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									  Stability Testing

           Rutendo Kuwana
           Technical Officer
Prequalification of Medicines Program
    •   Scope of presentation – Generic/Multisource preparations
    •   API - Stress Testing
    •   Selection of Batches
    •   Container Closure System
    •   Methods to be validated
    •   Specifications: Stability indicating quality parameters
    •   Testing Frequency
    •   Storage Conditions
    •   Evaluation of data
    •   Bracketing/Matrixing
    •   Common deficiencies

2        PQ Assessors training, Jan 2011
            The Role of Stability in Drug
    • Stability studies play a central role in drug
    • Permit understanding of the molecule
    • Essential for developing analytical methods
    • Essential for selecting packaging for drug substance
      and drug product
    • Essential for choosing storage conditions for drug
      substance and drug product

3      PQ Assessors training, Jan 2011
                              Stress Studies
    • When available, it is acceptable to provide relevant
      data published in the scientific literature to support
      the identified degradation pathways and products.
    • When no data are available, stress testing should be

4      PQ Assessors training, Jan 2011
           The Role of Stress Testing
    • Identification of degradation pathways
    • Identification of degradants
    • Determination of which type(s) of stress affect the
       –   Photostability
       –   High Temperature
       –   Low Temperature
       –   Oxidation
       –   pH extremes
       –   Water

5      PQ Assessors training, Jan 2011
                                   API stability
                                  Stress testing
    • Requirement: 1 API batch.
    • Photostability testing: generally as per Q1B, however
      for PQP, literature data can support/replace
      experimental data:
      If “protect from light” is stated in one of the officially
      recognized pharmacopoeia for the API, it is sufficient
      to state “protect from light” on labeling, in lieu of
      photostability studies, when the container closure
      system is shown to be light protective.

6       PQ Assessors training, Jan 2011
    • Typically done by placing the drug substance in
      aqueous solution with hydrogen peroxide
    • Goal is significant degradation (typically 10-30% of
       – Can identify degradants
       – Determine whether protective packaging is required
       – Determine if an antioxidant should be considered for the
         drug product formulation

7      PQ Assessors training, Jan 2011
                                  pH Extremes
    • Typically done by adding drug substance to buffered
      aqueous solutions at pH values from 1-10.
    • Can be complicated by limited solubility of the drug
      substance under different pH conditions
    • Again, the goal is significant degradation
       – Determine degradants
       – Decide if the molecule will survive passage through the stomach
            • Is enteric coating necessary?
            • Should the drug be given by injection?

8       PQ Assessors training, Jan 2011
                   API stability
    Stress testing – Typical Stress conditions

9   PQ Assessors training, Jan 2011
                  Identifying Degradants
     • Predicting routes of degradation
        – Acid/base hydrolysis of esters and amides
        – Oxidation of thiols, alcohols and amines
        – Loss of methyl groups
     • Synthesizing possible degradants
        – Prepare possible degradant
        – Known Structure
        – Test it in potential analytical method
             • Detectability
             • Separation from parent peak

10       PQ Assessors training, Jan 2011
                                  Stress studies:

     • Investigate impurities/degradants appearing at greater than (or
       approaching) the identification threshold, (the limit on
       individual unknowns) under long-term and accelerated
     • Mass balance assessment if required to be based on the
       decrease in assay value and the increase in the amount of
       degradation products.
     • Process related impurities to be monitored at release only with
       no need to monitor during long-term stability. However, if they
       increase during storage, or new impurities develop, they should
       be considered as “degradants” or “degradation products”, and
       analytical methods must be developed to monitor them.

11       PQ Assessors training, Jan 2011
     Examples of physical stability stress testing conditions
                     for drug substances
                    - Industry Perspective

        (Source Handbook of stability testing and pharmaceutical development regulations, methodologies, and best practices)

12       PQ Assessors training, Jan 2011
             API - Selection of Batches
     • Primary Batches : Batches used in stability studies to
       establish retest (API) or shelf-life (FPP).
     • Generally at least 3 pilot batches.
       Even though TRS 953 Annex 2 says for existing API known to be stable data
       from at least 2 batches should be provided
     • API - Pilot batches must be of the same synthesis
       route, and method of manufacture and procedure
       that simulate the final process for production

