Designing Stability Studies for Early Stages of Pharmaceutical Development

IVT Forum – Stability
Programs
Geoff Carr
http://www.patheon.com geoff.carr@patheon.com

Philadelphia, 07th Dec 2010

Designing Stability Programs for Early
Stages of Development
For more information on stability programs or to download the full presentation, please visit
http://www.ivtnetwork.com

Introduction

•  Requirements for conducting stability studies for
Marketing Authorisation Applications eg NDAs clearly set
out within ICH Q1 series of guidelines
•  Very explicit on
–  How many batches
–  Nature of batches
–  Duration of study required at time of application
–  How to evaluate the data
–  Etc
–  Etc

IQPC Conf – Stability Testing – Early Stage Stability Studies 2

Introduction

•  During development stages, stability studies are also
required
–  Provide initial indications of drug substance and drug
product stability
–  To monitor the suitability of clinical trial batches
–  To establish suitability of experimental formulations


Introduction

•  As a baseline, a typical full ICH stability protocol
something like this:


Introduction
Typical Study Schedule for an ICH Stability Program

* 30°C/65%RH stability samples to be pulled at their designated time points. Samples will be tested if those at 40°C/75%RH show significant
changes as defined by ICH Q1A: A 5% change in potency loss from initial assay, any specified degradant exceeding its specification limit,
failure to meet specifications for appearance and physical properties.


Introduction

•  Presentation will discuss some examples of suitable
stability protocols as follows:


Main Menu
Introduction
Experimental Stability Protocols
Stability Protocols for Phase 1
Stability Protocols for Phase 2/3
Placebo Stability
Dealing with Blinded Clinical
Comparators
Conclusions

7
IQPC Conf – Stability Testing – Early Stage Stability Studies 7 Confidential

Main Menu
Introduction
Placebo Stability
Comparators
Conclusions

8


•  Early studies that may be conducted to prepare for later
long term studies eg
–  Forced Degradation Studies
–  Very important but being covered in separate presentations
•  Conducted to assist with product development studies
eg
–  Drug Excipient Compatibility Studies


Experimental Stability Studies –
Excipient Compatibility Studies
•  Very important to provide Formulation Development
Scientists with some initial data to help select
appropriate excipients
•  Or more importantly to help deselect
inappropriate excipients


•  Study may be conducted using binary mixtures of API +
excipient
•  Design of experiments approach may be more
appropriate but a suitable schedule will look something
like:


STABILITY TESTING SCHEDULE FOR A DRUG EXCIPIENT
COMPATIBILITY STUDY

* 40°C/75%RH and 25°C/60%RH stability samples to be pulled at their designated time points. Samples will be tested if
those at 60˚C show excessive degradation


•  Samples will typically be tested for:
–  Appearance
–  Potency assay by HPLC
–  Related substances by HPLC


Main Menu
Introduction
Placebo Stability
Comparators
Conclusions

14


•  Company requirements for speed
•  No time to develop a robust formulation and this is
probably not needed because:
–  Clinical study of short duration eg a few weeks
–  Limited number of subjects
–  Small batch size
•  Quite likely that API availability very limited



•  Good example of Phase 1 formulation is Powder in Bottle
(PIB)
•  Individual subject doses of API are accurately weighed
into separate bottles and shipped to study centre
•  Prior to administration to subjects they are then
constituted with appropriate vehicle (usually water but
see later)



•  Requires minimal development or analytical support
because:
–  API not mixed with other ingredients prior to shipment to
study centre and so no issues of possible incompatibilities or
concerns about adequacy of blending
–  Vehicle added very shortly before administration and so very
little risk of inducing instability


Stability Testing Schedule for a Phase 1 Powder in Bottle (PIB)

* Samples stored at 5°C are available as controls and will only be tested if needed for an investigation



•  Samples to be tested for:
–  Appearance



•  Must also consider “in use” stability
•  PIBs must be constituted prior to administration to
subjects
•  In busy clinical centre likely to be conducted in
pharmacy then taken to ward
•  Take into account that constitution immediately prior to
administration could in reality mean constitution several
hours prior to administration



•  Constitution vehicle usually water but could be
–  Aqueous surfactant to assist solubility
–  Fruit juice to provide some taste masking
–  In case of fruit juice, important to use the same batch for
•  Development
•  Stability
•  Constitution for administration to subjects



