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					                Pharmaceutical Development

         Training Workshop on
   Pharmaceutical Development with
    focus on Paediatric Formulations
                                     Protea Hotel
                             Victoria Junction, Waterfront
                              Cape Town, South Africa
                               Date: 16 to 20 April 2007

Slide 1 Walters April 2007
                Pharmaceutical Development

                Stability testing of Finished
               Pharmaceutical Products (FPPs)
     Presenter:              Susan Walters
     Fax:                    (61) 2 6281 6948 (email is preferred)

Slide 2 Walters April 2007
                             Stability testing of FPPs
                                 Outline of presentation

     We will:
      Review relevant guidelines

      Define the objectives of stability testing

      Outline the design & conduct of stability studies for finished

      Determine a shelf life based on study results

      Discuss what to include in reports of stability studies

Slide 3 Walters April 2007
                      Objectives of stability testing:
                             What is the purpose?

 "…… to provide evidence on how the quality of a drug
  substance or drug product varies with time under the
  influence of a variety of environmental factors such as
  temperature, humidity & light, & enables recommended
  storage conditions, re-test periods & shelf lives to be

                                                     (ICH) 2003

Slide 4 Walters April 2007
Variables that might affect the stability of a given
               API & dosage form

        Formulation

        Packaging

        Site and method of manufacture
               – API
               – Finished product

        Batch size

        Batch to batch variability
               – The importance of process validation & quality risk management

        Container labelling

        Changes to product

Slide 5 Walters April 2007
                                 Stability testing

         - Development studies
                - Characterise compatibility with common excipients
                - Characterise stability profile of API
                   - Eg susceptibility to acid, base, light, oxygen etc……
                - Characterise stability profile of early formulations
                   - Especially susceptibility to heat, humidity & light

         - Confirmatory studies
                -    Long term & accelerated studies on the product as it is to be registered
                -    In practice design is now largely dictated by ICH guidelines

Slide 6 Walters April 2007
What does a regulator want to see demonstrated in the
                registration dataset?

     - The product maintains relevant quality
       characteristics within the acceptable range:
             - In proposed registration formulation & container/closure system
             - For whole of shelf life
             - At permitted extremes of storage
             - Over all batches
             - When manufactured at all registered sites (API & finished
             - After any changes

Slide 7 Walters April 2007
                             Relevant guidelines
      Many countries have their own guidelines concerning stability testing & other
       registration topics
      But if a manufacturer wishes to market a product in several countries, it is
       simpler to use one of the international guidelines, such as those of WHO &
     So how widely are WHO & ICH guidelines accepted?
      Most countries will accept data generated according to ICH guidelines
      Many countries will accept data generated according to WHO guidelines, &
       especially when the product in question has been prequalified by WHO
              – But possibly not ICH countries

      Whilst ICH guidelines are more detailed than those of WHO, there are few
       ‗in-principle‘ differences, except in relation to testing conditions for hot &
       humid climates

Slide 8 Walters April 2007
                    ICH stability guidelines - 1

   Q1A(R2) Stability Testing of New Drug Substances
    & Products

   Q1B Stability Testing : Photostability Testing of
    New Drug Substances & Products

   Q1C Stability Testing for New Dosage Forms

  Available via

Slide 9 Walters April 2007
                    ICH stability guidelines - 2

      Q1D Bracketing and Matrixing Designs for Stability
       Testing of New Drug Substances and Products

      Q1E Evaluation of Stability Data

      Q1F Stability Data Package for Registration
       Applications in Climatic Zones III and IV Withdrawn

     Also available via

Slide 10 Walters April 2007
                ICH stability guidelines - 3

       Remember that these have been adopted in the
        European Union, the United States, and Japan
       Technically ICH guidelines apply only to new
        APIs & products made from them. But most
        regulators give ICH guidelines considerable
        weight when deciding requirements for non-new

Slide 11 Walters April 2007
                  WHO stability guidelines - 1
      “Guidelines for stability testing of pharmaceutical
       products containing well established drug
       substances in conventional dosage forms”
                                                             WHO (1996)
              Available via
              – Applies to ‗Well established drug substances‘
              – Applies to ‗Conventional dosage forms‘
              – These guidelines are under revision : See