13       PQ Assessors training, Jan 2011
                                 FPP Stability
                             Selection of Batches
     • Each strength and container type/size should be studied
       unless bracketing/matrixing is applied.
     • FPP batches should use different lots of API where possible;
     • NLT 2 batches of at least pilot scale
     • For uncomplicated FPP (e.g. immediate-release solid FPPs
       (some exceptions), non-sterile solutions), NLT 1 batch at least
       pilot scale and a second batch which may be smaller (e.g.
       solid oral dosage forms, 25 000 or 50 000 tablets/capsules)
     • Batches should be as proposed wrt:
        – Formulation
        – Container/closure system
        – Manufacturing process simulating production process

14       PQ Assessors training, Jan 2011
                 Container Closure System

     • Should be the same or simulate the container
       proposed for storage/distribution unless justification
       provided (i.e. container used in studies is less than or
       equally protective compared to proposed container)
     • a functionally similar container may be used to mimic
       the cardboard or plastic drum that is usually used to
       store raw material

15       PQ Assessors training, Jan 2011
     Importance of Analytical Methods in
       Development Stability Studies
     • Without analytical methods it is not possible to know
       what has happened during stability
        –   Assay
        –   Impurities/Degradation Products
        –   Dissolution
        –   Chiral Purity
        –   Preservative Content

16      PQ Assessors training, Jan 2011
     Methods Must be Stability-Indicating

     • Analytical methods must effectively separate and permit
       quantification of degradants (including use of purity tests)
     • Any significant changes in drug substance or drug product
       quality over time must be detectable
        – Increase in degradants
        – Change in dissolution behavior
        – Change in stereochemistry
             • cis to trans or vice-versa
             • optical isomers interconverting

17       PQ Assessors training, Jan 2011
                         Method Validation
     • Types of Analytical Procedures to be Validated
       – Identification tests;
       – Quantitative tests for impurities' content;
       – Limit tests for the control of impurities;
       – Quantitative tests of the active moiety in samples
         of drug substance or drug product or other
         selected component(s) in the drug product.
            • Drug product assay
            • This will also include quantifying dissolution results

18      PQ Assessors training, Jan 2011
                   API Stability: Specifications
       Specifications: test attributes susceptible to change.
     • Testing should cover physical, chemical, biological and
       microbiological attributes e.g. appearance, assay, degradation
       plus others susceptible to change.
     • For impurities, a specification for individual and total
       impurities must be set. Numerical data for individual (known
       and unknown) and total impurities to be reported instead of
       conforms or complies.
     • NB: The upper and lower acceptance criteria limits for
       innovator products are based on the potency and/or impurity
       levels of the clinical lots and safety and efficacy
       considerations. There is no justification, normally, for generic
       source to request for less stringent specifications.

19       PQ Assessors training, Jan 2011
                 Other parameters to be
     • Commonly where the API is low solubility and
       micronized, and the FPP is low dose - PSD is critical
     • Due to the potential for settling of material on
       storage, stability results for PSD should be provided to
       address this issue.
     • Moisture is particularly important for solid orals in
       blisters and strips.
     • Efficacy of additives and assay of preservatives
     • Container/closure interactions, when applicable

20      PQ Assessors training, Jan 2011
                            Testing Frequency

     Long term:
        Year 1: every 3 months
        Year 2: every 6 months
        Subsequent years: annually
        Minimum three points including t0 and tfinal, e.g. 0, 3, 6.
        Four points including t0 and tfinal, e.g. 0, 6, 9, 12.

21       PQ Assessors training, Jan 2011
       Minimum Data Requirements at time of
            submission – API and FPP
           Storage Temp (◦C)                       RH (%)           Min. Time period
     Accelerated 40±2                       75±5                6
     Intermediate *                         *                   *
     Long-term 30±2                         65±5 or 75±5 (API   6
                                            75±5 (FPP)
     *Where long-term conditions are 30ºC±2ºC/65%±5%RH or
     30ºC±2ºC/75%±5%RH, there is no intermediate condition.
     For API when a valid CEP is provided or APIMF is referred to: no data is required
     if the proposed retest is as per retest on CEP/APIMF; if retest period longer than
     the CEP is proposed, submit data meeting above requirements

