Topical Pharmaceutical Testing | IVRT & IVPT Testing

In vitro Release Testing (IVRT)

MedPharm leverages its 20 years of experience to help develop and validate IVRT methods for its clients. We successfully perform IVRT based on FDA and EMA guidelines and continue to influence how these methods are utilised in regulatory submissions.

IVRT is the established method recognised by regulators, and is commonly used for measuring the release of the active component(s) from semisolid products. Regulators are increasingly requiring validated IVRT methods as part of product release and stability specification.

MedPharm has successfully used validated IVRT studies, along with other performance tests, to obtain biowaivers for clients’ during the approval of generic products. This significantly reduces the cost of development and accelerates the time to market, as no clinical testing is required.

The assay can be used:

In formulation development, optimisation and selection.
During development to ensure product quality and performance is maintained through quality by design (QbD).
When making scale-up and post-approval changes to ensure that the final product shows equivalence. The FDA has guidance on how to use this assay for scale-up and post-approval changes for semi-solids (SUPAC-SS).

Automated Vertical Diffusion Cells

MedStat-HT is an automated system of 24 vertical diffusion cells (VDC), also known as ‘Franz’ or ‘static’ cells. This system is used to measure the in vitro release of drug from topical medicines across synthetic membranes (IVRT). Unique design features, along with automated collection, provide significant reduction in variation associated with sampling and fluidics compared to manually operated VDC systems.

The key benefits of the new system are:

Better characterisation of formulation drug release properties for potential patent claim support
Formulation optimisation and comparison
Robust product quality and stability specifications
A reduction in experimental time with less variability
Compliance with FDA, EMA and OECD guidelines

In vitro Permeation Testing (IVPT)

MedPharm offers its customers options for IVPT, including our unique MedFlux-HT® automated flow-through system or classic static cells.

IVPT is used to measure the permeation and penetration of a drug through tissue and is an essential tool for optimising topical and transdermal formulations. This is because a drug’s ability to permeate any tissue is very dependent on the quantity and quality of the excipients used. It cost-effectively provides a measure of performance of a product using human tissue and removes the uncertainty and ethics of working with ex vivo animal models.

MedPharm has spent many years perfecting procedures to minimise variation in this complex technique with a large number of potential variables. IVPT is often central to any bioequivalence justification for a topical generic product and regulatory authorities insist on a rigorous level of validation that can only be achieved after considerable experience.

IVPT is a cost-effective method used to demonstrate:

The optimisation and characterisation of formulation performance
De-risking clinical trial decisions
Product performance to potential investors
The bioequivalence of a generic compared to an originator product
New marketing claims to educate key opinion leaders

MedPharm have four key methods for IVPT:

Classic Franz (static) cell

The classic static cell used for ex vivo permeation and penetration testing. They can be adapted to test diseased tissue biopsies.

Automated Flow-Through Cells

A unique flow-through method for ex vivo permeation and penetration testing. MedFlux-HT incorporates an automated higher throughput platform.

ChubTur®

MedPharm’s unique ChubTur model is a static cell specific for measuring permeation and penetration through hard tissue such as nails.

TurChub®

Unique high throughput screen for measuring anti-microbiological activity through hard and soft tissue.

Static Cells

Static ‘Franz’ vertical diffusion cells are the industry standard for IVPT. MedPharm has also has created micro static cells to work with small pieces of tissue that may be more difficult to source such as:

Healthy human skin, buccal and oesophageal tissue
Psoriatic plaque biopsies
Eyelids
Hyperkeratised skin
Biological molecules

ChubTur®

Measuring the permeation and penetration of a drug through nails and other hard tissues present specific challenges. MedPharm’s unique ChubTur model is a modified static cell specifically designed to measure the permeation and penetration of a drug through hard tissues such as nails. This proprietary validated model is widely accepted by regulatory authorities worldwide as the gold standard for modelling penetration through nails.

