1. Welcome
to
Risk-Based Drug Quality
System
FDA & ICH JOINT PROPOSAL FOR DESIRED STATE
Revisit Presentation By
Satendra K Vishwakarma PhD
May 27, 2011 1

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INFORMATION, NOT for IMPLEMENTATION.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 2

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 quality
manufacturing by design space.
 Manufacturing process science and
understanding of critical controls (PAT).
 Risk- based quality review and management.
Summary, Thoughts & Questions.
May 27, 2011 3

4. UNDERSTANDING THE BASICS
Rigorous Manufacturing Standards
Same Drug
Purity Check
Solid Dosages Generic Formulations
Quality standards comparable to Reference Listed Drug (RLD)
May 27, 2011 4

5. Introduction
Current State of Affairs
Thesis of Critical Path : There has been a Failure of Predictability
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.
May 27, 2011 5

6. Introduction
Current State of Affairs
Thesis of Critical Path : There has been a Failure of Predictability
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.”
May 27, 2011 6

7. Current Affairs
Findings & Recommendations
 Inadequate QA  Drug not made at site
Functions 2% 8%
 Inadequate SOP 2%  Contamination 13%
 Facility withdrawn  Pending Regulatory
3% Action 18%
 Previous Deviations  Firm Not Ready 25%
persists 7%  Inadequate Lab
 Others 15% controls 7%
FDA’s Risk-Based “cGMPs for the 21st Century”
“PAT Initiative” and “Generic Drug Equivalence”
issues are on the agenda.
May 27, 2011 7
Thomas J Arista, FDA’s Data Sep 2003 – April 2004

8. Vision
Desired State of 21st Century
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.
May 27, 2011 8

9. Vision
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.
May 27, 2011 9

10. Vision
Desired State of 21st Century
OVERALL CONCLUSION
■ “The desired state, by contrast, would
focus on data analysis, understanding
critical to quality attributes, measuring
process capability, performing
continuous quality verification, and
undertaking continuous improvement to
maintain consistent product quality.”
■ Minimize risks of poor process quality
and reduce (regulatory) concerns.
May 27, 2011 10

11. Guidelines
GMPSPECIFICATIONDESIGN
 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,
May 27, 2011 extensions, revision or maintenance. 11

12. Guidelines
Highlights of ICH Q6A
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.
 Characterization  Consistency
 Potency  Purity
 Degradation / Impurity  Identity
May 27, 2011 12

13. ICH
Pharmaceutical Development
CURRENT STATE : TESTING TO DOCUMENT QUALITY
ICH Q6A :Terminology
Decision Characteristics
Specifications
In Process Controls
Development
Design
Process Validation
GMP Controls
May 27, 2011 13

14. PAT
The Goal and Characteristics of
Pharmaceutical Quality Decision
System
Goal ICH Q6A

Characteristics
“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.”
Life-cycle
May 27, 2011 14
Ajaz S. Hussain CDER FDA Ball State University Muncie, IN, 2005

15. ICH
Therapeutic Equivalence Matter
Pharmaceutical Product Development Information
Current Paradigm 21st Century Paradigm
Same Drug, Strength, Same Drug, Strength,
Dosage form, Safety, Quality Dosage form, Safety, Quality
+Pharmaceutical +Quality by Design
Equivalence (Designed to be equivalent )
+Bioequivalence +Verified by in-vivo Testing
(Demonstrate bioequivalence)
= Therapeutic Equivalence = Therapeutic Equivalence
 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.
May 27, 2011 15
Modified from Robert Lionberger, Office of Generic Drugs, FDA

16. ICH
What is the ICH Q8 Opportunity?
DESIRED STATE : DESIGNING TO BUILD QUALITY
Specifications
In Process Controls
Development Absent or
variable in
US CMC
Design Sections
Process Validation ICH Q8

GMP Controls
“…where the provision of greater understanding of pharmaceutical and
manufacturing sciences can create a basis for flexible regulatory approaches.”
May 27, 2011 16

17. PAT
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.
May 27, 2011 17

18. ICH
ICH Q8 Journey
CMC: The Desired State
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.
"real time release“ means Quality Control Reduction of End Product
May 27, 2011 Release Testing 18

