Building discriminatory power into dissolution testing in late development – a key milestone for the fast product approval
Dissolution testing was introduced into pharmaceutical practice following the occurrence of serious side effects of phenytoin after calcium sulfate was replaced by lactose . As a result, the FDA introduced the USP Dissolution type 1 (Basket method) test as a QC test in 1971 followed by USP Dissolution type 2 (Paddle method) test in 1978. Over the years, FDA developed further guidance to advance in-vitro dissolution testing into an important tool for development, quality control and drug approval. Statistical methods were implemented to compare the similarity or dissimilarity between two dissolution profiles, bio-relevant media were requested for predicting IVIVC and more specific guidelines were release for immediate and modified released products as well as the solubility and permeability characteristics of the drugs according to the BCS drug classification . With the growing knowledge of biopharmaceutics and predictive in-silico tools, dissolution testing has evolved into a key element for drug development and regulatory assessments [3, 4]. This includes that the dissolution test method must have clinically relevant dissolution specification  and must have proven discriminating power between variations outside the acceptance criteria .
Under increasing time pressure in the early development (e.g. phase 1) of new drugs, enhanced therapeutics (e.g. 505(b)(2)), or generics, the development of appropriate dissolution test methods is often limited to determination of an adequate dissolution media, which provides sink conditions across the entire dose range of the product. Developing a predictive and discriminatory dissolution test method following the first in human trials has to be considered essential for rapid development of the pivotal clinical trial samples, commercial formulation, the regulatory filing and efficient commercial manufacturing. The earlier this important milestone is achieved in the development phase, the faster and more reliably approval and commercialization will occur .
A known small molecule with a water solubility > 1 mg/ml showed promising results to slow down the progression of multiple sclerosis at a dose of 100 mg tid. The product was formulated as an immediate release capsule. For the phase 1 clinical trial the standard USP type 2 (paddle) dissolution test method with a pH adjusted buffer was used to prove consistent dissolution between the development and the clinical batch. During pre-NDA discussions, the FDA challenged the existing dissolution test and requested evidence that the dissolution method chosen had sufficient discriminating power to assure that the product specification and hence critical clinical performance criteria are met.
Using Ardena’s expertise, a pragmatic yet rational and systematic scientific approach was defined to develop the discriminatory dissolution method in due time. An assessment on the critical material attributes and critical process parameter of the product led to the manufacturing of 9 aberrant small batches serving for comparison to the clinical phase 1 batch as a reference. The available data from the existing dissolution method were analyzed to select potential dissolution media for the dissolution screen of the 10 different samples. The similarity factor (ƒ2) test was applied to the dissolution profiles of the batches and the reference batch at each time interval. The results demonstrated high sensitivity for one dissolution media discriminating between batches. . In a final design of experiments, the dissolution method was further fine-tuned by modifying the dissolution test procedural parameter (e.g. paddle speed) for the greatest discriminating power using again the similarity factor (ƒ2) test according to the FDA guidelines . With the newly developed discriminating dissolution test method, 3 of the aberrant batches were found to be outside the similarity specification providing important understanding on the product and process parameter required to consistently meet the quality criteria of the product.
Development of discriminative dissolution method during phase 3 results in 3-6 months time win
While the project passed all IND phases successfully without any further delay, the discriminatory dissolution test revealed important formulation factors like composition, excipients grades and processing affecting the dissolution of the active. This confirms that a discriminating dissolution method available in late phase 2 or early phase 3 of the project, can accelerate the NDA process by 3 to 6 months . Partnering with Ardena’s expertise and scientific resources covering the entire development cycle into the clinics and beyond can mitigate the risk to reach the clinical proof of concept and regulatory approval on schedule.
1 Tyrer et al (1970) Outbreak of anticonvulsant intoxication in an Australian city. Med. J. 4 (5730), 271–273
2 Amidon et al (2006) A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation in Vitro Drug Product Dissolution and in Vivo Pharm Res, 12 (3), 413–420
3 EMA (2012) Guideline on quality of oral modified release products EMA/492713/2012
4 FDA (2017) Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. Guidance for Industry
5 Heimbach et al (2019) Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro-In Vivo Link—a Workshop Summary Report. AAPS J 21:29
6 Gray (2018) Power of the Dissolution Test in Distinguishing a Change in Dosage Form Critical Quality Attributes. AAPS PharmSciTech 19(8): 3328.3332
7 McAllister et al (2020) Developing Clinically Relevant Dissolution Speciﬁcations for Oral Drug Products—Industrial and Regulatory Perspectives. Pharmaceutics 12: 19 (2020)].
