Embed Size (px)
Citation preview
May 27, 2011 1
Welcome to
Risk-Based Drug QualitySystem
Satendra K Vishwakarma PhD
FDA & ICH JOINT PROPOSAL FOR DESIRED STATE
Revisit Presentation By
May 27, 2011 2
Announcement
The contents, views and graphics, in this presentation, are collected from various sources.
Presenter of this presentation believes that all the reported materials are Up-to-Date and is ONLY for
INFORMATION, NOT for IMPLEMENTATION.
For more Information, visit FDA & ICH web sites.
Thank You
May 27, 2011 3
Current State of Affairs in Pharma Industry.
Introduction – Summary of ICH Quality Topics.
Desired Guiding Principles & Fulfillments.
Why best available science-based policies and standards.
Identification of desired state of qualitymanufacturing by design space.
Manufacturing process science and understanding of critical controls (PAT).
Risk- based quality review and management.
Summary, Thoughts & Questions.
May 27, 2011 4
UNDERSTANDING THE BASICS
Solid Dosages Generic Formulations
Purity CheckSame Drug
Rigorous Manufacturing Standards
Quality standards comparable to Reference Listed Drug (RLD)
May 27, 2011 5
INDUSTRY FACTORS■ Reluctance to innovate / invest in manufacturing sector
compared to R&D.
■ Most processes are fixed with variable materials, resulting in variable quality of product.
■ Emphasis on getting product out discourages early work on process and changes after marketing.
PRODUCT FACTORS■ Increasing trend towards manufacturing-related problems.
■ Low manufacturing process efficiency-cost implications.
■ Excessive amounts of product non-conformances/OOS.
■ Slow innovation, modernization & technologies adoption.
■ Rising trend of recalls 176/1998–354/2002 & Supplements.
Current State of AffairsThesis of Critical Path : There has been a Failure of Predictability
Introduction
May 27, 2011 6
REGULATORY FACTORS■FDA’s emphasis was on institution of basic
procedures and recordkeeping--evolved to cGMP.
■Empirical quality methodologies are approaching their theoretical effectiveness.
■High burden on FDA resources.
OVERALL CONCLUSION
“The present state is focused on documentation, following SOPs validating the process, changing SOPs meeting specifications, and not changing the process leading to high risk of drug efficacy and public health.”
Current State of AffairsThesis of Critical Path : There has been a Failure of Predictability
Introduction
May 27, 2011 7
Inadequate QA
Functions 2%
Inadequate SOP 2%
Facility withdrawn
3%
Previous Deviations
persists 7%
Others 15%
Drug not made at site
8%
Contamination 13%
Pending Regulatory
Action 18%
Firm Not Ready 25%
Inadequate Lab
controls 7%
Findings & RecommendationsCurrent Affairs
Thomas J Arista, FDA’s Data Sep 2003 – April 2004
FDA’s Risk-Based “cGMPs for the 21st Century”
“PAT Initiative” and “Generic Drug Equivalence”
issues are on the agenda.
May 27, 2011 8
FUTURE CHALLENGES AND OPPORTUNITY
■ Currently FDA attempting to drive innovation and investment in manufacturing sector via compliance / enforcement actions.
■ New level of scientific understanding & new technologies can provide Science & Engineering-Based Approach over Rule-Based Approach.
Product quality achieved and assured by design of processes. Product specifications based on mechanistic understanding of how formulation and process factors impact product performance.
■ Accelerate GGP, setup and adopt ICH Q6A + PAT-based efficient approach (as a platform) to achieve ICH Q10.
Desired State of 21st CenturyVision
May 27, 2011 9
Desired State of 21st Century
SCIENCE & RISK – BASED REGULATORY
APPROACH
■ Regulatory support and flexibility during development &
implementation.
■ Regulatory policies tailored to recognize the level of
scientific knowledge supporting product applications,
process validation, and process capability.
■ Risk-based regulatory scrutiny relate to the level of
scientific understanding of how formulation and
manufacturing process factors affect product quality
and performance, and the capability of process control
strategies to prevent or mitigate risk of producing a
poor quality product.
Vision
May 27, 2011 10
OVERALL CONCLUSION
■ “The desired state, by contrast, would focus on data analysis, understanding critical to quality attributes, measuring process capability, performingcontinuous quality verification, and undertaking continuous improvement to maintain consistent product quality.”
■ Minimize risks of poor process quality and reduce (regulatory) concerns.