19. PAT
FDA Journey
FDA Review: The Desired State
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).
Design Space is the established range of scientific parameters that
has been demonstrated to provide assurance of quality.
May 27, 2011 19

20. PAT
Product & Process Quality Knowledge
Science-Risk Based CMC & cGMPs
Quality by Design cGMP/CMC FOCUS
Process Design First Design qualification
Principle
MECHANISTIC
Yes, Limited to UNDERSTANDING Focused; Critical
Experimental Process Control
Design Space CAUSAL LINKS Points (PAT)
PREDICT PERFORMANCE
DECISIONS BASED ON Extensive;
Maybe, UNIVARIATE APPROACH
Every Step
Difficult to
(Current)
Assesses DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
May 27, 2011 20
Concept initiated by Ajaz S. Hussain, CDER, FDA, PQRI 2005

21. Variability
Variability Process Capability
Stability
May 27, 2011 21
Modified from Original Concept Ajaz S. Hussain, CDER, US FDA

22. Variability
Measuring Process Variability
 Total variability σ2Total
■ The overall understanding of variation contributed by
measurement systems and product components is critical for
statistical analysis. Assuming independent variable –
■ σ2Product + σ2Measurement = σ2Total
■ + =
True Product Variation Measurement Variation Experimental Variation
■ σ2Measurement = σ2Repeatability + σ2Reproducibility
 Common Cause Vs. Special Cause Variability
 Process capability = Customer Needs / Process Ability
May 27, 2011 22
Modified from Lucinda Buhse, Division of Pharmaceutical Analysis, FDA

23. Variability
Analytical Variability Control
Chemical Imaging Technologies…Next?
High Speed Molecular Microscopy
Chemical Information Content
and Data Processing
Raman Mid-IR
SEM/EDS
NIR
Luminescence
UV-Visible Absorbance
SEM
Increasing Molecular Size or Molecular Complexicity
May 27, 2011 23
Finger Printing Molecular State and Complexicity in Process

24. PAT
FDA’s PAT Journey
from “Testing Quality in…” to “Building Quality in…”
Pharmaceutical Process Analytical Technology
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.
May 27, 2011 24

25. PAT
FDA’s PAT Journey
from “Testing Quality in…” to “Building Quality in…”
Pharmaceutical Process Analytical Technology
Process Analytical Technology involves
optimal applications of process analytical
chemistry tools, feedback process control
strategies, 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.
May 27, 2011 25

26. FDA’s End of PAT Journey PAT
from “Testing Quality in…” to “Building Quality in…”
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. Gallager
It is not mandatory to change. Survival is not
mandatory – W. Edward Deming
Quality by
May 27, 2011
PAT = ∫∫∫ SbK + QbD + QbR ? 26

27. PAT
KNOWLEDGE–BASED QUALITY
Moving Towards cGMP End Point
Six
 Sigma
Quality
System
“The cGMP”     “The Big Q or GMP +”
May 27, 2011 27
Modified from Ajaz S. Hussain, CDER, FDA, PQRI 2005

28. Beginning of End
Good Guidance Practices
A
Control
How can we assure the process stays fixed?
M
Quality
and Improve
Customer How can we fix the process?
G
Regulatory
Strategy Analyze
What are the root cause of problem?
Manufacturing Design
I
and Quality Solution Measure
Quality Formulation Development How frequent is it occurring?
and Technology Transfer
S
Understand and Define
Materials, Reverse-engineering, Analytical What is the scope of problem?
Supports and Information Technology
6
FDA’S CMCs & cGMPs
May 27, 2011 28

29. QbR
Risk–Based Review
Question–Based Review for CMC and ANDAs
Risk or question–based CMC Review concentrate
on Scientific Relationship between CMC and the
Product Characteristic and its ultimate impact on
Therapeutics Performance as promised in the
label to the customer.
The objectives of QbR System are to transform
CMC REVIEW into science- and risk- based
pharmaceutical 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.
FDA Regulation in FLEXIBILE STATE on DESIRED STATE
May 27, 2011 29

