Case Studies
Pharmaceutical Development and Formulation
Reformulation to Achieve Acceptable Stability Profile for NDA Submission and Commercialization
Benefits of Case:
• Reformulation of unstable Phase 3 dose form
• Progress client to NDA submission with an acceptable dose form
Background and Challenge:
The Client had progressed into a Phase 3 clinical program with a controlled release combination drug formulation in which one of the drug substances exhibited an unacceptable long term stability profile. An alternate formulation had to be rapidly developed. Additionally, the new formulation could not infringe upon existing patents covering methods to stabilize the drug in the solid dose form.
PharmaDirections Strategy:
• Tailor multidisciplinary team of formulation, chemistry, manufacturing, and patent personnel to identify possible approaches for formulation development
• Review patent literature on the protected technologies used to stabilize the drug substance in the dose form and determine formulation approaches withat permitted “freedom to operate”
• Execute experiments to understand the degradation pathway for the drug substance, and explore possible formulation approaches for stabilization
• Identify a stable formula and manufacture registration batches to support an NDA filing
The Objectives:
• Identify anapproach for a stable formulation with freedom to operate
• Complete formulation work without disruption to the proposed NDA submission schedule
Value for the Client:
• PharmaDirections Pharmaceutical Development staff identified a stable formulation that met the sponsor’s needs for planned NDA submission and intellectual property requirements
Results from PharmaDirections Combined Experience and Expertise:
PharmaDirections quickly assembled a team with expertise in formulations, chemistry, patents, and manufacturing to perform a thorough analysis of technologies that could potentially solve the formula stability problem without infringing on existing patents. To quickly evaluate potential solutions to the stability problem, numerous experiments evaluating alternative formulation approaches were designed and performed at a number of contract labs within the PharmaDirectNet™ network simultaneously. Once formulations were narrowed down, stability batches were made to identify the formula that would solve the stability problem and allow the development of the NDA to meet the previously established schedule.
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Risk Mitigation and Formulation Development of a Once Daily Controlled Release Oral Product
Benefits of Case:
• Development of a high potency, low dose once daily controlled release dose form
• Create a medical and market advantage with new dose form
• Rapid solution of manufacturing issues during development
Background and Challenge:
The Client identified medical and market advantages to introducing a once-daily dose form (with improved tolerability) to compete with a commercially available immediate release product marketed by another pharmaceutical firm. The Client sought a partner to perform development of the product since development was particularly challenging due to the small dose (less than 1 mg daily) to be released in a controlled and sustained manner.
PharmaDirections Strategy:
• Tailored a multidisciplinary team of personnel to drive the formulation development and optimization based on the target drug release dissolution profiles recommended by in silico pharmacokinetic modeling
• Devoted and responsive oversight of development activities to insure on-time completion of development program
The Objectives:
• Develop three controlled release formulations with predicted in vivo behavior
• Assess pharmacokinetic performance and clinical safety/tolerability of proposed formulations
• Select one of three formulations with the targeted clinical pharmacokinetic profile for further development
• Manage development execution through network of service providers
• Execute GMP manufacture for clinical trial materials
Value for the Client:
• PharmaDirections managed all scientific development activities including formulation, analytical, in silico PK modeling to established IVIVC to generate product dissolution targets, and manufacturing to successfully complete development of the desired dose form
• PharmaDirections selected, managed and provided scientific oversight to multiple contractors for rapid execution of the analytical steps and development activities
• Risk mitigation of project activities by applying a multidisciplinary approach to solve development and manufacturing challenges
• Placed a person in the plant to investigate and rapidly solve a drug content uniformity problem to permit project to move forward on schedule
Results from PharmaDirections Combined Experience and Expertise:
Phase 1 clinical trial was performed with dose form and met requirements for once-daily sustained release target maintaining drug plasma levels with reduced peak plasma level.
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