1-6_Stability-APIs

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					               API Stability Testing
        WHO PQ Requirements
                                Presented by
                               Rutendo Kuwana




Accra, Ghana   December 2009
                                                Overview

Scope of presentation – Generic/Multisource preparations

 API - Stress Testing

 Selection of Batches

 Container Closure System

 Specifications: Stability indicating quality parameters

 Testing Frequency

 Storage Conditions
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                                                Overview

 Evaluation/Extrapolation of data

 Statements/Labelling

 Ongoing Stability Studies




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                                Stability Assessment
                                     References
 Main Generics Guideline
 Supplement 2 to Main Generics Guideline
 TRS 863 Annex 5, current stability guideline
 TRS 937 (amendment of above)
 TRS 908 (modification of storage conditions)
 TRS 929 Annex 5 and Appendix 3
 TRS 948
 ICH Q1A, B, C, D and E
 TRS 943 Variation Guide Appendix 4 (Stability Requirements for Variations)
 EMR Regional Guideline based on QAS/06.179
 QAS/06.179/Rev.3
 Manual for Drug Regulatory Authorities (Annex 11) Etc…
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                                 Stability Assessment
                                      References

     Practical Approach:

 Main Generics Guideline (2005) and Supplement 2 (2006)
  [Referred to as “Main Guide” and S2 in this talk]

 ICH Q1A (2003)

 New WHO Stability Guide in TRS953 (2009): Annex 2:
  “Stability Testing of API’s and FPP’s”




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                                  Stability - purpose

 To establish a re-test period* for the API or a shelf-life for
  the FPP.

 To establish storage conditions.

     *In exceptional cases, eg for unstable API’s, a shelf-life is
     given.




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                                              API
                                         Stress Studies
 Stress testing is an important part of developmental
  studies. Used to:

        - establish degradation pathways and intrinsic stability,

        - validate stability-indicating power of methods

 In considering drug stability, attention must be paid to
  processes which may lead to instability of the product.




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                                            API
                                       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
  performed.




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                                 API Stress Testing

 New Guide: should include the effect of:

     - temperature, in 10◦ increments above accelerated (ie
     50◦C, 60◦C …)

     - humidity (75% or greater)

     - oxidation and photolysis, where appropriate

     - susceptibility of the API to hydrolysis across a justified
     range of pH values when in solution or suspension (as per
     Q1A).

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                                              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 the PhInt, USP or EP states in the monograph for the
       API or FPP, "Protect from light", there is no need to
       request photostability data or testing.




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                                           API stability
                                          Stress testing
 Main Generic guideline 2.7.1 suggested conditions




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  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)


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                                            Stress studies:
                                               Approach

       The impurities/degradants that must be closely investigated are those appearing
       at greater than (or approaching) the identification threshold, (the limit on
       individual unknowns) when stored at long-term and accelerated conditions.

       A mass balance assessment may be necessary and should 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 any of these impurities are shown
       to increase during storage, or if new impurities are developed, they should be
       considered as “degradants” or “degradation products”, and analytical methods
       must be developed to monitor them.




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                                Selection of Batches

        Definition of Primary Batches : Batches used in stability
       studies to establish retest (API) or shelf-life (FPP). [ICH
       Q1A and New Guide]

 3 pilot batches* : For stable API, 2 pilot batches.

       *For API - Pilot batches must be of the same synthesis
       route, and method of manufacture and procedure that
       simulate the final process for production batches.




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                          Container Closure System

 Should be the same or simulate the container proposed for
  storage/distribution unless justification provided (ie 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.

 simulated small telescope drums are typically used for these types
  of studies. Ensure that thickness of the telescoped drum does not
  provide more or less protection than the warehouse drum




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                               API Stability Testing




                                     PART TWO


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                                             API Stability:
                                             Specifications
       Specifications: test attributes susceptible to change.

 Testing should cover physical, chemical, biological and
  microbiological attributes.
 Appendix 2 of the New Guide states 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.
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                                             Test Methods


 Only validated methods to be used and evidence of validation to be
  submitted or referenced to dossier

 Stability indicating methods must be developed to monitor the purity
  of the API as well as identification and quantitation of impurities

 Reference standards – information on sources and/or preparation
  and characterisation of in house primary and secondary working
  standards should be available

 Care required for methods used where no reference standard
  exists e.g. for related substances

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          Other parameters to be monitored

       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.




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                                         Polymorphism

 If there is evidence that polymorph stability may be an
  issue, polymorphic stability should be demonstrated as
  part of routine stability studies.