Slide 12 Walters April 2007
                     WHO stability guidelines - 2

      So what are the types of product to which WHO
       guidelines (1996) do not apply?
        – New chemical entities (NCEs)
                    • And possibly also new dosage forms of NCEs
              – New combinations of actives
              – Modified release dosage forms, including
                    • Slow release products
                    • Transdermal patches
                    • Modified release injections

Slide 13 Walters April 2007
 Stability guidelines for WHO‘s Prequalification
                Program (PQP) - 1

   Stability testing: Section 3.11 of Guideline on
    Submission of Documentation for Prequalification of
    Multisource (Generic) Finished Pharmaceutical Products
    (FPPs) Used in the Treatment of HIV/AIDS, Malaria &
          – Available via
          – Are consistent with ICH guidelines
          – There are extensive cross references to ICH guidelines
          – Effectively the PQP text is a practical interpretation of ICH guidelines

Slide 14 Walters April 2007
Stability guidelines for WHO‘s PQP - 2

      “Extension of the WHO list of stable (not easily
        degradable ARV) APIs”
                                                      WHO (2006)
              – Also available via
              – Read this carefully. It describes circumstances in
                which a tentative 2-year shelf life may be allocated
                to certain APIs & FPPs, subject to a number of
                strict conditions.

Slide 15 Walters April 2007
Stability report formats for WHO‘s PQP

      Annex 3: Model stability report of API
      Annex 4: Model stability report of
      Also available via

Slide 16 Walters April 2007
                                 Terminology –
                              adapted from ICH 2000 (1)

    - Production batch:
            - A batch manufactured at production scale using production
              equipment & in a production facility as specified in the
              registration application

    - Pilot scale batch:
            - A batch manufactured by a procedure ―fully representative
              of & simulating‖ full production scale. For tablets & capsules,
              this means 100,000 units or 1/10th of production scale,
              whichever is the larger

Slide 17 Walters April 2007
                                 Terminology –
                              adapted from ICH 2000 (2)

Re-test period: API
       – The period of time for which the API remains within
         specification when stored under the recommended conditions
         in the proposed bulk storage container
       – ―After this period, the batch should be retested for compliance
         with specifications & then used immediately‖ [if in compliance]

Slide 18 Walters April 2007
                                 Terminology –
                              adapted from ICH 2000 (3)

    - Accelerated testing
            -   Studies designed to increase the rate of chemical degradation or physical
                change by means of exaggerated storage conditions

    - Intermediate testing
            -   Studies at 30degC/60%RH, intended for extrapolation to long term storage at
                25degC [provided that 25degC is appropriate for the market in question]

    - Stress testing
            -   API: Studies which elucidate intrinsic stab of API. Normally during development.
                Normally more stressful than ‗accelerated‘ testing.
            -   Finished product: Studies of effect of ‗severe‘ conditions. Eg freeze/thaw cycling
                for suspensions & emulsions, low humidity for aqueous liquids in moisture-
                permeable containers.

Slide 19 Walters April 2007
                                   Terminology –
                              adapted from ICH 2000 (4)

           In-use stability testing:
                  – Establishes the ―period of time during which a multidose
                    product can be used whilst retaining quality within an
                    accepted specification once the container is opened‖
                                                                                ICH 2000
                     • For example:
                         – liquids that are reconstituted prior to use
                         – effervescent tablets in a moisture-proof container (eg Al screw-
                           cap tube)
                         – ophthalmic products (especially with respect to preservative

Slide 20 Walters April 2007
                                 Terminology –
                              adapted from ICH 2000 (5)

            Climatic zones:
                   – Partition of the world into three temperature classes based
                     on kinetic averaging of monthly temperatures, &
                     subdivision of the hottest class into predominantly wet or
                     predominantly dry
                   – Zones (Futscher & Schumacher 1972):
                      • I      Temperate (21oC/45%RH)
                      • II     Subtropical (25oC/60%RH with possibly high RH)
                      • III Hot & dry (30oC/35%RH)
                      • IV Hot & wet (30oC/70%RH)
                   – The temperatures above are kinetic averages