30. QbR
Risk–Based Review
The Major Critical Review Areas
 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.
“Quality can not be assessed, tested or inspected into the
product. It has to be built into it.”
May 27, 2011 30

31. QbR
Risk–Based Review
The Major Critical Review Chapters
 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.
May 27, 2011 31

32. QbR
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.
May 27, 2011 32

33. QbR
Formulation Science & Design
Elements of QbD : Bioavailability
MANUFACTURING PROCESS SCIENCE

DRUG (s) EXCIPIENTS
PHYSICAL-CHEMICAL PHYSICAL-CHEMICAL
PROPERTIES FORMULATION PROPERTIES
IN-VITRO PHYSICAL
CHEMICAL ATTRIBUTES  IN-VIVO PHYSICAL
CHEMICAL ATTRIBUTES
Gastrointestinal Track
PHARMACOKINETIC
 PROPERTIES
PHYSIOLOGICAL
Whole Body
VARIABLES CLINICAL
 PROPERTIES
May 27, 2011 Bioavailability 33

34. QbR
Formulation Science & Design
Significance of Connectivity and Longevity in
Product Development through PAT
Early and
Analytical Testing
Preformulation
Procedures
Stability
Specifications
Evaluation
In vitro
Vendor
Core Formulation Release
Testing
Qualification Functional
Method
Activities Validation
Reverse Transfer
Engineering
Reference Method
Standard Development
Characterization Optimization
May 27, 2011 34

35. QbR
Formulation Science & Design
Significance of Connectivity and Longevity in
Product Development through PAT
Disintegration
of
Formulation
Drug Drug
Characteristics Dissolution
PC and Stability
Bioequivalence
____________________________________
Bioavailability Drug
Drug
Absorption
Excretion
Drug Drug
Metabolism Distribution
May 27, 2011 35

36. QbR
Formulation Science & Design
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.
May 27, 2011 36
Lawrence Yu, Office of Generic Drugs, FDA, 2004

37. QbR
Formulation Science & Design
Why Design Process Critical to FDA?
 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.
May 27, 2011 37
Lawrence Yu, Office of Generic Drugs, FDA, 2004

38. QbR
Formulation Science & Design
 Current Practice
Reasons for design decisions not fully explained.
Example of Deficiency  QbD
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)  PAT
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?  SbK
May 27, 2011 38
Modified from Gary Buehler & Lawrence Yu, OGD, FDA, 2005

39. QbR
Formulation Science & Design
Product Design for an ANDA of a Highly Variable Drug
 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.”
May 27, 2011 39
Lawrence Yu, Office of Generic Drugs, FDA, 2004

40. QbR
Manufacturing Process Science
 Current Practice
Limited information submitted
Example of Deficiency  QbD + PAT
Please explain how you will provide assurance
that the product batches are mixed adequately”
 Question-based Review  PAT + SbK
Q: How were the critical steps in the process
identified?  PAT + SbK
Q: What are the critical process parameters for
each critical step and how were they identified,
monitored, and/or controlled?
May 27, 2011 40
Modified from Gary Buehler Director, Office of Generic Drugs, FDA, 2005

41. Beginning of End
Measuring and Development Data
Control of Variability through Intelligent Automation
 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.
May 27, 2011 41

42. Summary
Take Home Points
Establish 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).
May 27, 2011 42

43. Summary
Take Home Points
Better 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.
May 27, 2011 43

44. Summary
Take Home Points
Pharmaceutical Development is a learning
process that describe both success and failures
as a part of the story which demonstrates
Quality 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 on
in-process testing, not on end product testing,
when making regulatory decisions.
May 27, 2011 44

45. Thoughts
Technology Replaces Technology
“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.”
“Majority of current off-line chemical
analytical methodology is equivalent to
narrow range pH test strips.”
A Fundamental Analytical Variability
May 27, 2011 45

46. Acknowledgements
Ajaz S. Hussain
&
FDA’s Visionary PAT Team
May 27, 2011 46
Out of Control (OOC)?...... Just like OOS and OOT?

47. Thank You
Are you ready to move on to PAT from PAC?
May 27, 2011 47

48. “If we can’t describe scientifically and technologically what
we are doing as a process, we don’t know what we’re doing.”
May 27, 2011 48