FDA Trend: New Validation Strategies

FDA Trends: New Validation
Strategies
2ND INTERNATIONAL CONFERENCE ON CONTINUED AND ON-GOING PROCESS VERIFICATION
20TH MARCH 2017, NOVOTEL HAMBURG, GERMANY
3/19/2017Ajaz S Hussain | Insight, Advice & Solutions LLC
1
Ajaz Insights ajaz@ajazhussain.com

Outline
• Part 1: FDA Trends
• Background: The little secret – swept under the rug? No more!
• Challenge or opportunity: Unprecedented juxtaposition – at the Tipping Point!
• Questions: What consideration are needed for building your validation roadmap?
Three options: Pathfinder, Standard or Emergency; what will you choose?
• Part II: A higher level of confidence in quality assurance : State of Control
(stability, capability with statistical confidence)
• Case example: Challenges of implementing a roadmap to process capability for some
currently commercialized products.
2

A story about manufacturing two products, medicinal product and
documented data, and a “little secret”
• Little Secret? Perhaps some of you may remember and recall the front page
article in the Wall Street Journal dated 3 September 2003
• “The Pharmaceutical Industry Has a Little Secret”
• “Even as it invents futuristic new drugs, its manufacturing techniques lag far behind
those of potato-chip and laundry soap makers.”
3

[Pharmaceutical]
Industrial Revolutions:
1.0, 2.0, 3.0, and 4.0?
• Background: How did the journey
begin in 2000 and progress until 2005?
If you are interested please click on
the video message from the past
• Pharmaceutical cGMPs for the 21st
Century — A Risk-Based Approach
• Today we have an
unprecedented juxtaposition of the
main forces necessary for the US
pharmaceutical manufacturing
renaissance – we are at the Tipping
Point
3/19/2017
Ajaz S Hussain | Insight, Advice & Solutions LLC
4

Hello, I am Dr. Ajaz S. Hussain.
I am passionate about making
high pharmaceutical quality
affordable to all.
• President, the National Institute for Pharmaceutical
Technology & Education http://nipte.org/
• Ajaz S Hussain Insight, Advice & Solutions LLC
http://www.ajazhussain.com/
• Professional practice related to development of complex
generics, biosimilars, QbD, Real-Time-Release, Continuous
Manufacturing & strengthening culture of pharmaceutical
quality
• Not-for-profit
• Advocacy of NIPTE Education & Research Programs
• Advisor (pro bono) to the USP & C-SOPS; Programing for
Continuous Manufacturing
• Commercial
• Advisor to several pharmaceutical, biopharmaceutical,
software and consulting firms
• Advisor & shareholder, CONTINUUS Pharmaceuticals
Academia: Currently Adjunct Professor
@ Long Island University; previously
tenured faculty @ University of
Cincinnati (1989-1994)
US FDA: CDER /OPS Deputy Director
(2000-2005) and other positons (1995-
2000); Lead PAT & Pharmaceutical
Quality for the 21st Century Initiatives &
related ICH efforts
Industry: Formerly President & CSO @
Wockhardt (USA, 6/2012 to 6/2013),
CSO & VP @ Philip Morris International
(Switzerland, 2009-2012), Global Head
& VP @ Sandoz (USA & Germany, 2005-
2009)
5

Unprecedented juxtaposition – at the Tipping Point
• In the 21st Century, Quality entangled
with Security
• With rapid globalization, societies are
experiencing increasing level of
fear/apprehension
• Quality – Clinical entanglement remains
elusive while placebo/nocebo effects are
increasing
• The progress in pharmaceutical
technologies such as real-time controls
and continuous manufacturing,
• legislative recognition of the need for
efficient pharmaceutical manufacturing
as in the 21st Century Cures Act, and
• President Trump’s focus on
manufacturing in the USA.
6
Increasing societal demand for higher assurance of pharmaceutical quality and lower prices, historical
regulatory opposition and uncertainty is turning to regulatory preference for PAT based real-time-
controls, continuous manufacturing and digital manufacturing enablers – the Tipping Point!

