The document discusses the evolution of the FDA's Process Analytical Technology (PAT) guidance over the past 10 years. It notes that while the PAT initiative helped start a cultural transformation at the FDA to prepare for globalization, fully implementing a quality by design approach and common understanding of new terminology remains a challenge. It provides advice to both the FDA and industry to continue focusing on integrated systems thinking, science-based approaches, and prevention to further the goals of the PAT guidance.

1. 28. und 29. November 2013
in Ludwigshafen am Rhein / Deutschland
US FDA’s PAT Guidance –
10 years ago and now
1
Ajaz S. Hussain, Ph.D.
Insight, Advice & Solutions LLC
Ajaz@ajazhussain.com
11/28/2013

2. Insight
2
At FDA the PAT Initiative was a ‘door opener’ to a cultural transformation to
prepare for globalization in the 21st Century
Cultural transformation takes time and discipline, needs collaborative
vocabulary, constancy of purpose, and link to the heart and bottom-line
The transformation process has progressed to create common regulatory
guidelines (ICH Q8 – 11), it is currently struggling to get to a common
understanding of the new vocabulary and integrated systems thinking and actions
Ajaz@ajazhussain.com
11/28/2013

3. Quality of pharmaceutical products
3
Tablet, capsule, injection, etc.
Information, marketing
messages, etc.
Scientific evidence supporting
societal license to market
Ajaz@ajazhussain.com
11/28/2013

4. Pharmaceutical processes
4
Process for
• Developing a product (safety, efficacy, quality)
• Manufacturing a product (quality - reproducible and
repeatable safety and efficacy profile)
• Developing the scientific evidence (safety, efficacy, quality)
• Communicating about the product (ensure reproducible and
repeatable safety and efficacy profile)
Ajaz@ajazhussain.com
11/28/2013

5. License to Manufacture and Market
5
Regulatory Authority
Manufacturing
Market share
R&D
Revenues
Marketing
Pre-market review & inspection
Ajaz@ajazhussain.com
Post-market review & inspection
11/28/2013

6. FDA’s Process Validation Guidance 1987
6
Quality can not be tested into products, it has
to be built-in by design → Quality by Design
Scientific evidence that process is capable of
consistently delivering quality products
Scientific evidence that product is of
acceptable quality
Ajaz@ajazhussain.com
11/28/2013

7. Quality by Design Vs. Cheating by Design
Right first time, ontime review & approval
7
Deliberate adulterated drugs
Compliance with cGMP,
GLP, GCP,…… GXP
Counterfeit and
falsified medicines
Customer satisfaction
with trust & credibility
Deliberate false claims
Ajaz@ajazhussain.com
11/28/2013

8. Companies trying to be on the QbD side…
facing challenges
• 28 November 2013
• “AAA’s BBB unit gets US FDA
import alert”
• 4 November 2013
• “XXX promotion of YYY for
unapproved uses threatened the
most vulnerable populations of our
society - children, the elderly and
those with developmental
disabilities," said Zane Memeger,
U.S. Attorney for the Eastern
District of Pennsylvania
Ajaz@ajazhussain.com
8
• In 2010 a British drugs giant paid
£475million to settle allegations
it knowingly made and sold
adulterated drugs; agreed to
Corporate Integrity Agreement
(CIA)
• In 2007 a company in New Jersey
pleaded guilty to the charge –
“Conspiracy to commit an offense
against the United States” &
“duping the FDA for six years.”
11/28/2013

9. Quality of the FDA Review & Inspections?
US FDA is
regarded as the
toughest
regulatory
authority; it takes
steps to improve
its processes
Ajaz@ajazhussain.com
9
• The PAT Initiative was an attempt to “open
the door” significant improvement in
multiple functions
• PAT Initiative (2001)
• CGMP for the 21st Century (2002);
Pharmaceutical Quality for the 21st
Century (US, EU and Japan via ICH)
• Critical Path Initiative (2003)
11/28/2013

