1
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`RDD Europe 2007
`
`Office of New Drug Quality Assessment
`
`(ONDQA), OPS, CDER
`
`Prasad Peri, Ph.D.
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`APPROACHES FOR ORALLY INHALED
`
`QUALITY BY DESIGN (QbD)
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`AND NASAL DRUG PRODUCTS
`
`(OINDPs) IN THE USA
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`Eton Ex. 1062
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`RDD Europe 2007
`
`Office of New Drug Quality Assessment
`
`(ONDQA), OPS, CDER
`
`Prasad Peri, Ph.D.
`
`APPROACHES FOR ORALLY INHALED
`
`QUALITY BY DESIGN (QbD)
`
`AND NASAL DRUG PRODUCTS
`
`(OINDPs) IN THE USA
`
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`(cid:132)Blinded case studies where QbD could have
`
`helped shorten approval time
`
`(cid:132)Design and Setting Specifications in the
`(cid:132)Process Design (e.g. micronization)
`(cid:132)Container Closure System Design
`(cid:132)Formulation Design
`(cid:132)Product Design
`
`Future
`
`(cid:132)QbD applied to OINDPs
`
`(cid:132)Why use QbD for OINDPs?
`(cid:132)What is QbD/Design Space
`
`(cid:132)General QbD principles
`
`Outline
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`shared with FDA
`QbD information and conclusions should be
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`performance
`attributes and process relate to product
`
`(cid:132)Full understanding of how product
`
`conception through commercialization
`(cid:132)Deliberate design effort from product
`
`(cid:132)Scientific, risk-based, holistic and proactive
`
`approach to pharmaceutical development
`
`(cid:132)Quality by Design is:
`
`What is QbD?
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`3
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`(Q10)
`Systems
`Quality
`Pharm.
`
`Management
`Quality Risk
`
`(Q9)
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`QbD(Q8R)
`Dev.(Q8)/
`Pharm.
`
`State
`Desired
`
`ICH Quality Roadmap
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`Risk assessment and risk control
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`process parameters on
`material attributes and
`Understand impact of
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`product CQAs
`
`Design formulation and
`
`product CQAs
`process to meet
`
`sources of variability
`Identify and control
`
`in material and
`
`process
`
`Continually monitor
`
`consistent quality
`process to assure
`
`and update
`
`product performance
`
`Define desired
`
`identify product CQAs
`
`upfront;
`
`Quality
`
`Design
`
`by
`
`Product & process design and development
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`QbD System
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`(cid:132)Design space is proposed by the applicant and is subject
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`to regulatory assessment and approval
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`(cid:132)Important to Notice
`
`(cid:132)Working within the design space is not considered a
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`change
`
`(cid:132)Regulatory Flexibility
`
`Q8 definition and will not lead to “regulatory flexibility”
`(cid:132)Traditional one dimensional process range doesn’t meet
`assurance of quality
`parameters that have been demonstrated to provide
`of input variables (e.g., material attributes) and process
`(cid:132)The multidimensional combination and interaction
`
`(cid:132)Definition
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`ICH Q8 –Design Space
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`Process Controls/PAT
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`or Attributes
`Parameters
`Monitoring of
`
`Parameters
`
`Process
`
`Variability
`Process
`
`(or Intermediate)
`Attributes
`Product Quality
`
`Variability
`Variability
`Product
`Product
`Reduced
`
`(or Process Step)
`
`Process
`
`attributes
`Materials
`
`Space
`Design
`
`Reducing Product Variability
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`(cid:132)CQAs for materials, products, and process parameters (CPPs)
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`are better understood
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`(cid:132)Controls are rationally designed to fit end-use performance
`
`criteria in light of CQAs and CPPs
`
`(cid:132)The entire manufacturing system is more flexible; accounting
`
`and process, within a known design space
`for and responding to variability in materials, environment,
`
`not otherwise have been considered
`with variability in ingredients and process that would
`(cid:132)May reduce product failures after approval associated
`
`launch)
`
`(cid:132)May reduce overall approval time (time to approval +
`
`demonstration and use of knowledge
`
`(cid:132)More flexible regulatory framework which relies on the
`
`Why Use QbD for OINDPs?
