Porter William Q4 Stability by Design Pres

Stability by Design
Reduce Risk When Designing Stability

Studies from IND to NDA
William R. Porter, PhD
Principal Scientist
Peak Process Performance Partners LLC
PPPP-LLC@comcast.net
Q4: Wednesday 3:305:00 PM
Understanding the API & excipientsPreformulation studies

Stability concerns in the design of dosage forms for clinical trials
and commercial dosage forms.
STABILITY BY DESIGN (SbD) IN

NEW PRODUCT DEVELOPMENT
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Quality goals
for drug product stability
Minimal expectations for drug product stability are
outlined in ICH guidelines:
The early ICH Guidelines Q1Q5 failed to address
issues relating to the DESIGN of stable APIs and
dosage forms.
ICH Q6A and ICH Q6B: (Specificationstest
procedures and acceptance criteria) and ICH Q7:
(Good manufacturing practice guide for active
pharmaceutical ingredients) both fail to incorporate
strategies to facilitate scientific risk management and
modern quality practices aimed at continuous
improvement.
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ICH Q8/Q9/Q10
ICH drafted three guidelines (ICH Q8/Q9/Q10) that
describe how to apply Quality by Design (QbD)
principles to pharmaceutical product development:
ICH Q8(R2) (Pharmaceutical Development) incorporates
elements of risk and quality by design throughout the life cycle of
the product. [November 2005, R2 August 2009]
ICH Q9 (Quality Risk Management) focuses on defining the
principles by which risk management will be integrated into
decisions by regulators and industry regarding quality.
[November 2005]
ICH Q10 (Pharmaceutical Quality Systems) develops a
framework for an integrated quality management system which
will promote continual improvement in quality across the life
cycle of the product. [June 2008]
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Some history:
Quality by design (QbD)
Quality guru J. M. Juran outlined the basic steps for
achieving quality by design in the early 1990s:
Establish quality goals.
Identify the stakeholdersthose who will be impacted by our
efforts to meet these goals.
Determine the stakeholders needs.
Develop product features that respond to stakeholders needs.
Develop processes that are able to produce those product
features.
Establish process controls and transfer the resulting plans and
processes to production colleagues.
Juran JM. Juran on Quality by Design: The New Steps for Planning Quality into
Goods and Services. New York; The Free Press, 1992. READ THIS BOOK!
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QA in pharmathe early years

Approaches to quality assurance in the pharmaceutical
industry became codified in current Good Manufacturing
Processes (cGMPs) enforced by regulatory agencies.
Industry personnel typically sought compliance by adhering as
closely as possible to cGMPs.
This practice stifled innovation, because any innovation triggered
regulatory actions that could delay or prevent approval for
marketing.
The resulting development process was costly and

inefficient, and frequently failed to deliver optimal
products.
But quality specialists in industry, academia and regulatory
agencies began lobbying for change.
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A revolution in quality management

In the late 1980s, beginning at Motorola, a new concept in
quality management evolved, based on using
statistically-based tools aimed at identifying and
removing the causes of defects and reducing variability
in manufacturing and business processes.
Called Six Sigma in reference to the goal of reducing
product variability so that less than 3.4 defects per
million units could be achieved, the management
process focused on continuous improvement,
implemented by tightly focused Six Sigma projects in
which sources of poor quality were systematically
identified and minimized.
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Six Sigma quality management

In addition to traditional quality assurance goals,
Six Sigma programs aim to:
Have a clear focus on achieving measurable and quantifiable
financial returns from any Six Sigma project.
Have an increased emphasis on strong and passionate
management leadership and support.
Use a special infrastructure of "Champions", "Master Black
Belts", "Black Belts", "Green Belts", "Red Belts" etc. to lead and
implement the Six Sigma approach.
Make a clear commitment to making decisions on the basis of
verifiable data, rather than assumptions and guesswork.
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Design for Six Sigma (DFSS)

Although originally conceived as a process improvement tool for
existing manufacturing processes, Six Sigma principles were also
extended to a scientific risk-based approach for new product
development:
Define design goals that are consistent with customer demands and
the enterprise strategy.
Measure and identify CtQs (characteristics that are Critical To Quality),

product & process capabilities to meet expectations, and risks.
Analyze data to develop and design alternatives, create a high-level

design and evaluate design capability to select the best design.
Design details, optimize the design, and plan for design verification.
This phase may require simulations.
Verify the design, set up pilot runs, implement the production process
and hand it over to the process owner(s).
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The FDA gets involved

In 2004, FDA issued a draft proposal to incorporate a
scientific risk-based approach to new product
development that captured elements of Jurans 1992
QbD proposals.
Pharmaceutical cGMPs for the 21st Century A Risk-Based

