Regulatory Assessment, ICH, November 2010,Disclaimer,The information within this presentation is based on the ICH Q-IWG members expertise and experience, and represents the views of the ICH Q-IWG members for the purposes of a training workshop., ICH, November 2010,Presentation Overview,Goal of Regulatory Quality Assessment Review of the case study Considerations during regulatory evaluation Areas of consideration by assessors will be presented in the form of questions for the assessor The questions presented here are not necessarily the ones which are finally communicated in regulatory deficiency letters API and Formulation Manufacturing Process Development Quality Risk Management Design Space Proposed Control Strategy and Real Time Release Testing Assessors - Inspector Interaction, ICH, November 2010,Goal of Regulatory Quality Assessment,Assess That the product is capable of consistently meeting the required quality That the manufacturing process is capable of producing quality product That throughout product shelf life and life cycle commercial batches will link to clinical batches in all relevant aspects These can be accomplished by Process development and control strategy according to traditional standards Process development and control strategy according to new paradigm, ICH, November 2010,Principles of Assessment,Assessment principles are the same regardless of the development approach Meet Quality Target Product Profiles (QTPPs) Areas of assessment: API Formulation Manufacturing process Control strategy Analytical Procedures Stability,Regulatory Assessment API and Formulation, ICH, November 2010,API General Considerations,QbD principles apply to APIs QbD principles can guide manufacturing process design and control strategy development Design space can be developed for API processes, ICH, November 2010,API- Assessors Evaluation,Have starting materials and process been adequately described? Are there toxicity concerns with degradants and/or related substances? Have adequate specifications and methods been proposed? Have adequate process controls been described? Was the design space adequately developed and data provided to support it?, ICH, November 2010,Formulation - General Considerations,Design space formulation aspects Variable composition or component attributes Based on input raw material attributes Lot to lot variability Justified by data (Prior knowledge, DoE, etc) API attributes To be considered in the development of formulation and choice of dosage form to meet QTPP Additional information may be needed for the development of the formulation e.g. BCS, PK, stability, excipient compatibility, ICH, November 2010,Assessors Evaluation of the Formulation,Is dosage form designed to meet QTPP? Are the roles of ingredients identified? Have the safety and compatibility of ingredients been adequately addressed? Is the formulation adequately understood and specified? Does the proposed formulation differ from the formulation used in the pivotal clinical trials?, ICH, November 2010,Assessors Evaluation of the Case Study Formulation,Why was Calcium Hydrogen Phosphate Hydrate chosen with a water sensitive API? Concern about compatibility and stability Has material variability effects been understood? Adequacy of NIR testing Adequacy of dissolution model and method What is the function of D-mannitol in the formulation? Described only as excipient in the case study Needs to be further explained,Regulatory Assessment Manufacturing Process Development, ICH, November 2010,Assessment of Manufacturing Process Development,Production process description needs to have sufficient detail to enable assessment Assessment should evaluate Process design Use of risk management processes including risk assessments Design space Robustness, ICH, November 2010,Initial Quality Risk Assessment,Tablet Manufacturing Operation,Aids assessor in understanding how different aspects of the process can affect product quality Incorporates known risk factors of drug product degradation pathways (e.g., moisture sensitivity), solubility factors, etc. Includes effects of unit operations and starting materials (including excipient properties) Atypical or unusual findings should be explained in greater detail, ICH, November 2010,Assessors Evaluation of the Risk Assessment,Assessors to evaluate methodologies and outcome Explanation of risk ranking and score Setting of risk threshold Assurance that relevant factors have been considered Are results consistent with scientific principles and prior knowledge? Was there a linkage of results to the development of design space and control strategy?, ICH, November 2010,DoE to Support Design Space,Multifactorial DoE study of variables affecting dissolution,Use an appropriate experimental design (e.g., some screening designs cannot determine interactions),Provide more relevant experimental data and statistical analysis for critical unit operations,Address what parameters were not varied in the design space experiments,