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Designing Stability Studies for Early Stages of Pharmaceutical Development

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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 …

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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  • 1. 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 DevelopmentFor more information on stability programs or to download the full presentation, please visit http://www.ivtnetwork.com
  • 2. 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 –  EtcIQPC Conf – Stability Testing – Early Stage Stability Studies 2
  • 3. 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 formulationsIQPC Conf – Stability Testing – Early Stage Stability Studies 3
  • 4. Introduction•  As a baseline, a typical full ICH stability protocol something like this:IQPC Conf – Stability Testing – Early Stage Stability Studies 4
  • 5. IntroductionTypical 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. IQPC Conf – Stability Testing – Early Stage Stability Studies 5
  • 6. Introduction•  Presentation will discuss some examples of suitable stability protocols as follows:IQPC Conf – Stability Testing – Early Stage Stability Studies 6
  • 7. Main MenuIntroductionExperimental Stability ProtocolsStability Protocols for Phase 1Stability Protocols for Phase 2/3Placebo StabilityDealing with Blinded Clinical ComparatorsConclusions7IQPC Conf – Stability Testing – Early Stage Stability Studies 7 Confidential
  • 8. Main MenuIntroductionExperimental Stability ProtocolsStability Protocols for Phase 1Stability Protocols for Phase 2/3Placebo StabilityDealing with Blinded Clinical ComparatorsConclusions8IQPC Conf – Stability Testing – Early Stage Stability Studies 8 Confidential
  • 9. Experimental Stability Protocols•  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 StudiesIQPC Conf – Stability Testing – Early Stage Stability Studies 9
  • 10. 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 excipientsIQPC Conf – Stability Testing – Early Stage Stability Studies 10
  • 11. Experimental Stability Studies –Excipient Compatibility Studies•  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:IQPC Conf – Stability Testing – Early Stage Stability Studies 11
  • 12. Experimental Stability Studies –Excipient Compatibility Studies 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 IQPC Conf – Stability Testing – Early Stage Stability Studies 12
  • 13. Experimental Stability Studies –Excipient Compatibility Studies•  Samples will typically be tested for: –  Appearance –  Potency assay by HPLC –  Related substances by HPLCIQPC Conf – Stability Testing – Early Stage Stability Studies 13
  • 14. Main MenuIntroductionExperimental Stability ProtocolsStability Protocols for Phase 1Stability Protocols for Phase 2/3Placebo StabilityDealing with Blinded Clinical ComparatorsConclusions14IQPC Conf – Stability Testing – Early Stage Stability Studies 14 Confidential
  • 15. Stability Protocols for Phase 1•  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 limitedIQPC Conf – Stability Testing – Early Stage Stability Studies 15
  • 16. Stability Protocols for Phase 1•  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)IQPC Conf – Stability Testing – Early Stage Stability Studies 16
  • 17. Stability Protocols for Phase 1•  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 instabilityIQPC Conf – Stability Testing – Early Stage Stability Studies 17
  • 18. Stability Protocols for Phase 1 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 IQPC Conf – Stability Testing – Early Stage Stability Studies 18
  • 19. Stability Protocols for Phase 1•  Samples to be tested for: –  Appearance –  Potency assay by HPLC –  Related substances by HPLCIQPC Conf – Stability Testing – Early Stage Stability Studies 19
  • 20. Stability Protocols for Phase 1•  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 administrationIQPC Conf – Stability Testing – Early Stage Stability Studies 20
  • 21. Stability Protocols for Phase 1•  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 subjectsIQPC Conf – Stability Testing – Early Stage Stability Studies 21
  • 22. Stability Protocols for Phase 1•  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 periodsIQPC Conf – Stability Testing – Early Stage Stability Studies 22
  • 23. Main MenuIntroductionExperimental Stability ProtocolsStability Protocols for Phase 1Stability Protocols for Phase 2/3Placebo StabilityDealing with Blinded Clinical ComparatorsConclusions23IQPC Conf – Stability Testing – Early Stage Stability Studies 23 Confidential
  • 24. Stability Protocols for Phase 2/3•  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 studyIQPC Conf – Stability Testing – Early Stage Stability Studies 24
  • 25. Stability Protocols for Phase 2/3 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 anysignificant changes IQPC Conf – Stability Testing – Early Stage Stability Studies 25
  • 26. Stability Protocols for Phase 2/3•  Samples to be tested for: –  Appearance –  Potency assay by HPLC –  Related substances by HPLC –  Pharmaceutical performance eg •  Dissolution for solid oral dosage forms •  pH for solutions •  Viscosity for topicalsIQPC Conf – Stability Testing – Early Stage Stability Studies 26