Approach: Second Progress Report and Implementation Plan.
In 2007, these were updated:

Pharmaceutical Quality for the 21st Century: A Risk-Based
Approach Progress Report
[http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalPr
oductsandTobacco/CDER/ucm128080.htm].
FDA contributed to drafting ICH Q8/Q9/Q10.
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Additional quality goals

for drug product stability
Business goals must also be considered.
Inventory control, warehousing needs, production cycling,
distribution logistics, marketing, etc.
Specific shelf-life requirements for successful distribution

and marketing must be set BEFORE the product is
designed.
Both minimum acceptable as well as desirable goals should be
made explicit.
Example (for a solution drug product): The drug product should at
least meet stability specifications when stored at 28 C for up to 6
months but ideally should continue to meet specifications when
stored at a mean kinetic temperature of 25 C for up to 24 months..
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How can we achieve

stability by design (SbD)?
Establish quality goals.
Identify stakeholders [those affected by efforts to meet
these goals].
Determine stakeholders needs.
Develop product features that meet stakeholders needs.
Develop processes that reliably produce those product
features
Establish process controls and transfer the resulting plans
and processes to production.
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Defining the problem

At the outset, we need to envision just what
type of product we aim to develop.
What disease will it be used to treat?
Who are the stakeholders, in addition to the
patients whom we plan to treat?
Stability concerns can restrict choices!
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Stakeholders
As product development
proceeds, the stakeholders
keep changing
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Designing for stability:

Safety issues
Product design can impact safe use of the
product & impact stability:
Need consistent, controlled bioavailability to prevent
wide swings in API delivery (unless pulsatile delivery
is a requirement for efficacy).
Need product design & packaging to promote patient
compliance with dosing regimens.
Need delivery systems & packaging to reduce
opportunities for contamination, adulteration or abuse.
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Designing for stability:

Efficacy issues
Product design can impact efficacious use of
drug & impact stability:
Product elegance should promote patient acceptance.
Product should be easy and convenient to use.
Product should have good organoleptic properties
(taste, appearance, mouth feel, etc.).
Product should have reasonable cost.
Product should be easy to transport & store.
Product must DELIVER THE API!
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Achieving stability by design:

The widget-making way
Make many trial batches of product.
Wait. (Years, if necessary.)
Watch.
Determine process capability.
Set specifications based on capability.
If capability is inadequate to meet stakeholder
needs, redesign product and repeat cycle.
Go directly out of business and do not collect any
revenue.
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All things degrade, if enough time

elapses.
Only the rate of degradation and the extent to which it is
influenced by
environmental factorstemperature, humidity,
exposure to radiant energy, exposure to oxidizing
agents
and by
intrinsic factorsother product components
(excipients), processes (manufacturing equipment,
personnel)
will determine whether the product will be stable enough to
be manufactured, shipped and used under ambient
conditions or require special, expensive handling.
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Time is the goal

The whole point of stability studies is to
define a period of time (the shelf life)
during which nothing happens.
Stakeholders expect ALL samples from ALL
batches will remain within specifications when
tested by ANY qualified laboratory using a
validated method.
Current ICH recommendations for stability
data analysis for the purpose of setting a shelf
life do not meet stakeholder expectations.
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Known knowns, known unknowns

and unknown unknowns
Reports that say that something hasn't happened
are always interesting to me because as we
know, there are known knowns. These are
things we know that we know. There are known
unknowns. That is to say, there are things that
we know we don't know. But there are also
unknown unknowns. There are things we don't
know we don't know.
Donald Rumsfeld (U.S. Secretary of Defense,
February 2002) [emphasis added]
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Unknown unknowns, known

unknowns and known knowns
At the outset of any stability experiment, Critical-to-Stability
(CtS) parameters are at some initial value.
With time, CtS parameters change for the worse.
At early times, the changes in CtS parameters are too small to
detect.
These changes are unknown unknowns.
At slightly later times, the changes in CtS parameters, while

detectable, are too small to quantify with acceptable
uncertainty.
These changes are known unknowns.
Eventually changes in CtS parameters become large enough to

quantify with acceptable uncertainty.
Only then do these changes become known knowns.
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Other knowable knowns (1)

Who are the current and future stakeholders?
What are their needs? How do these impact stability concerns?
How will the needs of future stakeholders differ from current
stakeholders?
What regulatory stability requirements must be met?

Regulatory expectations differ somewhat around the world.
Which regulations must you meet to do initial clinical trials? To
develop a commercial product?
Regulatory expectations change over time.