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`(cid:132)Drug/device combination issues
`(cid:132)Product stability
`(cid:132)Aerodynamic Particle Size Distribution (APSD)
`(cid:132)Delivered Dose Uniformity (DDU)
`performance (CQAs) such as
`
`(cid:132)To define desired product characteristics and
`
`(cid:132)CCS (compositions, extractable profile etc.)
`(cid:132)Physicochemical properties prior knowledge
`
`(cid:132)Site of activity (local) / absorption (systemic)
`(cid:132)PK / PD profile where applicable
`(cid:132)Therapeutic index
`(cid:132)Optimum dose or dose range
`(cid:132)Utilize early phase data such as
`
`If local, rescue versus chronic
`
`(cid:132)
`
`Desired Product Performance
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`(cid:132)Identify Critical Quality attributes (CQAs) such as
`
`product performance of DDU, APSD, etc.
`morphology, PSD which affect downstream drug
`moisture content, polymorph form, surface
`
`(cid:132)Drug Substance (DS)
`
`(cid:132)Delivery Platform
`
`(cid:132)MDI, DPI, Nasal Spray, Inhalation Spray, etc.
`
`(cid:132)Limited by pharmacology/toxicology concerns
`
`(cid:132)Limited excipient choices in all cases
`
`(cid:132)e.g., device metered versus pre-metered DPI
`(cid:132)e.g., suspension versus solution MDI
`
`(cid:132)Formulation/device subtype
`
`Formulation/Product Design
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`(cid:132)Leucine, DPPC, water, buffers, salts, preservatives, etc.
`
`(cid:132)PSD
`(cid:132)Compositional profile
`
`(cid:132)Magnesium stearate
`
`(cid:132)PSD
`(cid:132)Water content
`(cid:132)Surface morphology
`(cid:132)Hydrate form, amorphous content
`
`(cid:132)Lactose
`
`(cid:132)Compositional profile, surface active properties
`
`(cid:132)Propellant(s) and Ethanol
`
`(cid:132)Impurities
`(cid:132)Water content
`
`(cid:132)Surfactants
`
`Identify CQAs of Excipients
`
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`and flexible risk-based regulatory decisions.
`manufacturer would facilitate 1stcycle approval
`product manufacturer and the CCS designer/
`(cid:132)The sharing of knowledge between the drug
`(cid:132)Dose Counter recommended
`(cid:132)CCS design has always been critical to OINDPs
`
`drug product.
`delivery system, which is an integral part of the
`(cid:132)CCS or device components are part of the drug
`
`Container Closure System (CCS)
`
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`(cid:132)User friendly characteristics (ruggedness to
`(cid:132)Readily manufacturable
`
`variability in patient use)
`
`(cid:132)The following are desired throughout the
`
`(cid:132)Protection of the formulation
`(cid:132)Mechanically robust
`(cid:132)Stable and dimensionally consistent
`(cid:132)Reliable and accurate dose delivery
`shelf life
`
`CCS Performance Goals
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`(cid:132)Processing aids used in forming, cleaning, and assembly
`(cid:132)Additives in plastics and elastomers
`(cid:132)Fabrication methodology for each component
`(cid:132)Elastomers
`(cid:132)Plastics
`(cid:132)Metals
`This includes:
`outcomes and formulation compatibility considerations
`will be driven by the desired performance parameter
`(cid:132)Material choice for the CCS components of the OINDP
`
`(cid:132)Gather knowledge early in partnership with CCS
`
`component manufacturers/supplier(s)
`
`CCS Development in QbD
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`(cid:132)Determine who (NDA applicant or supplier) will do
`(cid:132)Rational Design of Experiments (DOE)
`performance as it pertains to your drug product.