•  Constituted samples should be kept at
–  25°C/60%RH
–  5°C/Amb RH
•  Up to 24 hours and probably tested at intervals such as
–  T=0
–  T=5 hours
–  T=12 hours
–  T=24 hours
•  Later time point(s) may also be applied for additional security
•  Duration limited by microbiological considerations.
Product would need preservative for longer periods


Main Menu
Introduction
Placebo Stability
Comparators
Conclusions

23


•  Clinical trials conducted on large patient populations
•  Durations of clinical studies likely to be longer eg several
months
•  Important now to be using formulations that are likely to
more closely resemble future commercial products
•  Stability protocol likely to be very close to an ICH study


Stability Schedule for Phase 2/3 Studies

* 30°C/65%RH stability samples to be pulled at their designated time points. Samples will be tested if those at 40°C/75%RH show any
significant changes



–  Appearance
–  Pharmaceutical performance eg
•  Dissolution for solid oral dosage forms
•  pH for solutions
•  Viscosity for topicals



•  Duration of stability studies may continue beyond clinical
study
–  Likely that by this stage, APIs and products much more
freely available
–  May be useful to use data from these studies as supportive
for registration stability


Main Menu
Introduction
Placebo Stability
Comparators
Conclusions

28

Placebo Stability

•  Many clinical trials conducted using placebo controls
•  Double blinded studies
•  In order for blinding to be secure, placebos are designed
to be visually identical to the active preparations
•  Security of clinical study could be compromised if this
situation is not maintained
•  Therefore important for placebos to be included in the
stability program
•  Likely that the most important stability test will be
appearance in the case of dosage forms such as tablets
and capsules
–  Sometimes, moisture content and disintegration also
requested


Placebo Stability

•  For formulations containing preservatives additional tests
that should be considered:
–  Preservative assay
–  Preservative efficacy test (PET)


Main Menu
Introduction
Placebo Stability
Comparators
Conclusions

31

Dealing with Blinded Comparators

•  The challenge – how to make the comparator look like
the product under investigation without compromising
its integrity and also demonstrating that this has been
achieved



•  Common practice in Phase 2/3 studies to look for clinical
comparisons between the drug under investigation and a
well established product already on the market –
Comparator
•  Regulatory Agencies require this as part of proof of
efficacy
–  Usually done using the generally accepted market leader
product
•  Quite likely that the comparator is manufactured by a
different Company



•  Important that neither investigators nor patients know
whether product being administered is:
–  NCE under investigation
–  Comparator
–  Placebo



•  Various ways of achieving this
–  Blinded comparators in which
•  NCE under investigation
•  Comparator
•  Placebo
–  All made to look alike
•  Double dummy design in which
–  NCE under investigation + placebo look alike
–  Comparator + different placebo look alike
•  Use of blinded comparator preferred and more powerful
study design



•  Blinding a comparator involves some manipulation of a
commercial product and we probably know very little
about the chemistry of the API
•  So how can we really claim that this is now a valid
comparator??
–  Possible changes to pharmaceutical performance
•  How can we be sure that we are not placing clinical
subjects at risk??
–  Due to inadvertently causing some degradation to a toxic
impurity



•  Approaches to blinding a comparator taking a tablet/
capsule as example could include:
–  Encapsulation of tablets and add a back fill
–  May require more than 1 tablet per capsule
•  Back fill should be a major diluent ingredient of the comparator
•  Considered minimal manipulation
–  Break tablet then encapsulate pieces with a back fill
•  May be necessary for very large tablets
–  Or if required strength not available
•  This is a more serious manipulation



•  Approaches to blinding a comparator taking a tablet/
capsule as example contd
–  Mill tablet/capsule then fill into new capsule shells
•  May be necessary for very large tablet/capsules and least
preferred approach
•  This is a very serious manipulation



•  For any of these manipulations, we must conduct
stability studies to demonstrate that we have not
altered:
–  Pharmaceutical performance
–  Chemical stability
•  Of the comparator product



•  Not addressed by FDA in IND Guidelines
•  Nor Health Canada
•  Addressed by EMA Guideline
–  Guideline on the Requirements to the Chemical and
Pharmaceutical Quality Documentation Concerning
Investigational Medicinal Products in Clinical Trials
–  Became effective in Oct 2006
•  See
http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2009/09/
WC500003484.pdf



•  Refers to Investigational Medicinal Products (IMPs)
•  Investigational Medicinal Product Dossiers (IMPDs)
•  IMPD is equivalent to US IND
•  Section 3 of Guideline deals with Modified Comparator
Products
•  Requires that we address the influence of modifications
on product quality
•  Need to demonstrate that quality and stability
comparable to unmodified product