What expectations must the product likely need to meet in the
future?
If you dont know, find out!

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What product features will best meet current stakeholders
needs? Are there stability considerations?
How might these differ from features demanded by future
stakeholders? Are there new stability considerations?
Can you design a product that will meet current needs, but
smoothly evolve into a product that will meet future needs?
What existing production processes can be adapted to making

the proposed new product? Will these impact stability?
If no existing processes meet requirements, can the necessary
skills and equipment be acquired? Or, can the work be
outsourced to a skilled third party?

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What tools will be needed to adequately measure the CtS
parameters of the proposed new product?
Measurement is a process! It, too, must be designed.
Do you have the facilities, equipment and skilled personnel to do
this? Or, will this need to be outsourced?
What intrinsic and extrinsic factors may impact product CtS

parameters ? How variable are these factors?
Nothing is constant or exact!
All processes have associated uncertainty, including the process
of measuring the uncertainty of other processes.

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What is already known about the physical and chemical
properties of the API?
Quiz medicinal chemists, process chemists, pharmacologists,
other discovery scientists.
What is already known about the physical and chemical

properties of any proposed excipients?
Quiz formulators, analysts working on other projects.
How will the new product be used?

Do you need rapid onset? Prolonged duration of action?
Who will administer the drug product to patients?
Will use requirements impact stability?

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Based on what you know

when a drug candidate is first approved for
development:
Propose a design for your new product and a process
for making it.
Describe the product to be designed.
Diagram a potential process to produce the design.
Conduct a virtual failure mode and effects analysis
(vFMEA) of the prospective product and process.
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Based on your vFMEA

Identify the known unknowns!
What experiments do you need to design to
acquire missing knowledge?
Are you sure that somebody else hasnt done this?
Double check with discovery scientists.
Are you sure these experiments are really
needed? Confirm with clinicians that your
proposed product really meets their needs.
Be always sure youre rightthen go ahead.

David Crockett (frontiersman and Tennessee congressman,
1834)
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API versus drug product stability

Experimental design
Selecting drug delivery systems
Evaluating stability liabilities of process changes
FORCED DEGRADATION STUDIES IN

NEW PRODUCT DEVELOPMENT
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Time is also the critical factor

It takes time to determine the rate of
degradation under actual conditions of
use; this is an unaffordable luxury for
companies that wish to be competitive in
the marketplace.
How can we reduce development time?
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Quantifying the known unknowns

Well, of course, you cantunless you
convert known unknowns into knowable
knowns by using STRESS
DEGRADATION EXPERIMENTS to speed
up degradation.
Find an elephant to step on your

product to make it fail!
Nelson W. Accelerated Testing:
Statistical Models, Test Plans, and Data
Analysis. New York: John Wiley & Sons
(1990).
Meeker WO, Escobar LA Statistical
Methods for Reliability Data, New York:
John Wiley & Sons (1998).
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What stress degradation

experiments do
is to allow degradation to proceed at a faster
rate, so that the amount of degradation products
formed become large enough not only to
quantify, but also to demonstrate trends.
When the stress is high enough, the unknown
unknowns and the known unknowns become
knowable knowns.
However, there is a danger of using too much stress,
introducing new degradation pathways.
Need to find the right balance using screening design
experiments, then iterate if needed.
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API vs. drug product stability

Formulation has consequences:
Components of drug delivery systems can
enhance API stability.
Components of drug delivery systems can
degrade API stability.
Stress degradation experiments on drug

delivery systems are required.
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Oxidative degradation
Prevention of oxidative degradation of the
API and excipients in a dosage form is
largely a packaging and formulation issue.
Dosage forms can be packaged to minimize
exposure to air.
Antioxidants and/or radical inhibitors can be
included as excipients.
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Photochemical degradation
Photochemical degradation can be
prevented almost entirely by packaging to
prevent exposure to ionizing radiation and
light.
Use knowledge of API and excipient
photochemical stability when designing
packaging for drug product.
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Degradation accelerated by heat

and moisture
Storage temperature (and relative humidity
for solid products) are the major factors
impacting drug product stability.
Stress degradation studies based on the
expanded Arrhenius model can and
should be conducted.
ln (tunstressed ) = ln (t stressed ) + B(hstressed
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Ea
hunstressed )
R
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1
Tstressed Tunstressed
35
Arrhenius kinetics
The effect of temperature on the rate at which a chemical
reaction proceeds is well-approximated by the Arrhenius
kinetic model for reactions in solution:
where t,T is the fraction of material degraded at time t

after storage at temperature T, f(t,T) is the reaction
model (which varies with reaction mechanism), k is the
reaction rate at any particular temperature T, A is the
Arrhenius frequency factor (the rate at infinite T), Ea is
the Arrhenius activation energy and R is the universal
gas constant (8.314 J mole1 K1).
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How long should I expose samples to thermal

stress to support a desired shelf-life?
Time Required to Achieve Constant Fractional Degradation in Solution as a Function
of Temperature for t(1 ) = 2 Years at 25 C
Temperature
C
K
50
25
298.15
32
305.15
459.91
40
313.15
277.99
48
321.15
172.29
56
329.15
109.30
65
338.15
67.21
75
348.15
40.32
85
358.15
24.90
t(1 ) (days) for Ea, kJoules/mole