7
Late1990s’(MedicalGas:Air
SeparationUnits)
2004-2005Sanofi-Aventis
ComparabilityProtocol(FDA
Approved-NotImplemented)
2006MSD/Merck
Several,….others(newdrugs);
genericsfacedOGDpush-back
NDA26038;Orkambi®,Vertex
Pharmaceuticals.25June2015
……………………………………
……Post-approval
change:NDA021976Prezista®
,Janssen.12April2016
(Continuousmanufacturing
withRTRT)
Opposition
FDA
Initiatives
Lessons
Learned
Progress
historical regulatory
opposition and
uncertainty is turning
to regulatory
preference for PAT
based real-time-
controls, continuous
manufacturing and
digital manufacturing
enablers
Regulatoryheterogeneity
US-EU-Japan-ROW
CMCReviewVsCGMPInspections
CompendialTesting
Other

The consequence of the little secret is now being
understood more broadly
8
http://www.fda.gov/ohrms/dockets/ac/02/briefing/3841B1_05_PFIZER.PDF ; FDA Science Board 16 November 2001

The “little secret” in (solid dosage) manufacturing
• Certificate of Analysis : Uncertainty in solid-state material attributes
• Research laboratory measurement systems such as dissolution : Life-
cycle stability and reproducibility in QC?
• Fixed equipment and process parameters: Committed in submissions,
difficult to change post approval; why bother finding the real cause?
• Uncertainty in the stability and capability of measurements and
manufacturing process: Raises questions on adequacy of sampling and
obstructs risk-based decisions
• Globalization – variable empowerment/oversight: “FDA Approved” and
“Validated”; frames the mindset and ease of rationalization - cheating by
design & breaches in data integrity
9
If you keep your head in the
sand, you don't know where the
kick's coming from. Herbie
Mann

Where there is a will there is a way!
10

NDA 26038; Orkambi®, Vertex Pharmaceuticals
25 June 2015
11
From: Martin Warman, Kelly Swinney and Justin Pritchard. PAT for In Process Control (IPC) and Real Time Release Testing (RTRT) in
Continuous Manufacturing. 7th Pharmaceutical Technology Conference on Continuous Manufacturing, Japan (December 2015)
Angle of Repose Tipping Point

Two illustrative examples (small molecules)
12
• FDA Awards $4.9 Million to
Rutgers-Led C-SOPS
• FDA invitation to prepare and
submit a proposal for an "FDA
guidance in Continuous
Manufacturing“
• FDAAwards $4.4 Million to
CONTINUUS Pharmaceuticals, Inc.
• “Advancement of Integrated
Continuous Manufacturing (ICM)
Unit Operations”; to develop a
science and risk-approach on how
drug quality can be monitored and
improved through integrated
continuous manufacturing (ICM).
C-SOPS GEA
MIT-Novartis: Continuus

The Manufacturing
USA Strategy is
rapidly evolving!
• Manufacturing USA
consists of multiple
linked Manufacturing
Innovation Institutes
• The National Institute for
Innovation in
Manufacturing
Biopharmaceuticals
NIIMBL
• USP and C-SOPS
Collaboration PCM
3/19/2017
13
https://energycommerce.house.gov/
Credit: Ron Sachs/SIPA/Newscom

Serious consideration needed for building your roadmap….
14
Remember Einstein’s challenge that we will never solve the problems tomorrow with the same order of consciousness
we are using to create the problems of today!

How?
• Pathfinder Option
• You have the “PAT spirit”; you are not waiting for “guidance”
from regulators
• You move now; engaging the regulators and taking them with
you on your visionary journey ; then you offer to train the
regulators!
• Standard Option
• You will wait for regulators to issue guidance
• You get ready to move in about 3 years; you complete
implementation of Process Validation 2011 and QbD (Q8-11) –
with a vigorous check for risk of breaches in the assurance of data
integrity (and prevent suspicion of “are these data too good to be
true?”)
• Emergency Option
• Oh no! A bad inspection with the “dreaded” observations!
• CAPA, process improvement & smart HPLC that says STOP to
“trial injections”
Leadership-drive and options
Industry 1.0
Industry 2.0
Industry 3.0
Industry 4.0
15