22        PQ Assessors training, Jan 2011
                       Storage Conditions
     • Conditions should test the API/Product's thermal
       stability and, if applicable, moisture sensitivity
     • For PQ submissions long-term studies should be
       conducted at 30°C ± 2 °C/75 % RH ± 5% to
       account for all climatic zones, including IVa/b
       countries. (strict requirement as of September 2011)
     • There is therefore no Intermediate Condition
     • use of alternative long-term conditions to be justified
       and should be supported with appropriate evidence
       e.g. products unstable under these conditions

23      PQ Assessors training, Jan 2011
                        Accelerated Stability
     • Stability study run under more stressful conditions than expected for long
       term storage to account for excursions outside the label storage conditions
       e.g. during shipping or handling
     • Acc Storage condition should be guided by intended climatic condition in
       which API/FPP will be stored
     • Different from stress studies in that the goal is to get a quick understanding
       of what may be expected from a long term study
     Long-term conditions                    Accelerated Conditions

     Room temperature (25-30°C)              40°C ± 2°C/75% RH ± 5%

     Refrigerated (5°  3°C)                 25°C ± 2°C/60% RH ± 5% RH          or
                                             30°C ± 2°C/65% RH ± 5%

     Freezer (-20°C 5°C)                    Can range from 5°C ± 3°C or 25°C ± 2°C or 30°C
                                             ± 2°C

24         PQ Assessors training, Jan 2011
                                    FPP Stability
                                   In-use studies
     • In-use studies are for FPP intended to be diluted or
       reconstituted. (multi-use FPP)
     • Two different batches (at least pilot), one near the end of its
       shelf-life should be used.
       NB: there is no in-use requirement (e.g. labelling “use within
       30 days”) for dispersible tablets; a single dose is intended to
       be dispersed just prior to use.

25       PQ Assessors training, Jan 2011
                        “Significant Change”
     For API - defined as failure to meet its specification
     For an FPP, significant change under accelerated and
       intermediate testing conditions is any of:
     • More than 5% change in assay from initial;
     • Degradant exceeding acceptance limit
     • Failure to meet acceptance criteria for appearance, physical
       attributes and functionality (e.g. colour, phase separation)
     • For tablets e.g. Failure to pass S2/L2 dissolution testing, i.e.
       n=12 (i.e. after failing S1/L1 as well)
     • For FPP’s in semi-permeable containers, a 5% loss of water
       from initial (3 months at 40◦C/25%)

26       PQ Assessors training, Jan 2011
                   ICH Q1E Extrapolation
     • Can extend expiration dating or retest date beyond
       available long-term stability data if
        – Sufficient long-term data is available to assess any trends
        – No significant change is observed within 6 months under
          accelerated conditions
        – Little or no variability
     • This process is spelled out in Q1E decision trees
     • Shelf-lives/retest dates established based on extrapolation
       must be confirmed by long-term data when available

27       PQ Assessors training, Jan 2011
                  Use of Statistics – Q1E
     • to establish, with a high degree of confidence, whether a retest
       period or shelf life during which a quantitative attribute will
       remain within acceptance criteria for all future batches
       manufactured, packaged, and stored under similar
     • Not necessary if data show so little degradation and so little
       variability that it is apparent from looking at the data that the
       requested shelf-life will be granted
     • Regression analysis is considered appropriate
     • Examples of statistical approaches included in Appendix B

28       PQ Assessors training, Jan 2011
              Ongoing Stability Studies
     • Purpose: to monitor and determine that API/FPP remains
       within specifications under the storage conditions, within the
       re-test period/shelf life in all future batches
     • The programme should be described in a written protocol
     • The programme should include at least one production batch
       per year, tested at least annually.
     • An ongoing study should be conducted after any significant
       change to the synthetic route/manufacturing process or
       container which may impact stability.