10. Challenges
10
Before the launch of the PAT Initiative
• Drug shortages due to manufacturing difficulties
• Process deviations coupled with frequent inconclusive investigations
• Batch failures and rejections
• In-process test debates (e.g., blend uniformity)
• Slow and protracted cGMP remediation
• Warning Letters, permanent injunctions and consent decree
• Multiple review cycles for certain products (e.g., inhalation drugs)
• CMC review (and cGMP) harmonization efforts between US, EU and Japan at a
impasse on Common Technical Document, Section P2 - ‘Pharmaceutical
Development’
Ajaz@ajazhussain.com
11/28/2013

11. Internal challenge to FDA staff
11
Questions posed by Dr. Woodcock
• “Will this $ x00 million “consent decree” improve quality of the real
product?
• How effective is “process validation”? Is it not just a “well rehearsed
demonstration…. 3 times”?
• Is our system truly a “modern quality system”?
• Are our “specifications” based on sound science and risk principles?
• How is “c” in cGMP established?
• Do current regulations support “continuous improvement”?
• How efficient is pharmaceutical manufacturing?
Ajaz@ajazhussain.com
11/28/2013

12. Process understanding is a key to effective
control
Ajaz@ajazhussain.com
11/28/2013
12

13. Powder Blend Uniformity
13
Refers to active ingredient
(or preservative) distribution
or homogeneity in the
“final” blend or mix.
• Adequacy of Mixing - satisfactory
blending step to assure uniformity
and homogeneity [21 Code of
Federal Regulation 211.110
(a)(3),1978]
Ajaz@ajazhussain.com
11/28/2013

14. GMP lessons from a Federal Judge
United
States of
America v.
Barr Labs,
Inc.
812 F. Supp
458,
3/30/93
• Judge Wolines’ opinion [also] provides
scientific and legal guidance to
generic and pioneer drug
manufacturers about their compliance
obligations under the FD&C Act.
• Validation studies … and blend
uniformity
• Test averaging
• Retesting
• Investigation of batches of failed
products
• Equipment cleaning and
• Record-keeping.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm2
12214.htm
Ajaz@ajazhussain.com
The
appropriate
sample size
for Blend
Uniformity
Analysis
(BUA) is, at
most, three
times the
weight of
the final
dosage unit.
14
• “C” in cGMPs
• The sample thief is the
state-of-the-art powder
sampling technology
used by the
pharmaceutical industry
today for purposes of
BUA …. It is prone to
sampling error.
PDA J Pharm Sci Technol. 1997;51 Suppl 3:i-iii, S1-99
11/28/2013

15. Struggling with sampling…
Stop & go sampling
Ajaz@ajazhussain.com
A thief
15
Engineering practice
11/28/2013

16. The acronym PAT
16
Process Analytical Technology (PAT)
Putting analyzers on-line
without process
understanding would be like
“putting ear-rings on a pig”
• Process [P]
• Analyzer, Analytical…? [A]
• Chemistry, System,…
Technologies, or
Technology? [C, S, or T]
Ajaz@ajazhussain.com
Analytical
• “….. the term analytical in
PAT is viewed broadly to
include chemical, physical,
microbiological,
mathematical, and risk
analysis conducted in an
integrated manner”
Technology (from Greek τέχν
η, techne, "art, skill"; and λογία, -logia[1])
• the making, modification,
usage, and knowledge
of tools, machines,
techniques, crafts, systems, and
methods of organization, in
order to solve a problem,
improve a pre-existing solution
to a problem, achieve a goal,
handle an applied input/output
relation or perform a specific
function
11/28/2013

17. PAT definition
17
• “The Agency considers PAT to be a system for designing,
analyzing, and controlling manufacturing through timely
measurements (i.e., during processing) of critical
quality and performance attributes of raw and inprocess materials and processes, with the goal of
ensuring final product quality”
Ajaz@ajazhussain.com
11/28/2013

