Both structural and physical properties can influence the release rate of an active pharmaceutical ingredient (API) in semi-solid topical formulations. Measuring API release is critical throughout the drug development process and lifecycle, from early-phase clinical candidate selection to specification setting in late phase development, and post-approval QC and product changes/modifications. For semi-solid topical formulations, in vitro release testing (IVRT) is becoming a more prevalent and essential tool to determine the release rate and diffusion of API in topical products.
In Vitro Release Testing Explained
During all phases of the drug development process and lifecycle, dissolution testing, which detects physical changes in API and the drug formulation, is required for all solid oral dosage forms. Similarly, for non-oral dosage forms, including semi-solid topical formulations, in vitro release testing is needed to evaluate drug release properties.
IVRT measures the release rate of a drug by using Franz diffusion cells and a non-interactive synthetic membrane or skin, and can be used to develop methods for analyzing a range of semi-solid dosage forms, including:
- Topical Aerosols
In Vitro Release Testing Guidance & Applications
FDA first released its guidance for industry, Scale-Up and Post-Approval Changes: Chemistry, Manufacturing, and Controls (CMC); In Vitro Release Testing and In Vivo Bioequivalence Documentation for Non-Sterile Semi-Solid Dosage Forms (SUPAC-SS) in May 1997. SUPAC-SS speaks to non-sterile semi-solid dosage forms with intended topical routes of administration, and defines:
- Levels of change
- CMC tests to support each level of change
- Recommended in vitro release tests and/or in vivo bioequivalence tests to support each level of change
- Documentation to support the change
Lately, the FDA has published several specific guidelines in an attempt to overcome barriers to development of generics and improving patient care. Such clear and strict guidelines are helping the industry with bioequivalence (BE) assessments using in-vitro release and in-vitro permeation methodologies in lieu of clinical studies.
Surrogate Approaches to Demonstrate Bioequivalence (BE) for Topical Dermatological Products
Some such sensitive and efficient surrogate approaches to demonstrate BE for specific topical dermatological products are provided in these guidelines:
- Acyclovir Ointment: Q1/Q2/Q3 + IVRT
- Silver Sulfadiazine Cream: Q1/Q2/Q3 + IVRT
- Acyclovir Cream: Q1/Q2/Q3 + IVRT + IVPT
- Benzyl Alcohol Lotion: Q1/Q2/Q3 + IVRT + Lice Assay
General definitions are as follows:
- Formulation Q1/Q2 Sameness: The test and RLD products are qualitatively and quantitatively the same.
- Q3 Similarity: The physicochemical properties of test and RLD products are similar.
- In Vitro Release Test (IVRT) Studies: The test and RLD products have an equivalent rate of acyclovir release.
- In Vitro Permeation Test (IVPT) Studies: The rate and extent of acyclovir permeation through excised human skin from the test and reference products are comparable.
How Avomeen can Support your IVRT/IVPT and Q1/Q2/Q3 Requirements for Accelerated Generic Drug Development
At Avomeen, we are equipped with the technology and our advanced staff of industrial pharmacists and organic chemists to support your IVRT/IVPT and Q1/Q2/Q3 requirements for accelerated development of generic drug products. A brief overview of our in vitro release testing (IVRT) and in vitro permeation testing (IVPT) capabilities is as follows:
- Particle size
- Globule size
- pH, specific gravity, and/ or water content
IVRT and IVPT to Support Bioequivalence Waiver and Sameness Testing
- Industry standard Franz vertical diffusions cells from Permegear
- Identification of appropriate simulated membranes
- Development of flux conditions
- Product dose
- Sampling intervals
- Stirring rate
- Selection of receptor solution
- Development and validation of selective and robust test methods
- IVRT and IVPT apparatus qualification, membrane qualification, receptor solution qualification
- Reconcile donor/acceptor part of cell
- Designing of IVPT pilot and pivotal studies
- Statistical analyses of data per USP <1090>
- Completed projects include Q3 sameness verification and addressing deficiencies that clients have received from FDA regarding discriminating IVRT methods and insufficient scope of development
- Completed projects include Topical and Ophthalmic products
Do you have a specific project in mind? Get in touch with our regulatory and scientific experts.
Our expert blogger is Neelam Varshney, Avomeen’s Senior Technical Director of Biopharmaceutical Sciences. She has extensive experience in all CMC aspects of pharmaceutical products, and her expertise ranges from preclinical to post approval regulatory requirements.
Learn more about Neelam’s expertise and experience.