PAT, CGMP For The 21st Century and ICH Q8, Q9, Q10

PAT, cGMP for the 21st Century, and
ICH Q8, Q9, Q10

Ajaz S. Hussain, Ph.D.
Vice President & Global Head Biopharmaceutical
Development Sandoz, Inc.
10 September 2007, The British Pharmaceutical
Conference 2007, Manchester, UK.
a Novartis company
Outline
• The FDA Initiative: Vision Vs. Reality

• The “desired state”
• Journey towards the “desired state”: Where are we today?
2 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

A Transforming Agenda
PAT Initiative CG M
P In
itiat
2001 i ve
20
02
Cr
itic
al
Pa
th
“Desired State”
In
itia
200
tiv
3
e
FDA’s Pharmaceutical cGMPs for the 21st
Century:Risk-Based Approach
• Pharmaceutical manufacturing is evolving from an art form to one that is
now science and engineering based.
• Effectively using this knowledge in regulatory decisions in establishing
specifications and evaluating manufacturing processes can substantially
improve the efficiency of both manufacturing and regulatory processes.
• Desired future state
− Product quality and performance achieved and assured by design of
effective and efficient manufacturing processes
− Product specifications based on mechanistic understanding of how
formulation and process factors impact product performance
− Continuous "real time" assurance of quality
− Regulatory policies and procedures tailored to recognize the level of
scientific knowledge supporting product applications, process validation,
and process capability
− Risk based regulatory scrutiny that relates 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
http://www.fda.gov/cder/gmp/21stcenturysummary.htm
Why did FDA launch this initiative?
• FDA stands in for the patient/public and must define what constitutes
acceptable quality
• During the 1999 – 2003 period FDA had to reexamine its definition of
quality
− Recurring OOS, Warning Letters, Consent Decree’s
− Drug Shortages and safety related issues
− Increasing complexity of products, lacking ability to approve complex
generics, etc.
− Slow innovation and continuous improvement
− High cost of manufacturing
Source: The PAT Team and Manufacturing Science Working Group Report:
Acrobat Document

Example: An Validated Process – Could not be manufactured reliably:
Did the FDA ask the “right” questions?
A potent narcotic analgesic solid oral dosage form

– FDA Warning Letter
http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf
Real & Surrogate Customers: Are the “two
products” aligned?
• FDA leaders posed the question (to staff)

- What is Quality?
− Different (CMC Vs. GMP) interpretation
within FDA (and industry); but
primarily focused on “complying with
Specs - CGMP’s”
− “C” in CGMP’s based on inspectional
findings; not via a science based
process
− CGMP’s established 25 years ago!
− “Validated” processes – recurring
manufacturing difficulties. Why?
− Are we focusing on the “right”
product?
• Quality of Documentation- Quality of
(real) Products
The Need for “Vision 2020”
Source: Ajaz
8 PAT, cGMP 21st Hussain. FDA
Century / Ajaz Pharmaceutical
Hussain / 10 September Inspectorate
2007 Training Lecture, August 5, 2004
Regulatory oversight can be tailored to reflect scientific rigor
demonstrated in an application when it is realized through company’s
robust quality system
First
Principles
Knowledge based decisions
Why?
MECHANISTIC Desired State

KNOWLEDGE
Need for regulatory oversight
How?
“CAUSAL" KNOWLEDGE
What “Causes” What?
CORRELATIVE KNOWLEDGE Current State

What Is Correlated to What?
DESCRIPTIVE KNOWLEDGE:
What?

Specific opportunities (but only under PAT/QbD system)
• Regulatory flexibility
− Risk based inspections (when site is considered to be “low risk”)
− Post approval changes without “prior approval supplements”
− Increased opportunities for post approval biowaivers
− Increased likelihood of acceptance of scientific justification
(deviation investigations, number of conformance batches, scale-
up criteria, etc.)
− Opportunity to justify rational regulatory specifications
− Opportunity to seek alternate regulatory pathway for approval of
complex generic products (in US)
− Opportunity to avoid the review back-log and enhanced
opportunity for regulatory communication (in US; but for limited
time)

Specific opportunities (but only under PAT/QbD system)
• Continuous improvement
− Eliminate recalls, deviations, investigations
− Improve yield
− Cycle time reduction
− Maximize Stock Turn
− Other “lean metrics”
• Development – right first time
− Leveraging prior knowledge
− Reducing development time & cost (over time; after initial
investment)
• Leaving competition behind
− Continuous manufacturing; small footprint
− Real time release
Challenges
• Regulatory uncertainty
− Will the initiatives be fully implemented?
− Will the implementation be harmonized across ICH regions?
− Will regional regulatory authorities adopt these principles?
− How should regulatory submissions be modified to incorporate
the new concepts?
• Organizational divide
− Different levels of understanding of the concepts
− Past experience and culture
− Performance metrics narrowly focused
• Training and inter-disciplinary communication
− Multivariate statistics, engineering, material science,…..

