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API Stability. Lynda Paleshnuik. Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009. Overview. Stress Testing Selection of Batches Container Closure System Specifications Testing Frequency Storage Conditions Stability Commitment. Overview.

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Api stability

API Stability

Lynda Paleshnuik

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009


  • Stress Testing

  • Selection of Batches

  • Container Closure System

  • Specifications

  • Testing Frequency

  • Storage Conditions

  • Stability Commitment


  • Evaluation

  • Statements/Labelling

  • Ongoing Stability Studies

  • Common Deficiencies

Stability assessment references
Stability AssessmentReferences

  • Main Generics Guideline

  • Supplement 2 to Main Generics Guideline

  • Supplement 3 (not yet published)

  • 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…

Stability assessment references1
Stability Assessment References

Practical Approach:

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

2) Supplement 3 (S3)

3) ICH Q1A (2003)

Stability assessment references2
Stability Assessment References

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

    - Referred to as “New Guide” in this talk.

    - Follows ICH Q1A with key differences noted below.

Stability definition
Stability - definition

How the quality of an API or FPP varies with time under factors such as temperature, humidity and light.

Studies also show how product-related factors influence stability: the properties of API/excipients, FPP composition, manufacturing process, and container-closure system.

Stability purpose
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.

Before starting assessment of stability data
Before starting assessment of stability data

  • Is there a valid CEP (EDQM Certification Database)

  • If yes: was the valid version provided and does it include a retest date? If yes, this retest is acceptable without further review. If the applicant is requesting a longer retest (see label/specifications) then data must be assessed.

Before you start other points cont d
Before you start: Other points – cont’d

  • Is/are the API(s) listed in Supplement 2?

    If yes, data requirements are reduced, see “storage conditions” below.

Api stress studies
APIStress Studies

  • Stress testing is an important part of developmental studies. Used to:

    - establish degradation pathways and intrinsic stability,

    - validate stability-indicating power of methods

Api stress studies1
APIStress 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.

Api stress testing
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).

Api stability stress testing
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.

Api stability stress testing1
API stability Stress testing

  • See the Main Generic guideline 2.7.1 for suggested conditions (heat, humidity, acid/base, oxidative, photo, metal ions).

Stress studies approach for assessment
Stress studies: Approach for Assessment


  • Check if data is provided, either generated by supplier/applicant or from literature references

  • Check for compendial statement, “protect from light”.

  • Check that conditions are adequate (suggested conditions and extent of degradation)

  • Check the extent of degradation (no degradation after 10 days = stable, or 10-30% = adequate degradation)

  • Confirm the stability-indication of methods where intended (ie mass balance, peak homogeneity)

Stress studies approach
Stress studies: Approach


- spend excessive time with degradants generated in stress studies.

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

Api stability selection of batches
API Stability:Selection of Batches

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

  • Main Guide: NLT 3 (1 production and 2 at least pilot-scale)

  • New Guide: 3 pilot batches* (as per Q1A), plus, unique to new guideline: For stable API, 2 pilot batches.

    *Pilot batches must be of the same synthesis route, and with method of manufacture and procedure with simulates the final process for production batches.

Api stability container closure system
API Stability: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)

Api stability specifications
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.


- If same as in API specs, cross-reference

- If different, provide validation data for impurity/degradant and assay methods

- methods should be stability-indicating

Example problem
Example Problem

The API is low solubility and micronized, and the FPP is low dose (common for RH products). PSD is critical for this API.

Example comment:

Due to the potential for settling of material on storage, stability results for PSD should be provided to address this issue.


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

Api stability testing frequency
API Stability:Testing Frequency

Not in Main Guide: Q1A and New Guide state:

Long term:

Year 1: every 3 months

Year 2: every 6 months

Subsequent years: annually


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


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

Api stability storage conditions
API Stability: Storage Conditions

Requirements at time of submission:

Stable API: (Supplement 2, Supplement 3)

6 months at 40◦C/75%

6 months at 30◦C/65%

Unstable API: (Supplement 3)

6 months at 40◦C/75%

12 months at 30◦C/65%

Api stability storage conditions1
API Stability: Storage Conditions

The New Guide is in agreement with Q1A, plus:

  • Refers to stable API’s as indicated above, ie 6 months long-term data

  • Includes optional long-term condition for Zone IVb 30◦C/75% (ie long-term options 25◦C/60%, 30◦C/65%, 30◦C/75%)

    The actual conditions are determined by the climatic condition under which the API is intended to be stored. (Discussed at end of talk.)

  • Includes optional accelerated conditions 30◦C/65% and 30◦C/75% where fridge/freezer is the long-term storage.

  • Includes guidance on storage facility equipment tolerances.

Api stability storage conditions2
API Stability: Storage Conditions

  • 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%).

