IVT Forum – Stability Programs Geoff Carr Philadelphia, 07 th 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 http://www.patheon.com [email protected]
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Designing Stability Studies for Early Stages of Pharmaceutical Development
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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IVT Forum – Stability Programs
Geoff Carr
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
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.
• 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
• 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
• 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
* 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
• 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 topicals
• 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
• 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
• 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
• 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
* 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
• 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 packaging
• 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
• 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
• 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
• 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