Desired State of 21st CenturyVision
May 27, 2011 11
GMPSPECIFICATIONDESIGN ICH Q1 Stability
ICH Q2 Analytical Procedures
ICH Q3 Impurities
ICH Q4 Pharmacopoeia
ICH Q5 Biotechnological / Biological Products
ICH Q6 Specifications
ICH Q7 current GMPs / current GGPs
ICH Q8 Pharmaceutical Development
ICH Q9 Quality Risk Management
ICH Q10 Quality Management
M4 Q Common Technical Document
Visit ICH Web Page for Guideline details on definition, development,
extensions, revision or maintenance.
Guidelines
May 27, 2011 12
Highlights of ICH Q6AGuidelines
Specifications
Test Procedures and Acceptance Criteria for New
Drug Substances and New Drug Products.
Definition of Specification
A list of tests, references to analytical procedure,
and appropriate acceptance criteria which are
numerical limits, ranges, or other criteria for the
tests described.
Consistency
Purity
Identity
Characterization
Potency
Degradation / Impurity
May 27, 2011 13
Pharmaceutical Development
ICH
Q6
A:T
erm
ino
log
yD
ecis
ion
Ch
ara
cte
ris
tic
s
CURRENT STATE : TESTING TO DOCUMENT QUALITY
ICH
Specifications
In Process Controls
Development
Design
Process Validation
GMP Controls
May 27, 2011 14
The Goal and Characteristics of
Pharmaceutical Quality Decision
System
“The quality of drug substances and drug
products is determined by their design,
development, in-process controls, GMP
controls, process validation, and by
specifications applied to them throughout
development and manufacture.”Ch
ara
cte
risti
cs Goal
Life-cycle
ICH Q6A
Ajaz S. Hussain CDER FDA Ball State University Muncie, IN, 2005
PAT
May 27, 2011 15
Therapeutic Equivalence Matter
Current Paradigm 21st Century Paradigm
Same Drug, Strength,
Dosage form, Safety, Quality
Same Drug, Strength,
Dosage form, Safety, Quality
+Pharmaceutical
Equivalence
+Quality by Design
(Designed to be equivalent )
+Bioequivalence +Verified by in-vivo Testing
(Demonstrate bioequivalence)
= Therapeutic Equivalence = Therapeutic Equivalence
Modified from Robert Lionberger, Office of Generic Drugs, FDA
Pharmaceutical Product Development Information (PPDI)
(ICH CTD, ICH Q8) in ANDA may help OGD be more efficient.
PPDI is an opportunity and the only existing mechanism to
justify rational specifications & emphasize quality by design.
Pharmaceutical Product Development Information
ICH
May 27, 2011 16
Absent or
variable in
US CMC
Sections
What is the ICH Q8 Opportunity?
Specifications
In Process Controls
Development
Design
Process Validation
GMP Controls
ICH
ICH Q8
“…where the provision of greater understanding of pharmaceutical and
manufacturing sciences can create a basis for flexible regulatory approaches.”
DESIRED STATE : DESIGNING TO BUILD QUALITY
May 27, 2011 17
Desired State and Regulation
Science based mechanistic process understanding & development & improvement.
Process integrated quality manufacturing and process control system.
Predictability quality by design & design space.
Consistency quality system guidelines assuring the processes, performing continuous quality verification, undertaking evaluation and continuous improvement.
Regulatory science knowledge in control, simulation, process, preformulation, bioceutics.
Risk based approach for quality attributes, comprehensive CMC & ANDA review.
PAT
May 27, 2011 18
ICH Q8 Journey
Product specifications based on mechanistic
understanding of how formulation and process
factors impact product performance.
Product quality and performance achieved and
assured by design of effective & efficient
(robust) manufacturing processes (QbD).
An ability to effect continuous improvement &
continuous "real time release" assurance of
quality.
CMC: The Desired State
"real time release“ means Quality Control Reduction of End Product
Release Testing
ICH
May 27, 2011 19
FDA Journey
Science & Risk based Specifications.
Greater product and process knowledge allows regulatory decisions based on actual risks (Mantra : Increase Analytical & Statistical tools to reduce Source of Process Variabilities and relate to Clinical Relevance).
Define design space and manage the changes within design space (Mantra : Manage your own SUPAC Concept & Real Time Release).
FDA Review: The Desired State
Design Space is the established range of scientific parameters that
has been demonstrated to provide assurance of quality.