Slide 21 Walters April 2007
          Extract of WHO Technical Report Series 937
Expert committee on specifications for pharmaceutical preparations
       (2006): Quality assurance: Stability testing conditions

          ―The Secretariat reminded the Committee that the WHO guidelines had
             been revised in the light of harmonization efforts in collaboration with
             ICH. Subsequently focus had been placed within regional
             harmonization initiatives on the recommendations for hot and humid
             conditions (referred to as Zone IV). After extensive discussion the
             Committee reached consensus that the WHO stability guidelines be
             amended to reflect conditions for Zone IV as follows:
               — Zone IVa (30 degrees Celsius and 65% relative humidity); and
               — Zone IVb (30 degrees Celsius and 75% relative humidity).
               It was agreed that each individual Member State within the former
               Zone IV would need to indicate whether its territory should be
               classified as Zone IVa or IVb.‖

   Slide 22 Walters April 2007

       Each nation within zone IV must now
        decide whether to adopt a stability test
        condition of
               – 30oC & 65%RH, or
               – 30oC & 75%RH
       ASEAN nations & Brazil have adopted 30oC
        & 75%RH

Slide 23 Walters April 2007
                                Terminology –
                              adapted from ICH 2000 (6)

     Reduced study designs:
             - Bracketing
                    - A design in which only the extremes are tested
                      at all time points, eg strength, pack size,
                      container fill
             - Matrixing
                    - Designs in which a selected subset of samples
                      is tested, eg different strengths,
                      container/closure systems, batches

Slide 24 Walters April 2007
            Example of a bracketing design

 Strength                         50mg           75mg            100mg
 Batch                        1     2    3   1     2     3   1     2     3
 Container 15ml               T     T    T                   T     T     T
 size      100ml
           500ml              T    T     T                   T    T      T

                                  T = Sample is tested

Slide 25 Walters April 2007
              Example of a matrixing design
                  “One half reduction”
      Time point (months)     0    3   6    9   12   18   24   36
                              T    T        T    T        T    T
              S1              T    T        T    T   T         T
                              T        T         T   T         T
                              T        T         T        T    T
              S2              T    T        T    T   T         T
                              T        T         T        T    T

                              T = Sample is tested

Slide 26 Walters April 2007
 When might bracketing & matrixing be appropriate?
(NB The following is not from ICH ! You must argue the case!)

         - Container size?

         - Batch size?

         - Formulation of coating?

         - With varying amounts of an excipient (eg starch, Mg

  Slide 27 Walters April 2007
The risk associated with bracketing & matrixing

       - If the results are not what you expected, you
         may have insufficient to propose an
         intermediate shelf life

       - Would be risky to use bracketing & matrixing if
         you did not have a good idea as to what the
         product‘s stability will be

       - Consequently: Bracketing & matrixing designs
         are used mainly for confirmatory studies

 Slide 28 Walters April 2007
           ICH minimum dataset at submission - 1
         General case
                                                          Minimum time period covered
               Study              Storage condition
                                                             by data at submission
                              25oC ±2oC/60%RH ±5%RH or
         Long term                                                  12 months
                              30oC ±2oC/65%RH ±5%RH
         Intermediate         30oC ±2oC/65%RH ±5%RH                  6 months
         Accelerated          40oC ±2oC/75%RH ±5%RH                  6 months

         ICH: “It is up to the applicant to decide whether long term stability studies are
              performed at 25oC ±2oC/60%RH ±5%RH or 30oC ±2oC/65%RH

         PQP: “Unless otherwise justified, 30oC ±2oC/65%RH ±5%RH is the real-time
              condition for the prequalification project.”
              And: The minimum time period for intermediate storage is 12 months.