How Did FDA Progress the Initiative?

End of PAT – Transformed into QbD
• Distributed “ownership” of the PAT principles for

leaders & functions of the regulatory enterprise
• Will this hold?

Opportunity Framework: “Right Specification” to “Continuous
Improvement” to “Maximize Efficiency” to “Customer Satisfaction &
Profit”
Manufacturing &
Quality Assurance
Innovation
PAT - ICH Q8 & Continuous
“Design Space” Improvement
Options
Development
Managed under
The Company’s
“Fisher” -“Shewart” -“Deming” Quality System;
Theory of experimental design Subject to
Statistical Process Control Maintain CGMP Inspections
Theory of Variation “State of Control” (no-change or variation)

Quality System Requirements QS-9000
Third Edition element 4.2.5—Continuous Improvement (1998).
• For those product characteristics and process parameters that can

be evaluated using variable data, continuous improvement means
optimizing the characteristics and parameters at a target value and
reducing variation around the value.
• For those product characteristics and process parameters that can
only be evaluated using attribute data, continuous improvement is
not possible until characteristics are conforming.
• If attribute data results do not equal zero defects, it is by definition
nonconforming product. Improvements made in these situations are
definition corrective actions, not continuous improvement.
• Continuous improvement [shall be undertaken] in processes that
have demonstrated stability, acceptable capability and performance.

Is your “cause” special or common?
Corrective Actions Reduce “Common Cause” On the Continuous

Eliminate “Special Cause” Variability Improvement Path
Minor,
Frequent,
Occasional
Major
OOS
OOS
Unstable
Stable- Yes; Capable? Stable & Capable

If you can’t measure it, you can’t improve it
Process Capability: If you can’t measure it, you can’t improve it
Process Capability Roadmap:

Gage R&R
& Calibration
1 STOP!
0 No
Has Measurement Do not compute
Challenge
Specs! System capability Proc. Cap. statistics.
been verified? Improve the Meas. System.
Yes
SPC Charts
STOP!
2 Do not compute
Unstable
Is the process stable Proc. Cap. statistics.
or unstable via SPC? Investigate special causes.
Improve process stability.
Stable
p-value > 0.05
p-value < 0.05
3
4
Yes Is the data normal No STOP!
Compute
“enough” via the Transform data.
Cpk
Normality Test?
© Light Pharma

Pharmaceutical “Customer” Specifications
• Often combine attribute (no unit outside..) and continuous

variable (RSD) in quality decision process
• For example: Dose Content Uniformity
− Upper Specification Limit = 125%
− Lower Specification Limit = 75%
− Standard Deviation not to exceed 7.8%
− Test sample size 30
− “No unit in 30 is outside 75-125%”

Process Capability and Variability
• Without the “attribute” criterion

− Assuming a stable process; normal distribution
− Mean = 100%, %RSD = 7.8%, n=30
• Cp=Cpk = 1.07 and
• ~ “3σ” process
− Standard Deviation = 2.0%
• Cp=Cpk = 4.17
• >”6σ” process

Combined Criteria
~ 10% can be rejected

“σ < 2”
> 40% can be rejected
PQRI Blend Uniformity Working Group Report

Other Challenges
Difficult questions faced by

Manufacturing Groups and Regulators…
• If we chose to use a calibrator tablet for a
Gauge R&R study....
• σ2(Total for Calib.)
• = σ2(Calib.) + σ2C*Measurement
• What is the measurement for the Calibrator and what
is its variability? σ2(C*Measurement)
• Since σ2(Calib.) is not known; we have to use σ2(Total for
Calib.)
• σ2Total for Product = σ2Product + σ2Total for Calib.
Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests

for Drug Products, A Look Into the Future. USP Annual Scientific Meeting
"The Science of Quality“. September 26–30, 2004
Other Challenges
Difficult questions faced by