18. PAT: Validation
18
A focus on process understanding can reduce the burden for validating
systems by providing more options for justifying and qualifying systems
intended to monitor and control biological, physical, and/or chemical
attributes of materials and processes.
• In the absence of process knowledge, when proposing a new process
analyzer, the test-to-test comparison between an online process
analyzer and a conventional test method on collected samples may be
the only available validation option. In some cases, this approach may
be too burdensome and may discourage the use of some new
technologies (FDA PAT Guidance 2004)
Ajaz@ajazhussain.com
11/28/2013

19. Value of ‘Process Understanding”
19
Systems that promote greater product and process understanding can
provide a high assurance of quality on every batch and provide
alternative, effective mechanisms to demonstrate validation (per 21 CFR
211.100(a), i.e., production and process controls are designed to ensure
quality).
• In a PAT framework, validation can be demonstrated through continuous
quality assurance where a process is continually monitored, evaluated,
and adjusted using validated in-process measurements, tests, controls,
and process end points (FDA PAT Guidance 2004)
Ajaz@ajazhussain.com
11/28/2013

20. Integrated systems thinking
20
The fast pace of innovation in today's information age necessitates
integrated systems thinking for evaluating and timely application
of efficient tools and systems that satisfy the needs of patients and
the industry.
• Many of the advances that have occurred, and are anticipated to
occur, are bringing the development, manufacturing, quality
assurance, and information/knowledge management functions so
closely together that these four areas should be coordinated in an
integrated manner (FDA PAT Guidance 2004)
Ajaz@ajazhussain.com
11/28/2013

21. Integrated systems thinking at FDA
21
• “Turf” battles to PAT Team Approach
• Vocabulary: Negative to Collaborative (“process
validation to process understanding”)
• “Pharmaceutical Development” information kept
at site to shared with CMC reviewers (Quality by
Design -ICHQ8)
• Risk-based decisions (ICH Q9)
• Minimize Prior-Approval Supplements to Change
Control within company Quality System (“ICH
Q10”)
• Reduce regulatory fear to promote continues
learning
Ajaz@ajazhussain.com
11/28/2013

22. PAT Review – Inspection -OPS Team (PATRIOT)
Investigators
• Robert Coleman (ORA/ATL-DO),
Rebeca Rodriguez (ORA/SJN-DO), Erin
McCaffery (ORA/NWJ-DO), George
Pyramides (PHI-DO), Dennis Guilfoyle
(ORA/NERL),
Ajaz@ajazhussain.com
Compliance Officers
• Albinus D’Sa (CDER), Mike Gavini
(CDER), William Bargo (CVM), Brenda
Uratani (CDER)
Reviewers
• Norman Schmuff (CDER), Lorenzo
Rocca (CDER) Vibhakar Shah (CDER),
Rosario D’Costa (CDER), Raafat Fahmy
(CVM), Brian Riley (CDER)
11/28/2013
22

23. Preparing the regulatory system for
globalization
PAT
Ajaz@ajazhussain.com
ICH Q 8-11
Process
Validation
23
FDASIA
11/28/2013

24. Process Validation keeps the focus on PAT
24
Process validation
• Stage 1: Process Design
• Stage 2: Process Qualification
• Stage 3: Continued Process Verification
ASTM
• ASTM E2474-06 Standard Practice for Pharmaceutical Process Design Utilizing Process Analytical
Technology.
• ASTM E2476-09 Standard Guide for Risk Assessment and Risk Control as it Impacts the Design,
Development, and Operation of PAT Processes for Pharmaceutical Manufacture.
• ASTM E2281-03 Standard Practice for Process and Measurement Capability Indices.
• ASTM E2500-07 Standard Guide for Specification, Design, and Verification of Pharmaceutical and
Biopharmaceutical Manufacturing Systems and Equipment.
• ASTM E2709-10 Standard Practice for Demonstrating Capability to Comply with a Lot Acceptance
Procedure.
Ajaz@ajazhussain.com
11/28/2013