Slide 29 Walters April 2007
           ICH minimum dataset at submission - 2

    FPPs packaged in impermeable containers need not be
     stored under controlled humidity conditions

    There are different minimum conditions for:
           – Liquid products packaged in semi-permeable containers
             [relating to potential loss of solvent]
           – Products intended for storage in a refrigerator, freezer or deep-

Slide 30 Walters April 2007
                      Classes of degradation

                 - Chemical
                 - Physical
                 - Microbiological

Slide 31 Walters April 2007
                        Chemical degradation

                Has been dealt with by Dr Elder

Slide 32 Walters April 2007
                              Physical degradation
                     (≡ physicochemical degradation)

  - Physical properties can change too!
  - Important attributes vary with dosage form
          - Bottom line is relevance to quality, safety & efficacy

  - Examples for liquid formulations:
          -   Appearance, colour, odour, pH, clarity (solutions) and freedom from visible particulate
              contamination, size range of particulate contamination (large volume parenterals),
              particle size distribution (suspensions), micelle size distribution (micellar solutions),
              resuspendability (suspensions), viscosity, moisture content (powders for
              reconstitution), phase separation (emulsions)

  - See other examples at

Slide 33 Walters April 2007
Other forms of physical deterioration may include:

        -   Leaching
        -   Absorption (into container walls)
        -   Adsorption (on to container walls)
        -   Volatilisation (eg sertraline base, glyceryl trinitrate)
        -   Altered particle size distribution
        -   Loss of higher order molecular structure (normally
            only for biological medicines)
             - Denaturation
             - Aggregation

 Slide 34 Walters April 2007
                Minimising physical deterioration

      - Some examples:
              - When prone to adsorption on to, or absorption into,
                packaging materials, use resistant packaging
                materials, such as good quality glass
              - When prone to volatilisation:
                     - Use a non-volatile salt (if possible)
                     - Use packaging materials that are resistant to vapour transfer
              - When prone to altered particle size in suspensions:
                     - Formulate a continuous phase in which the active is less soluble

Slide 35 Walters April 2007
                      Microbiological deterioration

           Proliferation of microbes in non-sterile products

           Consequences may include:
                  –   Infection of the patient
                  –   Formation of endotoxins (≡ pyrogens)
                  –   Foul odour
                  -   Formation of gas
                  -   Change in colour
                  -   Cloudiness
                  -   Hydrolysis

Slide 36 Walters April 2007
  Minimising microbiological deterioration of non-
                 sterile products

    - Control the microbial load of API &
    - Validate & monitor manufacturing
    - Include antimicrobial preservatives in
            - NB Normally only bacteriostatic & not bactericidal

Slide 37 Walters April 2007
Appropriate tests for stability studies - 1

 - Normally test same attributes as for routine

 - May use other methodology for stability testing
   (avoid for dissolution rate) but must be

 - Avoid changing methodology mid-study
   (unless correcting a clear deficiency)

Slide 38 Walters April 2007
Appropriate tests for stability studies - 2

     - Quantitate degradation products if possible, even if
       the assay is specific for the API
             - But can be difficult to quantitate impurities if there are no
               reference standards & relative response factors are
               unknown → semiquantitative estimates
             - Regulatory authorities usually expect an approximate
               mass balance

     - Appropriate physical tests vary with dosage form.
     - Remember to conduct preservative efficacy tests too,
       in addition to assay of any antimicrobial preservative

Slide 39 Walters April 2007
                       For all stability studies

     Validate the analytical methodology!
            – See relevant guidelines, especially:
                   • Validation of analytical procedures: Terminology
                         – ICH Q2B 1994
                   • Validation of analytical procedures: Methodology
                         – ICH Q2B 1996

     Use stability-indicating assays

Slide 40 Walters April 2007
                              Dissolution rate

- Avoid using a method different to that in routine

- Most regulatory authorities, including PQP, prefer
  dissolution profiles rather than single time points
  during stability testing. Better ability to detect

Slide 41 Walters April 2007
Frequency of testing during a stability study - ICH

      ―For long term studies, frequency of testing should be
       sufficient to establish the stability profile of the pharmaceutical

      ―For products with a proposed shelf life of at least 12 months,
       the frequency of testing in the long term storage condition
       should normally be every 3 months over the first year, every 6
       months over the second year, & annually thereafter
       throughout the proposed shelf life.