•  Typical stability protocol similar to the Phase 2/3
protocol shown earlier:


Stability Schedule for Blinded Comparator Studies

* 30°C/65%RH stability samples to be pulled at their designated time points. Samples will be tested if those at 40°C/75%RH show any significant
changes



1.  Appearance
2.  Potency assay by HPLC (Recommended but may not
be required by EMA Guideline)
3.  Related substances by HPLC
4.  Dissolution
•  Except that in the cases of tests 2., 3. and 4. would be
done on the basis of comparisons with unblinded
tablets/capsules from the same batch and in their
primary commercial packaging



•  Object of study
–  Not to investigate the stability of our competitors’ products
–  To demonstrate that we have not inadvertently altered
stability
•  This is all very well but where we supposed to get the
appropriate analytical methods from??



•  Refer to compendial monographs
–  USP
–  Ph Eur for APIs
–  BP
•  Since we are usually dealing with market leaders, very
likely that compendial monographs will be available
•  For potency assays and related substances tests, no
guarantees that these methods will be stability indicating
so forced degradation study may be needed
–  Methods will probably need to be validated
•  Verified for USP as per <1226>


•  Dissolution tests may be even more challenging
•  If dissolution tests provided in USP/BP generally single point
tests based on requirements of “not less than x% release in y
minutes”
•  Not good enough to demonstrate no differences in
performance
•  Better approach based on dissolution profile comparisons
•  Required by CHMP IMP Guideline in Section 3
•  Recommends to follow CHMP Guideline
–  Note for Guidance on Bioavailability and Bioequivalence
Annex II Dissolution Testing
•  This Guideline has been adopted and became effective in Oct
2006



•  Also well described in FDA Guidance for Industry
–  “Dissolution Testing of Immediate Release Solid Oral Dosage
Forms”
–  See
http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
ucm070237.pdf
•  Categorised under Biopharmaceutics section
•  CHMP and FDA Guidelines both recommend dissolution profile
comparisons



•  Guideline recommends profile comparisons for:
–  SUPAC related changes
•  SUPAC = Scale up and post approval changes
–  Other situations where Company wishes to justify
bioequivalence waivers
•  Eg with blinded clinical comparators



•  Guidance identifies 2 approaches
–  f1 comparison – Difference Factor
–  f2 comparison – Similarity Factor
•  For both cases we need a dissolution profile
–  Probably 4 time points
–  Must have only 1 time point with release value >85%
•  So a test method that meets these requirements must
be developed and validated
–  Probably using a compendial method as start point



•  Comparisons require that 12 dosage units be tested for
each of the 2 products being compared
•  Difference factor (f1) calculated from:
–  f1 = {[Σt=1t=n | Rt - Tt | ]/[Σt=1t=n Rt ]}x100
•  Similarity factor (f2) calculated from:
–  f2 = 50xlog{[1+(1/n)Σt=1t=n ( Rt - Tt )2 ]-0.5x100}
•  For a satisfactory comparison
–  f1 = 0 – 15
–  f2 = 50 – 100



•  In making judgments, beware of differences simply due
to encapsulation ie lag time during which capsule
dissolves
•  May be appropriate to remove the tablets from capsules
first
•  CHMP IMP Guideline makes it clear that if we are unable
to demonstrate in-vitro equivalence then it may be
necessary to get clinical data to demonstrate
equivalence of manipulated comparators


Main Menu
Introduction
Placebo Stability
Comparators
Conclusions

53

Conclusions

•  Early phase stability studies important for getting early
information from excipient compatibility studies and on
suitability of experimental formulations as well as
monitoring quality of clinical trials materials
•  Useful to follow ICH Q1 principles but to modify in
accordance with early development requirements
•  So for Phase 1 batches, very short term studies may be
sufficient
•  May however require in use stability data eg for powder
in bottle presentations that require constitution prior to
administration


Conclusions

•  Phase 2/3 stability data may provide useful supportive
data for Marketing Authorisation Applications so could be
useful to continue them beyond clinical requirements
•  Necessary to monitor stability of placebos especially for
appearance
•  Clinical comparators present a special challenge and very
important to demonstrate that any manipulations carried
out in order to blind them does not adversely affect their
stability or pharmaceutical performance
•  Important to take note of requirements of CHMP IMP
Guideline
–  Became effective Oct 2006


Designing Stability Studies for Early Stages of Pharmaceutical Development

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