CAPA is important and should remain a key focus in the pharmaceutical industry. That being said, from a scientist’s perspective, dissolution testing deserves closer attention and a stronger emphasis.
There are many pharmaceutical analysis tools used in the characterization of a drug product, but dissolution is often a key factor in defining the performance of a drug and ensuring product quality.
There are several reasons why dissolution is so important. Dissolution is the only pharmaceutical tool that can assess both drug product performance and adherence to key quality attributes based on the design of the drug. From simple immediate-release formulations to complex modified-release formulations, an accurately developed dissolution method is critical for confirming product quality over time and under various conditions. If an in-vitro dissolution testing procedure shows significant correlation with in-vivo clinical data, it can provide predictive modeling that may eliminate the need for additional clinical studies over the product’s lifetime.
Not only can dissolution provide valuable predictive modeling, but it also can help resolve unexpected bioavailability results. Biorelevant dissolution media are used to bridge the gap between a quality control procedure and predictive modeling as a measure of pharmacological clinical relevance. It provides support for formulation development and prototype selection—either during early phase development or in support of post-approval changes.
With time being such a critical factor in drug development projects, dissolution offers important and timely information scientists can use to make decisions. The right dissolution procedure can detect changes within a formulation over time, such as hydration of a drug product. And it can be used as a surrogate to content uniformity during initial screening of formulation activities.
Unlike traditional testing procedures—such as assay analyses routinely used for drug product formulations—dissolution also can determine if a morphological change occurred.
Only dissolution can detect a morphological change outside of additional characterization tools, such as X-Ray Powder Diffraction (XRPD). This is another way dissolution provides important information for scientists making decisions. Regulatory agencies continue to place more emphasis on dissolution testing from concept of design to validity of the procedure.
While stability indication of an assay and the impurities procedure is scrutinized during Chemistry, Manufacturing and Controls (CMC) review, dissolution continues to gain focus to ensure the optimal procedure is developed. Indeed, many regulatory guidance documents have been published requiring a gradual progression of dissolution throughout the phases of drug development or in support of Scale-Up and Post-Approval Changes (SUPAC) requirements.
Dissolution can remain “king” as compared to other testing procedures only if the right dissolution procedure is developed. The dissolution procedure should evolve over time as a product matures from early-phase development to post-approval as part of life-cycle management.
Platforms need to be developed to efficiently identify an optimal dissolution procedure. Here are some attributes to consider:
- What is the purpose of the product and how will it be designed (e.g. targeted selection)?
- What is the phase of development and how will the data be used to define the product’s performance?
- What do we know about the classification (BCS) of the drug substance? What if that information is not available?
- What information can we learn from the characterization of the drug substance such as pH solubility?
- What is the current and proposed particle size of the drug substance? Is there a robust milling or micronization step in the process?
For example, Metrics Contract Services has been given late-phase dissolution methods to redevelop or optimize and often, there is no justification to the selection of dissolution medium, apparatus type and speed. There is no doubt that the industry favors certain surfactants, such as sodium lauryl sulphate, and “1%” is a well-documented, standard concentration used for many poorly soluble drugs. Furthermore, paddle speeds at or above 100 rpms also are selected without much justification and adequate discrimination.
While these parameters can be selected, the current regulatory environment requires the product-specific, data-driven justification of them; reliance on industry standards is not sufficient.
Regulatory agencies seem to agree by applying high standards when it comes to selecting parameters so that the desired optimal dissolution procedure is achieved. There appears to be an increase in the level of questions surrounding the development and suitability of a dissolution procedure. An effective dissolution procedure can ensure a true “baseline” is established for a newly registered product that will enable comparability for potential changes in the manufacturing process, site transfers or even formulation changes. It is clear by reviewing agency guidance documents that dissolution testing for non-BCS Class 1 drugs is key to establishing acceptability for proposed changes.
Even in early-phase development, when the formulation can change, it is still critical to establish a suitable dissolution method to allow for predictive modeling. Pharmacological pH solubility, pKa data, thermodynamics, morphology, particle size and other characterization data should be well understood.
Also, when you shift through the various development phases, the dissolution method should shift as well. Prior to initiation of Phase III clinical studies, the dissolution procedure should be optimized to represent your final registered method. The method should have been challenged by formulation designs designed to produce failures (if applicable) as part of formulation Quality by Design (QbD) activities.
After the dissolution procedure has been optimized, there should be a clearly documented pathway regarding how the dissolution procedure was developed. Statistical design approaches from the various activities should be utilized, such QbD analyses, during drug development.
A good way to challenge a dissolution procedure that will be used to support a future commercial product is to determine if the following criteria can be answered:
- What is the purpose of drug product? Specifically, what is targeted release profile of the drug?
- Does the dissolution medium selection concur with the pharmacological relevance of the drug? And how does the selection of the dissolution medium compare to the solubility and stability of the drug substance?
- Is disintegration or diffusion the rate-limiting step in the dissolution process or is it solubility of the drug substance?
- If there were deviations from the drug substance and drug product manufacturing process, is the method specific enough to detect these changes?
- Can you justify the selection of other key dissolution parameters such as speed and apparatus type? Are the parameters optimized?
As Vice President of Analytical Services at Metrics Contract Services, Keith Moore is responsible for the day-to-day leadership of the company’s analytical services team, comprising some 100 chemists. His division helps clients determine and ensure the identity, purity, potency and performance of drug products by conducting analytical chemistry and microbiology tests, method development and validation, and stability studies in compliance with international standards. Moore also is responsible for laboratory operational teams, as well as quality-control functions that involve raw materials, cleaning verification, quality control-finish product, and the microbiological laboratory. Moore joined Metrics Contract Services in 1998 as a laboratory analyst and consistently took on roles of increasing responsibility to become senior manager of analytical services by 2012. Prior to his current appointment, he served as senior manager of technical operations at Salix Pharmaceuticals, where he managed R&D and commercial activities at numerous contract organizations.