Regulatory guidelines on stability testing are mainly designed to address studies that will be applied to support NDAs. However, in any pharmaceutical development program, a number of other stability studies are also required, for example, to help select appropriate formulations and to support regulatory applications for clinical programs. This session from the Institute of Validation Technology's Stability Programs Forum outlines a number of examples of early development stability studies.
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Designing Stability Studies for Early Stages of Pharmaceutical Development
1. IVT Forum β 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
2. Introduction
β’β― Requirements for conducting stability studies for
Marketing Authorisation Applications eg NDAs clearly set
out within ICH Q1 series of guidelines
β’β― Very explicit on
ββ― How many batches
ββ― Nature of batches
ββ― Duration of study required at time of application
ββ― How to evaluate the data
ββ― Etc
ββ― Etc
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3. Introduction
β’β― During development stages, stability studies are also
required
ββ― Provide initial indications of drug substance and drug
product stability
ββ― To monitor the suitability of clinical trial batches
ββ― To establish suitability of experimental formulations
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4. Introduction
β’β― As a baseline, a typical full ICH stability protocol
something like this:
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5. Introduction
Typical Study Schedule for an ICH Stability Program
* 30Β°C/65%RH stability samples to be pulled at their designated time points. Samples will be tested if those at 40Β°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.
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6. Introduction
β’β― Presentation will discuss some examples of suitable
stability protocols as follows:
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7. 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 β Stability Testing β Early Stage Stability Studies 7 Confidential
8. 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
8
IQPC Conf β Stability Testing β Early Stage Stability Studies 8 Confidential
9. Experimental Stability Protocols
β’β― Early studies that may be conducted to prepare for later
long term studies eg
ββ― Forced Degradation Studies
ββ― Very important but being covered in separate presentations
β’β― Conducted to assist with product development studies
eg
ββ― Drug Excipient Compatibility Studies
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10. Experimental Stability Studies β
Excipient Compatibility Studies
β’β― Very important to provide Formulation Development
Scientists with some initial data to help select
appropriate excipients
β’β― Or more importantly to help deselect
inappropriate excipients
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11. Experimental Stability Studies β
Excipient Compatibility Studies
β’β― Study may be conducted using binary mixtures of API +
excipient
β’β― Design of experiments approach may be more
appropriate but a suitable schedule will look something
like:
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12. Experimental Stability Studies β
Excipient Compatibility Studies
STABILITY TESTING SCHEDULE FOR A DRUG EXCIPIENT
COMPATIBILITY STUDY
* 40Β°C/75%RH and 25Β°C/60%RH stability samples to be pulled at their designated time points. Samples will be tested if
those at 60ΛC show excessive degradation
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13. Experimental Stability Studies β
Excipient Compatibility Studies
β’β― Samples will typically be tested for:
ββ― Appearance
ββ― Potency assay by HPLC
ββ― Related substances by HPLC
IQPC Conf β Stability Testing β Early Stage Stability Studies 13
14. 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
14
IQPC Conf β Stability Testing β Early Stage Stability Studies 14 Confidential
15. Stability Protocols for Phase 1
β’β― Company requirements for speed
β’β― No time to develop a robust formulation and this is
probably not needed because:
ββ― Clinical study of short duration eg a few weeks
ββ― Limited number of subjects
ββ― Small batch size
β’β― Quite likely that API availability very limited
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16. Stability Protocols for Phase 1
β’β― Good example of Phase 1 formulation is Powder in Bottle
(PIB)
β’β― Individual subject doses of API are accurately weighed
into separate bottles and shipped to study centre
β’β― Prior to administration to subjects they are then
constituted with appropriate vehicle (usually water but
see later)
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17. Stability Protocols for Phase 1
β’β― Requires minimal development or analytical support
because:
ββ― 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
ββ― Vehicle added very shortly before administration and so very
little risk of inducing instability
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18. Stability Protocols for Phase 1
Stability Testing Schedule for a Phase 1 Powder in Bottle (PIB)
* Samples stored at 5Β°C are available as controls and will only be tested if needed for an investigation
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19. Stability Protocols for Phase 1
β’β― Samples to be tested for:
ββ― Appearance
ββ― Potency assay by HPLC
ββ― Related substances by HPLC
