.
  • Preservatives: Maintain sterility.
  • Stabilizers: Prevent degradation.
  • Excipients: Fillers, buffers, etc.
• Analytical methods - specific methods are established to characterize and quantify the antigen, impurities, and excipients.
• Raw materials and excipients - selection and qualification to ensure purity, consistency, and suitability for vaccine production.

Manufacturing:

• Process development: Designing a scalable and reproducible process for antigen production, purification, formulation, and filling.
• Process validation: Demonstrating the consistency and control of the manufacturing process through extensive testing.
• Quality control: Implementing measures throughout the process to ensure product quality and adherence to specifications.

Controls:

• Stability studies: Evaluating the vaccine's shelf life under various storage conditions.
• Packaging and storage: Defining appropriate packaging and storage protocols to maintain potency and sterility.
• Batch release testing: Each batch undergoes rigorous testing to ensure it meets all quality standards before release.

Additional considerations for vaccine CMC:

• Highly sensitive materials: Many vaccine components require careful handling and processing to avoid degradation or contamination.
• Aseptic processing: Ensuring sterility throughout the manufacturing process is crucial for vaccine safety.
• Regulatory requirements: Stringent regulations govern vaccine development, manufacturing, and testing, demanding detailed documentation and compliance.

For details, please review FDA guidance listed in the section of resources.

Resources:

• FDA Guidance: Content & Format CMC for Vaccine & Related Product. Accessed on Feb 07, 2024.
• Maria Monica Castellanos, CMC Strategies and Advanced Technologies for Vaccine Development to Boost Acceleration and Pandemic Preparedness, Vaccines (Basel). 2023 Jul; 11(7): 1153

Outline of CMC for Biologics

 CMC (Chemistry, Manufacturing, and Controls) is a critical aspect of bringing biologics, such as vaccines, blood products, and gene therapies, to market. It ensures that the biologics are safe, pure, potent, and consistent between batches.

Here are the key steps involved in CMC for biologics:

1. Chemistry:

   • Characterization of the biologic drug substance and drug product, including its structure, purity, and stability.
   • Development of analytical methods to measure these attributes.
   • Selection and qualification of raw materials and excipients.

2. Manufacturing:

   • Development of a robust and scalable manufacturing process that consistently produces a high-quality product.
   • Validation of the manufacturing process to ensure it meets all regulatory requirements.
   • Implementation of quality control measures throughout the manufacturing process.

3. Controls:

   • Development of stability studies to determine the shelf life of the biologic.
   • Development of packaging and storage specifications to protect the biologic from degradation.
   • Ongoing monitoring of the manufacturing process and product quality.

CMC documentation:

All of the CMC activities are documented in a comprehensive set of reports that are submitted to regulatory agencies, such as the FDA, for approval. This documentation is essential for ensuring the safety and efficacy of the biologic.

CMC considerations for biologics:

• Biologics are complex molecules that can be difficult to characterize and manufacture.
• The manufacturing process for biologics can be very sensitive to changes, so it is important to have a robust and well-controlled process.
• Biologics can be very potent, so it is important to ensure that they are sterile and free of impurities.