67
71.74
84
100
730.50 days
392.96
376.10
335.76 289.55
200.15
182.63
144.11 105.79
105.43
91.93
64.52
40.64
57.29
47.85
30.03
16.35
29.86
23.82
13.27
6.18
15.06
11.44
5.62
2.23
7.89
5.73
2.50
0.85
117
247.40
76.17
24.87
8.57
2.75
0.83
0.27
Temperatures shown result in ~2 increase in time-to-failure

going from higher T to next lower T @ Ea = 71.74 kJ/mol
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Chemical kinetics
In solution:
In solids:
Traditionally based on
Based on models in which
kinetic models in which
fraction degraded () is
concentration (C) is
monitored as a function of time.
monitored as a function of
Reaction order models less
time.
common.
Reaction order concept
Diffusion models
Geometric contraction models
In stability experiments, most
Reaction order models
kinetic models can be replaced
Induction models
by a zero-order model with little
Power law growth
loss of accuracy.
You see nothing,
Stress experiments are usually
nothing,
run under conditions such that
nothing
either zero- or first-order kinetic
models can be fitted to the
then WHAM! you get explosive
data.
growth, and your product fails
catastrophically.
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Stability by Design
Peak
Process
Performance
Partners
LLC
December 4, 2013
dominates model choices.
Solid-state kinetic models

Many different theoretical models have been
proposed to explain solid state decomposition.
These fall into the following categories:
Reaction order models (similar to solution kinetic
models)
Nucleation models (power law models)
Diffusion models
Geometrical contraction models
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Solid state reaction mechanisms

Integralform
g() = kt
(t)
Limitas0
1DDiffusion(D1)
Diffusion
(kt)(1/2)
2DDiffusion(D2)
Diffusion
[(1 )ln(1 )]+
(2kt)(1/2)
3DDiffusionJander(D3)
Diffusion
[1 (1 )(1/3)]2
(9kt)(1/2)
GinstlingBrounshtein(D4)
Diffusion
1 (2/3) (1)(2/3)
Contractingline(R1)
Geometrical contraction
(9kt)(1/2)
kt
Contractingarea(R2)
1 (1 )(1/2)
kt/2
Contractingvolume(R3)
1 (1 )(1/3)
kt/3
Zeroorder(F0)
Reactionorder
kt
Firstorder(F1)
Reactionorder
ln(1 )
kt
Secondorder(F2)
Reactionorder
(1 )1 1
kt
Thirdorder(F3)
Powerlaw(P2)
Reactionorder
0.5[(1 )2 1]
kt
Nucleation
(1/2)
k2t2
Powerlaw(P3)
Nucleation
(1/3)
k3t3
Powerlaw(P4)
Nucleation
(1/4)
k4t4
AvaramiErofeyev(A2)
Nucleation
[ln(1 )](1/2)
k2t2
AvaramiErofeyev(A3)
Nucleation
[ln(1 )](1/3)
k3t3
AvaramiErofeyev(A4)
Nucleation
[ln(1 )](1/4)
ProutTompkins(B1)
Nucleation
ln[/(1 )]+cb
k4t4
Modela
Type
I
N
F
I
N
I
T
E
D
I
L
U
T
I
O
N
Adapted from: Vyazovkin A & Wight CA. Kinetics in Solids Annu Rev Phys Chem. 48:127-1128 (1977)
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Implications of solid state kinetics

The models can be simplified, when the
extent of degradation is small, to:
lim (t ) = t =0 + c(kt ) , r = ,1, 2, 3, 4
r
t =0
Manufacturing impurity
The exponent r is for diffusion-controlled models, 1 for simple

geometrical contraction or reaction order models, and 2, 3 or 4
for nucleation models
Of course, if the reaction is allowed to proceed further, the kinetic
behavior becomes more complex. However, these empirical
approximations serve well when degradation is limited to the
small fraction proposed in the ICH guideline for impurities.
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Mechanistic model approximation