8 FDA (1997) Dissolution Testing of Immediate Release Solid Oral Dosage Forms; Guidance for Industry
Apply the science of advanced dissolution testing to accelerate product approval
Drug repurposing has become a rich source of safe and effective new therapeutic options against unmet medical needs. With the appearance of SARS CoV2 and the pandemic spread of severe Covid-19, drug repurposing has been intensively used to identify potential new drug candidates . One of the potential drug candidates was a small molecule prodrug which has poor solubility in ethanol, is practically insoluble in water, and undergoes rapid hydrolyzation in aqueous media. The drug was marketed as an immediate release tablet for short term acute treatment. Since the drug showed efficacy against viruses including promising results for effectiveness against SARS CoV2 reformulation was required to achieve sufficient plasma levels over the duration of 12 hours for a twice daily oral dosing regimen. Using available PK data from existing formulations (e.g. IR) combined with application of in-silico tools like PBBK modeling, predictions on formulation enhancements can be made . For this compound it was predicted that an extended release formulation could lower the dose by ~ 40 % while maintaining constant plasma levels in the therapeutic range. An extended release oral formulation was developed for the clinical trials that met the release characteristics determined in the Target Product Profile for the new indication. Following successful phase 3 clinical trials of the extended release formulation, the FDA challenged the use of the dissolution test method derived from the immediate release formulation. Due to the BCS classification of the compound and the extended release properties of the formulation, a dissolution method should serve as a surrogate for the in-vivo performance with sufficient discriminatory power. Consequently and following the pre-NDA meeting, a discriminatory dissolution test had to be developed that is capable of demonstrating similarity between the extended release clinical formulation batches as well as providing an understanding of the critical quality attributes (CQA) and the critical process parameter (CPP) . The ambitious time lines required the expertise and flexibility of Ardena’s resources to respond timely to the FDA requirements and finalize the NDA program as scheduled.
After reviewing the data and available samples from the immediate and extended release formulation Ardena defined a rational set of Design of Experiments. In a first step, a series of dissolution media, varying in pH and composition were performed using the USP type 2 (paddle) method at standard conditions for the immediate release as well as the newly developed extended release formulation. The dissolution screening included the quantification of the drug and its hydrolyzed derivative. The multi-media screening provided important dissolution patterns enabling the selection of two lead media compositions for the surfactant screening. After screening multiple surfactants a single surfactant was identified at two different concentrations to yield in the highest dissolution rate of the active and its degradation product. Additional comparative dissolution experiments were conducted on the available samples from the immediate and extended release formulation comparing the two media and surfactant levels which led to the selection of the most discriminatory composition. Finally, the conditions of the USP Type 2 method were modified to optimize the method by using different temperatures, vessel geometries and rotational speeds. To fulfill the regulatory requirements the method was validated according to the FDA guidelines on dissolution testing across the different product samples available. The final dissolution method then served to demonstrate the similarity between the clinical batches as well as to serve process and product understanding for manufacturing and filing. A risk assessment was therefore performed and thirteen aberrant samples batches were manufactured to investigate the impact of the critical material attribute and process parameter variabilities. The comparative discriminatory dissolution data of this aberrant and the 3 registration batches are shown in figure 1. The dissolution method demonstrated the similarity of the clinical batches and identified the critical variabilities through non-similarity of the respective aberrant batch. Preferably representative aberrant batches should be produced on full scale equipment.
Figure 1: Dissolution profiles of aberrant core tablets and registration reference batches
The case study confirmed that advanced dissolution testing is an underestimated tool in accelerating drug product development into the clinics. The discriminatory dissolution test should be established early on in the program, ideally late phase 2 or early phase 3, to guide formulation development and clinical supplies as well as it is a tool to mitigate risk throughout the development, especially for drug repurposing or 505(b)(2) submissions . Ardena’s experienced scientists can be relied on provide fast and flexible resources for discriminatory dissolution test method development to support even the most ambitious development programs.
1 Wang & Guan (2021) COVID-19 drug repurposing: A review of computational screening methods, clinical trials, and protein interaction assays. Med Res Rev. 2021;41:5–28
2 Miller et al (2019) Physiologically based pharmacokinetic modelling for First-In-Human Predictions: An updated model building strategy illustrated with challenging industry case studies. Clin Pharmacokin 58:727–746
3 Yu et al (2014) Understanding pharmaceutical Quality-by-Design AAPS J 16(4):771-783
4 Freije et al (2020) Review of Drugs Approved via the 505(b)(2) Pathway: Uncovering drug development trends and regulatory requirements. Ther Innov 54(1):128-38