25. FDASIA & “adulterated”: What did the
Congress intend?
Ajaz@ajazhussain.com
25
11/28/2013

26. Current state of QbD
26
Data from: Ted Fuhr, McKinsey & Company. 17 July 2011: FDA Advisory Committee Presentation
New
Drugs
Novice: 22%
Pilot: 33%
Roll-out: 22%
Full
implementation:
23%
Generics
Novice: 40%
Pilot: 20%
Roll-out: 40%
Full
implementation:
0%
Biologics
Novice: 17%
Pilot: 67%
Roll-out: 17%
Full
implementation:
0%
Ajaz@ajazhussain.com
11/28/2013

27. QbD Comments & Challenges
27
Data from: Ted Fuhr, McKinsey & Company. 17 July 2011: FDA Advisory Committee Presentation
Comments
“Generics are all about file first
and figure out later”
“R&D is incentivized on shots on
goal not QbD”
“We really don’t understand what
effects what”
“Huge amount of reviewer
inconsistency”
Ajaz@ajazhussain.com
Challenges
(fully implemented)
Alignment with 3rd parties
Regulators not prepared
Current interaction (FDA) not
conducive to QbD
11/28/2013

28. A 10-year research collaboration aimed at
transforming pharmaceutical production
Novartis – MIT Continuous
Manufacturing (started in 2009)
November 18,
2011 FDA WL to
Sandoz/Novartis:
•"Corporate
management has the
responsibility to ensure
the quality, safety,
and integrity of its
products. Neither
upper management at
Novartis nor at Sandoz
... ensured global,
adequate, or timely
resolution of the
issues.“
GMP Problems
Result in 300 Jobs
Chopped At
Novartis Plant
After
Manufacturing
Gaffes, Worried
Novartis CEO
Insists 'Quality
Matters’
Novartis CEO
Joseph Jimenez
..his company
plans to build a
commercial-scale
continuousmanufacturing
facility by 2015
28
“This will change
the way medicine
is made around
the world”
http://www.technologyreview.com/view/427895/the-future-of-pharma-is-incredibly-fast/
11/28/2013

29. On-going organization changes at CDER, FDA
At FDA, focused attention on changes to ensure a more rational
approach to CMC review and cGMP inspections
Understand
and control
sources of
variances
relevant to
quality
during
development
and review
process
Ajaz@ajazhussain.com
Improved understanding to make risk-based inspections
Rational
question
based review
to ensure
QbD; science
based process
validation,…
Improve ability to detect “too good to be true data and
claims” (protracted detection and correction time)
Focus on prevention and reduce reliance on “whistleblowers” and need for DOJ intervention? Additional
‘quality metrics’.
11/28/2013
29

30. Advice
30
Focus on prevention and
reduce reliance on
“whistle-blowers” and
need for DOJ
intervention. Utilize
‘quality metrics 'to
gauge performance
FDA
Rational question based
review to ensure QbD;
science based process
validation,…
Pay specific attention to
the vocabulary; it can be
perceived as a window
to your intentions
Take proactive steps to
prevent catastrophic
risks, improve
predictability and create
competitive advantage
by utilizing the
principles outlined in
the PAT and ICH
guidelines
Industry
Integrative systems
approach to decisions by
understanding sources of
variances relevant to
quality
Ajaz@ajazhussain.com
Emphasize integrative
systems approach to
decisions …. Start now,
it is a long journey
11/28/2013

31. A useful document to read
31
• The FDA’s PAT Team and Manufacturing Science Working
Group Report
• A Summary of Learning, Contributions and Proposed Next Steps for Moving
towards the "Desired State" of Pharmaceutical Manufacturing in the 21st
Century (2004)
• Innovation and Continuous Improvement in
Pharmaceutical Manufacturing Pharmaceutical CGMPs
for the 21st Century
• http://www.fda.gov/ohrms/dockets/ac/04/briefing/20044080b1_01_manufSciWP.pdf
Ajaz@ajazhussain.com
11/28/2013

32. By design; conveys your intention
32
• “The notion ‘by design,’ in the phrase ‘Quality by Design,’
conveys the intention to deliver a product or service with a predefined ‘quality’ so as to satisfy intended customers.”
• Ajaz S. Hussain. SWISS PHARMA 34 (2012) Nr. 6.
Ajaz@ajazhussain.com
11/28/2013