All solid state degradation
reaction mechanisms
can be approximated by
simple empirical
models:
CtQ = CtQ t =0 c(kT ,h , g t )
if degradation is limited
to very low levels per
ICH guideline.
Note that low degradant
levels may not be
detectable or
quantifiable.
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Impact of humidity on solid state

reaction kinetics
To accommodate the effects of moisture, Genton &
Kesselring* proposed this modified Arrhenius model:
Ea
ln (kT ,% RH ) = ln ( A)
+ Bh
RT
kT ,% RH
Ea
= A exp Bh
RT
* Effect of temperature and relative humidity on nitrazepam stability in solid state. J Pharm Sci 66: 676
680 (1977)
The fraction degraded at time t for small is:
lim (t ) = t =0 + c Ag e
t =0
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)t
Bh E a RT r r
Manufacturing impurity
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Implications for solid state kinetics

Vyazovkin & Wight demonstrated that
isoconversional methods gave consistent
results and were model-free.
Isoconversional (e.g., time-to-failure) methods
require allowing degradation to proceed to the
same extent under different conditions.
fail
ln (t fail ) = ln
c
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Model-dependent terms
1
r
Ea
ln (kT ,h ) = C ln (Ag ) +
Bh
RT
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Isoconversional Arrhenius
Experiments
For any particular reaction model g, the Arrhenius frequency factor A is
a function of g, but g itself is independent of the temperature T or
relative humidity h for solid-state reactions. The time t to reach the
specified constant fraction degraded is a function of T (and h) alone if
is constant. More to the point, in the isoconversional case where
is constant, the Arrhenius energy of activation Ea and humidity
sensitivity B are independent of the reaction model g.
ln ( g ( constant )) ln (Ag ) = ln t ,T1 ,h1
Model free:
Ea
ln (tunstressed ) = ln (t stressed ) + B (hstressed hunstressed )
R
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Ea
Ea
+ Bh1
= ln t ,T2 ,h2 + Bh2
RT1
RT2
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Tstressed Tunstressed
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Isoconversional method
implications
The natural logarithm of the time-to-failure is inversely
proportional to the absolute temperature T and directly
proportional to the relative humidity h (for solids).
When ln(tfail) is plotted versus 1/T and h, the points lie on a
plane.
There exists a contiguous set of points in Th space for

which the time-to-failure is constant.
You can compensate for a change in T by changing h and viceversa.
This is the Storage Condition Th Design Space for the

drug product.
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Isoconversional degradation
experimental design
Design of temperature and humidity excursion
experiments is likely to be product-specific due
to differences in Ea (and B for solids) for each
product.
Simple generic protocols may require adjustment.
Physical changes (non-Arrhenius behavior) set
design space boundaries.
Defining the temperature and humidity ranges over

which the extended Arrhenius model is valid is
essential to successful experimental design.
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Watermans ASAP designs

Ken Waterman* has pioneered the use of time-tofailure designs in what he calls an Accelerated
Stability Assessment Program
Explore temperature-humidity design space.
Waterman presentation S5 Thursday 10:30 am.
ASAP can be adapted to any CtS problem, not just

initial screening!
* Waterman KC, Carella AJ, Gumkowski MJ, Lukulay P, MacDonald BC, Roy MC, Shamblin SL. Improved
protocol and data analysis for accelerated shelf-life estimation. Pharm Res 24(4):780790 (2007)
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Regulatory considerations
Resource allocation and facilities issues
Process changes and supply chain issues
Distribution and marketing issuesExcursions in the design
space for storage conditions
THE BEST DEFENSE IS A GOOD

OFFENSEPLANNING FOR
STABILITY AND WORKING THE PLAN
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Content of ICH Q10

Pharmaceutical Quality System
Management Responsibility
Continual Improvement of Process Performance and
Product Quality
Stability evaluation can evolve!
Continual Improvement of the Pharmaceutical Quality
System
Glossary
Annex 1 - Potential Opportunities to Enhance Science and Risk
Based Regulatory Approaches
Annex 2 - Diagram of the ICH Q10 Pharmaceutical Quality
System Model
Adapted from: ICH Pharmaceutical Quality System General Presentation [see ICH web site]
Copyright 2012 W. R. Porter
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Continual improvement of process

performance & product quality (1)
3.1 Lifecycle Stage Goals 4 stages
Pharmaceutical Development
Rapid stability evaluation
Design product and process to consistently deliver the intended

performance and meet the needs of stakeholders.
Exploratory and clinical development studies are inputs.
Rapid stability change control monitoring
Technology Transfer
Transfer product/process knowledge between development and
manufacturing, and within or between sites.
Commercial Manufacturing
Rapid stability batch monitoring