Manufacturing Groups and Regulators…
• Assumption of independent variable?
• Another aspect – is the measurement capability for a
Calibrator tablet representative of the drug product?
What if there are differences such as disintegration
mechanism and buoyancy between the Calibrator and
the drug product?
Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests

for Drug Products, A Look Into the Future. USP Annual Scientific Meeting
"The Science of Quality“. September 26–30, 2004
The Goal and Characteristics of
Pharmaceutical Quality Decision System
Goal
“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.”
Characteristics
Life-cycle
ICH Q6A
What is the ICH Q8, 9, 10 Opportunity?
ICH Q6A
Decision Characteristics
Specifications
In process controls
Development
Design
Process validation
GMP Controls
“…where the provision of greater understanding of pharmaceutical and

manufacturing sciences can create a basis for flexible regulatory approaches.”

Towards a Risk- and Science-Based Approach to
Pharmaceutical Quality
• For mass-produced pharmaceuticals,

statements about quality must be probabilistic
− Risk (probability of harm * severity of harm)
connects desired clinical attributes – clinical
performance as labeled, absence of Good
contamination, and availability – to attributes pharmaceutical
Quality:
measurable during production
“an acceptably
− What is the link between measurement and low risk of
risk? Quality by Design failing to
achieve the
• Product and process performance desired clinical
characteristics are scientifically designed attributes”.
to meet specific objectives
• Not merely empirically derived from
performance of test batches
Source: Janet Woodcock’s Paper (2004) is attached – click on the Acrobat icon Acrobat Document
The “desired state” is a continual journey to
improve…
Product quality and Develop effective CAPA – eliminate

performance achieved “special cause” variability
and assured by design of Utilize Process capability analysis –
effective and efficient reduce/control “common cause”
manufacturing processes variability
Identify, understand and acquire ability

Product specifications to predict critical to quality
based on mechanistic attributes of materials (CQA)
understanding of how (product/process/measurement)
formulation and process Focus on the “critical few”
factors impact product
performance Establish CQA target values and
acceptable variability around the
target value
An ability to effect Utilize a monitoring system that
continuous improvement demonstrates “state of control”
and continuous "real preferably based on critical material
time" assurance of attributes (not just end product
quality testing)

An Perspective on Pharmaceutical Process Efficiency:
Early signs that a few companies can take the lead…..
“Although there's been plenty of interest in

process improvement in the pharma
industry in recent years, the
methodology's history with the industry is
still very new. Profit margins have
declined in recent years, but they're still
much larger than in other industries, a
sign that the industry could still slip in its
newfound dedication to urgent cost-
reduction methodologies. Whether the
industry is serious about quality is still
unclear, though there have been early
signs that a few companies can take the
lead and show their competitors how to
trim the proverbial fat and succeed in a
new pharmaceutical market.” L. Smith,
Quality Digest, September 9, 2007
http://www.qualitydigest.com/mar06/articles/01_article.shtml

PAT, CGMP For The 21st Century and ICH Q8, Q9, Q10

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PAT, cGMP for the 21st Century, and

ICH Q8, Q9, Q10

• The FDA Initiative: Vision Vs. Reality

2 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

5 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

A potent narcotic analgesic solid oral dosage form

• FDA leaders posed the question (to staff)

MECHANISTIC Desired State

CORRELATIVE KNOWLEDGE Current State

9 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

10 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

12 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

13 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

• Distributed “ownership” of the PAT principles for

14 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

15 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

• For those product characteristics and process parameters that can

16 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

Corrective Actions Reduce “Common Cause” On the Continuous

17 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

Process Capability: If you can’t measure it, you can’t improve it

Process Capability Roadmap:

18 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

• Often combine attribute (no unit outside..) and continuous

19 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

• Without the “attribute” criterion

20 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

~ 10% can be rejected

> 40% can be rejected

PQRI Blend Uniformity Working Group Report

Difficult questions faced by

Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests

Difficult questions faced by

Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests

“The quality of drug substances and

“…where the provision of greater understanding of pharmaceutical and

25 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

• For mass-produced pharmaceuticals,

Product quality and Develop effective CAPA – eliminate

Identify, understand and acquire ability

27 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

“Although there's been plenty of interest in

28 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

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