PAT
May 27, 2011 20
Quality by Design
Process Design
cGMP/CMC FOCUS
Design qualification
MECHANISTIC
UNDERSTANDING
CAUSAL LINKS
PREDICT PERFORMANCE
DECISIONS BASED ON
UNIVARIATE APPROACH
DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
First
Principle
Focused; Critical
Process Control Points (PAT)
Yes, Limited to
Experimental
Design Space
Maybe,
Difficult to
Assesses
Extensive;
Every Step
(Current)
Product & Process Quality Knowledge
Science-Risk Based CMC & cGMPs
Concept initiated by Ajaz S. Hussain, CDER, FDA, PQRI 2005
PAT
May 27, 2011 21
Process Capability
Sta
bil
ity
Va
ria
bil
ity
Modified from Original Concept Ajaz S. Hussain, CDER, US FDA
Variability
May 27, 2011 22
Total variability σ2Total
■ The overall understanding of variation contributed by measurement systems and product components is critical for statistical analysis. Assuming independent variable –
■ σ2Product + σ2
Measurement = σ2Total
■ + =
■ σ2Measurement = σ2
Repeatability + σ2Reproducibility
Common Cause Vs. Special Cause Variability
Process capability = Customer Needs / Process Ability
Measuring Process VariabilityVariability
Modified from Lucinda Buhse, Division of Pharmaceutical Analysis, FDA
True Product Variation Measurement Variation Experimental Variation
May 27, 2011 23
Analytical Variability ControlC
hem
ical In
form
ati
on
Co
nte
nt
SEM/EDS
NIR
Luminescence
UV-Visible Absorbance
SEM
Mid-IRRaman
Increasing Molecular Size or Molecular Complexicity
Chemical Imaging Technologies…Next?
VariabilityH
igh
Sp
eed
Mo
lecu
lar M
icro
sc
op
y
an
d D
ata
Pro
cessin
g
Finger Printing Molecular State and Complexicity in Process
May 27, 2011 24
FDA’s PAT Journeyfrom “Testing Quality in…” to “Building Quality in…”
Process Analytical Technology (PAT) is a
system for designing, analyzing, and
controlling manufacturing processes based
on timely measurements (i.e., during
processing) of critical quality parameters
and performance attributes of raw and in-
process materials and processes to assure
acceptable end product quality at the
completion of the process.
Pharmaceutical Process Analytical Technology
PAT
May 27, 2011 25
Process Analytical Technology involves optimal applications of process analytical chemistry tools, feedback process controlstrategies, information management tools,and /or product /process optimization strategies to the manufacture of pharmaceuticals.
Note The term Analytical in PAT is viewed broadly to include chemical, physical,microbiological, mathematical, and risk analysis conducted in an integrated manner.
FDA’s PAT Journey
Pharmaceutical Process Analytical Technology
from “Testing Quality in…” to “Building Quality in…”
PAT
May 27, 2011 26
FDA’s End of PAT Journey
You Said for Process Analytical Technology
The goal of PAT is to understand and control the
manufacturing process science – Ajaz S. Hussain
<<The quality can not be tested into products;
it should be built-in or should be by design>>
Change is inevitable – except from vending
machine – Robert C. GallagerIt is not mandatory to change. Survival is not
mandatory – W. Edward Deming
= ∫∫∫ SbK + QbD + QbR ?PATQuality by
from “Testing Quality in…” to “Building Quality in…”
PAT
May 27, 2011 27
Six
Sigma
Quality
System
KNOWLEDGE–BASED QUALITY
Modified from Ajaz S. Hussain, CDER, FDA, PQRI 2005
“The cGMP” “The Big Q or GMP +”
Moving Towards cGMP End Point
PAT
May 27, 2011 28
Good Guidance Practices
Understand and Define
What is the scope of problem?
Measure
How frequent is it occurring?
Analyze
What are the root cause of problem?
Improve
How can we fix the process?
Control
How can we assure the process stays fixed?
6 S
I G
M
A
FDA’S CMCs & cGMPs
Quality and
Customer
Regulatory Strategy
Manufacturing Designand Quality Solution
Quality Formulation Development and Technology Transfer
Materials, Reverse-engineering, Analytical Supports and Information Technology
Beginning of End
May 27, 2011 29
Risk or question–based CMC Review concentrate on Scientific Relationship between CMC and theProduct Characteristic and its ultimate impact onTherapeutics Performance as promised in the label to the customer.
The objectives of QbR System are to transform CMC REVIEW into science- and risk- basedpharmaceutical quality assessment that incorporates the CONCEPT & PRINCIPLES of Pharmaceutical cGMPs for the 21st Century : A Risk-Based Approach and Process Analytical Technology initiatives. QbR acts as an interface.
