Outline
��General QbD principles
��What is QbD/Design Space
��Why use QbD for OINDPs?
��QbD applied to OINDPs
��Product Design
��Formulation Design
��Container Closure System Design
��Process Design (e.g. micronization)
��Design and Setting Specifications in the Future
��Blinded case studies where QbD could have helped shorten approval time
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What is QbD?
��Quality by Design is:
��Scientific, risk-based, holistic and proactive approach to pharmaceutical development
��Deliberate design effort from product conception through commercialization
��Full understanding of how product attributes and process relate to product performanceQbD information and conclusions should be shared with FDA
ICH Quality RoadmapPharm.QualitySystems (Q10)Pharm.Dev.(Q8)/QbD(Q8R)DesiredStateQuality RiskManagement(Q9)
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QbD SystemDefine desired product performance upfront;identify product CQAsDesign formulation and process to meet product CQAsUnderstand impact of material attributes and process parameters on product CQAsIdentify and control sources of variability in material and processContinually monitor and update process to assure consistent qualityRisk assessment and risk controlProduct & process design and developmentQualitybyDesign
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ICH Q8 –Design Space
��Definition
��The multidimensional combination and interactionof input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality
��Traditional one dimensional process range doesn't meet Q8 definition and will not lead to "regulatory flexibility"
��Regulatory Flexibility
��Working within the design space is not considered a change
��Important to Notice
��Design space is proposed by the applicant and is subject to regulatory assessment and approval
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Reducing Product VariabilityProcess (or Process Step)Design SpaceMonitoring ofParametersor AttributesProcess Controls/PATProcessParametersMaterialsattributesProduct Quality Attributes(or Intermediate)ProductVariabilityReducedProductVariabilityProcessVariability
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Why Use QbD for OINDPs?
��CQAs for materials, products, and process parameters (CPPs) are better understood
��Controls are rationally designed to fit end-use performance criteria in light of CQAs and CPPs
��The entire manufacturing system is more flexible; accounting for and responding to variability in materials, environment, and process, within a known design space
��More flexible regulatory framework which relies on the demonstration and use of knowledge
��May reduce overall approval time (time to approval + launch)
��May reduce product failures after approval associated with variability in ingredients and process that would not otherwise have been considered
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Desired Product Performance
��Utilize early phase data such as
��Optimum dose or dose range
��Therapeutic index
��PK / PD profile where applicable
��Site of activity (local) / absorption (systemic)
��If local, rescue versus chronic
��Physicochemical properties prior knowledge
��CCS (compositions, extractable profile etc.)
��To define desired product characteristics and performance (CQAs) such as
��Delivered Dose Uniformity (DDU)
��Aerodynamic Particle Size Distribution (APSD)
��Product stability
��Drug/device combination issues
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Formulation/Product Design
��Drug Substance (DS)
��Identify Critical Quality attributes (CQAs) such as moisture content, polymorph form, surface morphology, PSD which affect downstream drug product performance of DDU, APSD, etc.
��Delivery Platform
��MDI, DPI, Nasal Spray, Inhalation Spray, etc.
��Formulation/device subtype
��e.g., suspension versus solution MDI
��e.g., device metered versus pre-metered DPI
��Limited excipient choices in all cases
��Limited by pharmacology/toxicology concerns
Identify CQAs of Excipients
��Propellant(s) and Ethanol
��Water content
��Impurities
��Surfactants
��Compositional profile, surface active properties
��Lactose
��Hydrate form, amorphous content
��Surface morphology
��Water content
��PSD
��Magnesium stearate
��Compositional profile
��PSD
��Leucine, DPPC, water, buffers, salts, preservatives, etc.
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Container Closure System (CCS)
��CCS or device components are part of the drug delivery system, which is an integral part of the drug product.
��CCS design has always been critical to OINDPs
��Dose Counter recommended
��The sharing of knowledge between the drug product manufacturer and the CCS designer/ manufacturer would facilitate 1stcycle approval and flexible risk-based regulatory decisions.
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CCS Performance Goals
��The following are desired throughout the shelf life
��Reliable and accurate dose delivery
��Stable and dimensionally consistent
��Mechanically robust
��Protection of the formulation
��Readily manufacturable
��User friendly characteristics (ruggedness to variability in patient use)