Breaking Down the Complexities of Topical Dermatologic Development
From Discovery and Development through Approval
Dermal drug delivery continues to gain success for a variety of reasons including: localized and targeted drug delivery, enhanced bioavailability, emergence of topical generics and cosmeceuticals, patient compliance and lifecycle management. Absorption Systems recently hosted a webinar, “Performance Matrix for Topical Dermatologic Products: Development through Approval”. The webinar focused on:
- Models to Evaluate the Performance of Complex Topical Drug Products
- Applications to Support Development through Approval
- Formulation Optimization and Selection for Novel and Generic Products
- In Vitro Bioequivalence Testing for ANDA Submission
- Excipient Safety and Toxicity Assessments for 505(b)(2) Products
There are many questions surrounding topical drug delivery, including; which types of testing are required for IVRT and IVPT studies, understanding test formulation and excipient formulation, disease models and more. Below are a few selected questions and answers from the webinar, focusing in on many of these points.
How many lots of RLD and tests do we need to test in Pivotal IVRT and IVPT?
I am assuming this with reference to a generic product. There is an index guidance, acyclovir guidance, that the FDA published and based on this guidance, we really, for the pivotal studies, just need test a minimum of one lot RLD and one lot of the exhibit batch. Now in the pilot of the optimization phase, we may be testing additional lots. In fact, we always request additional lots because we need to confirm or establish the inter lot variability, and therefore this is something that we have to take into consideration for the preliminary studies.
Test Formulation with excipient variation – Could a completely different dosage form like an ointment work?
Yes, I think you’re talking about supplemental selectivity here, where sometimes depending on the formulation characteristics, you might need to use a completely different dosage form, if you’re testing a cream, you may need to look at an ointment to demonstrate that your IVPT method is discriminatory.
What should the dose applied for IVPT studies be since this is finite dosing?
Typically, the IVPT dose is 5-15 milligrams. This is a finite dose and is the standard dose that is applied to IVPT studies.
I would like to ask about qualification using hydrocortisone cream, which RLD should we buy? Or do we have to buy from USP?
I believe you’re trying to ask with reference to the development of a generic product that you want to qualify either the IVRT or IVPT method. If there are different reference products available, the RLD depends on the one that you’re trying to match, whether that’s the European RLD or the US RLD. So API of course can be procured from USP to do some initial suitability studies, but the actual product has to be whichever reference product, you are trying to match.
Do you have other disease models for testing efficacy?
Yes, we do have other disease models. For example, we have a psoriasis model, and we’ll be happy to provide information if you want to follow up separately about this.
How can we develop receptor media for poor solubility of drug products in buffer solutions?
Yes and this is in respect to IVPT. With the IVRT, we have a lot more flexibility with inclusion of the alcoholic though the organic solvents that you can add through the receptor medium in order to enhance the solubility. IVPT is a more restricted because you have to make sure that the components of the receptor medium do not impact the skin integrity. We have identified the maximum solubility of the API that can be achieved, and then this can then be utilized in the IVPT model to make sure that there are no issues impacting the integrity of the skin barrier using suitable controls. After which we can then move forward with selecting this as the receptor medium for the IVPT studies. I don’t know if we really use protein in the receptor medium for IPVT studies. We’ve certainly used BSA, for example, to help solubilize compounds.
Can permeation testing using excised tissue be used in lieu of in vivo testing?
It depends on what the goal is here because with the excised issues, the benefit of the ex vivo model is that you’re able to perform this in a more reproducible, manner because we can control the experimental parameters. So if you’re trying to establish equivalence for example, ex vivo IVPT model is the way to go, however if you’re developing a novel new product or a reformulated product, then in vivo dermal PK and maybe some safety testing is warranted because now there are other end-points that you’re looking at, because of the product.
Do you have an alopecia model? And/or can delivery to the hair follicle be targeted?