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20. Stability Protocols for Phase 1
β’β― Must also consider βin useβ stability
β’β― PIBs must be constituted prior to administration to
subjects
β’β― In busy clinical centre likely to be conducted in
pharmacy then taken to ward
β’β― Take into account that constitution immediately prior to
administration could in reality mean constitution several
hours prior to administration
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21. Stability Protocols for Phase 1
β’β― Constitution vehicle usually water but could be
ββ― Aqueous surfactant to assist solubility
ββ― Fruit juice to provide some taste masking
ββ― In case of fruit juice, important to use the same batch for
β’β― Development
β’β― Stability
β’β― Constitution for administration to subjects
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22. Stability Protocols for Phase 1
β’β― Constituted samples should be kept at
ββ― 25Β°C/60%RH
ββ― 5Β°C/Amb RH
β’β― Up to 24 hours and probably tested at intervals such as
ββ― T=0
ββ― T=5 hours
ββ― T=12 hours
ββ― T=24 hours
β’β― Later time point(s) may also be applied for additional security
β’β― Duration limited by microbiological considerations.
Product would need preservative for longer periods
IQPC Conf β Stability Testing β Early Stage Stability Studies 22
23. 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
23
IQPC Conf β Stability Testing β Early Stage Stability Studies 23 Confidential
24. Stability Protocols for Phase 2/3
β’β― Clinical trials conducted on large patient populations
β’β― Durations of clinical studies likely to be longer eg several
months
β’β― Important now to be using formulations that are likely to
more closely resemble future commercial products
β’β― Stability protocol likely to be very close to an ICH study
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25. Stability Protocols for Phase 2/3
Stability Schedule for Phase 2/3 Studies
* 30Β°C/65%RH stability samples to be pulled at their designated time points. Samples will be tested if those at 40Β°C/75%RH show any
significant changes
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26. Stability Protocols for Phase 2/3
β’β― Samples to be tested for:
ββ― Appearance
ββ― Potency assay by HPLC
ββ― Related substances by HPLC
ββ― Pharmaceutical performance eg
β’β― Dissolution for solid oral dosage forms
β’β― pH for solutions
β’β― Viscosity for topicals
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27. Stability Protocols for Phase 2/3
β’β― Duration of stability studies may continue beyond clinical
study
ββ― Likely that by this stage, APIs and products much more
freely available
ββ― May be useful to use data from these studies as supportive
for registration stability
IQPC Conf β Stability Testing β Early Stage Stability Studies 27
28. 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
28
IQPC Conf β Stability Testing β Early Stage Stability Studies 28 Confidential
29. Placebo Stability
β’β― Many clinical trials conducted using placebo controls
β’β― Double blinded studies
β’β― In order for blinding to be secure, placebos are designed
to be visually identical to the active preparations
β’β― Security of clinical study could be compromised if this
situation is not maintained
β’β― Therefore important for placebos to be included in the
stability program
β’β― Likely that the most important stability test will be
appearance in the case of dosage forms such as tablets
and capsules
ββ― Sometimes, moisture content and disintegration also
requested
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30. Placebo Stability
β’β― For formulations containing preservatives additional tests
that should be considered:
ββ― Preservative assay
ββ― Preservative efficacy test (PET)
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31. 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
31
IQPC Conf β Stability Testing β Early Stage Stability Studies 31 Confidential
32. Dealing with Blinded Comparators
β’β― The challenge β how to make the comparator look like
the product under investigation without compromising
its integrity and also demonstrating that this has been
achieved
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33. Dealing with Blinded Comparators
β’β― 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 β
Comparator
β’β― Regulatory Agencies require this as part of proof of
efficacy
ββ― Usually done using the generally accepted market leader
product
β’β― Quite likely that the comparator is manufactured by a
different Company
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34. Dealing with Blinded Comparators
β’β― Important that neither investigators nor patients know
whether product being administered is:
ββ― NCE under investigation
ββ― Comparator
ββ― Placebo
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35. Dealing with Blinded Comparators
β’β― Various ways of achieving this
ββ― Blinded comparators in which
β’β― NCE under investigation
β’β― Comparator
β’β― Placebo
ββ― All made to look alike
β’β― Double dummy design in which
ββ― NCE under investigation + placebo look alike
ββ― Comparator + different placebo look alike
β’β― Use of blinded comparator preferred and more powerful
study design
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36. Dealing with Blinded Comparators
β’β― Blinding a comparator involves some manipulation of a
commercial product and we probably know very little
about the chemistry of the API
β’β― So how can we really claim that this is now a valid
comparator??