      Other frequencies are suggested for accelerated &
       intermediate storage conditions.
                                                              ICH 2003

  Slide 42 Walters April 2007
         Some notes concerning reporting (1)

    - It is rarely appropriate to cite only average results
            -   For the benefit of the manufacturer & the DRA
            -   Dissolution results on individual tablets (not only mean results)
            -   It‘s certainly OK to cite mean & derived results as well

    - Assay results should be reported as absolute values
            -   And not only as values normalised for initial results, ie % of initial

    - Test methods must be recorded with the study report
            -   By the time that stability studies are conducted on finished product, is possible that
                more than one method has been used

Slide 43 Walters April 2007
         Some notes concerning reporting (2)

     - Numerical results should be provided wherever possible
             - Not just ‗complies‘

     - If results are below the limit of quantitation, they should
       be reported as ‗below LQC‘ or similar wording
             - ‗Not detectable‘ is acceptable provided it is defined & reasonable

     - Results that are out of the ordinary should be discussed

     - Product labelling should be consistent with stability data.
       For example:
             - Solvents for reconstitution
             - Recommendations for mixing of injections with other injections

Slide 44 Walters April 2007
     Evaluation / Interpretation of the results

                        So what‘s the shelf life?

Slide 45 Walters April 2007
                              First point

   The validity of an assigned shelf life
    depends upon:
           - The results of stability studies, &
           - Whether the batches used in the stability
             studies accurately model those to be
             marketed, &
           - Whether analytical methodology was
             adequately validated

Slide 46 Walters April 2007
                              Assigning a shelf life

         Assigning a shelf life is easier if results are available:
                -   For the full duration of the proposed shelf life
                -   At the maximum recommended storage conditions
                -   For all formulations & manufacturing methods
                -   In exactly the packaging to be registered
                -   At all sites of manufacture of finished product & API

         If these conditions are not met, that‘s when shelf life
          assignment becomes difficult.
                – There will be arguments between manufacturers &
                  registration/prequalification authorities
                – There will be delays in approving the product

Slide 47 Walters April 2007
             Statistical estimation of shelf life - 1

        ―Where the data show so little degradation & so little variability
         that it is apparent from looking at the data that the requested
         shelf life will be granted, it is normally unnecessary to go
         through the formal statistical analysis but only to provide a
         justification for the omission‖
                                                          ICH 2003 & PQP 2005

         In other words: If it is blindingly obvious that there is minimal
         change in the parameter in question, is unnecessary to
         conduct the numerical/statistical analysis.

Slide 48 Walters April 2007
             Statistical estimation of shelf life - 2

        ―An approach for analyzing data of a quantitative
         attribute that is expected to change with time is to
         determine the time at which the 95% one-sided
         confidence interval for the mean curve intersects the
         acceptance criterion‖
                                                       ICH 2000

Slide 49 Walters April 2007
             Statistical estimation of shelf life - 3

            Is there any degradation of any relevant product
            • If no, then shelf life assignment is straightforward based on the labelled
              storage conditions & the time for which testing has been conducted
            • If yes (that is there is at least some degradation/change):
                 • Conduct a statistical analysis using a suitable software package
                 • Consider:
                       Statistical pooling of results for multiple batches
                       Estimation of time to degrade to expiry limits using a 95% confidence interval
                 • See the file concerning software packages
                      – NB I am not recommending any of these software packages!
                      – Conduct your own Internet search! Then evaluate cost against usefulness to
                        your company.

Slide 50 Walters April 2007
          Statistical estimation of shelf life - 4

                  Superimposition of a 95% confidence interval on to the
                      regression line for stability data from Bolton 1984
                        NB This is an old graph & it describes a very unstable product

Slide 51 Walters April 2007
   What are the limitations of this statistical

     - It applies only to quantitative attributes
             - Does not apply for example to colour tests, or to semiquantitative
               comparisons such as TLC limit tests

     - It may be unreliable for physical attributes
             - Such as dissolution tests & discoloration

     - Use your judgement! Look at the slope of the curve.
       Does the change accelerate with time?