What?
• Technology platforms
• Manufacturing with controls [PAT-RTRT partial or full]
• API only, DF only, Integrated API & DF
• Rapid development, manufacturing with controls
• PAT-RTRT with continuous manufacturing
• Other – human behavior motivation & monitoring , Big Data, pattern recognitions, etc.
• New (generic or brand) development Vs. Post Approval
• OSD IR: BCS Class I, Direct Compression,….
• OSD IR: BCS Class IV, Wet Granulation….
• OSD MR: Extended Release
• …….
• People & Organization Development , Partnerships & Collaboration
• Internal mindset shift and collaborations
• Regulator communication and collaboration
• Partnership & collaboration with Suppliers & Technical Experts
• Collaboration with Academia (e.g., NIPTE)
You need to consider
16

FDA Trends
Trend: a general direction in which something is developing or changing
2000-2016
• FDA Initiatives; PAT, CGMPs for 21st Century, Critical Path…
• ICH Desired State: Pharmaceutical Quality for the 21st Century
• Guidelines PAT, ICH Q8, 9, 10, Process Validation (2011), ICH Q11
and (Q 12)
• Guideline effectively practiced?
• 2007 – Heparin Tragedy, drug shortages, Warning Letters,.
Breeches in Data Integrity…..
• FDA reorganization: OPQ, One Quality Voice,.. Real-Time-Controls
& Continuous Mfg.
2017-
• 21st Century Cures Act (13 Dec 2016)
• President Trump’s Focus (2017-)
• We have got to get our drug industry back and
bring drug prices “way down,” and promised to
curb regulations and lower tax rates to boost
their competitiveness
• New Business, Process and Analytical
Method Validation Strategies
17

Summary: Part I
• The little secret – swept
under the rug? No more!
• Unprecedented juxtaposition
– at the Tipping Point!
• Serious consideration needed
for building your roadmap!
• Three options: Pathfinder,
Standard or Emergency; what
will you choose?
3/19/2017
18

What
• PAT based Real-Time Release Testing (RTRT) provides by
design a higher assurance of quality
• Statistically valid sampling and testing of starting and in-
process materials and finished dosage forms utilizing non-
destructive and non-compendial methods
• Simultaneous (real-time) recording of data with traceability
• Necessitates up-front design and development efforts while
considering product life-cycle; this yields a robust control
strategy based on knowledge and understanding of sources
of variability
• Technological advancement now allow rapid development
(even in the context of Breakthrough Therapies) with more
realistic definition of Design Space
• Availability of technological platforms to address concerns
associated with irrational human behaviors, reduce time and
cost of development and justification & motivation to
encourage manufacturing in the USA
FDA is encouraging real-time-controls
(and continuous manufacturing):
A higher level of
confidence in quality
assurance : State of Control
(stability, capability with
statistical confidence)
19

How?
• Pathfinder Option
• You have the “PAT spirit”; you are not waiting for “guidance”
from regulators
• You move now; engaging the regulators and taking them with
you on your visionary journey ; then you offer to train the
regulators!
• Standard Option
• You will wait for regulators to issue guidance
• You get ready to move in about 3 years; you complete
implementation of Process Validation 2011 and QbD (Q8-11) –
with a vigorous check for risk of breaches in the assurance of data
integrity (and prevent suspicion of “are these data too good to be
true?”)
• Emergency Option
• Oh no! A bad inspection with the “dreaded” observations!
• CAPA, process improvement & smart HPLC that says STOP to
“trial injections”
Leadership-drive and options
Industry 1.0
Industry 2.0
Industry 3.0
Industry 4.0
20

How to respond to
these Observation?
483 Observation # 3 relates to
process which delivers
products to patients
• Changes to written procedures are not drafted, reviewed and
approved by the appropriate organizational unit
• Procedures describing the handling of written and oral complaints
related to drug products are deficiently written or followed
• Control procedures are not established which monitor the
output and validate the performance of those manufacturing
processes that may be responsible for causing variability in
the characteristics of in-process material and the drug
product
• The accuracy, specificity, and reproducibility of test methods have
not been established . . .
• Laboratory controls do not include the establishment of scientifically
sound and appropriate test procedures . . .
• Laboratory records do not include complete data . . .
Following an FDA inspection at a
Generic Facility in the USA a Form
483 was issued with 6 observations
21