ββ― Possible changes to pharmaceutical performance
β’β― How can we be sure that we are not placing clinical
subjects at risk??
ββ― Due to inadvertently causing some degradation to a toxic
impurity
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37. Dealing with Blinded Comparators
β’β― Approaches to blinding a comparator taking a tablet/
capsule as example could include:
ββ― Encapsulation of tablets and add a back fill
ββ― May require more than 1 tablet per capsule
β’β― Back fill should be a major diluent ingredient of the comparator
β’β― Considered minimal manipulation
ββ― Break tablet then encapsulate pieces with a back fill
β’β― May be necessary for very large tablets
ββ― Or if required strength not available
β’β― This is a more serious manipulation
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38. Dealing with Blinded Comparators
β’β― Approaches to blinding a comparator taking a tablet/
capsule as example contd
ββ― Mill tablet/capsule then fill into new capsule shells
β’β― May be necessary for very large tablet/capsules and least
preferred approach
β’β― This is a very serious manipulation
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39. Dealing with Blinded Comparators
β’β― For any of these manipulations, we must conduct
stability studies to demonstrate that we have not
altered:
ββ― Pharmaceutical performance
ββ― Chemical stability
β’β― Of the comparator product
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40. Dealing with Blinded Comparators
β’β― Not addressed by FDA in IND Guidelines
β’β― Nor Health Canada
β’β― Addressed by EMA Guideline
ββ― Guideline on the Requirements to the Chemical and
Pharmaceutical Quality Documentation Concerning
Investigational Medicinal Products in Clinical Trials
ββ― Became effective in Oct 2006
β’β― See
http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2009/09/
WC500003484.pdf
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41. Dealing with Blinded Comparators
β’β― Refers to Investigational Medicinal Products (IMPs)
β’β― Investigational Medicinal Product Dossiers (IMPDs)
β’β― IMPD is equivalent to US IND
β’β― Section 3 of Guideline deals with Modified Comparator
Products
β’β― Requires that we address the influence of modifications
on product quality
β’β― Need to demonstrate that quality and stability
comparable to unmodified product
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42. Dealing with Blinded Comparators
β’β― Typical stability protocol similar to the Phase 2/3
protocol shown earlier:
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43. Dealing with Blinded Comparators
Stability Schedule for Blinded Comparator Studies
* 30Β°C/65%RH stability samples to be pulled at their designated time points. Samples will be tested if those at 40Β°C/75%RH show any significant
changes
IQPC Conf β Stability Testing β Early Stage Stability Studies 43
44. Dealing with Blinded Comparators
β’β― Samples to be tested for:
1.β― Appearance
2.β― Potency assay by HPLC (Recommended but may not
be required by EMA Guideline)
3.β― Related substances by HPLC
4.β― Dissolution
β’β― 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
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45. Dealing with Blinded Comparators
β’β― Object of study
ββ― Not to investigate the stability of our competitorsβ products
ββ― To demonstrate that we have not inadvertently altered
stability
β’β― This is all very well but where we supposed to get the
appropriate analytical methods from??