  • For an API, “significant change” is failure to meet the specification for any parameter

Api stability storage conditions3
API Stability: Storage Conditions

  • Where a valid CEP was 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.

Api stability stability commitment
API StabilityStability Commitment

  • Main Guide: “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.

  • See Q1A/New Guide Section 2.1.8 for the description of situations/commitments. Q1A = New Guide except where the definition of # of batches differs (see “Selection of Batches”, above.)

    Q1A – 3 production batches; New Guide 3/2 production.

    SOQR – 3 production batches (remaining “consecutive production batches”)

    The stability protocol used for the stability commitment should be the same as that used for primary batches.

Api stability evaluation
API StabilityEvaluation

  • 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. See New Guide = Q1A 2.1.9.

Api stability evaluation1
API StabilityEvaluation

  • Extrapolation of data:

    Common scenario: Data (6 mo acc/x mo LT) is within specifications with no significant change under accelerated conditions. The allowed re-test 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.

Api stability evaluation2
API StabilityEvaluation

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

For eg for a stable API, a re-test of 24 months may have been accepted based on 6mo acc + 6mo long-term, but to accept a longer re-test period, real-time data is required.

Api stability evaluation3
API StabilityEvaluation

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. [New Guide = Q1A]

Example problem 1 api re test and shelf life
Example Problem #1API Re-test and Shelf-life

  • Problem: The applicant has proposed a 12 month re-test period and a 60 month expiration period. They have provided data to support the re-test period, but not the shelf-life. Now what?

  • Answer: Except in exceptional situations, the shelf-life is not required and is considered an extra assurance. Since a re-test period is defined, the applicant must re-test the API immediately prior to its use once the re-test period has been exceeded. The re-test period, which is supported by data, is approved.

Example problem 2
Example problem #2

  • 12 months long-term data is provided at 25◦C/60%, not 30◦C/65%. Accelerated/long-term data is acceptable.


    Note that 30◦C/65% is the preferred condition. The applicant is not asked to regenerate all data at 30◦C/65%, instead the storage conditions over the retest period should be, “Do not store above 25◦C”.

    This example also applies to FPP’s.

Example problem 3
Example problem #3

  • 18 months long-term data is provided at 30◦C/65%. Significant change is noted under accelerated conditions.

  • There is no “intermediate” storage condition.

    Approach: as there is no intermediate data to support fluctuations over the higher temperature, extrapolation of the retest period (beyond long-term data) should be limited. A re-test of 18 months is acceptable.

    This example also applies to FPP’s.

Api stability statements labelling
API StabilityStatements/Labelling

  • Recommended labelling 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 should be based on evaluation, see previous examples. Based on:

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

    -Change(s) observed;

    -Actual LT storage conditions;

    -Batches (all production?), etc.

Api stability statements labelling1
API StabilityStatements/Labelling

  • Note: confirm that the re-test/storage on API specifications is in agreement with that proposed and/or considered supported by the data.

Api stability ongoing stability studies
API StabilityOngoing Stability Studies

New Guide (not in Q1A):

  • 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.

Api stability ongoing stability studies1
API StabilityOngoing 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.

Api stability appendix 1 to trs953
API Stability Appendix 1 to TRS953

  • Long term stability testing conditions are determined by the climatic condition under which the API 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 (Kenya) 30◦C/65%RH

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

Common deficiencies
Common Deficiencies

These deficiencies are commonly encountered and lead to questions and delays in approval of a re-test period:

1. Failure to state the size of the lots used in the trial.

2. Failure to describe clearly the packaging used in the trial and to confirm whether it is identical to the proposed packaging.

3. Failure to accumulate stability data on the required number of lots.

Common deficiencies1
Common Deficiencies

4. Failure to define accurately the temperature and humidity conditions applied during the trial. ±2◦C, ±5%RH

5. Failure to fully describe test methods.

6. Failure to provide validation of analytical methods.

Common deficiencies2
Common Deficiencies

7. Expression of results as passes test or similar when a quantitative figure would be available.

8. Failure to include quantitative or semiquantitative determinations of the content of degradation products, or to provide only total content rather than values for individual impurities.

9. 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.

Common deficiencies3
Common Deficiencies

10. Failure to comment or conduct additional tests when there is a lack of mass balance between the formation of degradation products and the loss of the active substance. For example, are the assay procedures sufficiently specific? Is the API volatile? Is it adsorbed on to the container wall?

11. Failure to conduct additional tests to investigate the significance of obvious alterations in the characteristics of the product. For example a distinct change in the colour of the product may necessitate additional investigation for degradation products.

12. Failure to include information on the physical characteristics of the product during storage, such as particle size etc.

Common deficiencies4
Common Deficiencies

13. Failure to provide results from intermediate time stations to facilitate assessment of any trends in the parameters measured, when significant change is noted at accelerated conditions.

14. Attempting to extrapolate data obtained in the trial beyond reasonable limits.