At this time we don’t have an alopecia model that we have already established in-house. We have done some initial work to look at delivery through the hair follicle and what the impact would be if you block hair follicle on the permeation or skin diffusion of certain products. With most of the efficacy models, this is something that requires a lot of optimization before we can to start utilizing it for actually evaluating products. So if you’re interested, we can certainly talk about how we can set this up. We have a lot of experience, even the hypertrophic scar model that I spoke about previously is a model that we didn’t have any prior experience with, which we basically established from scratch. We would have to define the parameters, but we could certainly look into it. We just recently looked at a wrinkle model, a cellulite model, and the pigmentation has come up, as well as some of the hair loss that are sequestered through the follicular pathways so we can certainly have a follow-up discussion on this.
In the development of release media, to which extent can we use hydro alcoholic solutions, % of ethanol for examples, can we use surfactant?
The percent of organic solvent that is used in the receptor medium has to stay within a certain pre-defined threshold or limit and this can vary depending on the organic solvent. As an example, you could go up to 10%, but the important thing to keep in mind is that organic solvents can cause the polymer to swell, so, the choice of receptor medium has to take into account all these aspects. This is not just a solubility of the active ingredient, but also the choice of the synthetic membrane that you’re using in the IVRT study. Typically, for a lot of products, we have not needed to significantly increase the percent of organic solvents in whatever medium that we have used. It really is on a case-by-case basis, like I said, we can go up to even 30% on some occasions, but in general, it’s a good idea to keep your organic threshold as low as possible.
Do test variants need to be large scale and GMP batches?
So the test variants that we use to establish the discriminatory aspect of the IVRT/IVPT study do not need to be GMP. In general, I think taking scale-up into account whether this is for your primary formulation or for the variance is always a good thing. This way you can take into account any changes that are introduced when going from a lab scale to a scale up batch. But no, these don’t need to be made like the exhibit batch. For the variant, these can be lab scale/non GMP.
Do you also have work on RHE model for toxicity evaluation? How do you power the pivotal IVPT based on pilot IVPT study (i.e. number of donors)?
Addressing the power of the pivotal IVPT/pilot IVPT – It really depends on if you’re taking this forward for the purpose of in vitro BE. A pilot IVPT it will certainly have a least three, if not, up to five donors because you really want to look at inter donor variability. This is largely taken through into the pivotal study where you have five-six donors. The purpose of having five donors at the pilot stage gives us the ability to look at whether that is sufficient and that the donors are properly qualified for us to be able to take into the pivotal study. Also whether we actually have to add a few additional donors to further address any variability that we are seeing in the pilot. I’m not familiar with the RHE model for tox evaluation but we are happy to look further into this. For the toxicity evaluation, depending on whether it’s just for something like irritation, sensitization, or biocompatibility, we might use a guinea pig or a rodent model. If you’re looking at much more significant GLP-type of toxicology work we would use a rodent or large animal model, and perform this under chronic dosing conditions and look at end points like histopathology or clinical pathology to determine any toxic effects of the formulation.
Do we have pH limitations for the receptor medium?
I think the general rule is that we want to choose a receptor medium where we can have the maximum solubility of the compound because the most important aspect of the IVRT assay to ensure that you have same conditions and for IVPT you just have to make sure that there is no impact on the integrity of the membrane. So within this, you can certainly have the flexibility in terms of choice of reception and other parameters like pH.
So how long has absorption systems been working with IVPT and IVRT models?
With new product development, this is something that we have experience with for close to two decades. We’ve established a lot of these models to look at the barriers to absorption and the disposition characteristics of different formulations. We’ve done a lot of formulation characterization work and this has been more R&D. More recently, especially with the advent of the different guidance documents, we have really focused on optimizing, qualifying, and validating these assays for the purpose of bioequivalences. So we’ve successfully supported selection formulations for many years, but now we’re just using those same tools for the purpose of actually establishing equivalence and waivers of clinical studies.
Absorption Systems’ unique portfolio of dermal models provides a comprehensive package of predictive testing. We employ a rational and multi-pronged approach which relies on well-validated, nonclinical models to bypass clinical studies and/or enhance quality by design (QbD). This approach allows you to advance your dermatological innovations with increased accuracy and confidence.
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