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46. Dealing with Blinded Comparators
β’β― Refer to compendial monographs
ββ― USP
ββ― Ph Eur for APIs
ββ― BP
β’β― Since we are usually dealing with market leaders, very
likely that compendial monographs will be available
β’β― For potency assays and related substances tests, no
guarantees that these methods will be stability indicating
so forced degradation study may be needed
ββ― Methods will probably need to be validated
β’β― Verified for USP as per <1226>
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47. Dealing with Blinded Comparators
β’β― Dissolution tests may be even more challenging
β’β― If dissolution tests provided in USP/BP generally single point
tests based on requirements of βnot less than x% release in y
minutesβ
β’β― Not good enough to demonstrate no differences in
performance
β’β― Better approach based on dissolution profile comparisons
β’β― Required by CHMP IMP Guideline in Section 3
β’β― Recommends to follow CHMP Guideline
ββ― Note for Guidance on Bioavailability and Bioequivalence
Annex II Dissolution Testing
β’β― This Guideline has been adopted and became effective in Oct
2006
IQPC Conf β Stability Testing β Early Stage Stability Studies 47
48. Dealing with Blinded Comparators
β’β― Also well described in FDA Guidance for Industry
ββ― βDissolution Testing of Immediate Release Solid Oral Dosage
Formsβ
ββ― See
http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
ucm070237.pdf
β’β― Categorised under Biopharmaceutics section
β’β― CHMP and FDA Guidelines both recommend dissolution profile
comparisons
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49. Dealing with Blinded Comparators
β’β― Guideline recommends profile comparisons for:
ββ― SUPAC related changes
β’β― SUPAC = Scale up and post approval changes
ββ― Other situations where Company wishes to justify
bioequivalence waivers
β’β― Eg with blinded clinical comparators
IQPC Conf β Stability Testing β Early Stage Stability Studies 49
50. Dealing with Blinded Comparators
β’β― Guidance identifies 2 approaches
ββ― f1 comparison β Difference Factor
ββ― f2 comparison β Similarity Factor
β’β― For both cases we need a dissolution profile
ββ― Probably 4 time points
ββ― Must have only 1 time point with release value >85%
β’β― So a test method that meets these requirements must
be developed and validated
ββ― Probably using a compendial method as start point
IQPC Conf β Stability Testing β Early Stage Stability Studies 50
51. Dealing with Blinded Comparators
β’β― Comparisons require that 12 dosage units be tested for
each of the 2 products being compared
β’β― Difference factor (f1) calculated from:
ββ― f1 = {[Ξ£t=1t=n | Rt - Tt | ]/[Ξ£t=1t=n Rt ]}x100
β’β― Similarity factor (f2) calculated from:
ββ― f2 = 50xlog{[1+(1/n)Ξ£t=1t=n ( Rt - Tt )2 ]-0.5x100}
β’β― For a satisfactory comparison
ββ― f1 = 0 β 15
ββ― f2 = 50 β 100
IQPC Conf β Stability Testing β Early Stage Stability Studies 51
52. Dealing with Blinded Comparators
β’β― In making judgments, beware of differences simply due
to encapsulation ie lag time during which capsule
dissolves
β’β― May be appropriate to remove the tablets from capsules
first
β’β― 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
IQPC Conf β Stability Testing β Early Stage Stability Studies 52
53. 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
53
IQPC Conf β Stability Testing β Early Stage Stability Studies 53 Confidential
54. Conclusions
β’β― 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
β’β― Useful to follow ICH Q1 principles but to modify in
accordance with early development requirements
β’β― So for Phase 1 batches, very short term studies may be
sufficient
β’β― May however require in use stability data eg for powder
in bottle presentations that require constitution prior to
administration
IQPC Conf β Stability Testing β Early Stage Stability Studies 54
55. Conclusions
β’β― Phase 2/3 stability data may provide useful supportive
data for Marketing Authorisation Applications so could be
useful to continue them beyond clinical requirements
β’β― Necessary to monitor stability of placebos especially for
appearance
β’β― 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
β’β― Important to take note of requirements of CHMP IMP
Guideline
ββ― Became effective Oct 2006
IQPC Conf β Stability Testing β Early Stage Stability Studies 55