Achieving product realization, establishing and maintaining a state
of control, and facilitating continual improvement.
Product Discontinuation
Manage the terminal stage of the product lifecycle effectively.
Adapted from: ICH Pharmaceutical Quality System General Presentation [see ICH web site]
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Stability evaluation timeline (1)

Work begins BEFORE an API candidate is
selected for development.
Stability properties are some of several key
Critical-to-Selection parameters.
Stress degradation studies in solution as a function
of pH, exposure to light, exposure to oxidizing/
reducing agents.
Elevated temperatures may be used to reduce
time required to produce measurable degradation.
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Stability evaluation is critical to selection of a
desired solid form (amorphous, crystalline
polymorph or solvate, salt)
Ideally completed before scale-up of
synthesis for IND clinical supplies.
Stress degradation studies accelerate solid
form selection from months to weeks.
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Stability evaluation of prototype formulations
is critical to selection of a desired
formulation for IND clinical studies.
Stress degradation studies accelerate
formulation selection from months to weeks.
Stability evaluation should be repeated if

major process changes are required
during clinical trials.
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Experimental designs
Stress degradation studies are used to map
the storage temperature (and, for solid
dosage forms, also the relative humidity)
design space.
More complex designs may be required for
mapping.
Simpler designs are appropriate for
screening and routine monitoring studies.
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Initial screening
Relatively simple factorial designs are
suitable for early screening.
Solutions: 4T 5t covers broad range.
Solids: Consider Waterman* ASAP design to
include relative humidity effects.
If solution data is available, may be able to reduce
or use worst-case humidity studies, may be able to
use only 3T 3t.
* Waterman KC, Carella AJ, Gumkowski MJ, Lukulay P, MacDonald BC, Roy MC, Shamblin SL. Improved
protocol and data analysis for accelerated shelf-life estimation. Pharm Res 24(4):780790 (2007)
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Design space mapping

Based on initial screening, may be able to
select 3T 2h 2t design for each other
factor to be tested.
Relative humidity h1, h2 should be selected for
each T if solid dosage form is being studied.
If no or low humidity sensitivity, use only high h
(75% RH?)
Sampling times t1, t2 should bracket shelf life

at each T.
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Routine monitoring
Ultimately, a design should be developed
that can be incorporated into release
testing for each new batch of drug product.
Need 2T 2h 2t if humidity is important,
else 2T 2t at high h.
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Resource allocation
Measurement tools must evolve from generic to
custom-tailored as development proceeds.
Rapid validation strategies are required.
Use adequate controls and standards.
Design sampling protocols to permit batch processing
of samples.
Formulators, process engineers and analysts must

work closely together as a single-purpose
project teamuse agile project management
strategies.
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59
Ongoing process development

Conventional stability testing is based upon the notion of
using rigidly controlled temperature and relative humidity
to simulate mean kinetic temperature and humidity to
which product may be exposed during storage and
distribution.
Temperature and humidity excursions are built into
the definition of mean conditions.
Stress testing at conditions within the storage temperature
(and, for solids, relative humidity) design space can
predict shelf life under conventional test conditions.
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60
Mean kinetic temperature

for liquid products
If the Arrhenius model is valid, you can balance high T with
low T to keep mean kinetic temperature (MKT) constant.
ICH Q1A(R2), USP
TK = MKT =
TK = MKT =
Ea R
e Ea
ln
RT1
+ e Ea
RT2
+ e Ea
RT3
Ea R
t1e Ea
ln
RT1
+ (t 2 t1 )e Ea
RT2
tn
Ea R
=
mi e Ea
+L
ln
mi
+ L + (t n t n 1 )e Ea
RT3
RTi
Assumes equal time

periods at all
temperatures,
conventional model
dependent on tr, r = 1.
(mi = # periods at Ti).
Ea R
(ti ti 1 )e Ea
ln i
tn
RTi
Assumes unequal time periods at all temperatures, conventional model dependent on tr, r = 1.
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61
Mean kinetic temperature and

relative humidity for solid products
If the extended Arrhenius model is valid for solids, you can
balance high h with low h as well as high T and low T to
control both mean kinetic humidity (MKh) and mean
kinetic temperature (MKT) simultaneously:
.
t1r e rBh rE RT + (t 2 t1 )r e rBh r E RT + L + (t n t n 1 )r e rBh rE RT
Ea
1
= ln
r
tn
RTK
Assumes unequal time periods at all humidity levels and

temperatures. If r = 1, then the power terms in time can be
factored out.
If both mean kinetic humidity and mean kinetic temperature are
controlled, then the shelf life will remain unchanged. There are
multiple pairs of MKh and MKT values that will keep shelf life
unchanged.
BhK
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62
MKT & MKh in the real world