Risk–Based ReviewQuestion–Based Review for CMC and ANDAs
QbR
FDA Regulation in FLEXIBILE STATE on DESIRED STATE
May 27, 2011 30
Science is understanding variability and reproducibility
in nature.
Chemometrics / Statistics is making decisions about
nature in the presence of variability.
Experimental Design is reducing and controlling
variability in ways which make statistical theory
applicable to decisions about nature.
Justification of design trials and statistical aspects
should be set out in the protocol.
Confirmatory Trials are necessary to provide firm
evidence of efficacy and safety.
Evaluation of Evidence and decision on approvability.
Risk–Based Review QbR
The Major Critical Review Areas
“Quality can not be assessed, tested or inspected into the
product. It has to be built into it.”
May 27, 2011 31
Risk–Based Review QbR
ICH Q8 – Drug Product Development Report.
M4Q eCTD - Drug Product Guidance.
cGMP Initiative – Quality by Design, mechanistic
understanding (Formulation, Polymorphism, and
Product Performance). Process Development Report.
Risk Assessment – SUPAC, In-vitro Performance Test
vs In-vivo QC Dissolution and Product’s Identity,
Stability, Strength, Purity and Quality, etc….etc….etc….
1. Assure product quality through the design and
performance-based specifications. Reduce OOS.
2. Maintain continuous improvement & reduce CMC
Supplements/Amendments through risk assessment.
3. Enhance review quality through review questions.
The Major Critical Review Chapters
May 27, 2011 32
Risk–Based Review Current
One size fits all including BE criteria.
Question-based Review
Three-tiered assessment of manufacturing
Tier 1 applies to all dosage forms.
Tier 2 applies to dosage forms that are not solutions (Equivalent to current practice).
Tier 3 applies to dosage forms that are not solutions, IR tablets, or IR capsules.
Process development report – CTD, ICH Q8
Strongly recommended for dosage forms that are not solutions, IR tablets, or IR capsules.
QbR
May 27, 2011 33
MANUFACTURING PROCESS SCIENCE
DRUG (s)
IN-VITRO PHYSICAL
CHEMICAL ATTRIBUTES
EXCIPIENTS
Gastrointestinal Track
PHYSICAL-CHEMICAL
PROPERTIES
PHYSIOLOGICAL
VARIABLESWhole Body
Bioavailability
PHARMACOKINETIC
PROPERTIES
IN-VIVO PHYSICAL
CHEMICAL ATTRIBUTES
PHYSICAL-CHEMICAL
PROPERTIES
Elements of QbD : Bioavailability
Formulation Science & Design
FORMULATION
CLINICAL
PROPERTIES
QbR
May 27, 2011 34
Core Formulation
Functional
Activities
Method
Development
Optimization
Method
Validation
Transfer
In vitro
Release
Testing
Analytical Testing
Procedures
Specifications
Reference
Standard
Characterization
Reverse
Engineering
Vendor
Qualification
Stability
Evaluation
Early and
Preformulation
Formulation Science & DesignQbR
Significance of Connectivity and Longevity in
Product Development through PAT
May 27, 2011 35
Drug
Characteristics
PC and Stability
Disintegration
of
FormulationDrug
Dissolution
Drug
Absorption
Drug
DistributionDrug
Metabolism
Drug
Excretion
Bioequivalence____________________________________
Bioavailability
Formulation Science & DesignQbR
Significance of Connectivity and Longevity in
Product Development through PAT
May 27, 2011 36
Why Design Process Critical to FDA?
Quality by Design paradigm.
Product Development Information Report is where you demonstrate the drug is highly variable. Source of Variability (Mechanistic Understanding).
Drug Substance (common between Generic & RLD), Formulation (Generic Biostudies could be higher/ lower)
Justify use of Bioequivalence Study design other than 80-125% confidence interval.
Product development report is where you justify equivalence of design.
Formulation Science & DesignQbR
Lawrence Yu, Office of Generic Drugs, FDA, 2004
May 27, 2011 37
Variability in API and inactive ingredient group (IIG).
Formulation design: rapid release.
Demonstrate by dissolution comparison under physiologically relevant conditions.
Waive if BCS class I.
Confirm with in vivo study.
Variability in the formulation of RLD.
Design for equivalence begins with characterization of RLD.
Generic product should recognize variability is an issue and target the mean performance.
Current system: no reward for generic that is less variable.