ChubTur® studies involving nails led to the first approval for demonstration of bioequivalence without the requirement of any clinical testing.

MedPharm has also developed a device called the TurSh™ which is used in combination with ChubTur® cells to explore the depth of permeation of drug substance within the nail.

Automated Flow-Through Cells

MedPharm has also developed an automated flow-through diffusion cell system MedFlux-HT® to more closely mimic the clinical situation. MedFlux-HT flows the receiver fluid under the tissue and then it is collected directly into 96 well plates. A robot works up the samples for direct injection in a quadpole LC-MS. A major advantage of this technique is that it prevents saturation of drugs with poor water solubility in the receiver fluid that can distort the results from static diffusion cells. The automation greatly improves the statistical variation.

Automated flow-through diffusion cells are useful for increasing accuracy in data from ex vivo permeation and penetration testing.

The significant benefits of MedFlux-HT:

increased confidence in clinical performance, in particular, for lipophilic drugs
increased opportunity to note patentable differences between formulations
more credible evidence to support marketing claims

TurChub®

MedPharm has developed a unique high throughput screen, TurChub® to quickly differentiate the anti-microbiological activity performance of topical drugs or medicines through a variety of hard or soft tissues. A drug’s efficacy and ability to permeate across a nail or other hard tissue is measured by an adapted zone of inhibition measurement (the area of no growth of the organism). The assay provides rapid direct measurement of the activity of the drug below the tissue.

Data generated using the TurChub® model has been accepted by regulatory authorities as a substitute for clinical bio-equivalence data.

The TurChub method is both time and cost-effective as multiple drug types can be screened quickly simultaneously, therefore, decreasing development time during drug development.

Disease Activity Models

When trying to de-risk a clinical trial decision it is highly desirable to establish that the active drug is not only getting to the site of action but is also bio-available and having the expected impact on a relevant biochemical pathway.

By leveraging our expertise in immunology, skin biology, microbiology, and tissue engineering, we have helped many clients mitigate risk using performance models. These models are also known as pharmacokinetic/pharmacodynamic (PK/PD) models because they give a readout of where the drug permeates alongside a measure of biological activity.

MedPharm has developed proprietary models relevant for major disease areas such as psoriasis, atopic dermatitis, herpes, onychomycosis and continue to develop new ones through our dedicated innovation group. These sophisticated ex vivo experiments provide additional confidence to clients and their investors about how a product might behave in the clinic.

MedPharm has used these PK/PD models to directly help clients:

Mitigate risk in programmes prior to making expensive clinical decisions
Inform API selection, dose ranges, posology, and formulation optimisation
Assess new targets and technologies for local activity
Achieve biowaivers for generics by showing equivalence with the originator product
Support marketing claims and educate key opinion leaders

We can keep ex vivo skin biologically functioning in a laboratory for over 14 days to provide more options for looking at long term biological effects.

Each of MedPharm’s models can be performed on the surface of the skin to model local topical delivery or ‘basolaterally’ from underneath to model systemic delivery.

MedPharm offers its clients, other activity-based models, to aid their product development:

Irritancy and Metabolism Models

For specific drugs, it may be critical to assess local, acute irritation from topical applications by using reconstructed human skin (RHE) models. The high reproducibility of our models means that they have been validated and standardised for the cosmetic and pharmaceutical industries. The models can be used to rank formulations and actives compared to known irritants.

Human skin contains many of the enzymes capable of drug metabolism, albeit at much lower levels compared to internal organs, such as the liver. MedPharm can monitor metabolism using several models such as keratinocytes, RHE, or a more holistic approach using freshly obtained human skin and monitoring metabolic pathway(s).

Skin binding models

MedPharm has developed skin binding models that have similarities to blood plasma binding but are specific to skin proteins. These are proven to be a leading predictor of drug penetration and potency. Our models have saved clients valuable time and costs in the initial stages of API selection and screening.

Performance Testing