 For solid dosage forms, the solubility, efficacy, and
  stability of a drug may depend on the particular crystalline
  state of the drug. The polymorphic content may be
  characterized by techniques such as x-ray powder
  diffraction, Raman and infrared spectroscopy.



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                                      Testing Frequency

Long term:

       Year 1: every 3 months

       Year 2: every 6 months

       Subsequent years: annually

Accelerated:

       Minimum three points including t0 and tfinal, eg 0, 3, 6.

Intermediate:

       Four points including t0 and tfinal, eg 0, 6, 9, 12.

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                                  Storage Conditions

Requirements at time of submission:

Stable API: (Supplement 2)

       6 months at 40◦C/75%

       6 months at 30◦C/65%

Other API:

       6 months at 40◦C/75%

       12 months at 30◦C/65%

PQP is moving towards long term at 30◦C/75% being the preferred

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                                 API Stability
                             Appendix 1 to TRS953
 Long term stability testing conditions are determined by
  the climatic condition under which the API or FPP is
  intended to be stored.

       Zone I: temperate                                                               21◦C/45%RH

       Zone II: subtropical/mediterranean                                              25◦C/60%RH

       Zone III: hot/dry                                                               30◦C/35%RH

       Zone VIa: hot/humid                                                             30◦C/65%RH

       Zone VIb: hot/very humid                                                        30◦C/75%RH
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                              Storage Conditions II

 When long term data is conducted at 25◦C/60% and
  significant change is observed at accelerated conditions,
  data should be provided at intermediate conditions (eg
  30◦C/65%).

 Tolerances - The chamber temperature must be
  controlled within ±2◦C, and the humidity controlled within
  ±5% relative humidity.




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                             Storage Conditions III

 Where a valid CEP is provided: no data is required if the
  proposed retest is as per retest on CEP; if longer than the
  CEP retest is proposed, requirements as above.




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                                                  Stability
                                                 Evaluation

 Establish the retest period and storage conditions based
  on stability data. “The approved retest date should be
  displayed on the container label and CoA.” (Main Guide).
 If little variability, statistical analysis is not necessary.




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                                                Evaluation
 Extrapolation of data:

       Common scenario: Data (6 months Accelerated and "x"
       months LT) is within specifications with no significant
       change under accelerated conditions. The allowed re-
       test (API) or shelf life (FPP) is double the long-term
       period "x", but NMT "x" + 12 months.

       Stable API: 24 months re-test is allowed based on 6
       months accelerated + 6 months long term data.



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                                                 Evaluation

       In prequalification, extensions beyond 24 months are not
       accepted without real-time long term data on production
       batches.

       e.g. for a stable API, a re-test (API) or Shelf Life (FPP) of
       24 months may have been accepted based on 6months
       accelerated + 6months long-term, but to accept a longer
       re-test period, real-time data is required.




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                                                API Stability
                                                 Evaluation
       Definition: re-test period
       The period of time during which the API is expected to remain
       within its specification and, therefore, can be used in the
       manufacture of a given FPP, provided that the API has been
       stored under the defined conditions. After this period, a batch of
       API destined for use in the manufacture of an FPP should be re-
       tested for compliance with the specification and then used
       immediately. A batch of API can be re-tested multiple times and a
       different portion of the batch used after each re-test, as long as it
       continues to comply with the specification. For most substances
       known to be labile, it is more appropriate to establish a shelf life
       than a re-test period. The same may be true for certain antibiotics.




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                                        Stability
                                  Statements/Labeling

 Recommended labeling statements provided in Appendix 3 of the
  New Guide. Note that “store below” is no longer an option.
  Storage is stated as, “Do not store above…”

 Storage statement and re-test (API) or shelf life (FPP) should be
  based on evaluation, based on:

             -Extent of data provided (x LT + 6 mo Acc);

             -Change(s) observed;

             -Actual LT storage conditions;

             -Batches (all production?), etc.


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                       Ongoing Stability Studies

 Purpose: to monitor the API and determine that it remains within
  specifications under the storage conditions, within the re-test period
  in all future batches

 The programme should be described in a written protocol and the
  results presented in a formal report.

 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, process or container which may impact
  stability.


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                       Ongoing Stability Studies

 OOS results or atypical trends should be investigated and
  reported immediately to the relevant finished product
  manufacturer. The possible impact on batches on the
  market should be considered.

 A summary of data should be written and maintained, and
  should be subjected to periodic review.




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                                 Stability Commitment
 Provide the post-approval stability protocol and stability-testing
  commitment, when applicable (Ref to ICH Q1A/B/E)


 A stability commitment is required when long term data does
  not cover the proposed re-test period



 If fewer than three submission batches are submitted then
  additional batches to be tested with the same stability protocol used
  for submission batches.



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