Meet the Expert: Dr. Samir Haddouchi
To kick off our Meet the Expert series, we’re excited to feature Dr. Samir Haddouchi, Managing Director at SOTAX Pharma Services (SPS), and a leading expert in dissolution testing of softgel capsules. Over the past two decades, Samir and his talented team at SPS have built a strong expertise in developing in vitro methods for a wide range of dosage forms, from simple immediate-release tablets to complex extended-release injectable, implantable, and inhalation products.
We sat down with Dr. HAddouchi to talk formulation trends, challenges in softgel testing, and best practices.
Q: As an expert in dissolution testing of softgels, what formulation trends have you observed recently?
A: Basically, over the past two decades, our company has built a very strong expertise in developing in vitro methods for all types of dosage forms, from very simple immediate-release tablets to very extended injectable, implantable, or inhalation products.
The major trend observed over that period is that most of the drug substances currently in development are poorly soluble. This is causing problems for the analysts but even more challenging situations when formulating them. For those poorly soluble compounds, using lipid-based formulations such as softgel capsules is a common option, but not everybody has the expertise to develop, manufacture, and analyze these products.
Q: What are the main challenges faced in softgel dissolution testing?
A: Softgels usually encapsulate lipidic content while dissolution testing mainly uses aqueous media. When you have lipids being released in an aqueous media, the major challenge is ensuring proper flux of the active ingredient(s) from the oil droplets to the aqueous media. Thus, the use of surfactants is critical, but the selection of type and amount of surfactant is always deeply scrutinized by the regulatory authorities during the dossier review.
Moreover, the dissolution technique should be wisely selected as the conventional paddle and basket do not always show good results. The European Pharmacopeia has been a pioneer in recommending a specific technique for lipidic formulations, described in Eur. Ph. §2.9.43 and based on the flow through cell method (aka USP4).
Finally, for softgels, the release itself is mainly driven by the CQA (Critical Quality Attributes) of the shell, including shell thickness, amount of plasticizers, and more. It is important to manufacture some variation/ defective batches in order to demonstrate that the in vitro method is capable of showing those differences.
Q: In your experience, what are the most common mistakes made during dissolution method development for softgels?
A: The objectives when developing a dissolution method are to achieve first reproducibility and then discrimination. Frequently, the first objective is complicated due to the behavior of lipids in aqueous media. Developers may be tempted to increase the amount of surfactant to accelerate the profiles and reduce the variability.
However, this approach then compromises the discrimination expected by the dossier reviewer. Another mistake could be related to the hydrodynamics during the dissolution test. Indeed, paddle and basket, when used for softgels, frequently show large variability because the oily content will float at the surface of the dissolution medium. This emphasizes the need for visual observations to understand the behavior of the product and the source of variability. Even using sophisticated automated testing systems, nothing compares to the eye of the analyst!
Q: How has the understanding and guidance from regulatory authorities on softgel dissolution testing evolved in recent years?
A: I frequently interact with regulatory authorities, as an expert advisor or trainer, if you will. I should say that, nowadays, most of the agencies are really considering science-based approaches rather than only "box-checking reviews". As an example, the US FDA is publishing regularly Product-Specific guidelines that present "non-binding" recommended approaches.
These documents are very helpful to sponsors in defining a starting development strategy. However, we have seen cases where the proposal published was not the best "state-of-the-art" solution. We worked with our customers to use alternative approaches, depicting better results and that product was accepted by the agency.
Want to read more about testing in general? Don’t forget to read our e-book, Quality Control Tests for Soft Capsules: A Comprehensive Guide
Q: Have you ever established an in vitro-in vivo correlation (IVIVC) for a softgel capsule formulation?
A: Achieving an in vitro method able to predict what will happen in vivo is the Graal. However, this is not always possible because, for many products, dissolution is not the limiting factor with regard to bioavailability. Therefore, in order to assess the feasibility of an IVIVC, one should consider all biopharmaceutical aspects including permeability, solubility, and also "rate of dissolution" of the drug substance. Then only the release rate from the formulation can be involved in the evaluation.
From my experience, softgels could be good candidates for IVIVC assuming that the bioavailability of the compound formulated is not driven by its permeability. However, establishing an IVIVC requires to have different formulations (fast, medium, and slow), tested in vitro and in vivo. Obtaining such different formulations with softgels is not always possible because changes in the CQA are unlikely to affect that much the profiles.
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