Formulation Science & DesignWhy Design Process Critical to FDA?
QbR
Lawrence Yu, Office of Generic Drugs, FDA, 2004
May 27, 2011 38
Formulation Science & Design Current Practice
Reasons for design decisions not fully explained.
Example of Deficiency
The drug substance has a primary amine group. Spray dried lactose is used as a diluent in the formulation.
Please discuss potential drug -excipient interaction.
Question - based Review (QbR)
Q: What is the formulation intended to do? (IR,MR, CR)
Q: What mechanism does it use to accomplish this?
Q: Were any other formulation alternatives investigated and how did these perform?
Q: Is the formulation design consistent with the dosage form classification in the label?
QbR
QbD
SbK
PAT
Modified from Gary Buehler & Lawrence Yu, OGD, FDA, 2005
May 27, 2011 39
Understand what the RLD is supposed to do and Origin of Variability.
Design for Equivalence.
Directly evaluate Equivalent Product Performance –verify the design.
Use Bioequivalence Study Design for highly variable drugs.
Review Pharmaceutical Development (Quality by Design) Report.
Understand what the problem is, as well as the real fundamentals i.e. physical and chemical parameters.”
Make coherent, science based decisions.”
Formulation Science & DesignProduct Design for an ANDA of a Highly Variable Drug
QbR
Lawrence Yu, Office of Generic Drugs, FDA, 2004
May 27, 2011 40
QbR
Manufacturing Process Science
Current Practice
Limited information submitted
Example of Deficiency
Please explain how you will provide assurance that the product batches are mixed adequately”
Question-based Review
Q: How were the critical steps in the process identified?
Q: What are the critical process parameters for each critical step and how were they identified, monitored, and/or controlled?
Modified from Gary Buehler Director, Office of Generic Drugs, FDA, 2005
QbD + PAT
PAT + SbK
PAT + SbK
May 27, 2011 41
Measuring and Development Data
Protocols are roadmap for required Data Quality.
Identification of all critical steps and variables.
Science-based specification and controls allow focus
on high risk areas to reduce supplements.
Lack of adequate development data suggests –
■ Possibility of unidentified critical steps.
■ Higher risk in post-approval changes.
When “Best Practices” are employed
■ Risk of poor product quality is minimized.
■ Lower risk in post-approval changes will allow
down regulation of reporting category.
Control of Variability through Intelligent Automation
Beginning of End
May 27, 2011 42
Take Home PointsEstablish formulatory material search and
match data base library within organization.
A fundamental scientific premise is that quality cannot be tested into a product. Rather, quality must be built into the product throughout the manufacturing process; one cannot assure quality by testing for it at the end of the manufacturing process or at a later point.
Design, evaluate and document preformulation & formulation development study protocols.
Optimized formulation variables at early stage of development. (pay now or pay later).
Summary
May 27, 2011 43
Take Home PointsBetter utilization of modern scientific, technical,
and chemometrics tools for pharmaceutical
product design space at the ground level.
Implement proper physiocharacterization
techniques, In Silico tools, Linear accelerated
temperature range effects on degradation.
Established qualified links between materials,
process, product and application (MPPA).
ICH Q6A – A suitable starting place for the
generic industry and regulators to move from
current state to ICH Q8, Q9, Q10 – desired state.
Summary
May 27, 2011 44
Take Home PointsPharmaceutical Development is a learning
process that describe both success and failures as a part of the story which demonstratesQuality by Design (QbD) and Design Space.
Early awareness on science - based review / question - based review after submission –development cycles, formulation time, formulation manufacturing parameters (critical process parameters), cycle deviation, etc.
Depend more on scientific justification and onin-process testing, not on end product testing, when making regulatory decisions.
Summary
May 27, 2011 45
Technology Replaces Technology
“Majority of current off-line chemical
analytical methodology is equivalent to
narrow range pH test strips.”
A Fundamental Analytical Variability
Thoughts
“eCTD Drug Submission is a 1-Step
Synthesis. QbD demands to change from
Current Solution State to Solid State
Technology to minimize Process and Drug
Quality Risk.”
May 27, 2011 46
AcknowledgementsAjaz S. Hussain
&
FDA’s Visionary PAT TeamOut of Control (OOC)?...... Just like OOS and OOT?
May 27, 2011 47
Thank You
Are you ready to move on to PAT from PAC?
May 27, 2011 48
“If we can’t describe scientifically and technologically what
we are doing as a process, we don’t know what we’re doing.”