`
`drug product
`component, and processing used in the CCS for your
`
`(cid:132)Understand sources of variability for each material,
`
`(cid:132)Evaluate the impact of this variability on CCS
`
`them
`
`(cid:132)Collaboration with your CCS supplier(s) to maximize
`
`assessment program
`the chances for success as part of a rational risk
`
`process controls for your CCS components
`
`(cid:132)Work with your supplier(s) to ensure appropriate in-
`
`CCS Development in QbD
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`Eton Ex. 1062
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`(cid:132)Evaluate risk in terms of severity, likelihood,
`
`and detectability
`
`(cid:132)Establish appropriate control strategy to
`(cid:132)Develop risk reduction strategies
`
`minimize effects of variability on CQAs
`
`(cid:132)Identify critical process parameters and
`
`materials attributes
`
`(cid:132)Conduct risk analysis/assessment to:
`
`(cid:132)Understand how process parameters affect
`
`CQAs
`
`(cid:132)For each unit operation
`
`Manufacturing Process Understanding
`
`Eton Ex. 1062
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`(cid:132)Data laden, but knowledge poor, system
`(cid:132)Sensitive to variability without being responsive to it
`(cid:132)Problematic with planned site, equipment, and scale, changes
`
`(cid:132)Tight controls over incoming non-micronized DS are usually
`
`necessary
`
`(cid:132)This approach is controlled but not robust
`
`(cid:132)Fixed process; almost any change requires Agency
`(cid:132)Time, temp, humidity set at predefined ranges
`
`approval
`
`(cid:132)Current recipe approach
`As an example, consider DS micronization
`
`Manufacturing Process Understanding
`
`Eton Ex. 1062
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`morphology, etc.) and is more robust
`endpoints (PSD, polymorph limits, surface
`(cid:132)A QbD approach controls the DS to desired
`
`(cid:132)Process is adjustable within design space without
`
`regulatory oversight
`
`(cid:132)Combination and interaction effects of time, temp,
`
`understood, and design space established
`and humidity on DS CQAs are studied and
`
`(cid:132)Alternatively, for a QbD approach
`
`Manufacturing Process Understanding
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`may be considered
`statistical approaches/PTIT for DCU)
`
`(cid:132)Alternative approaches (e.g.,
`(cid:132)Part of quality control strategy
`(cid:132)Science and risk based
`(cid:132)Clinical Relevance
`
`Designing/Setting specifications in
`
`the Future
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`Eton Ex. 1062
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`SPECIFICATIONS
`
`Manufacturing Process
`
`Identification
`
`Qualification
`
`and
`
`Device Operation
`
`Temperature)
`(Pressure,
`
`(Oils, Detergents, Soaps,
`Component Mfg. Process
`
`Surface Modifiers)
`
`Leachables
`
`Data
`
`Fabricator
`
`Reaction Kinetics
`
`Test Methods
`
`CCS Materials
`
`Selection
`
`Stability/Storage
`
`Conditions
`
`Formulation, Excipients
`
`Drug Substance,
`
`Leachables Specifications
`
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`testing
`several weeks at 40ºC ambient RH before release
`subsequent studies by storing the finished MDI for
`(cid:132)The firm is considering to address the problem for
`
`(cid:132)During early development the applicant discovers
`of Micronized DS Used in an MDI
`Case Study 1: MetastableReversion
`
`(cid:132)This initial trend is problematic. In both cases above, there
`(cid:132)Same drop over several months at 25ºC/60%RH
`(cid:132)20% drop over several weeks at 40ºC/75%RH
`with micronized DS physical instability
`(FPM) as collected on stages 3-5 of ACI associated
`that there is a drop in drug product fine particle mass
`
`is very little drop in FPM afterwards
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`(cid:132)Other changes that several weeks at 40ºC may induce in
`(cid:132)The role of moisture the FPM drop is unclear
`mitigate) the FPM drop have not been elucidated
`
`(cid:132)The material attributes and/or process parameters that cause (or
`
`(cid:132)Leachables may increase in response to the proposed operation
`(cid:132)Valve function changes in response to elastomer aging
`the CCS and formulation are not yet known
`
`(cid:132)Gaps in knowledge are not filled in
`(cid:132)Reliability and predictability are unknown
`
`(cid:132)Many uncertainties persist
`
`Case Study 1 Issues
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`(cid:132)Control of micronization CPPs
`
`(cid:132)Control of material CQAs (e.g., water content,
`storage”may be eliminated
`
`(cid:132)The need for (and effects of) several weeks of “hot
`
`feed PSD, etc.)