Hourly (blue) temperature and
humidity for Santa Rosa,
CA, 2010.
Storage at any point on MK
Th curve (red) will exhibit
EQUAL amount of
degradation.
USP MKT (green) ignores
humidity effects on
degradation.
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63
Process changes
Well-designed stress degradation experiments
provide a facile way to validate process change
impact on product stability if the storage
temperature (and relative humidity for solid
products) design space has been adequately
defined.
Just run experiments under those limited stress
conditions needed to confirm that CtS parameters are
not adversely affected by the change.
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64
Supply chain issues (1)

Stuff happens. Temperature and humidity excursions are
probable.
Use historical distribution records to determine how probable.
Determine upper limit for probable increase in MKT.
Option 1: Design formal stability trials at label claim MKT to

include added segment at higher Th (within design space) to
allow for excursions; include this extension in shelf life.
See, e.g., Friedman EM, Shum SC. Stability Models for Sequential
Storage. AAPS PharmSciTech, 12(1):96-103 (2011).
Option 2: Conduct formal stability trials at higher MKT than

needed to meet label claim to allow for excursions.
May require change in stability chamber settings.
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65
Supply chain issues (2)

Option 3:
Use knowledge and understanding of design
space to develop stress temperature (and
relative humidity for solid products)
experimental conditions to measure shelf-life
in less time.
Extrapolate to normal MKT & MKh conditions.
Advantage: Confirms upper bound of design
space.
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66
Shrink time!
By validating conditions under which the extended
Arrhenius model is operable for your product,
you can evaluate impact of process changes
(new formulations, new manufacturing
operations, changes in distribution supply chain
storage & handling any change that impacts
CtS parameters) by using appropriate stress
conditions at high Th edge of design space.
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67
Developing a detailed process map can aid the product

development team to conduct a virtual failure mode and effects
analysis of the entire process to identify steps where stability issues
critical to quality can arise, make plans for evaluating the potential
for problems, and design appropriate solutions.
INTERACTIVE EXERCISEPROCESS
MAP FROM IND TO NDA
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68
Pre-development
stability evaluation (1)
Discovery
Screening
Discovery
Lead
Optimization
In silico (virtual) FMEA by preformulation

scientists (with input from medicinal chemists).
Good, bad or ugly (needs more study)?
Additional in silico estimation of physical chemical

properties (pKa, logP, solubility) potentially
impacting stability and stability-indicating assay
design.
Targeted stress degradation experiments in
solution to support pharmacology. [Generic
analytical method.]
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69
Pre-development
stability evaluation (2)
Discovery
Candidate
Selection
Plan
solid form
selection
Execute
solid form
selection
Limited stress degradation studies in solution to

support assay development.
Full solution stress degradation study of lead
candidates (pH effects on Arrhenius activation energy,
photostability, reactivity to oxidizing agents).
Evaluate impact of solution stability on solid form
selection. Will moisture sensitivity testing be
required?
Evaluate impact of stability on drug delivery system
options.
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Go/no go development decisions

Summarize stress degradation studies and predict
shelf-life in solution.
Recommend potential solution product options.
Summarize work completed on solid form

selection.
Rank risks of solid drug delivery system options and
enumerate knowledge gaps.
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71
Post-discovery pre-IND stability

evaluation (1)
API solid
form
selection
Labscale API
batch
Trial
formulations
Stress degradation studies on selected API solid

form candidates.
Limited stress degradation study to confirm Arrhenius
activation energy (& moisture sensitivity if required).
Drug delivery system planning: vFMEA for product.
Project-specific stability-indicating analytical method
development begins.
Three or more model formulations prepared on lab
NO excipient compatibility studies!
scale.
Stress degradation studies on model formulations to
obtain Arrhenius activation energy (& moisture
sensitivity if required).
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72
Post-discovery pre-IND stability

evaluation (2)
IND
formulation
selection
Manufactur
e clinical
supplies
Release
clinical
batch
Evaluate stress degradation results and select best

formulation based on team criteria.
Propose storage temperature design space.
Complete stress degradation assay development &

validation.
Start formal stability study.