Slide 52 Walters April 2007
                              Estimation of shelf life

      ―Any evaluation should consider not only the assay
       but also the degradation products & other appropriate

                                                                ICH 2003

          In other words: If evaluation of different (but relevant) attributes
             leads to different conclusions as to shelf life, the shortest of
             these shelf lives should be chosen.

Slide 53 Walters April 2007
                              Estimation of shelf life

      ―Where appropriate, attention should be paid to
       reviewing the adequacy of the mass balance &
       different stability & degradation performance‖
                                                                         ICH 2003

               – In other words: If the loss of active is not of the same order
                 (=approximately the same) as formation of degradation products, more
                 investigation is needed.
               – Note however that mass balance will always be approximate; it is
                 rarely exact.

Slide 54 Walters April 2007
Factors to be taken into account when assigning a
    shelf life based on statistical analysis - 1

     - Release limits

     - Expiry limits

     - Results of stability studies

     - Is there any desired safety margin?
             - This is largely a matter for the manufacturer/supplier

Slide 55 Walters April 2007
Factors to be taken into account when assigning a
    shelf life based on statistical analysis - 2

           A batch may be released with a result anywhere
            in range of release limits

           Consequently a prudent manufacturer will take
            into account the lower limit of release when
            estimating shelf life

Slide 56 Walters April 2007
     Combining results for several


Slide 57 Walters April 2007
                  Poolability of multiple batches

      A statistical concept that allows the results for several
       batches to be combined
      If we estimated stability based on results for individual
       batches, we would have to select the shortest estimate
       of shelf life
      Pooling usually leads to a longer shelf life as compared
       with the results for one batch only
      But we must first test whether the batches can
       legitimately be pooled
              Are the batches statistically homogenous?

Slide 58 Walters April 2007
       Testing for poolability as described by Bolton 1997

                                                   Perform statistical
                                                 test for common slope

                                 Significantly                 Not significantly
                                   different                      different

                    Use separate slope                   Perform statistical test
                   & intercept for each                   for common intercept

                                            Significantly                 Not significantly
                                              different                      different

                         Use common slope but                                 Use common slope &
                          separate intercepts                                  common intercept

                Significance is on the basis of F tests (p>0.25) as modelled by Bolton 1997

Slide 59 Walters April 2007
                   Extrapolation beyond real-time data - 1

      ―Limited extrapolation of the real time data from the long
       term storage condition beyond the observed range to
       extend the shelf life can be undertaken at approval time, if
       justified. This justification should be based on what is
       known about the mechanisms of degradation, the results of
       testing under accelerated conditions, the goodness of fit of
       any mathematical model, batch size, existence of
       supporting stability data, etc. However, this extrapolation
       assumes that the same degradation relationship will
       continue to apply beyond the observed data.‖

                                                        ICH 2000

Slide 60 Walters April 2007
                   Extrapolation beyond real-time data - 2

      ―If long term data are supported by results from
       accelerated studies the retest period/shelf life
       may be extended beyond the end of the long-
       term studies. The proposed retest period or
       shelf life can be up to twice, but should not be
       more than 12 months beyond, the period
       covered by long-term data‖. ‖
                                                   PQP 2005

Slide 61 Walters April 2007

          References in your CD may be useful:

          - Regulatory guidelines

          - Sources of climate-controlled cabinets

          - Software for processing stability data
                  - Most include laboratory information management for the

Slide 62 Walters April 2007
                Pharmaceutical Development
                              Summary and conclusion

      Stability data submitted during the registration process
       should confirm that all batches of the FPP will remain
       of acceptable quality when stored in the marketing
       container, at the most extreme storage conditions
       permitted by container labelling & prescribing
       information, for the duration of the shelf life
      Any subsequent variations (for example to site or
       method of manufacture of the API or FPP) should be
       shown not to reduce the shelf life as defined above

Slide 63 Walters April 2007

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