`
`(cid:132)The proposed operation may be supported by thorough
`
`knowledge
`
`(cid:132)Possible outcomes
`(cid:132)DOE
`(cid:132)Conduct lab scale studies
`
`Case Study 1 Resolution
`
`Eton Ex. 1062
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`
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`(cid:132)Formulation was changed to add certain excipients
`
`(cid:132)DPI change after Phase 2 studies. Design of
`
`operated in the same general manner
`device was “optimized”and the new device
`
`manufacture
`claiming the drug product was easy to
`
`(cid:132)In vitro comparative data for several dose
`
`Case Study 2: Optimization of
`
`Device/Formulation
`
`24
`
`(cid:132)A substantial change that was deemed medically
`
`(cid:132)No scientific justification as to what caused the
`
`change in FPM
`
`relevant in the FPM (>20%) was noted
`
`strengths were compared to previous version
`
`Eton Ex. 1062
`24 of 31
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`developmental hurdles.
`emitted dose would have indicated possible
`the impact of these variables on FPM and total
`(cid:132)A design of experiments approach to evaluate
`
`content) prior to instituting the change.
`impact of formulation change, moisture
`airflow within the device, device resistance,
`dependence of FPM on APSD properties (e.g.,
`(cid:132)A QbD approach would have characterized the
`clinical trials. Development timelines extended.
`characterize the drug product performance in
`(cid:132)Sponsor asked to perform clinical studies to re-
`
`Case Study 2: Resolution
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`dose delivery.
`causing valve sticking and extensive variable
`handling were thought to play a role in
`
`(cid:132)Dimensional incompatibility and or/patient
`
`(cid:132)Modification of the actuator, necessary for
`
`release of the drug was impaired.
`condition where the valve return and the
`incorporating the dose counter led to a
`
`incorporating a dose counter.
`not behave as it did in phase 2 trials while
`applicant realized that the metering valve did
`(cid:132)During Phase 3 development of an MDI, the
`Case Study 3: MDI Valve Sticking
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`development time.
`patient use study with the device extending the
`incorporating the dose counter, and perform a
`made to the actuator as a result of
`components and evaluate the modification
`
`(cid:132)Recommendations were made to redesign the
`
`was unlikely to resolve the issues.
`“quick-fix”approach with labeling modifications
`sticking problem was never clearly identified, a
`
`(cid:132)However since the root cause of the valve
`
`modified device.
`labeling instructions for patient usage of the
`
`(cid:132)The sponsor proposed to include specific
`Case Study 3: Resolution
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`(cid:132)Therapeutic index for the active relatively low.
`(cid:132)More critical for device metered DPIs
`
`(cid:132)Emitted dose significantly different than
`
`specified.
`
`device failures during patient use.
`metered DPI, the sponsor submitted reports of
`
`(cid:132)During Phase 3 development of a device
`
`Case Study 4: DPI Device Failures
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`(cid:132)These design modifications appeared to reduce
`
`the likelihood of these problems recurring
`
`(cid:132)Under a QbD process, these issues hopefully
`
`times
`development to minimize the development
`would have been identified early on in
`
`design changes
`responded to the Agency with a series of
`engineering and mechanistic concepts and
`
`(cid:132)Sponsor was asked to address this problem of
`
`device failures
`
`(cid:132)Sponsor modified the device based on
`
`Case Study 4: Resolution
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`(cid:132)Culture change is necessary for implementing this sort
`(cid:132)Specifications only part of quality control strategy
`
`(cid:132)Ultimate goal is to make a quality product available to
`of development both by the applicants and regulators
`
`the consumer with less regulatory oversight
`
`assessing the CPAs and CPPs that define the product
`
`(cid:132)Proactive thought process should be involved in
`
`complex nature
`drug development, more so for OINDPs due to their
`(cid:132)QbD approach is recognized as the desired state for
`
`Concluding Remarks
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`(cid:132)Vibhakar Shah, Ph.D.
`(cid:132)Alan Schroeder, Ph.D.
`(cid:132)Moheb Nasr, Ph.D.
`(cid:132)Rik Lostritto, Ph.D.
`(cid:132)Blair Fraser, Ph.D.
`(cid:132)Chi-Wan Chen, Ph.D.
`(cid:132)Craig Bertha, Ph.D.
`
`Acknowledgements
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`Eton Ex. 1062
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