Run concurrent stress degradation study on clinical
batch to confirm Arrhenius model parameters and
validate storage temperature design space.
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73
Post-IND
Additional
clinical
batches
Process
changes
Formal
stability
studies
Design & conduct limited scope stress degradation

study on each new drug product clinical batch.
Create and maintain batch history stability database.
Design & conduct limited scope stress degradation
study (1 condition + 1 backup condition) for monitoring
process changes: assay only 1st condition samples.
Assay backup samples only to resolve unclear results.
Run concurrent stress degradation study on each
stability batch to confirm Arrhenius model parameters
and revalidate storage temperature design space.
Use at least two conditions in addition to ICH
recommended storage conditions.
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74
Moisture sensitivity
Many drug products do not exhibit marked
changes in degradation in response to
changing relative humidity.
Determine at pre-IND stage whether moisture
sensitivity is a CtS parameter.
If not, always use high humidity (e.g., 75% RH) for
stress studies on solid dosage forms.
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Photostability
For most drugs, only two photostability
studies may be required:
Initial preformulation study.
NDA batches.
For photolabile drugs and formulations,

additional small-scale photostability
studies may be required for each process
change.
Only small number of samples required.
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76
NDA
Summarize results of all stress degradation
studies to define storage temperature (&
relative humidity for solids if studied)
design space.
Define allowable excursions during storage
and transit based on design space.
Develop monitoring and control systems for
storage and distribution.
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77
Relevant articles
BONUS MATERIAL
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78
Recent publications in JVT

William R. Porter, Stability by Design. J Validation
Technol 17(3):8296 (2011).
William R. Porter, Thermally Accelerated Degradation and
Storage Temperature Design Space for Liquid Products.
J Validation Technol 18(3):7392 (2012).
William R. Porter, Degradation of Pharmaceutical Solids
Accelerated by Changes in Both Relative Humidity and
Temperature and Combined Storage Temperature and
Storage Relative Humidity (Th) Design Space for Solid
Products. J Validation Technol 19(2) (Jun 19, 2013).
Stability
by Design
11/26/2013
December 4, 2013
79
CMC guidance documents

For a list of FDA guidance documents, go to:
http://www.fda.gov/drugs/guidancecompliance
regulatoryinformation/guidances/ucm064979.
htm
Biotech types should also see:

http://www.ncbi.nlm.nih.gov/books/NBK92015/
Stability by Design
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80
Pharmaceutical project
management
ISPE Good Practice Guide:
http://www.ispe.org/ispe-good-practice-guides/projectmanagement-pharmaceutical-industry
Krimmer D. Project management of chemical,

analytical, and formulation development. In:
Kennedy T. Pharmaceutical Project
Management Second Edition, London: Informa
Healthcare (2008).
http://informahealthcare.com/doi/abs/10.3109/978142
0013924.004
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December 4, 2013
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Stability by Design

Reduce Risk When Designing Stability

Understanding the API & excipientsPreformulation studies

STABILITY BY DESIGN (SbD) IN

QA in pharmathe early years

The resulting development process was costly and

A revolution in quality management

Six Sigma quality management

Design for Six Sigma (DFSS)

Measure and identify CtQs (characteristics that are Critical To Quality),

Analyze data to develop and design alternatives, create a high-level

The FDA gets involved

Pharmaceutical cGMPs for the 21st Century A Risk-Based

In 2007, these were updated:

Additional quality goals

Specific shelf-life requirements for successful distribution

How can we achieve

Defining the problem

Stability concerns can restrict choices!

Designing for stability:

Designing for stability:

Achieving stability by design:

All things degrade, if enough time

Time is the goal

Known knowns, known unknowns

Unknown unknowns, known

At slightly later times, the changes in CtS parameters, while

Eventually changes in CtS parameters become large enough to

Other knowable knowns (1)

What regulatory stability requirements must be met?

Regulatory expectations change over time.

If you dont know, find out!

Other knowable knowns (2)

What existing production processes can be adapted to making

If you dont know, find out!

Other knowable knowns (3)

What intrinsic and extrinsic factors may impact product CtS

If you dont know, find out!

Other knowable knowns (4)

What is already known about the physical and chemical

How will the new product be used?

If you dont know, find out!

Based on what you know

Based on your vFMEA

Be always sure youre rightthen go ahead.

API versus drug product stability

FORCED DEGRADATION STUDIES IN

Time is also the critical factor

Quantifying the known unknowns

Find an elephant to step on your

What stress degradation

API vs. drug product stability

Stress degradation experiments on drug

Degradation accelerated by heat

where t,T is the fraction of material degraded at time t

How long should I expose samples to thermal

t(1 ) (days) for Ea, kJoules/mole

Temperatures shown result in ~2 increase in time-to-failure

dominates model choices.

Solid-state kinetic models

Solid state reaction mechanisms

[(1 )ln(1 )]+

Implications of solid state kinetics

The exponent r is for diffusion-controlled models, 1 for simple