  • 27. Stability Protocols for Phase 2/3•  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 stabilityIQPC Conf – Stability Testing – Early Stage Stability Studies 27
  • 28. Main MenuIntroductionExperimental Stability ProtocolsStability Protocols for Phase 1Stability Protocols for Phase 2/3Placebo StabilityDealing with Blinded Clinical ComparatorsConclusions28IQPC Conf – Stability Testing – Early Stage Stability Studies 28 Confidential
  • 29. 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 requestedIQPC Conf – Stability Testing – Early Stage Stability Studies 29
  • 30. Placebo Stability•  For formulations containing preservatives additional tests that should be considered: –  Preservative assay –  Preservative efficacy test (PET)IQPC Conf – Stability Testing – Early Stage Stability Studies 30
  • 31. Main MenuIntroductionExperimental Stability ProtocolsStability Protocols for Phase 1Stability Protocols for Phase 2/3Placebo StabilityDealing with Blinded Clinical ComparatorsConclusions31IQPC Conf – Stability Testing – Early Stage Stability Studies 31 Confidential
  • 32. 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 achievedIQPC Conf – Stability Testing – Early Stage Stability Studies 32
  • 33. Dealing with Blinded Comparators•  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 CompanyIQPC Conf – Stability Testing – Early Stage Stability Studies 33
  • 34. Dealing with Blinded Comparators•  Important that neither investigators nor patients know whether product being administered is: –  NCE under investigation –  Comparator –  PlaceboIQPC Conf – Stability Testing – Early Stage Stability Studies 34
  • 35. Dealing with Blinded Comparators•  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 designIQPC Conf – Stability Testing – Early Stage Stability Studies 35
  • 36. Dealing with Blinded Comparators•  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 impurityIQPC Conf – Stability Testing – Early Stage Stability Studies 36
  • 37. Dealing with Blinded Comparators•  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 manipulationIQPC Conf – Stability Testing – Early Stage Stability Studies 37
  • 38. Dealing with Blinded Comparators•  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 manipulationIQPC Conf – Stability Testing – Early Stage Stability Studies 38
  • 39. Dealing with Blinded Comparators•  For any of these manipulations, we must conduct stability studies to demonstrate that we have not altered: –  Pharmaceutical performance –  Chemical stability•  Of the comparator productIQPC Conf – Stability Testing – Early Stage Stability Studies 39
  • 40. Dealing with Blinded Comparators•  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.pdfIQPC Conf – Stability Testing – Early Stage Stability Studies 40
  • 41. Dealing with Blinded Comparators•  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 productIQPC Conf – Stability Testing – Early Stage Stability Studies 41
  • 42. Dealing with Blinded Comparators•  Typical stability protocol similar to the Phase 2/3 protocol shown earlier:IQPC Conf – Stability Testing – Early Stage Stability Studies 42
  • 43. Dealing with Blinded Comparators 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 significantchanges IQPC Conf – Stability Testing – Early Stage Stability Studies 43
  • 44. Dealing with Blinded Comparators•  Samples to be tested for: 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 packagingIQPC Conf – Stability Testing – Early Stage Stability Studies 44
  • 45. Dealing with Blinded Comparators•  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??IQPC Conf – Stability Testing – Early Stage Stability Studies 45
  • 46. Dealing with Blinded Comparators•  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>IQPC Conf – Stability Testing – Early Stage Stability Studies 46
  • 47. Dealing with Blinded Comparators•  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 2006IQPC Conf – Stability Testing – Early Stage Stability Studies 47
  • 48. Dealing with Blinded Comparators•  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 comparisonsIQPC Conf – Stability Testing – Early Stage Stability Studies 48
  • 49. Dealing with Blinded Comparators•  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 comparatorsIQPC Conf – Stability Testing – Early Stage Stability Studies 49
  • 50. Dealing with Blinded 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 pointIQPC Conf – Stability Testing – Early Stage Stability Studies 50
  • 51. Dealing with Blinded Comparators•  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 – 100IQPC Conf – Stability Testing – Early Stage Stability Studies 51
  • 52. Dealing with Blinded Comparators•  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 comparatorsIQPC Conf – Stability Testing – Early Stage Stability Studies 52
  • 53. Main MenuIntroductionExperimental Stability ProtocolsStability Protocols for Phase 1Stability Protocols for Phase 2/3Placebo StabilityDealing with Blinded Clinical ComparatorsConclusions53IQPC Conf – Stability Testing – Early Stage Stability Studies 53 Confidential
  • 54. 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 administrationIQPC Conf – Stability Testing – Early Stage Stability Studies 54
  • 55. 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 2006IQPC Conf – Stability Testing – Early Stage Stability Studies 55