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| Thomas Franz, M.D. | Paul Lehman, M.Sc., | Sam Raney, Ph.D., |
| Executive Medical Director, Clinical Dermatology | Director of Clinical and Pre-Clinical Dermatology | Associate Director, Pre-Clinical Dermatology |
Dr. Thomas Franz is the innovator of the Franz Diffusion cell, and as a team, Dr. Franz and Paul Lehman have earned renown across academia and industry for three decades of excellence in the study of in vivo and in vitrotopical pharmacokinetics. Dr. Raney has joined this team and brings 15 years of experience in the fields of in vitro topical percutaneous absorption, regulatory considerations and topical drug development.
Cetero’s Pre-Clinical Dermatology Research Division is located in Fargo, ND. Within our dedicated 5,000 sq. ft. laboratory, we conduct skin and nail penetration studies, as well as membrane rate of release studies, on as many as 200 parallel Franz diffusion cells. Our services include protocol development, analytical method development, statistical analysis, QC & QA, compliance with international regulatory standards, and guidance in drug development logistics. Franz cell sizes (dosable skin surface area) range from 0.25 cm2 to 12 cm2, with most studies being conducted on our 1 cm2 and 2 cm2 cells. In addition, our laboratory is designed for immediate expansion to allow for more cells and analytical instrumentation.
We routinely develop novel analytical methods and often modify sponsor-provided methods to improve sensitivity and selectivity for the compounds of interest. Penetration of topical drugs is often in the low- to mid-nanogram range requiring unique sample processing and analysis. The Pre-Clinical Laboratory currently has 4 HPLC/UV/MS systems, 4 HPLC/UV systems, and 1 GC/MS system. Further capabilities include ELISA Assay methods and licensed conduct of studies involving radiolabeled materials (14C, 3H and 125I).
Our mission is to provide quality, efficiency, and expertise in conducting studies for topical and transdermal formulation development. We primarily conduct in vitro percutaneous absorption studies, as well as routinely performing the Membrane Rate of Release assay based on the SUPAC-SS Guidance with full validation, analytical method development, sample analysis, in-process Quality Control & Quality Assurance reviews, and a comprehensive final report. Studies with new drugs or unusual formulations frequently initiate with a small pilot study to optimize the study design prior to conducting the pivotal study. Additionally, we are accustomed to conducting unconventional protocol designs involving fingernails and skin from various other body regions, or animal skin, as well as silastic membrane penetration studies. We also commonly evaluate unusual and unique formulation issues where product potency and stability problems need resolution.
The cost structure is based upon the number of Franz Cells and the number of analytical samples. The number of cells in a study is a function of the number of test formulations, the number of skin donors, and the number of replicates per formulation per donor. The per-cell cost depends upon whether the study is evaluating standard penetration parameters or additional mass balance factors (for accountability of the applied dose). For the analytical costs, the number of cells are multiplied by the number of samples per cell, and are charged per sample. Finally, the budget includes a single per-study “administrative” fee that encompasses protocol development, study documentation, binders and data management, compliance-related services, QC review, QA review, a comprehensive final report, and archiving. Analytical method development costs are separate from the in vitro study conduct costs.
Our starting recommendation is to test a formulation as a finite clinically relevant dose with no less than 3-5 replicates on ex-vivo human skin from 3-5 different donors. All skin sections are pre-tested for barrier function using our standardized tritiated water test. Reservoir solutions, which retain the drug that penetrates through the skin, can be sampled at multiple time-points after dose application (0, 2, 4, 8, 12, 24, 32 and 48 hrs, for example). For mass balance studies, the surface of the skin can be washed to recover the residual applied dose, and the skin can be separated into the stratum corneum, epidermis and dermis. All samples are then processed for analytical quantification of the compound of interest. Similar designs apply to nail and membrane penetration studies.
We are often asked about our GLP compliance. For the FDA GLP regulations (21 CFR Part 58), pre-clinical in vitro percutaneous absorption studies do not fall under the scope of these regulations as no live animal work is conducted. However, certain studies may fall under other GLP guidelines as described by the EPA or OECD. In our Pre-Clinical Dermatology Laboratory, we maintain the systems and infrastructure of documentation, monitoring, routine metrology, and quality review to be compatible with the principles of GLP for every study, whether it is a GLP study or not. Indeed, the industry is approaching a consensus that all studies should be conducted under the spirit and intent of GLP principles, and regulatory bodies have expressed recent interest in reviewing our pre-clinical data. We also offer analytical validation per FDA or ICH guidelines, or as requested. It is important to discuss the specific GLP standards that may be necessary or applicable to your study during initial conversations.
A few helpful guidelines which may be of interest include:
We have the experience to assist you in your study design to satisfy a wide variety of needs. For instance, a study can be designed to determine the time course of drug appearance in the epidermis and dermis, as well as the time course of penetration into the reservoir solution.
Percutaneous absorption represents the “A” in ADME (Absorption-Distribution-Metabolism-Excretion). Our early work in the 1970s and 1980s, which has since been confirmed by many others, demonstrates that for well-conceived studies conducted under identical conditions (dose, body site, duration, etc.), the in vitro results correlate with and will predict in vivo results. Using basic pharmacokinetic principles, this input-function (the absorption phase) thereafter allows for prediction of systemic blood levels, when the clearance and excretion for the drug of interest has been previously characterized.
We realize that timely availability of the data and final report is extremely important. We can provide you with data as it becomes available, as Interim reports, typically as a simple table or as a 1-2 page preliminary report. Understandably, this data is frequently provided before full QC and QA reviews have been completed and will be clearly labeled as “Preliminary and Un-Audited” to protect against any misinterpretation of the data.
Our goal is to provide a Final Report within 30 days of last sample collection. Understanding that many experimental studies develop in an unpredictable way, it can be difficult to anticipate the timeline for such situations. It is not uncommon to see studies expand in scope and design as the initial data becomes available. The following outline describes an example timeline for a basic study (e.g. 2-3 formulations on 3 Donors), without a pilot study, for a well-characterized drug and an uncomplicated analytical method.
| Receipt of signed protocol, contract and test articles | Week #1 |
| Skin mounting, dosing and sampling | Week #2-#3 |
| Analysis of samples | Week #3-#5 |
| QC of data | Week #4-#6 |
| Draft final report | Week #5-#7 |
| QA of final report | Week #5-#8 |
| Paul Lehman, M.Sc.Director, Pre-Clinical & Clinical Dermatology701-356-2480 dermatology@cetero.com | Mariya RzaszutakManager, Business Development701-461-8239 dermatology@cetero.com |
| Sam Raney, Ph.D.Associate Director, Pre-Clinical Dermatology701-356-2480 dermatology@cetero.com |
Copyright © 2008, PRACS Institute, Ltd.
