MedPharm’s industry leading performance testing capabilities give our clients and their potential investors the confidence they need regarding the penetration, target engagement and disease activity of drug at the site of action in order to de-risk expensive and complex clinical trials.
MedPharm has an array of established performance tests including:
- In vitro release testing (IVRT)
- In vitro permeation testing (IVPT):
- Unique flow through ex vivo permeation and penetration testing on an automated higher throughput platform (MedFlux HT®)
- Classic static/Franz cell ex vivo permeation and penetration testing adaptable to handle diseased tissue biopsies
- Modified static cell (ChubTur®) for measuring penetration through the nail and other hard tissue types
- Unique high throughput screen TurChub® for measuring anti-microbiological activity through hard and soft tissues
- Disease activity models for assessing drug and formulation pharmacokinetics and pharmacodynamics against key pathways associated with psoriasis, atopic dermatitis, bacterial infiltration, localised bacterial and fungal infections and other dermatological indications
- Models for assessing changes in local irritation and metabolism as part of non-clinical assessments
MedPharm has advanced tissue culture expertise to create bespoke models designed to assess the penetration and activity of drug substances and products against unique targets requested by clients.
At MedPharm performance tests are an integral part of any formulation development program and can be used strategically throughout the development process to mitigate development risks and failures due to inadequate product performance. These assays are consistently used to inform;
- API selection
- Formulation activity optimisation
- Posology and dose regime
- Equivalence testing
- Marketing claim support
- Patent claims support
- Toxicity assessment
- In vitro release testing (IVRT)
IVRT is the established method recognised by regulators for measuring the release of the active component(s) from semisolid products. The assay can be used during the development cycle to ensure product quality and performance is maintained. Regulators agree that this release test can be useful when making certain scale-up and post approval changes to ensure the final product shows ‘equivalence’.
MedPharm has been performing IVRT as part of clients’ regulatory submissions since the company was founded almost twenty years ago. It can be used as a simple model for distinguishing between the drug release rates of different formulations.
MedPharm has successfully used validated IVRT studies, along with other performance tests, to obtain bio-waivers for clients’ during approval of generic products. This greatly reduces the cost of development and also accelerates the time to market because no clinical testing is required.
Increasingly regulatory authorities are insisting IVRT methods have a higher level of validation and results be included in client’s submissions and specifications as part of product quality and stability assessments.
MedPharm has many years’ experience developing and validating IVRT methods based on the FDA and EMA guidelines and continues to help shape how these methods are used in regulatory submissions.
- In vitro Permeation Testing (IVPT)
MedPharm offers customers options for testing permeation and penetration using either its unique MedFlux HTTM automated flow-through system or classical static cells to handled diseased skin biopsies. MedPharm’s unique ChubTur model is a static cell specific for measuring permeation and penetration through hard tissues such as nails.
MedFlux HTTM – permeation and penetration testing
MedFlux HTTM is an automated flow-through system designed by MedPharm scientists to overcome the limitations associated with use of the commonly used static cells (i.e Franz Cells) and other commercially available flow-through diffusion cells.
The uniquely engineered MedFlux HTTM cells are designed for rapid local clearance of drug substance using human skin to generate more accurate pharmacokinetic profiles. Layers of the skin are subsequently analysed to determine exactly where the drug substance resides within the skin and establish if it is reaching site of action.
MedPharm’s unique MedFlux HTTM technology
MedFlux HTTM has become MedPharm’s preferred penetration and permeation method for all dermal products. MedFlux HT® studies have been submitted to and been accepted by regulatory authorities throughout the world. The method can be validated for specific drug substances.
Key benefits of the MedFlux HT® system are:
- Automated collection for more frequent sampling
- More consistent datasets
- Cost effective automation of data collection
- Flow through system eliminates need for solvents to maintain sink conditions
- Maximizes skin usage for larger number of replicates
- Minimizes tissue artefacts through biologically relevant receiver fluid
- More closely matches in vivo conditions
Static cell permeation and penetration testing
In certain circumstances MedPharm scientists will recommend the use of classic static cells to measure the permeation and penetration of drug substances or products through soft tissue such as human skin or other epithelium. This methodology is particularly applicable for clients’ who want to measure the movement of their drug and/or product into or through, for example:
- Normal human skin
- Psoriatic plaque biopsies
- Eye lids
- Hperkeratised skin
This type of model may also be applicable for large biological molecules. MedPharm have created micro static cells to work with very small pieces of normal or diseased skins to ensure customers get the optimal data set for their product.