483 Observation # 3
• A. Process Validation Protocols for My Head Aches Capsules, 1 mg
lack acceptance criteria. For example: In MyPV420 – Process
Validation Protocol for My Head Aches Intermediate Delayed-Release
Pellets (0.X%) lack acceptance criteria for Blend Uniformity from
drums, particle size and Dissolution.
• B. There is no data to support the critical process parameter ranges of
the My Favorite Fluid Bed Dryer in the current/proposed commercial
batch production record A1234 for My Head Aches Intermediate
Delayed-Release Pellets for the following:
• • Inlet Air Temperature: XX-YY C
• • Inlet Air Volume: XXX- YYYY m³/h
• • Microclimate Pressure: XX- YYY mbar
• • Dynamic Filter Pres. Max.: X-Y bar
• • Dynamic filter Pres. Min.: X -Y bar
• • Dynamic filter Time: X-YY seconds
• • Spray Air Pressure: X-Y bar
Control procedures are not
established which monitor the
output and validate the performance
of those manufacturing processes
that may be responsible for causing
variability in the characteristics of
in-process material and the drug
product.
To be Commercialized & Commercial Products
Development or validation reports contain no data
supporting identification of critical process parameters
and their ranges. Key focus: Process Validation
Guidance 2011.
22

How to address the 483 Observations
• Each observation should be addressed
specifically & comprehensively
Process capability roadmap a central theme
(for all products at the facility)
Plus – how are CQA’s linked to PPs; what
are CPPs’ and range for controlling?
How other observation impact/interact
informs the methodology and sequence of
work products?
• Measurement system capable for all QA’s &
PPs?
• Is the process stable for all CQA’s?
• What can we do to address special causes
we will observe?
• Are the processes capable?
• Plus +++
23

Roadmap to
process capability?
Challenge specs
Measurement system capability for all CQA’s
(including dissolution test)?
Is the process stable for all CQA’s?
What can we do to address special causes we
will observe?
Are the processes capable?
Plus – what is the link between CQA’s & PPs;
what are CPPs’ and range for controlling?
Scott conducted a training program (2004) at FDA for the PAT Team.3/19/2017
24

25

26
An integrated Statistical Assessment &
Scientific Impact Analysis provided a
way forward
STATISTICAL METHODOLOGY

27

28

The “little secret” in (solid dosage) manufacturing
• Certificate of Analysis : Uncertainty in solid-state material attributes
• Research laboratory measurement systems such as dissolution : Life-
cycle stability and reproducibility in QC?
• Fixed equipment and process parameters: Committed in submissions,
difficult to change post approval; why bother finding the real cause?
• Uncertainty in the stability and capability of measurements and
manufacturing process: Raises questions on adequacy of sampling and
obstructs risk-based decisions
• Globalization – variable empowerment/oversight: “FDA Approved” and
“Validated”; frames the mindset and ease of rationalization - cheating by
design & breaches in data integrity
29
If you keep your head in the
sand, you don't know where the
kick's coming from. Herbie
Mann

Summary: More
confident assurance
of pharmaceutical
quality
• Effective CAPA to continual improvement
• Process capability roadmap for legacy products
• Stability & capability in Continued Process
Verification with clearer understanding of Common
Cause Vs Special Cause Variations
• System wide implementation - an integrated
adoption of PAT, ICH Q8-11 and PV 2011
• Removing blind-spots and changing mindsets
• Compendial test: Release Test Vs. Market Standards
• Measurement system capability for all CQA’s
(including dissolution test)?
• Life-cycle validation for analytical methods ;
specifically these for physical attributes
Effective CAPA and
achievement and
communication on the
State of Control – stability
and capability (and
statistical confidence)
30

FDA Trends: New
Validation Strategies
• Why:
• Need for more confident assurance of pharmaceutical
quality has increased?
• FDA is encouraging PAT based real-time-controls (and
continuous manufacturing) as a preferred means to achieve
higher confidence?
• How:
• A higher level of confidence in quality assurance can be
achieved and demonstrated;
• Without real-time-controls (and continuous
manufacturing)?
• With real-time-controls (and continuous manufacturing)?
• What:
• Benefits can be expected for a company
• Benefits can be expected for patients and society
Summary
31

FDA Trend: New Validation Strategies

More Related Content

What's hot

Similar to FDA Trend: New Validation Strategies

More from Ajaz Hussain

Recently uploaded

FDA Trend: New Validation Strategies