VINOD P. SHAH, PH.D. SENIOR RESEARCH SCIENTIST OFFICE OF PHARMACEUTICAL SCIENCE CENTER FOR DRUG EVALUATION AND RESEARCH FOOD AND DRUG ADMINISTRATION Pharmacy.

VINOD P. SHAH, PH.D.SENIOR RESEARCH SCIENTIST

OFFICE OF PHARMACEUTICAL SCIENCECENTER FOR DRUG EVALUATION AND RESEARCH

FOOD AND DRUG ADMINISTRATION

Pharmacy Compounding Advisory CommitteeJuly 13, 2000

Difficulties for Compounding Because of Reasons of Safety or Effectiveness of the Drug

Product Transdermal Drug Delivery System

Transdermal Drug Delivery System (TDS)

• A self-contained, discrete dosage form

• It delivers a drug through intact skin at a controlled rate into the systemic circulation

• Delivery rate is controlled by the skin or membrane in the delivery system

TDS• A sophisticated complex drug delivery system difficult to formulate. It

requires specialized manufacturing process/equipment.

• Formulated to meet specific biopharmaceutical and functional characteristics. The materials of construction, configuration and combination of the drug with the proper cosolvent, excipient, penetration enhancer, and membrane are carefully selected and matched to optimize adhesive properties and drug delivery requirements.

• Formulated to deliver the drug at optimized rate into the systemic circulation– should adhere to the skin for the expected duration

– should not cause any skin irritation and/or sensitization.

Types of TDS• Liquid Reservoir Patch

Drug in solution or suspension between the backing layer and a rate controlling membrane

• Drug in Adhesive Patch

Drug dispersed in adhesive, in direct contact with skin• Polymer Matrix Patch

Drug in solution or suspension dispersed within a polymer• Multi-laminate Matrix Patch

Drug dispersed in adhesive in multi-layers separated by membranes

Factors Considered:Products are demonstrably difficult to

compound

• Drug delivery system

• Drug formulation and consistency

• Bioavailability

• Complexity of compounding

• Facilities and equipment

• Training

• Testing and quality assurance

Drug Delivery System

• Each TDS is optimized to deliver the drug at desired rate into systemic circulation. The components are selected based on physicochemical and pharmacological properties of the drug to optimize the drug penetration rate.

• Variability in the component mixture or manufacturing process maynot ensure adequate biopharmceutics quality of the product.

• Appropriate quality control measures and stability of the formulation are essential to ensure dosing accuracy and reproducibility.

Drug Formulation and Consistency

• Proper formulation is essential to provide consistent and reproducible drug delivery. Components of the formulation, vehicle, penetration enhancers or surfactant and adhesives must be adequately tested and studied for compatibility. These components effect the release rate of the drug and adherence of the device to the skin, which is essential for efficacy.

Drug Formulation and Consistency

• Vehicle selection is important. A vehicle that optimally delivers one drug substance may not be appropriate for delivery of a different drug substance.

• Vehicles can grossly affect drug bioavailability and influence the clinical outcome of the drug.

• The adhesive selected should provide good skin contact over the total area of application for entire duration to ensure adequate drug delivery.

• Interactions with all components including skin irritation and sensitization need to be evaluated to ensure dosing accuracy and reproductivity.

Drug Formulation and Consistency

Transdermal Drug Delivery SystemBiopharmaceutics Considerations

• From biopharmaceutics point of view, to ensure product effectiveness, rate and extent of drug delivery, PK reproducibility and optimization of application site with the formulation need to be considered.

Bioavailability

• The appropriate biopharmaceutical properties of the TDS is most vital to deliver the drug at optimized rate for therapeutic effectiveness of the drug product.

• Lower rates of delivery may result in ineffective drug concentrations, and higher rates of delivery may result in toxic and adverse reactions.

• The optimized formulation with adequate adhesive properties at the site of application are important to assure reproducible bioavailability and drug effectiveness.

Testing and Quality Assurance

• The product must be tested for its potency, content uniformity, purity, residual solvents, residual monomers, release liner peel force, adhesion, microbial testing, release rate and pouch integrity to ensure product performance.

Preliminary FindingsDifficulties in compounding result from the following characteristics and requirements:

• TDS are sophisticated and complex drug delivery systems. It requires extensive experience to develop a product that can ensure dosing accuracy and reproducibility.

• Sophisticated equipment and facilities are needed to ensure proper compounding of TDS.

• Specialized technical training is essential to ensure proper compounding of TDS products.

• Sophisticated, difficult to perform testing of the compounded product is required to ensure product-to-product-uniformity, potency, purity, and quality of the drug product prior to dispensing.

Preliminary Conclusion

• We have tentatively determined that TDS drug products present demonstrable difficulties for compounding.

• These difficulties would likely have an adverse effect on the safety and effectiveness of such drug products.