Nail permeation and penetration model (ChubTur®)
Measuring the permeation and penetration of a drug through nails and other hard tissues presents specific challenges. After many years of research MedPharm have perfected the methodology and the unique ChubTur® model is widely accepted by regulatory authorities worldwide as the gold standard for modelling penetration through nails. ChubTur® studies involving nails have been used as part of a full package for the demonstration of bioequivalence and the achievement of biowaivers from regulatory authorities without the requirement of any clinical testing.
The technology is based on specially modified static cells to ensure no product leakage around the nail. MedPharm has also developed a device called the TurSh™ used in combination with ChubTur® cells to explore the depth of permeation of drug substance within the nail.
High throughput screen (TurChub®) for microbiological activity
The TurChub® high throughput screen, unique to MedPharm, is a system specially designed to quickly differentiate the anti-microbiological activity performance of topical drugs or medicines through a variety of hard or soft tissues. The drug’s efficacy and ability to permeate across the human nail or biological matrix is measured by an adapted zone of inhibition measurement (the area of no growth of the organism). The assay rapidly provides semi-quantitative data without the need for specific analytical methods for each drug. Multiple drug types can be screened quickly at the same time decreasing the development time.
The TurChub® model has been validated to demonstrate no leakage around the tissue and provides a direct measurement of the activity of the drug below the tissue.
Data generated using the TurChub® model has been accepted by regulatory authorities in lieu of clinical bio-equivalence data resulting in clients obtaining bio-waivers for their generic products.
- Disease/Activity Models
The major limitation of any permeation and penetration model is that it tells you how the drug is moving into the biological tissue, but does not give any indication of whether the drug is bio-available, engages the target and is able to act on the desired pathway.
MedPharm has the capability of keeping ex vivo skin alive and biologically functioning for over a week. MedPharm has also been successful in developing an array of disease models for many pathways indicated in some of the major areas (e.g. psoriasis, atopic dermatitis, vitiligo, alopecia, etc).
These models have the advantage of being able to measure the penetration and efficacy of the drug to establish a PK/PD relationship.
MedPharm is a world leading developer of these pharmacokinetic/pharmacodynamic activity models. Its scientists are regularly called upon to advise major pharmaceutical companies and regulators alike on the current technology for testing of topical and transdermal products.
MedPharm has developed disease activity models using nails and other biological matrices as well as skin and mucosal membranes. Along with the other models these sophisticated ex vivo experiments provide additional confidence to clients and their investors about how a product will behave in the clinic.
By leveraging expertise in immunology, skin biology, microbiology, and tissue engineering, MedPharm has helped many clients de-risk their development programmes or provided support for specific marketing claims by developing bespoke disease activity models. MedPharm scientists are constantly working with clients to build new models relevant to the specific indications and biochemical pathways.
MedPharm have used these sophisticated models to directly help clients:
- De-risk programmes prior to making expensive clinical decisions
- API selection within chemical libraries
- Inform formulation optimisation
- Explore dose ranges and posology prior to the clinic
- Assess new targets and technologies for local activity
- Achieve bio-waivers for generics by showing equivalence with benchmark products
- Support marketing claims for OTC products
- Support API selection decisions
Models already developed include:
- Atopic dermatitis (acute and chronic)
- Other inflammatory skin diseases
- Infected Wounds – epidermal and dermal
- Bacterial (acne, MRSA)
- Viral (herpes)
- Fungal (onychomycoses, Tinea pedis)
- Non-neuronal pain
MedPharm offers its clients other activity based models to aid their product development:
Irritancy and Metabolism Models
It is important that topical and transdermal formulations are designed to minimise the risk of local irritation. From its years of experience MedPharm knows to avoid excipients that are known to amplify such effects.
MedPharm has the capability of assessing local acute irritation from topical application using reconstructed human skin and these models have been validated and standardized for the cosmetic industry. The primary advantage of these models are that they are highly reproducible and are fast becoming the industry standard. MedPharm uses such models 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 the liver. MedPharm can monitor metabolism using several models such as keratinocytes, reconstructed human epidermis (RHE), or a more holistic approach using freshly obtained human skin and monitoring metabolic pathway(s).
Skin binding model
Any potential drug that penetrates the skin must be bioavailable and able to engage its target on the disease pathway. In MedPharm’s long experience it is crucial for clients to understand the affinity of their compounds to bind to different layers of tissue because this can have a major impact on both penetration and potency.
MedPharm has developed skin binding models that are similar to blood plasma binding but specific to skin proteins. These models have proved to be one of the best predictors of penetration and potency and have saved clients valuable time and costs in the initial stages of API selection and screening.