29       PQ Assessors training, Jan 2011
                         Stability Commitment
     • This is required when data did not cover the proposed re-test/shelf life
       (Primary Stability Study Commitment) and/or the primary stability batches
       studied did not consist of three production scale batches (Commitment
       Stability Studies)
     • The applicant must commit to conducting long-term stability trials on the
       next production scale batches that are manufactured. The number of
       batches required depends on the number of production scale batches
       provided in the primary studies (to make at least 3 production batches)

     For all post-approval commitments:
     • A signed and dated commitment is required.
     • An authorised, dated and detailed protocol should be provided, including
        storage conditions, testing frequency, specifications, test methods…

30        PQ Assessors training, Jan 2011
     • Outlines recommendations, principles, and
       considerations for reduced designs.
     • Rarely submitted in PQP dossiers

       – Bracketing: testing samples on the extremes of certain design
         factors (e.g., strengths, container sizes and/or fills)
       – Matrixing: testing a selected subset of the total number of
         possible samples for all factor combinations at a specified time
         point, while testing another subset of samples at a
         subsequent time point

31      PQ Assessors training, Jan 2011
     • Bracketing - Strengths:
       – Applicable: strengths of identical or closely related formulations
       – Applicable with additional justification (e.g., supporting data): strengths
         where the relative amounts of the drug substance and excipients vary
         within the product line
       – Not applicable: different excipients among strengths
     • Bracketing – Container Size, Fill:
       – Applicable: same container closure system where either the container
         size or fill varies while the other remains constant
       – Applicable with additional justification (e.g., supporting data): same
         container closure system but both the container size and fill vary
       – Not applicable: different container closure systems

32      PQ Assessors training, Jan 2011
     Bracketing - Considerations:

       • If stability of extremes are shown to be different, the
         intermediates should be considered no more stable than the
         least stable extreme
       • Selected extreme may be dropped from proposed market

33     PQ Assessors training, Jan 2011
     • Matrixing:
       – applicable:
          • strengths with identical or closely related formulations
          • container sizes or fills of the same C/C system
          • different batches made with the same equipment and process
       – applicable with additional justification:
          • where the relative amounts of excipients change or different
            excipients are used
       – not applicable:
          • different storage conditions
          • different test attributes

34      PQ Assessors training, Jan 2011
                   Common Deficiencies
     During assessment problem areas that warrant a closer
       look/more questions include:
     • Data is provided in such a way that trends cannot be
       determined, e.g. range of dissolution values but no
       average, or limits cannot be assessed, OR average
       dissolution but no range of individual values.
     • Data shows a lack of mass balance, or variability in
       results without trends - may indicate problems with
       analytical methods.

35      PQ Assessors training, Jan 2011
                    Common Deficiencies
     • Expression of results as passes test or similar when a
       quantitative figure would be available.
     • Failure to include quantitative or semiquantitative
       determinations of the content of degradation products, or to
       provide only total content rather than values for individual
     • Use of an HPLC assay procedure to detect impurities without
       validation for the purpose. HPLC assay procedures as used for
       determination of the API are often unsuitable for separation
       and detection of impurities as they use too short a run time.
       Such a procedure would be acceptable if validated for
       impurity detection. Note, however, that long run times do not
       in themselves ensure good separation.

36       PQ Assessors training, Jan 2011
                              Reference Documents
Recommended documents that should be consulted for Stability requirements:

      – Guideline on submission of documentation for multisource (generic) finished
        pharmaceutical product (FPP): Quality Part (In PQP supersedes any other
        guidance if there is conflict)
      – The WHO stability guideline Stability testing of active pharmaceutical
        ingredients and finished pharmaceutical products (WHO Technical Report
        Series, No. 953, Annex 2, 2009)
      – Health Canada (
      – FDA (
        •   Stability Testing of Drug Substances and Drug Products (draft, 1998)
        •   Drug Substance - CMC Information (draft, 2004)
        •   Drug Product - CMC Information (draft, 2003)
        •   SUPAC series (IR, MR, SS) (and Q&A Document)
        •   Changes to an Approved NDA/ANDA (04/2004) (and Q&A Document)

 37         PQ Assessors training, Jan 2011
     • EU EMEA (
         Manufacture of the Finished        Stability Testing Annex - In-Use
        Dosage Form Annex - Start of        Stability Testing of Human
        Shelf -Life of the Finished         Medicinal Products (02/2001)
        Dosage Form (05/2001)                Stability Testing for a Type II
         Maximum Shelf-Life for Sterile    Variation to a Marketing
        Products after First Opening or     Authorisation (04/1998)
        Following Reconstitution            Stability Testing for Applications
        (01/1998)                           for Variations to a Marketing
        Stability Testing Annex -          Authorisation (draft 04/2004)
        Declaration of Storage
        Conditions for Medicinal Products
        Particulars and Active
        Substances (04/2003)

38      PQ Assessors training, Jan 2011

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